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Does Abaloparatide and Acebutolol interact?

•Drug A: Abaloparatide •Drug B: Acebutolol •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Acebutolol is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the management of hypertension and ventricular premature beats in adults. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Acebutolol is a cardioselective, beta-adrenoreceptor blocking agent, which possesses mild intrinsic sympathomimetic activity (ISA) in its therapeutically effective dose range. In general, beta-blockers reduce the work the heart has to do and allow it to beat more regularly. Acebutolol has less antagonistic effects on peripheral vascular ß2-receptors at rest and after epinephrine stimulation than nonselective beta-antagonists. Low doses of acebutolol produce less evidence of bronchoconstriction than nonselective agents like propranolol but more than atenolol. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Acebutolol is a selective β1-receptor antagonist. Activation of β1-receptors by epinephrine increases the heart rate and the blood pressure, and the heart consumes more oxygen. Acebutolol blocks these receptors, lowering the heart rate and blood pressure. This drug then has the reverse effect of epinephrine. In addition, beta blockers prevent the release of renin, which is a hormone produced by the kidneys which leads to constriction of blood vessels. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Well absorbed from the Gl tract with an absolute bioavailability of approximately 40% for the parent compound. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 26% •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Subject to extensive first-pass hepatic biotransformation (primarily to diacetolol). •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Elimination via renal excretion is approximately 30% to 40% and by non-renal mechanisms 50% to 60%, which includes excretion into the bile and direct passage through the intestinal wall. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The plasma elimination half-life is approximately 3 to 4 hours. The half-life of its metabolite, diacetolol, is 8 to 13 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Symptoms of overdose include extreme bradycardia, advanced atrioventricular block, intraventricular conduction defects, hypotension, severe congestive heart failure, seizures, and in susceptible patients, bronchospasm, and hypoglycemia. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Sectral •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Acebutolol Acebutololum Acetobutolol •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Acebutolol is a selective β1-receptor antagonist used for the management of hypertension and ventricular premature beats in adults.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Acebutolol interact? Information: •Drug A: Abaloparatide •Drug B: Acebutolol •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Acebutolol is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the management of hypertension and ventricular premature beats in adults. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Acebutolol is a cardioselective, beta-adrenoreceptor blocking agent, which possesses mild intrinsic sympathomimetic activity (ISA) in its therapeutically effective dose range. In general, beta-blockers reduce the work the heart has to do and allow it to beat more regularly. Acebutolol has less antagonistic effects on peripheral vascular ß2-receptors at rest and after epinephrine stimulation than nonselective beta-antagonists. Low doses of acebutolol produce less evidence of bronchoconstriction than nonselective agents like propranolol but more than atenolol. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Acebutolol is a selective β1-receptor antagonist. Activation of β1-receptors by epinephrine increases the heart rate and the blood pressure, and the heart consumes more oxygen. Acebutolol blocks these receptors, lowering the heart rate and blood pressure. This drug then has the reverse effect of epinephrine. In addition, beta blockers prevent the release of renin, which is a hormone produced by the kidneys which leads to constriction of blood vessels. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Well absorbed from the Gl tract with an absolute bioavailability of approximately 40% for the parent compound. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 26% •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Subject to extensive first-pass hepatic biotransformation (primarily to diacetolol). •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Elimination via renal excretion is approximately 30% to 40% and by non-renal mechanisms 50% to 60%, which includes excretion into the bile and direct passage through the intestinal wall. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The plasma elimination half-life is approximately 3 to 4 hours. The half-life of its metabolite, diacetolol, is 8 to 13 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Symptoms of overdose include extreme bradycardia, advanced atrioventricular block, intraventricular conduction defects, hypotension, severe congestive heart failure, seizures, and in susceptible patients, bronchospasm, and hypoglycemia. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Sectral •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Acebutolol Acebutololum Acetobutolol •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Acebutolol is a selective β1-receptor antagonist used for the management of hypertension and ventricular premature beats in adults. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Aldesleukin interact?

•Drug A: Abaloparatide •Drug B: Aldesleukin •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Aldesleukin is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For treatment of adults with metastatic renal cell carcinoma. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Used to treat renal cell carcinoma, Aldesleukin induces the enhancement of lymphocyte mitogenesis and stimulation of long-term growth of human interleukin-2 dependent cell lines, the enhancement of lymphocyte cytotoxicity, the induction of killer cell (lymphokine-activated (LAK) and natural (NK)) activity; and the induction of interferon-gamma production. IL-2 is normally produced by the body, secreted by T cells, and stimulates growth and differentiation of T cell response. It can be used in immunotherapy to treat cancer. It enhances the ability of the immune system to kill tumor cells and may interfere with blood flow to the tumor. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Aldesleukin binds to the IL-2 receptor which leads to heterodimerization of the cytoplasmic domains of the IL-2R beta and gamma(c) chains, activation of the tyrosine kinase Jak3, and phosphorylation of tyrosine residues on the IL-2R beta chain. These events led to the creation of an activated receptor complex, to which various cytoplasmic signaling molecules are recruited and become substrates for regulatory enzymes (especially tyrosine kinases) that are associated with the receptor. These events stimulate growth and differentiation of T cells. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 0.18 l/kg •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): The pharmacokinetic profile of Proleukin is characterized by high plasma concentrations following a short IV infusion, rapid distribution into the extravascular space and elimination from the body by metabolism in the kidneys with little or no bioactive protein excreted in the urine. Following the initial rapid organ distribution, the primary route of clearance of circulating proleukin is the kidney. Greater than 80% of the amount of Proleukin distributed to plasma, cleared from the circulation and presented to the kidney is metabolized to amino acids in the cells lining the proximal convoluted tubules. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 13 min-85 min •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Proleukin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Aldesleukin is a recombinant analog of interleukin-2 used to induce an adaptive immune response in the treatment of renal cell carcinoma.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Aldesleukin interact? Information: •Drug A: Abaloparatide •Drug B: Aldesleukin •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Aldesleukin is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For treatment of adults with metastatic renal cell carcinoma. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Used to treat renal cell carcinoma, Aldesleukin induces the enhancement of lymphocyte mitogenesis and stimulation of long-term growth of human interleukin-2 dependent cell lines, the enhancement of lymphocyte cytotoxicity, the induction of killer cell (lymphokine-activated (LAK) and natural (NK)) activity; and the induction of interferon-gamma production. IL-2 is normally produced by the body, secreted by T cells, and stimulates growth and differentiation of T cell response. It can be used in immunotherapy to treat cancer. It enhances the ability of the immune system to kill tumor cells and may interfere with blood flow to the tumor. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Aldesleukin binds to the IL-2 receptor which leads to heterodimerization of the cytoplasmic domains of the IL-2R beta and gamma(c) chains, activation of the tyrosine kinase Jak3, and phosphorylation of tyrosine residues on the IL-2R beta chain. These events led to the creation of an activated receptor complex, to which various cytoplasmic signaling molecules are recruited and become substrates for regulatory enzymes (especially tyrosine kinases) that are associated with the receptor. These events stimulate growth and differentiation of T cells. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 0.18 l/kg •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): The pharmacokinetic profile of Proleukin is characterized by high plasma concentrations following a short IV infusion, rapid distribution into the extravascular space and elimination from the body by metabolism in the kidneys with little or no bioactive protein excreted in the urine. Following the initial rapid organ distribution, the primary route of clearance of circulating proleukin is the kidney. Greater than 80% of the amount of Proleukin distributed to plasma, cleared from the circulation and presented to the kidney is metabolized to amino acids in the cells lining the proximal convoluted tubules. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 13 min-85 min •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Proleukin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Aldesleukin is a recombinant analog of interleukin-2 used to induce an adaptive immune response in the treatment of renal cell carcinoma. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Aliskiren interact?

•Drug A: Abaloparatide •Drug B: Aliskiren •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abaloparatide is combined with Aliskiren. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Aliskiren is used for the treatment of hypertension in children above 6 years and adults. This drug may also be used in conjunction with antihypertensives such as calcium channel blockers and thiazides in products form to provide additional blood pressure control. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Aliskiren reduces blood pressure by inhibiting renin. This leads to a cascade of events that decreases blood pressure, lowering the risk of fatal and nonfatal cardiovascular events including stroke and myocardial infarction. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Aliskiren is a renin inhibitor. Renin is secreted by the kidneys when blood volume and renal perfusion decrease. It normally cleaves the protein angiotensinogen to form angiotensin I. Angiotensin I is then converted to angiotensin II, an active protein. Angiotensin II is a potent vasoconstrictor that causes the release of catecholamines into the circulation. It also promotes the secretion of aldosterone in addition to sodium reabsorption, increasing blood pressure. Additionally, angiotensin II acts on the adrenal cortex where it stimulates aldosterone release. Aldosterone increases sodium reabsorption and potassium excretion in the nephron. Aliskiren prevents the above process via binding to renin at its active site, stopping the cleavage of angiotensin, in turn inhibiting the formation of angiotensin I. This ends the cascade of angiotensin II mediated mechanisms that normally increase blood pressure. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Aliskiren is absorbed in the gastrointestinal tract and is poorly absorbed with a bioavailability between 2.0 and 2.5%. Peak plasma concentrations of aliskiren are achieved between 1 to 3 hours after administration. Steady-state concentrations of aliskiren are achieved within 7-8 days of regular administration. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Unchanged aliskiren accounts for about 80% of the drug found in the plasma. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): The plasma protein binding of aliskiren ranges from 47-51%. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): About 80% of the drug in plasma following oral administration is unchanged. Two major metabolites account for about 1-3% of aliskiren in the plasma. One metabolite is an O-demethylated alcohol derivative and the other is a carboxylic acid derivative. Minor oxidized and hydrolyzed metabolites may also be found in the plasma. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Aliskiren is mainly excreted via the hepatobiliary route and by oxidative metabolism by hepatic cytochrome enzymes. Approximately one-quarter of the absorbed dose appears in the urine as unchanged parent drug. One pharmacokinetic study of radiolabeled aliskiren detected 0.6% radioactivity in the urine and more than 80% in the feces, suggesting that aliskiren is mainly eliminated by the fecal route. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Plasma half-life for aliskiren can range from 30 to 40 hours with an accumulation half-life of about 24 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Aliskiren is partially cleared in the kidneys, and safety data have not been established for patients with a creatinine clearance of less than 30 mL/min. One pharmacokinetic study revealed an average renal clearance of 1280 +/- 500 mL/hour in healthy volunteers. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The oral LD50 of aliskiren in rats is >2000 mg/kg. Overdose information is limited in the literature, however, an overdose with aliskiren is likely to result in hypotension. Supportive treatment should be initiated in the case of an overdose. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Rasilez, Tekturna, Tekturna Hct •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Aliskiren is a direct renin inhibitor used to manage hypertension.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Aliskiren interact? Information: •Drug A: Abaloparatide •Drug B: Aliskiren •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abaloparatide is combined with Aliskiren. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Aliskiren is used for the treatment of hypertension in children above 6 years and adults. This drug may also be used in conjunction with antihypertensives such as calcium channel blockers and thiazides in products form to provide additional blood pressure control. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Aliskiren reduces blood pressure by inhibiting renin. This leads to a cascade of events that decreases blood pressure, lowering the risk of fatal and nonfatal cardiovascular events including stroke and myocardial infarction. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Aliskiren is a renin inhibitor. Renin is secreted by the kidneys when blood volume and renal perfusion decrease. It normally cleaves the protein angiotensinogen to form angiotensin I. Angiotensin I is then converted to angiotensin II, an active protein. Angiotensin II is a potent vasoconstrictor that causes the release of catecholamines into the circulation. It also promotes the secretion of aldosterone in addition to sodium reabsorption, increasing blood pressure. Additionally, angiotensin II acts on the adrenal cortex where it stimulates aldosterone release. Aldosterone increases sodium reabsorption and potassium excretion in the nephron. Aliskiren prevents the above process via binding to renin at its active site, stopping the cleavage of angiotensin, in turn inhibiting the formation of angiotensin I. This ends the cascade of angiotensin II mediated mechanisms that normally increase blood pressure. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Aliskiren is absorbed in the gastrointestinal tract and is poorly absorbed with a bioavailability between 2.0 and 2.5%. Peak plasma concentrations of aliskiren are achieved between 1 to 3 hours after administration. Steady-state concentrations of aliskiren are achieved within 7-8 days of regular administration. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Unchanged aliskiren accounts for about 80% of the drug found in the plasma. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): The plasma protein binding of aliskiren ranges from 47-51%. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): About 80% of the drug in plasma following oral administration is unchanged. Two major metabolites account for about 1-3% of aliskiren in the plasma. One metabolite is an O-demethylated alcohol derivative and the other is a carboxylic acid derivative. Minor oxidized and hydrolyzed metabolites may also be found in the plasma. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Aliskiren is mainly excreted via the hepatobiliary route and by oxidative metabolism by hepatic cytochrome enzymes. Approximately one-quarter of the absorbed dose appears in the urine as unchanged parent drug. One pharmacokinetic study of radiolabeled aliskiren detected 0.6% radioactivity in the urine and more than 80% in the feces, suggesting that aliskiren is mainly eliminated by the fecal route. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Plasma half-life for aliskiren can range from 30 to 40 hours with an accumulation half-life of about 24 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Aliskiren is partially cleared in the kidneys, and safety data have not been established for patients with a creatinine clearance of less than 30 mL/min. One pharmacokinetic study revealed an average renal clearance of 1280 +/- 500 mL/hour in healthy volunteers. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The oral LD50 of aliskiren in rats is >2000 mg/kg. Overdose information is limited in the literature, however, an overdose with aliskiren is likely to result in hypotension. Supportive treatment should be initiated in the case of an overdose. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Rasilez, Tekturna, Tekturna Hct •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Aliskiren is a direct renin inhibitor used to manage hypertension. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Ambrisentan interact?

•Drug A: Abaloparatide •Drug B: Ambrisentan •Severity: MINOR •Description: Abaloparatide may increase the hypotensive activities of Ambrisentan. •Extended Description: The use of two drugs that both lower blood pressure may result in a more pronounced hypotensive effect. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Ambrisentan is indicated for treatment of idiopathic (‘primary’) pulmonary arterial hypertension (IPAH) and pulmonary arterial hypertension (PAH) associated with connective tissue disease in patients with WHO functional class II or III symptoms. In the United States of America, ambrisentan is also indicated in combination with tadalafil to reduce the risks of disease progression and hospitalization for worsening PAH, and to improve exercise ability. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Ambrisentan 10 mg daily had no significant effect on the QTc interval, whereas a 40 mg daily dose of ambrisentan increased mean QTc at tmax by 5 ms with an upper 95% confidence limit of 9 ms. Significant QTc prolongation is not expected in patients taking ambrisentan without concomitant metabolic inhibitors. Plasma concentrations of B-type natriuretic peptide (BNP) in patients who received ambrisentan for 12 weeks were significantly decreased. Two Phase III placebo-controlled studies demonstrated a decrease in BNP plasma concentrations by 29% in the 2.5 mg group, 30% in the 5 mg group, and 45% in the 10 mg group (p < 0.001 for each dose group) and an increase by 11% in the placebo group. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Endothelin-1 (ET-1) is an endogenous peptide that acts on the endothelin type A (ETA) and endothelin type B (ETB) receptors in vascular smooth muscle and endothelium. ETA-mediated actions include vasoconstriction and cell proliferation, whereas ETB predominantly mediates vasodilation, anti-proliferation, and ET-1 clearance. In patients with pulmonary arterial hypertension, ET-1 levels are increased and correlate with increased right arterial pressure and severity of disease. Ambrisentan is one of several newly developed vasodilator drugs that selectively target the endothelin type A (ETA) receptor, inhibiting its action and preventing vasoconstriction. Selective inhibition of the ETA receptor prevents phospholipase C-mediated vasoconstriction and protein kinase C-mediated cell proliferation. Endothelin type B (ETB) receptor function is not significantly inhibited, and nitric oxide and prostacyclin production, cyclic GMP- and cyclic AMP-mediated vasodilation, and endothelin-1 (ET-1) clearance is preserved. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Ambrisentan is rapidly absorbed with peak plasma concentrations occuring around 2 hours after oral administration. Cmax and AUC increase proportionally with dose across the therapeutic dosing range. Absolute oral bioavailability of ambrisentan is unknown. Absorption is not affected by food. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Ambrisentan has a low distribution into red blow cells, with a mean blood:plasma ratio of 0.57 and 0.61 in males and females, respectively. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Ambrisentan is 99% plasma protein bound, primarily to albumin (96.5%) and to a lesser degree alpha1-acid glycoprotein. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Ambrisentan is a metabolized primarily by uridine 5’-diphosphate glucuronosyltransferases (UGTs) 1A9S, 2B7S,1A3S to form ambrisentan glucuronide. Ambrisentan is also metabolized to a lesser extent by CYP3A4, CYP3A5 and CYP2C19 to form 4- hydroxymethyl ambrisentan which is further glucuronidated to 4-hydroxymethyl ambrisentan glucuronide. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Ambrisentan is primarily cleared by non-renal pathways. Along with its metabolites, ambrisentan is primarily found in the feces following hepatic and/or extra-hepatic metabolism. Approximately 22% of the administered dose is recovered in the urine following oral administration with 3.3% being unchanged ambrisentan. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Ambrisentan has a terminal half-life of 15 hours. It is thought that steady state is achieved after around 4 days of repeat-dosing. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The mean oral clearance of ambrisentan was found to be 38 mL/min in healthy subjects and 19 mL/min in patients with pulmonary artery hypertension. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Ambrisentan is teratogenic and has a high risk of embryo-fetal toxicity. LD50 was found to be greater than or equal to 3160 mg/kg when studied in rats. There was no evidence of carcinogenic potential in 2 year oral daily dosing studies in rats and mice. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Letairis •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ambrisentan •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Ambrisentan is a selective type A endothelin receptor antagonist used to treat primary pulmonary arterial hypertension and pulmonary arterial hypertension based on diagnostic classifications.

The use of two drugs that both lower blood pressure may result in a more pronounced hypotensive effect. The severity of the interaction is minor.

Question: Does Abaloparatide and Ambrisentan interact? Information: •Drug A: Abaloparatide •Drug B: Ambrisentan •Severity: MINOR •Description: Abaloparatide may increase the hypotensive activities of Ambrisentan. •Extended Description: The use of two drugs that both lower blood pressure may result in a more pronounced hypotensive effect. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Ambrisentan is indicated for treatment of idiopathic (‘primary’) pulmonary arterial hypertension (IPAH) and pulmonary arterial hypertension (PAH) associated with connective tissue disease in patients with WHO functional class II or III symptoms. In the United States of America, ambrisentan is also indicated in combination with tadalafil to reduce the risks of disease progression and hospitalization for worsening PAH, and to improve exercise ability. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Ambrisentan 10 mg daily had no significant effect on the QTc interval, whereas a 40 mg daily dose of ambrisentan increased mean QTc at tmax by 5 ms with an upper 95% confidence limit of 9 ms. Significant QTc prolongation is not expected in patients taking ambrisentan without concomitant metabolic inhibitors. Plasma concentrations of B-type natriuretic peptide (BNP) in patients who received ambrisentan for 12 weeks were significantly decreased. Two Phase III placebo-controlled studies demonstrated a decrease in BNP plasma concentrations by 29% in the 2.5 mg group, 30% in the 5 mg group, and 45% in the 10 mg group (p < 0.001 for each dose group) and an increase by 11% in the placebo group. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Endothelin-1 (ET-1) is an endogenous peptide that acts on the endothelin type A (ETA) and endothelin type B (ETB) receptors in vascular smooth muscle and endothelium. ETA-mediated actions include vasoconstriction and cell proliferation, whereas ETB predominantly mediates vasodilation, anti-proliferation, and ET-1 clearance. In patients with pulmonary arterial hypertension, ET-1 levels are increased and correlate with increased right arterial pressure and severity of disease. Ambrisentan is one of several newly developed vasodilator drugs that selectively target the endothelin type A (ETA) receptor, inhibiting its action and preventing vasoconstriction. Selective inhibition of the ETA receptor prevents phospholipase C-mediated vasoconstriction and protein kinase C-mediated cell proliferation. Endothelin type B (ETB) receptor function is not significantly inhibited, and nitric oxide and prostacyclin production, cyclic GMP- and cyclic AMP-mediated vasodilation, and endothelin-1 (ET-1) clearance is preserved. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Ambrisentan is rapidly absorbed with peak plasma concentrations occuring around 2 hours after oral administration. Cmax and AUC increase proportionally with dose across the therapeutic dosing range. Absolute oral bioavailability of ambrisentan is unknown. Absorption is not affected by food. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Ambrisentan has a low distribution into red blow cells, with a mean blood:plasma ratio of 0.57 and 0.61 in males and females, respectively. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Ambrisentan is 99% plasma protein bound, primarily to albumin (96.5%) and to a lesser degree alpha1-acid glycoprotein. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Ambrisentan is a metabolized primarily by uridine 5’-diphosphate glucuronosyltransferases (UGTs) 1A9S, 2B7S,1A3S to form ambrisentan glucuronide. Ambrisentan is also metabolized to a lesser extent by CYP3A4, CYP3A5 and CYP2C19 to form 4- hydroxymethyl ambrisentan which is further glucuronidated to 4-hydroxymethyl ambrisentan glucuronide. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Ambrisentan is primarily cleared by non-renal pathways. Along with its metabolites, ambrisentan is primarily found in the feces following hepatic and/or extra-hepatic metabolism. Approximately 22% of the administered dose is recovered in the urine following oral administration with 3.3% being unchanged ambrisentan. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Ambrisentan has a terminal half-life of 15 hours. It is thought that steady state is achieved after around 4 days of repeat-dosing. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The mean oral clearance of ambrisentan was found to be 38 mL/min in healthy subjects and 19 mL/min in patients with pulmonary artery hypertension. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Ambrisentan is teratogenic and has a high risk of embryo-fetal toxicity. LD50 was found to be greater than or equal to 3160 mg/kg when studied in rats. There was no evidence of carcinogenic potential in 2 year oral daily dosing studies in rats and mice. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Letairis •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ambrisentan •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Ambrisentan is a selective type A endothelin receptor antagonist used to treat primary pulmonary arterial hypertension and pulmonary arterial hypertension based on diagnostic classifications. Output: The use of two drugs that both lower blood pressure may result in a more pronounced hypotensive effect. The severity of the interaction is minor.

Does Abaloparatide and Amifostine interact?

•Drug A: Abaloparatide •Drug B: Amifostine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Amifostine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For reduction in the cumulative renal toxicity in patients with ovarian cancer (using cisplatin) and moderate to severe xerostomia in patients undergoing post-operative radiation treatment for head and neck cancer. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Amifostine is an organic thiophosphate cytoprotective agent indicated to reduce the cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian cancer or non-small cell lung cancer and also to reduce the incidence of moderate to severe xerostomia in patients undergoing post-operative radiation treatment for head and neck cancer. Amifostine is a prodrug that is dephosphorylated by alkaline phosphatase in tissues to a pharmacologically active free thiol metabolite, believed to be responsible for the reduction of the cumulative renal toxicity of cisplatin and for the reduction of the toxic effects of radiation on normal oral tissues. Healthy cells are preferentially protected because amifostine and metabolites are present in healthy cells at 100-fold greater concentrations than in tumour cells. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): The thiol metabolite is responsible for most of the cytoprotective and radioprotective properties of amifostine. It is readily taken up by cells where it binds to and detoxifies reactive metabolites of platinum and alkylating agents as well as scavenges free radicals. Other possible effects include inhibition of apoptosis, alteration of gene expression and modification of enzyme activity. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Amifostine is rapidly dephosphorylated by alkaline phosphatase in tissues primarily to the active free thiol metabolite and, subsequently, to a less active disulfide metabolite. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): After a 10-second bolus dose of 150 mg/m2 of ETHYOL, renal excretion of the parent drug and its two metabolites was low during the hour following drug administration, averaging 0.69%, 2.64% and 2.22% of the administered dose for the parent, thiol and disulfide, respectively. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 8 minutes •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Rat LD 50: 826 mg/kg •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Ethyol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Amifostina Amifostine Amifostinum Aminopropylaminoethyl thiophosphate Ethiofos •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Amifostine is a cytoprotective adjuvant used for reduction in the cumulative renal toxicity in patients with ovarian cancer and moderate to severe xerostomia in patients undergoing post-operative radiation treatment for head and neck cancer.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Amifostine interact? Information: •Drug A: Abaloparatide •Drug B: Amifostine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Amifostine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For reduction in the cumulative renal toxicity in patients with ovarian cancer (using cisplatin) and moderate to severe xerostomia in patients undergoing post-operative radiation treatment for head and neck cancer. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Amifostine is an organic thiophosphate cytoprotective agent indicated to reduce the cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian cancer or non-small cell lung cancer and also to reduce the incidence of moderate to severe xerostomia in patients undergoing post-operative radiation treatment for head and neck cancer. Amifostine is a prodrug that is dephosphorylated by alkaline phosphatase in tissues to a pharmacologically active free thiol metabolite, believed to be responsible for the reduction of the cumulative renal toxicity of cisplatin and for the reduction of the toxic effects of radiation on normal oral tissues. Healthy cells are preferentially protected because amifostine and metabolites are present in healthy cells at 100-fold greater concentrations than in tumour cells. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): The thiol metabolite is responsible for most of the cytoprotective and radioprotective properties of amifostine. It is readily taken up by cells where it binds to and detoxifies reactive metabolites of platinum and alkylating agents as well as scavenges free radicals. Other possible effects include inhibition of apoptosis, alteration of gene expression and modification of enzyme activity. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Amifostine is rapidly dephosphorylated by alkaline phosphatase in tissues primarily to the active free thiol metabolite and, subsequently, to a less active disulfide metabolite. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): After a 10-second bolus dose of 150 mg/m2 of ETHYOL, renal excretion of the parent drug and its two metabolites was low during the hour following drug administration, averaging 0.69%, 2.64% and 2.22% of the administered dose for the parent, thiol and disulfide, respectively. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 8 minutes •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Rat LD 50: 826 mg/kg •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Ethyol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Amifostina Amifostine Amifostinum Aminopropylaminoethyl thiophosphate Ethiofos •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Amifostine is a cytoprotective adjuvant used for reduction in the cumulative renal toxicity in patients with ovarian cancer and moderate to severe xerostomia in patients undergoing post-operative radiation treatment for head and neck cancer. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Amiloride interact?

•Drug A: Abaloparatide •Drug B: Amiloride •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Amiloride is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For use as adjunctive treatment with thiazide diuretics or other kaliuretic-diuretic agents in congestive heart failure or hypertension. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Amiloride, an antikaliuretic-diuretic agent, is a pyrazine-carbonyl-guanidine that is unrelated chemically to other known antikaliuretic or diuretic agents. It is an antihypertensive, potassium-sparing diuretic that was first approved for use in 1967 and helps to treat hypertension and congestive heart failure. The drug is often used in conjunction with thiazide or loop diuretics. Due to its potassium-sparing capacities, hyperkalemia (high blood potassium levels) are occasionally observed in patients taking amiloride. The risk is high in concurrent use of ACE inhibitors or spironolactone. Patients are also advised not to use potassium-containing salt replacements. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Amiloride works by inhibiting sodium reabsorption in the distal convoluted tubules and collecting ducts in the kidneys by binding to the amiloride-sensitive sodium channels. This promotes the loss of sodium and water from the body, but without depleting potassium. Amiloride exerts its potassium sparing effect through the inhibition of sodium reabsorption at the distal convoluted tubule, cortical collecting tubule and collecting duct; this decreases the net negative potential of the tubular lumen and reduces both potassium and hydrogen secretion and their subsequent excretion. Amiloride is not an aldosterone antagonist and its effects are seen even in the absence of aldosterone. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Readily absorbed following oral administration. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Amiloride is not metabolized by the liver but is excreted unchanged by the kidneys. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Amiloride HCl is not metabolized by the liver but is excreted unchanged by the kidneys. About 50 percent of a 20 mg dose of amiloride HCl is excreted in the urine and 40 percent in the stool within 72 hours. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Plasma half-life varies from 6 to 9 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No data are available in regard to overdosage in humans. The oral LD 50 of amiloride hydrochloride (calculated as the base) is 56 mg/kg in mice and 36 to 85 mg/kg in rats, depending on the strain. The most likely signs and symptoms to be expected with overdosage are dehydration and electrolyte imbalance. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Midamor •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Amilorid Amilorida Amiloride Amiloridum Amipramidin Amipramidine Amyloride •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Amiloride is a pyrizine compound used to treat hypertension and congestive heart failure.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Amiloride interact? Information: •Drug A: Abaloparatide •Drug B: Amiloride •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Amiloride is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For use as adjunctive treatment with thiazide diuretics or other kaliuretic-diuretic agents in congestive heart failure or hypertension. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Amiloride, an antikaliuretic-diuretic agent, is a pyrazine-carbonyl-guanidine that is unrelated chemically to other known antikaliuretic or diuretic agents. It is an antihypertensive, potassium-sparing diuretic that was first approved for use in 1967 and helps to treat hypertension and congestive heart failure. The drug is often used in conjunction with thiazide or loop diuretics. Due to its potassium-sparing capacities, hyperkalemia (high blood potassium levels) are occasionally observed in patients taking amiloride. The risk is high in concurrent use of ACE inhibitors or spironolactone. Patients are also advised not to use potassium-containing salt replacements. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Amiloride works by inhibiting sodium reabsorption in the distal convoluted tubules and collecting ducts in the kidneys by binding to the amiloride-sensitive sodium channels. This promotes the loss of sodium and water from the body, but without depleting potassium. Amiloride exerts its potassium sparing effect through the inhibition of sodium reabsorption at the distal convoluted tubule, cortical collecting tubule and collecting duct; this decreases the net negative potential of the tubular lumen and reduces both potassium and hydrogen secretion and their subsequent excretion. Amiloride is not an aldosterone antagonist and its effects are seen even in the absence of aldosterone. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Readily absorbed following oral administration. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Amiloride is not metabolized by the liver but is excreted unchanged by the kidneys. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Amiloride HCl is not metabolized by the liver but is excreted unchanged by the kidneys. About 50 percent of a 20 mg dose of amiloride HCl is excreted in the urine and 40 percent in the stool within 72 hours. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Plasma half-life varies from 6 to 9 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No data are available in regard to overdosage in humans. The oral LD 50 of amiloride hydrochloride (calculated as the base) is 56 mg/kg in mice and 36 to 85 mg/kg in rats, depending on the strain. The most likely signs and symptoms to be expected with overdosage are dehydration and electrolyte imbalance. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Midamor •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Amilorid Amilorida Amiloride Amiloridum Amipramidin Amipramidine Amyloride •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Amiloride is a pyrizine compound used to treat hypertension and congestive heart failure. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Amiodarone interact?

•Drug A: Abaloparatide •Drug B: Amiodarone •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Amiodarone is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): The FDA approved indications for amiodarone are recurrent ventricular fibrillation (VF) and recurrent hemodynamically unstable ventricular tachycardia (VT). The FDA emphasizes that this drug should only be given in these conditions when they are clinically documented and have not responded to normal therapeutic doses of other antiarrhythmic agents, or when other drugs are not tolerated by the patient. Off-label indications include atrial fibrillation and supraventricular tachycardia. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): After intravenous administration, amiodarone acts to relax smooth muscles that line vascular walls, decreases peripheral vascular resistance (afterload), and increases the cardiac index by a small amount. Administration by this route also decreases cardiac conduction, preventing and treating arrhythmias. When it is given orally, however, amiodarone does not lead to significant changes in the left ventricular ejection fraction. Similar to other anti-arrhythmic agents, controlled clinical trials do not confirm that oral amiodarone increases survival. Amiodarone prolongs the QRS duration and QT interval. In addition, a decreased SA (sinoatrial) node automaticity occurs with a decrease in AV node conduction velocity. Ectopic pacemaker automaticity is also inhibited. Thyrotoxicosis or hypothyroidism may also result from the administration of amiodarone, which contains high levels of iodine, and interferes with normal thyroid function. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Amiodarone is considered a class III anti-arrhythmic drug. It blocks potassium currents that cause repolarization of the heart muscle during the third phase of the cardiac action potential. As a result amiodarone increases the duration of the action potential as well as the effective refractory period for cardiac cells (myocytes). Therefore, cardiac muscle cell excitability is reduced, preventing and treating abnormal heart rhythms. Unique from other members of the class III anti-arrhythmic drug class, amiodarone also interferes with the functioning of beta-adrenergic receptors, sodium channels, and calcium channels channels. These actions, at times, can lead to undesirable effects, such as hypotension, bradycardia, and Torsades de pointes (TdP). In addition to the above, amiodarone may increase activity of peroxisome proliferator-activated receptors, leading to steatogenic changes in the liver or other organs. Finally, amiodarone has been found to bind to the thyroid receptor due to its iodine content, potentially leading to amiodarone induced hypothyroidism or thyrotoxicosis. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): The Cmax of amiodarone in the plasma is achieved about 3 to 7 hours after administration. The general time to onset of action of amiodarone after one dose given by the intravenous route is between 1 and 30 minutes, with therapeutic effects lasting from 1-3 hours. Steady-state concentrations of amiodarone in the plasma ranges between 0.4 to 11.99 μg/ml; it is advisable that steady-state levels are generally maintained between 1.0 and 2.5 μg/ml in patients with arrhythmias. Interestingly, its onset of action may sometimes begin after 2 to 3 days, but frequently takes 1 to 3 weeks, despite the administration of higher loading doses. The bioavailability of amiodarone varies in clinical studies, averaging between 35 and 65%. Effect of food In healthy subjects who were given a single 600-mg dose immediately after consuming a meal high in fat, the AUC of amiodarone increased by 2.3 and the Cmax by 3.8 times. Food also enhances absorption, reducing the Tmax by about 37%. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): In a pharmacokinetic study of 3 healthy individuals and 3 patients diagnosed with supraventricular tachycardia (SVT), the volume of distribution was found to be 9.26-17.17 L/kg in healthy volunteers and 6.88-21.05 L/kg in the SVT patients. Prescribing information mentions that the volume of distribution of amiodarone varies greatly, with a mean distribution of approximately 60 L/kg. It accumulates throughout the body, especially in adipose tissue and highly vascular organs including the lung, liver, and spleen. One major metabolite of amiodarone, desethylamiodarone (DEA), is found in even higher proportions in the same tissues as amiodarone. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): The protein binding of amiodarone is about 96%. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): This drug is metabolized to the main metabolite desethylamiodarone (DEA) by the CYP3A4 and CYP2C8 enzymes. The CYP3A4 enzyme is found in the liver and intestines. A hydroxyl metabolite of DEA has been identified in mammals, but its clinical significance is unknown. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion. A small amount of desethylamiodarone (DEA) is found in the urine. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The terminal half-life of amiodarone varies according to the patient, but is long nonetheless, and ranges from about 9-100 days. The half-life duration varies according to different sources. According to the prescribing information for amiodarone, the average apparent plasma terminal elimination half-life of amiodarone is of 58 days (ranging from 15 to 142 days). The terminal half-life range was between 14 to 75 days for the active metabolite, (DEA). The plasma half-life of amiodarone after one dose ranges from 3.2 to 79.7 hours, according to one source. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The clearance of amiodarone after intravenous administration in patients with ventricular fibrillation and ventricular tachycardia ranged from 220 to 440 ml/hr/kg in one clinically study. Another study determined that the total body clearance of amiodarone varies from 0.10 to 0.77 L/min after one intravenous dose. Renal impairment does not appear to affect the clearance of amiodarone, but hepatic impairment may reduce clearance. Patients with liver cirrhosis exhibited significantly lower Cmax and mean amiodarone concentration for DEA, but not for amiodarone. Severe left ventricular dysfunction prolongs the half-life of DEA. A note on monitoring No guidelines have been developed for adjusting the dose of amiodarone in renal, hepatic, or cardiac abnormalities. In patients on chronic amiodarone treatment, close clinical monitoring is advisable, especially for elderly patients and those with severe left ventricular dysfunction. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The LD50 of oral amiodarone in mice and rats exceeds 3,000 mg/kg. An overdose with amiodarone can have a fatal outcome due to its potential to cause arrhythmia. Signs or symptoms of an overdose may include, hypotension, shock, bradycardia, AV block, and liver toxicity. In cases of an overdose, initiate supportive treatment and, if needed, use fluids, vasopressors, or positive inotropic agents. Temporary pacing may be required for heart block. Ensure to monitor liver function regularly. Amiodarone and its main metabolite, DEA, are not removable by dialysis. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Nexterone, Pacerone •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Amiodarona Amiodarone Amiodaronum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Amiodarone is a class III antiarrhythmic indicated for the treatment of recurrent hemodynamically unstable ventricular tachycardia and recurrent ventricular fibrillation.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Amiodarone interact? Information: •Drug A: Abaloparatide •Drug B: Amiodarone •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Amiodarone is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): The FDA approved indications for amiodarone are recurrent ventricular fibrillation (VF) and recurrent hemodynamically unstable ventricular tachycardia (VT). The FDA emphasizes that this drug should only be given in these conditions when they are clinically documented and have not responded to normal therapeutic doses of other antiarrhythmic agents, or when other drugs are not tolerated by the patient. Off-label indications include atrial fibrillation and supraventricular tachycardia. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): After intravenous administration, amiodarone acts to relax smooth muscles that line vascular walls, decreases peripheral vascular resistance (afterload), and increases the cardiac index by a small amount. Administration by this route also decreases cardiac conduction, preventing and treating arrhythmias. When it is given orally, however, amiodarone does not lead to significant changes in the left ventricular ejection fraction. Similar to other anti-arrhythmic agents, controlled clinical trials do not confirm that oral amiodarone increases survival. Amiodarone prolongs the QRS duration and QT interval. In addition, a decreased SA (sinoatrial) node automaticity occurs with a decrease in AV node conduction velocity. Ectopic pacemaker automaticity is also inhibited. Thyrotoxicosis or hypothyroidism may also result from the administration of amiodarone, which contains high levels of iodine, and interferes with normal thyroid function. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Amiodarone is considered a class III anti-arrhythmic drug. It blocks potassium currents that cause repolarization of the heart muscle during the third phase of the cardiac action potential. As a result amiodarone increases the duration of the action potential as well as the effective refractory period for cardiac cells (myocytes). Therefore, cardiac muscle cell excitability is reduced, preventing and treating abnormal heart rhythms. Unique from other members of the class III anti-arrhythmic drug class, amiodarone also interferes with the functioning of beta-adrenergic receptors, sodium channels, and calcium channels channels. These actions, at times, can lead to undesirable effects, such as hypotension, bradycardia, and Torsades de pointes (TdP). In addition to the above, amiodarone may increase activity of peroxisome proliferator-activated receptors, leading to steatogenic changes in the liver or other organs. Finally, amiodarone has been found to bind to the thyroid receptor due to its iodine content, potentially leading to amiodarone induced hypothyroidism or thyrotoxicosis. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): The Cmax of amiodarone in the plasma is achieved about 3 to 7 hours after administration. The general time to onset of action of amiodarone after one dose given by the intravenous route is between 1 and 30 minutes, with therapeutic effects lasting from 1-3 hours. Steady-state concentrations of amiodarone in the plasma ranges between 0.4 to 11.99 μg/ml; it is advisable that steady-state levels are generally maintained between 1.0 and 2.5 μg/ml in patients with arrhythmias. Interestingly, its onset of action may sometimes begin after 2 to 3 days, but frequently takes 1 to 3 weeks, despite the administration of higher loading doses. The bioavailability of amiodarone varies in clinical studies, averaging between 35 and 65%. Effect of food In healthy subjects who were given a single 600-mg dose immediately after consuming a meal high in fat, the AUC of amiodarone increased by 2.3 and the Cmax by 3.8 times. Food also enhances absorption, reducing the Tmax by about 37%. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): In a pharmacokinetic study of 3 healthy individuals and 3 patients diagnosed with supraventricular tachycardia (SVT), the volume of distribution was found to be 9.26-17.17 L/kg in healthy volunteers and 6.88-21.05 L/kg in the SVT patients. Prescribing information mentions that the volume of distribution of amiodarone varies greatly, with a mean distribution of approximately 60 L/kg. It accumulates throughout the body, especially in adipose tissue and highly vascular organs including the lung, liver, and spleen. One major metabolite of amiodarone, desethylamiodarone (DEA), is found in even higher proportions in the same tissues as amiodarone. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): The protein binding of amiodarone is about 96%. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): This drug is metabolized to the main metabolite desethylamiodarone (DEA) by the CYP3A4 and CYP2C8 enzymes. The CYP3A4 enzyme is found in the liver and intestines. A hydroxyl metabolite of DEA has been identified in mammals, but its clinical significance is unknown. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion. A small amount of desethylamiodarone (DEA) is found in the urine. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The terminal half-life of amiodarone varies according to the patient, but is long nonetheless, and ranges from about 9-100 days. The half-life duration varies according to different sources. According to the prescribing information for amiodarone, the average apparent plasma terminal elimination half-life of amiodarone is of 58 days (ranging from 15 to 142 days). The terminal half-life range was between 14 to 75 days for the active metabolite, (DEA). The plasma half-life of amiodarone after one dose ranges from 3.2 to 79.7 hours, according to one source. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The clearance of amiodarone after intravenous administration in patients with ventricular fibrillation and ventricular tachycardia ranged from 220 to 440 ml/hr/kg in one clinically study. Another study determined that the total body clearance of amiodarone varies from 0.10 to 0.77 L/min after one intravenous dose. Renal impairment does not appear to affect the clearance of amiodarone, but hepatic impairment may reduce clearance. Patients with liver cirrhosis exhibited significantly lower Cmax and mean amiodarone concentration for DEA, but not for amiodarone. Severe left ventricular dysfunction prolongs the half-life of DEA. A note on monitoring No guidelines have been developed for adjusting the dose of amiodarone in renal, hepatic, or cardiac abnormalities. In patients on chronic amiodarone treatment, close clinical monitoring is advisable, especially for elderly patients and those with severe left ventricular dysfunction. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The LD50 of oral amiodarone in mice and rats exceeds 3,000 mg/kg. An overdose with amiodarone can have a fatal outcome due to its potential to cause arrhythmia. Signs or symptoms of an overdose may include, hypotension, shock, bradycardia, AV block, and liver toxicity. In cases of an overdose, initiate supportive treatment and, if needed, use fluids, vasopressors, or positive inotropic agents. Temporary pacing may be required for heart block. Ensure to monitor liver function regularly. Amiodarone and its main metabolite, DEA, are not removable by dialysis. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Nexterone, Pacerone •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Amiodarona Amiodarone Amiodaronum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Amiodarone is a class III antiarrhythmic indicated for the treatment of recurrent hemodynamically unstable ventricular tachycardia and recurrent ventricular fibrillation. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Amlodipine interact?

•Drug A: Abaloparatide •Drug B: Amlodipine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Amlodipine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Amlodipine may be used alone or in combination with other antihypertensive and antianginal agents for the treatment of the following conditions: • Hypertension • Coronary artery disease • Chronic stable angina • Vasospastic angina (Prinzmetal’s or Variant angina) • Angiographically documented coronary artery disease in patients without heart failure or an ejection fraction < 40% •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): General pharmacodynamic effects Amlodipine has a strong affinity for cell membranes, modulating calcium influx by inhibiting selected membrane calcium channels. This drug's unique binding properties allow for its long-acting action and less frequent dosing regimen,. Hemodynamic effects After the administration of therapeutic doses of amlodipine to patients diagnosed with hypertension, amlodipine causes vasodilation, which results in a reduction of supine and standing blood pressure. During these blood pressure reductions, there are no clinically significant changes in heart rate or plasma catecholamine levels with long-term use. Acute intravenous administration of amlodipine reduces arterial blood pressure and increases heart rate in patients with chronic stable angina, however, chronic oral administration of amlodipine in clinical studies did not cause clinically significant alterations in heart rate or blood pressures in patients diagnosed with angina and normal blood pressure. With long-term, once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. Electrophysiologic effects Amlodipine does not change sinoatrial (SA) nodal function or atrioventricular (AV) conduction in animals or humans. In patients who were diagnosed with chronic stable angina, the intravenous administration of 10 mg of amlodipine did not cause clinically significant alterations A-H and H-V conduction and sinus node recovery time after cardiac pacing. Patients administered amlodipine with concomitant beta-blockers produced similar results. In clinical trials in which amlodipine was given in combination with beta-blockers to patients diagnosed with hypertension or angina, no adverse effects on electrocardiographic parameters were noted. In clinical studies comprised of angina patients alone, amlodipine did not change electrocardiographic intervals or produce high degrees of AV block. Effects on angina Amlodipine relieves the symptoms of chest pain associated with angina. In patients diagnosed with angina, daily administration of a single amlodipine dose increases total exercise time, the time to angina onset, and the time to 1 mm ST-segment depression on ECG studies, decreases anginal attack frequency, and decreases the requirement for nitroglycerin tablets. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Mechanism of action on blood pressure Amlodipine is considered a peripheral arterial vasodilator that exerts its action directly on vascular smooth muscle to lead to a reduction in peripheral vascular resistance, causing a decrease in blood pressure. Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) that inhibits the influx of calcium ions into both vascular smooth muscle and cardiac muscle. Experimental studies imply that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites, located on cell membranes. The contraction of cardiac muscle and vascular smooth muscle are dependent on the movement of extracellular calcium ions into these cells by specific ion channels. Amlodipine blocks calcium ion influx across cell membranes with selectivity. A stronger effect of amlodipine is exerted on vascular smooth muscle cells than on cardiac muscle cells. Direct actions of amlodipine on vascular smooth muscle result in reduced blood pressure. Mechanism of action in angina The exact mechanism by which amlodipine relieves the symptoms of angina have not been fully elucidated to this date, however, the mechanism of action is likely twofold: Amlodipine has a dilating effect on peripheral arterioles, reducing the total peripheral resistance (afterload) against which the cardiac muscle functions. Since the heart rate remains stable during amlodipine administration, the reduced work of the heart reduces both myocardial energy use and oxygen requirements. Dilatation of the main coronary arteries and coronary arterioles, both in healthy and ischemic areas, is another possible mechanism of amlodipine reduction of blood pressure. The dilatation causes an increase in myocardial oxygen delivery in patients experiencing coronary artery spasm (Prinzmetal's or variant angina) and reduces coronary vasoconstriction caused by smoking. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Amlodipine absorbed slowly and almost completely from the gastrointestinal tract. Peak plasma concentrations are achieved 6-12 hours after oral administration. The estimated bioavailability of amlodipine is 64-90%. Steady-state plasma amlodipine levels are achieved after 7-8 days of consecutive daily dosing. Absorption is not affected by food. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 21 L/kg,. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): About 98%,. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Amlodipine is heavily (approximately 90%) converted to inactive metabolites via hepatic breakdown with 10% of the parent compound and 60% of the metabolites found excreted in the urine. Ex vivo studies have shown that about 93% of the circulating drug is bound to plasma proteins in hypertensive patients. Characteristics that add to amlodipine's unique pharmacologic profile include nearly complete absorption, late-peak plasma concentrations, high bioavailability, and slow hepatic breakdown. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Elimination from the plasma occurs in a biphasic with a terminal elimination half-life of about 30–50 hours. Steady-state plasma levels of amlodipine are reached after 7-8 days of consecutive daily dosing. Amlodipine is 10% excreted as unchanged drug in the urine. Amlodipine can be initiated at normal doses in patients diagnosed with renal failure,. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The terminal elimination half-life of about 30–50 hours. Plasma elimination half-life is 56 hours in patients with impaired hepatic function, titrate slowly when administering this drug to patients with severe hepatic impairment. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Total body clearance (CL) has been calculated as 7 ± 1.3 ml/min/kg (0.42 ± 0.078 L/ h/kg) in healthy volunteers,. Elderly patients show a reduced clearance of amlodipine with an AUC (area under the curve) increase of about 40–60%, and a lower initial dose may be required. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Acute oral toxicity (LD50): 37 mg/kg (mouse). Overdose An overdose of amlodipine could result in a high degree of peripheral vasodilatation with a possibility of reflex tachycardia. Significant and prolonged hypotension leading to shock and fatal outcomes have been reported. Carcinogenesis, mutagenesis, impairment of fertility Rats and mice treated with amlodipine maleate in the diet on a long-term basis for up to 2 years demonstrated no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was comparable to the maximum recommended human dose of 10 mg amlodipine per day. For the rat, the highest dose was measured to be about twice the maximum recommended human dose. Mutagenicity studies using amlodipine maleate showed no drug-related gene or chromosomal effects. There was no impact on the fertility of rats given oral amlodipine maleate (males for 64 days and females for 14 days before mating) at doses up to 10 mg amlodipine/kg/day (8 times the maximum recommended human dose). Use in pregnancy The safety of amlodipine in human pregnancy or lactation has not been proven. Amlodipine is therefore considered a pregnancy category C drug. Use amlodipine only if the potential benefit justifies the potential risk. Use in nursing Discontinue when administering amlodipine. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Amlobenz, Azor, Caduet, Dafiro, Exforge, Exforge Hct, Katerzia, Lotrel, Norliqva, Norvasc, Prestalia, Tribenzor, Twynsta, Viacoram •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Amlodipine Amlodipino Amlodipinum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Amlodipine is a calcium channel blocker used to treat hypertension and angina.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Amlodipine interact? Information: •Drug A: Abaloparatide •Drug B: Amlodipine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Amlodipine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Amlodipine may be used alone or in combination with other antihypertensive and antianginal agents for the treatment of the following conditions: • Hypertension • Coronary artery disease • Chronic stable angina • Vasospastic angina (Prinzmetal’s or Variant angina) • Angiographically documented coronary artery disease in patients without heart failure or an ejection fraction < 40% •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): General pharmacodynamic effects Amlodipine has a strong affinity for cell membranes, modulating calcium influx by inhibiting selected membrane calcium channels. This drug's unique binding properties allow for its long-acting action and less frequent dosing regimen,. Hemodynamic effects After the administration of therapeutic doses of amlodipine to patients diagnosed with hypertension, amlodipine causes vasodilation, which results in a reduction of supine and standing blood pressure. During these blood pressure reductions, there are no clinically significant changes in heart rate or plasma catecholamine levels with long-term use. Acute intravenous administration of amlodipine reduces arterial blood pressure and increases heart rate in patients with chronic stable angina, however, chronic oral administration of amlodipine in clinical studies did not cause clinically significant alterations in heart rate or blood pressures in patients diagnosed with angina and normal blood pressure. With long-term, once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. Electrophysiologic effects Amlodipine does not change sinoatrial (SA) nodal function or atrioventricular (AV) conduction in animals or humans. In patients who were diagnosed with chronic stable angina, the intravenous administration of 10 mg of amlodipine did not cause clinically significant alterations A-H and H-V conduction and sinus node recovery time after cardiac pacing. Patients administered amlodipine with concomitant beta-blockers produced similar results. In clinical trials in which amlodipine was given in combination with beta-blockers to patients diagnosed with hypertension or angina, no adverse effects on electrocardiographic parameters were noted. In clinical studies comprised of angina patients alone, amlodipine did not change electrocardiographic intervals or produce high degrees of AV block. Effects on angina Amlodipine relieves the symptoms of chest pain associated with angina. In patients diagnosed with angina, daily administration of a single amlodipine dose increases total exercise time, the time to angina onset, and the time to 1 mm ST-segment depression on ECG studies, decreases anginal attack frequency, and decreases the requirement for nitroglycerin tablets. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Mechanism of action on blood pressure Amlodipine is considered a peripheral arterial vasodilator that exerts its action directly on vascular smooth muscle to lead to a reduction in peripheral vascular resistance, causing a decrease in blood pressure. Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) that inhibits the influx of calcium ions into both vascular smooth muscle and cardiac muscle. Experimental studies imply that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites, located on cell membranes. The contraction of cardiac muscle and vascular smooth muscle are dependent on the movement of extracellular calcium ions into these cells by specific ion channels. Amlodipine blocks calcium ion influx across cell membranes with selectivity. A stronger effect of amlodipine is exerted on vascular smooth muscle cells than on cardiac muscle cells. Direct actions of amlodipine on vascular smooth muscle result in reduced blood pressure. Mechanism of action in angina The exact mechanism by which amlodipine relieves the symptoms of angina have not been fully elucidated to this date, however, the mechanism of action is likely twofold: Amlodipine has a dilating effect on peripheral arterioles, reducing the total peripheral resistance (afterload) against which the cardiac muscle functions. Since the heart rate remains stable during amlodipine administration, the reduced work of the heart reduces both myocardial energy use and oxygen requirements. Dilatation of the main coronary arteries and coronary arterioles, both in healthy and ischemic areas, is another possible mechanism of amlodipine reduction of blood pressure. The dilatation causes an increase in myocardial oxygen delivery in patients experiencing coronary artery spasm (Prinzmetal's or variant angina) and reduces coronary vasoconstriction caused by smoking. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Amlodipine absorbed slowly and almost completely from the gastrointestinal tract. Peak plasma concentrations are achieved 6-12 hours after oral administration. The estimated bioavailability of amlodipine is 64-90%. Steady-state plasma amlodipine levels are achieved after 7-8 days of consecutive daily dosing. Absorption is not affected by food. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 21 L/kg,. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): About 98%,. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Amlodipine is heavily (approximately 90%) converted to inactive metabolites via hepatic breakdown with 10% of the parent compound and 60% of the metabolites found excreted in the urine. Ex vivo studies have shown that about 93% of the circulating drug is bound to plasma proteins in hypertensive patients. Characteristics that add to amlodipine's unique pharmacologic profile include nearly complete absorption, late-peak plasma concentrations, high bioavailability, and slow hepatic breakdown. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Elimination from the plasma occurs in a biphasic with a terminal elimination half-life of about 30–50 hours. Steady-state plasma levels of amlodipine are reached after 7-8 days of consecutive daily dosing. Amlodipine is 10% excreted as unchanged drug in the urine. Amlodipine can be initiated at normal doses in patients diagnosed with renal failure,. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The terminal elimination half-life of about 30–50 hours. Plasma elimination half-life is 56 hours in patients with impaired hepatic function, titrate slowly when administering this drug to patients with severe hepatic impairment. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Total body clearance (CL) has been calculated as 7 ± 1.3 ml/min/kg (0.42 ± 0.078 L/ h/kg) in healthy volunteers,. Elderly patients show a reduced clearance of amlodipine with an AUC (area under the curve) increase of about 40–60%, and a lower initial dose may be required. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Acute oral toxicity (LD50): 37 mg/kg (mouse). Overdose An overdose of amlodipine could result in a high degree of peripheral vasodilatation with a possibility of reflex tachycardia. Significant and prolonged hypotension leading to shock and fatal outcomes have been reported. Carcinogenesis, mutagenesis, impairment of fertility Rats and mice treated with amlodipine maleate in the diet on a long-term basis for up to 2 years demonstrated no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was comparable to the maximum recommended human dose of 10 mg amlodipine per day. For the rat, the highest dose was measured to be about twice the maximum recommended human dose. Mutagenicity studies using amlodipine maleate showed no drug-related gene or chromosomal effects. There was no impact on the fertility of rats given oral amlodipine maleate (males for 64 days and females for 14 days before mating) at doses up to 10 mg amlodipine/kg/day (8 times the maximum recommended human dose). Use in pregnancy The safety of amlodipine in human pregnancy or lactation has not been proven. Amlodipine is therefore considered a pregnancy category C drug. Use amlodipine only if the potential benefit justifies the potential risk. Use in nursing Discontinue when administering amlodipine. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Amlobenz, Azor, Caduet, Dafiro, Exforge, Exforge Hct, Katerzia, Lotrel, Norliqva, Norvasc, Prestalia, Tribenzor, Twynsta, Viacoram •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Amlodipine Amlodipino Amlodipinum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Amlodipine is a calcium channel blocker used to treat hypertension and angina. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Amobarbital interact?

•Drug A: Abaloparatide •Drug B: Amobarbital •Severity: MODERATE •Description: Amobarbital may increase the hypotensive activities of Abaloparatide. •Extended Description: The use of barbiturates may increase hypotension.1,2 Therefore, the concomitant administration of barbiturates and hypotensive agents may lead to dangerous hypotension due to additive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): No indication available •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Amobarbital (like all barbiturates) works by binding to the GABAA receptor at either the alpha or the beta sub unit. These are binding sites that are distinct from GABA itself and also distinct from the benzodiazepine binding site. Like benzodiazepines, barbiturates potentiate the effect of GABA at this receptor. This GABAA receptor binding decreases input resistance, depresses burst and tonic firing, especially in ventrobasal and intralaminar neurons, while at the same time increasing burst duration and mean conductance at individual chloride channels; this increases both the amplitude and decay time of inhibitory postsynaptic currents. In addition to this GABA-ergic effect, barbiturates also block the AMPA receptor, a subtype of glutamate receptor. Glutamate is the principal excitatory neurotransmitter in the mammalian CNS. Amobarbital also appears to bind neuronal nicotinic acetylcholine receptors. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): No half-life available •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Amobarbital Amobarbitale Amylobarbitone Barbamil Barbamyl •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Amobarbital is a barbiturate derivative used for the induction of sedation during procedures, short-term management of insomnia, and acute management of refractory tonic-clonic seizures.

The use of barbiturates may increase hypotension.1,2 Therefore, the concomitant administration of barbiturates and hypotensive agents may lead to dangerous hypotension due to additive effects. The severity of the interaction is moderate.

Question: Does Abaloparatide and Amobarbital interact? Information: •Drug A: Abaloparatide •Drug B: Amobarbital •Severity: MODERATE •Description: Amobarbital may increase the hypotensive activities of Abaloparatide. •Extended Description: The use of barbiturates may increase hypotension.1,2 Therefore, the concomitant administration of barbiturates and hypotensive agents may lead to dangerous hypotension due to additive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): No indication available •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Amobarbital (like all barbiturates) works by binding to the GABAA receptor at either the alpha or the beta sub unit. These are binding sites that are distinct from GABA itself and also distinct from the benzodiazepine binding site. Like benzodiazepines, barbiturates potentiate the effect of GABA at this receptor. This GABAA receptor binding decreases input resistance, depresses burst and tonic firing, especially in ventrobasal and intralaminar neurons, while at the same time increasing burst duration and mean conductance at individual chloride channels; this increases both the amplitude and decay time of inhibitory postsynaptic currents. In addition to this GABA-ergic effect, barbiturates also block the AMPA receptor, a subtype of glutamate receptor. Glutamate is the principal excitatory neurotransmitter in the mammalian CNS. Amobarbital also appears to bind neuronal nicotinic acetylcholine receptors. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): No half-life available •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Amobarbital Amobarbitale Amylobarbitone Barbamil Barbamyl •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Amobarbital is a barbiturate derivative used for the induction of sedation during procedures, short-term management of insomnia, and acute management of refractory tonic-clonic seizures. Output: The use of barbiturates may increase hypotension.1,2 Therefore, the concomitant administration of barbiturates and hypotensive agents may lead to dangerous hypotension due to additive effects. The severity of the interaction is moderate.

Does Abaloparatide and Amphotericin B interact?

•Drug A: Abaloparatide •Drug B: Amphotericin B •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Amphotericin B is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Used to treat potentially life threatening fungal infections. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Amphotericin B shows a high order of in vitro activity against many species of fungi. Histoplasma capsulatum, Coccidioides immitis, Candida species, Blastomyces dermatitidis, Rhodotorula, Cryptococcus neoformans, Sporothrix schenckii, Mucor mucedo, and Aspergillus fumigatus are all inhibited by concentrations of amphotericin B ranging from 0.03 to 1.0 mcg/mL in vitro. While Candida albicans is generally quite susceptible to amphotericin B, non- albicans species may be less susceptible. Pseudallescheria boydii and Fusarium sp. are often resistant to amphotericin B. The antibiotic is without effect on bacteria, rickettsiae, and viruses. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Amphotericin B is fungistatic or fungicidal depending on the concentration obtained in body fluids and the susceptibility of the fungus. The drug acts by binding to sterols (ergosterol) in the cell membrane of susceptible fungi. This creates a transmembrane channel, and the resultant change in membrane permeability allowing leakage of intracellular components. Ergosterol, the principal sterol in the fungal cytoplasmic membrane, is the target site of action of amphotericin B and the azoles. Amphotericin B, a polyene, binds irreversibly to ergosterol, resulting in disruption of membrane integrity and ultimately cell death. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Bioavailability is 100% for intravenous infusion. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Highly bound (>90%) to plasma proteins. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Exclusively renal •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): An elimination half-life of approximately 15 days follows an initial plasma half-life of about 24 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): 39 +/- 22 mL/hr/kg [febrile neutropenic cancer and bone marrow transplant patients receiving infusion of 1 mg/kg/day at Day 1] 17 +/- 6 mL/hr/kg [febrile neutropenic cancer and bone marrow transplant patients receiving infusion of 1 mg/kg/day 3-20 days later] 51 +/- 44 mL/hr/kg [febrile neutropenic cancer and bone marrow transplant patients receiving infusion of 2.5 mg/kg/day at Day 1] 22 +/- 15 mL/hr/kg [febrile neutropenic cancer and bone marrow transplant patients receiving infusion of 2.5 mg/kg/day 3-20 days later] 21 +/- 14 mL/hr/kg [febrile neutropenic cancer and bone marrow transplant patients receiving infusion of 5 mg/kg/day at Day 1] 11 +/- 6 mL/hr/kg [febrile neutropenic cancer and bone marrow transplant patients receiving infusion of 5 mg/kg/day 3-20 days later] •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Oral, rat: LD 50 = >5 gm/kg. Amphotericin B overdoses can result in cardio-respiratory arrest. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Abelcet, Ambisome, Amphotec, Fungizone •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Amphotericin B is an antifungal used to treat fungal infections in neutropenic patients, cryptococcal meningitis in HIV infection, fungal infections, and leishmaniasis.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Amphotericin B interact? Information: •Drug A: Abaloparatide •Drug B: Amphotericin B •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Amphotericin B is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Used to treat potentially life threatening fungal infections. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Amphotericin B shows a high order of in vitro activity against many species of fungi. Histoplasma capsulatum, Coccidioides immitis, Candida species, Blastomyces dermatitidis, Rhodotorula, Cryptococcus neoformans, Sporothrix schenckii, Mucor mucedo, and Aspergillus fumigatus are all inhibited by concentrations of amphotericin B ranging from 0.03 to 1.0 mcg/mL in vitro. While Candida albicans is generally quite susceptible to amphotericin B, non- albicans species may be less susceptible. Pseudallescheria boydii and Fusarium sp. are often resistant to amphotericin B. The antibiotic is without effect on bacteria, rickettsiae, and viruses. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Amphotericin B is fungistatic or fungicidal depending on the concentration obtained in body fluids and the susceptibility of the fungus. The drug acts by binding to sterols (ergosterol) in the cell membrane of susceptible fungi. This creates a transmembrane channel, and the resultant change in membrane permeability allowing leakage of intracellular components. Ergosterol, the principal sterol in the fungal cytoplasmic membrane, is the target site of action of amphotericin B and the azoles. Amphotericin B, a polyene, binds irreversibly to ergosterol, resulting in disruption of membrane integrity and ultimately cell death. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Bioavailability is 100% for intravenous infusion. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Highly bound (>90%) to plasma proteins. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Exclusively renal •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): An elimination half-life of approximately 15 days follows an initial plasma half-life of about 24 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): 39 +/- 22 mL/hr/kg [febrile neutropenic cancer and bone marrow transplant patients receiving infusion of 1 mg/kg/day at Day 1] 17 +/- 6 mL/hr/kg [febrile neutropenic cancer and bone marrow transplant patients receiving infusion of 1 mg/kg/day 3-20 days later] 51 +/- 44 mL/hr/kg [febrile neutropenic cancer and bone marrow transplant patients receiving infusion of 2.5 mg/kg/day at Day 1] 22 +/- 15 mL/hr/kg [febrile neutropenic cancer and bone marrow transplant patients receiving infusion of 2.5 mg/kg/day 3-20 days later] 21 +/- 14 mL/hr/kg [febrile neutropenic cancer and bone marrow transplant patients receiving infusion of 5 mg/kg/day at Day 1] 11 +/- 6 mL/hr/kg [febrile neutropenic cancer and bone marrow transplant patients receiving infusion of 5 mg/kg/day 3-20 days later] •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Oral, rat: LD 50 = >5 gm/kg. Amphotericin B overdoses can result in cardio-respiratory arrest. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Abelcet, Ambisome, Amphotec, Fungizone •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Amphotericin B is an antifungal used to treat fungal infections in neutropenic patients, cryptococcal meningitis in HIV infection, fungal infections, and leishmaniasis. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Amyl Nitrite interact?

•Drug A: Abaloparatide •Drug B: Amyl Nitrite •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Amyl Nitrite is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the rapid relief of angina pectoris. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Amyl nitrite, in common with other alkyl nitrites, is a potent vasodilator. It expands blood vessels, resulting in lowering of the blood pressure. Alkyl nitrite functions as a source of nitric oxide, which signals for relaxation of the involuntary muscles. Adverse effects are related to this pharmacological activity and include hypotension, headache, flushing of the face, tachycardia, dizziness, and relaxation of involuntary muscles, especially the blood vessel walls and the anal sphincter. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Amyl nitrite's antianginal action is thought to be the result of a reduction in systemic and pulmonary arterial pressure (afterload) and decreased cardiac output because of peripheral vasodilation, rather than coronary artery dilation. Amyl nitrite is a source of nitric oxide, which accounts for the mechanism described above. As an antidote (to cyanide poisoning), amyl nitrite promotes formation of methemoglobin, which combines with cyanide to form nontoxic cyanmethemoglobin. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Amyl nitrite vapors are absorbed rapidly through the pulmonary alveoli, manifesting therapeutic effects within one minute after inhalation. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Hepatic. The drug is metabolized rapidly, probably by hydrolytic denitration; approximately one-third of the inhaled amyl nitrite is excreted in the urine. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): No half-life available •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Overdose symptoms include nausea, emesis (vomiting), hypotension, hypoventilation, dyspnea (shortness of breath), and syncope (fainting) •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Amyl Nitrite is a fast acting vasodilator used for rapid relief of angina pectoris.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Amyl Nitrite interact? Information: •Drug A: Abaloparatide •Drug B: Amyl Nitrite •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Amyl Nitrite is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the rapid relief of angina pectoris. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Amyl nitrite, in common with other alkyl nitrites, is a potent vasodilator. It expands blood vessels, resulting in lowering of the blood pressure. Alkyl nitrite functions as a source of nitric oxide, which signals for relaxation of the involuntary muscles. Adverse effects are related to this pharmacological activity and include hypotension, headache, flushing of the face, tachycardia, dizziness, and relaxation of involuntary muscles, especially the blood vessel walls and the anal sphincter. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Amyl nitrite's antianginal action is thought to be the result of a reduction in systemic and pulmonary arterial pressure (afterload) and decreased cardiac output because of peripheral vasodilation, rather than coronary artery dilation. Amyl nitrite is a source of nitric oxide, which accounts for the mechanism described above. As an antidote (to cyanide poisoning), amyl nitrite promotes formation of methemoglobin, which combines with cyanide to form nontoxic cyanmethemoglobin. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Amyl nitrite vapors are absorbed rapidly through the pulmonary alveoli, manifesting therapeutic effects within one minute after inhalation. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Hepatic. The drug is metabolized rapidly, probably by hydrolytic denitration; approximately one-third of the inhaled amyl nitrite is excreted in the urine. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): No half-life available •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Overdose symptoms include nausea, emesis (vomiting), hypotension, hypoventilation, dyspnea (shortness of breath), and syncope (fainting) •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Amyl Nitrite is a fast acting vasodilator used for rapid relief of angina pectoris. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Apomorphine interact?

•Drug A: Abaloparatide •Drug B: Apomorphine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Apomorphine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Apomorphine is indicated to treat acute, intermittent treatment of hypomobility, off episodes associated with advanced Parkinson's disease. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Apomorphine is a dopaminergic agonist that may stimulate regions of the brain involved in motor control. It has a short duration of action and a wide therapeutic index as large overdoses are necessary for significant toxicity. Patients should be counselled regarding the risk of nausea, vomiting, daytime somnolence, hypotension, oral mucosal irritation, falls, hallucinations, psychotic-like behaviour, impulsive behaviour, withdrawal hyperpyrexia, and prolongation of the QT interval. Given the incidence of nausea and vomiting in patients taking apomorphine, treatment with trimethobenzamide may be recommended prior to or during therapy. Antiemetic pretreatment may be started three days prior to beginning therapy with apomorphine - it should only be continued as long as is necessary and generally for no longer than two months. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Apomorphine is a non-ergoline dopamine agonist with high binding affinity to dopamine D2, D3, and D5 receptors. Stimulation of D2 receptors in the caudate-putamen, a region of the brain responsible for locomotor control, may be responsible for apomorphine's action. However, the means by which the cellular effects of apomorphine treat hypomobility of Parkinson's remain unknown. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Apomorphine has a plasma T max of 10-20 minutes and a cerebrospinal fluid T max. The C max and AUC of apomorphine vary significantly between patients, with 5- to 10-fold differences being reported. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The apparent volume of distribution of subcutaneous apomorphine is 123-404L with an average of 218L. The apparent volume of distribution of sublingual apomorphine is 3630L. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Apomorphine is expected to be 99.9% bound to human serum albumin, as no unbound apomorphine is detected. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Apomorphine is N-demethylated by CYP2B6, 2C8, 3A4, and 3A5. It can be glucuronidated by various UGTs, or sulfated by SULTs 1A1, 1A2, 1A3, 1E1, and 1B1. Approximately 60% of sublingual apomorphine is eliminated as a sulfate conjugate, though the structure of these sulfate conjugates are not readily available. The remainder of an apomorphine dose is eliminated as apomorphine glucuronide and norapomorphine glucuronide. Only 0.3% of subcutaneous apomorphine is recovered as the unchanged parent drug. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Data regarding apomorphine's route of elimination is not readily available. A study in rats has shown apomorphine is predominantly eliminated in the urine. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The terminal elimination half life of a 15mg sublingual dose of apomorphine is 1.7h, while the terminal elimination half life of an intravenous dose is 50 minutes. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The clearance of a 15mg sublingual dose of apomorphine is 1440L/h, while the clearance of an intravenous dose is 223L/h. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Patients experiencing an overdose of apomorphine may present with nausea, hypotension, and loss of consciousness. Treat patients with symptomatic and supportive measures. The intraperitoneal LD 50 in mice is 145µg/kg. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Apokyn •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Apomorfina Apomorphin Apomorphine •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Apomorphine is a morphine derivative D2 dopamine agonist used to treat hypomobile "off" episodes of advanced Parkinson's disease.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Apomorphine interact? Information: •Drug A: Abaloparatide •Drug B: Apomorphine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Apomorphine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Apomorphine is indicated to treat acute, intermittent treatment of hypomobility, off episodes associated with advanced Parkinson's disease. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Apomorphine is a dopaminergic agonist that may stimulate regions of the brain involved in motor control. It has a short duration of action and a wide therapeutic index as large overdoses are necessary for significant toxicity. Patients should be counselled regarding the risk of nausea, vomiting, daytime somnolence, hypotension, oral mucosal irritation, falls, hallucinations, psychotic-like behaviour, impulsive behaviour, withdrawal hyperpyrexia, and prolongation of the QT interval. Given the incidence of nausea and vomiting in patients taking apomorphine, treatment with trimethobenzamide may be recommended prior to or during therapy. Antiemetic pretreatment may be started three days prior to beginning therapy with apomorphine - it should only be continued as long as is necessary and generally for no longer than two months. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Apomorphine is a non-ergoline dopamine agonist with high binding affinity to dopamine D2, D3, and D5 receptors. Stimulation of D2 receptors in the caudate-putamen, a region of the brain responsible for locomotor control, may be responsible for apomorphine's action. However, the means by which the cellular effects of apomorphine treat hypomobility of Parkinson's remain unknown. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Apomorphine has a plasma T max of 10-20 minutes and a cerebrospinal fluid T max. The C max and AUC of apomorphine vary significantly between patients, with 5- to 10-fold differences being reported. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The apparent volume of distribution of subcutaneous apomorphine is 123-404L with an average of 218L. The apparent volume of distribution of sublingual apomorphine is 3630L. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Apomorphine is expected to be 99.9% bound to human serum albumin, as no unbound apomorphine is detected. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Apomorphine is N-demethylated by CYP2B6, 2C8, 3A4, and 3A5. It can be glucuronidated by various UGTs, or sulfated by SULTs 1A1, 1A2, 1A3, 1E1, and 1B1. Approximately 60% of sublingual apomorphine is eliminated as a sulfate conjugate, though the structure of these sulfate conjugates are not readily available. The remainder of an apomorphine dose is eliminated as apomorphine glucuronide and norapomorphine glucuronide. Only 0.3% of subcutaneous apomorphine is recovered as the unchanged parent drug. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Data regarding apomorphine's route of elimination is not readily available. A study in rats has shown apomorphine is predominantly eliminated in the urine. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The terminal elimination half life of a 15mg sublingual dose of apomorphine is 1.7h, while the terminal elimination half life of an intravenous dose is 50 minutes. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The clearance of a 15mg sublingual dose of apomorphine is 1440L/h, while the clearance of an intravenous dose is 223L/h. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Patients experiencing an overdose of apomorphine may present with nausea, hypotension, and loss of consciousness. Treat patients with symptomatic and supportive measures. The intraperitoneal LD 50 in mice is 145µg/kg. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Apokyn •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Apomorfina Apomorphin Apomorphine •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Apomorphine is a morphine derivative D2 dopamine agonist used to treat hypomobile "off" episodes of advanced Parkinson's disease. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Aripiprazole lauroxil interact?

•Drug A: Abaloparatide •Drug B: Aripiprazole lauroxil •Severity: MINOR •Description: Aripiprazole lauroxil may increase the hypotensive activities of Abaloparatide. •Extended Description: Aripiprazole may cause orthostatic hypotension through antagonism of the α1-adrenergic receptor.3,2,4 Cases of orthostatic hypotension, postural dizziness, and syncope have been reported with the short-term use of aripiprazole in clinical trials. The risk for developing a decrease in blood pressure may be enhanced with concurrent use of aripiprazole with other agents known to cause hypotension, including antihypertensive medications. Contrary to these findings, one case report looking at two patients found that aripiprazole may increase hypertension. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Aripiprazole lauroxil is indicated for the treatment of schizophrenia and related psychotic disorders. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Aripiprazole, which is a major pharmacological metabolite of aripiprazole lauroxil, serves to improve the positive and negative symptoms of schizophrenia by modulating dopaminergic signalling pathways. Aripiprazole lauroxil is reported to have minimal effects on sexual function or prolactin levels. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): The pharmacological activity of aripiprazole lauroxil is thought to be mainly mediated by its metabolite aripiprazole, and to a lesser extent, dehydro-aripiprazole. Aripiprazole functions as a partial agonist at the dopamine D2 and the serotonin 5-HT1A receptors, and as an antagonist at the serotonin 5-HT2A receptor. The desired outcome of antipsuchotic agents in schizophrenia is to inhibit dopaminergic transmission in the limbic system and enhance dopaminergic transmission in the prefrontal cortex. As a partial agonist at D2 receptors in the mesolimbic dopaminergic pathway, aripiprazole acts as a functional antagonist in the mesolimbic dopamine pathway and reduces the extent of dopaminergic pathway activity. This results in reduced positive symptoms in schizophrenia and extrapyramidal motor side effects. In contrast, aripiprazole is thought to act as a functional agonist in the mesocortical pathway, where reduced dopamine activity is seen in association with negative symptoms and cognitive impairment. Antagonism at 5-HT2A receptors by aripiprazole alleviates the negative symptoms and cognitive impairment of schizophrenia. 5-HT2A receptors are Gi/Go-coupled that upon activation, produce neuronal inhibition via decreased neuronal excitability and decreased transmitter release at the nerve terminals. In the nigrostriatal pathway, 5-HT2A regulates the release of dopamine. Through antagonism of 5-HT2A receptors, aripiprazole disinhibits the release of dopamine in the striatum and enhance the levels of the transmitters at the nerve terminals. The combined effects of D2 and 5-HT2A antagonism are thought to counteract the increased dopamine function causing increased extrapyramidal side effects. Blocking 5-HT2A receptors may also lead to the modulation of glutamate release in the mesocortical circuit, which is a transmitter that plays a role in schizophrenia. 5-HT1A receptors are autoreceptors that inhibit 5-HT release upon activation. Aripiprazole is a partial agonist at theses receptors and reduces 5-HT release; this results in potentiated dopamine release in the striatum and prefrontal cortex. It is reported that therapeutic doses of aripiprazole occupies up to 90% of brain D2 receptors in a dose-dependent manner. Apripiprazole targets different receptors that lead to drug-related adverse reactions; for example, the antagonist activity at the alpha-1 adrenergic receptors results in orthostatic hypotension. Aripiprazole's antagonism of histamine H1 receptors may explain the somnolence observed with this drug. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Following a single extended-release intramuscular injection of aripiprazole lauroxil, aripiprazole can be detected in the systemic circulation from 5 to 6 days and is continued to be released for an additional 36 days. The concentrations of aripiprazole increases with consecutive doses of aripiprazole lauroxil and the steady state is reached following the fourth monthly injection. The systemic exposure to aripiprazole was similar when comparing deltoid and gluteal intramuscular injections. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Based on population pharmacokinetic analysis, the apparent volume of distribution of aripiprazole following intramuscular injection of aripiprazole lauroxil was 268 L, indicating extensive extravascular distribution following absorption. Health human volunteer study indicates that aripiprazole crosses the blood-brain barrier. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Serum protein binding of aripiprazole and its major metabolite is >99% at therapeutic concentrations, where they are primarily bound to albumin. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Aripiprazole lauroxil is hydrolyzed to form N-hydroxymethyl-aripiprazole via esterases. N-hydroxymethyl-aripiprazole undergoes a rapid, nonenzymatic spontaneous cleavage, or water-mediated hydrolysis, to form aripiprazole, which mainly contributes to the pharmacological actions of aripiprazole lauroxil. Aripiprazole is further metabolized by hepatic CYP3A4 and CYP2D6 to form dehydro-aripiprazole, which retains some pharmacological activity. Dehydro-aripiprazole displays affinities for D2 receptors similar to aripiprazole and represents 30-40% of the aripiprazole exposure in plasma. Cytochrome P450 2D6 is subject to genetic polymorphism, which results in pharmacokinetic differences among CYP2D6 metabolizer phenotypes and dosage adjustments accordingly. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Based on the pharmacokinetic study for aripiprazole, less than 1% of unchanged aripiprazole was excreted in the urine and approximately 18% of the oral dose was recovered unchanged in the feces. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The mean aripiprazole terminal elimination half-life ranged from 29.2 days to 34.9 days after every 4-week injection of aripiprazole lauroxil 441, 662 and 882 mg. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): In rats, the clearance for aripiprazole lauroxil was 0.32 ± 0.11 L/h/kg following injection of aripiprazole lauroxil molar equivalent to 5 mg aripiprazole/kg. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): LD50 in rat following intramuscular injection was >60 mg aripiprazole equivalents. Oral LD50 of aripiprazole in female rat, male rat, and monkey were 705 mg/kg, 965 mg/kg, and >2000 mg/kg, respectively. Most common adverse reaction of aripiprazole was akathisia. A case of drug overdosage occurred followinga acute ingestion of 1260 mg aripiprazole, which is approximately 42 times the maximum recommended daily dose. Overdose was associated with vomiting, somnolence, and tremor. Other clinically important signs and symptoms observed in one or more patients with aripiprazole overdoses (alone or with other substances) include acidosis, aggression, aspartate aminotransferase increased, atrial fibrillation, bradycardia, coma, confusional state, convulsion, blood creatine phosphokinase increased, depressed level of consciousness, hypertension, hypokalemia, hypotension, lethargy, loss of consciousness, QRS complex prolonged, QT prolonged, pneumonia aspiration, respiratory arrest, status epilepticus, and tachycardia. Aripiprazole is an antipsychotic drug that may develop Neuroleptic Malignant Syndrome (NMS), which is manifested with hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability. In case of NMS, aripiprazole should be discontinued immediately, and intensive symptomatic treatment and medical monitoring should be initiated. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Aristada •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Aripiprazole lauroxil is an antipsychotic used to treat schizophrenia in adults.

Aripiprazole may cause orthostatic hypotension through antagonism of the α1-adrenergic receptor.3,2,4 Cases of orthostatic hypotension, postural dizziness, and syncope have been reported with the short-term use of aripiprazole in clinical trials. The risk for developing a decrease in blood pressure may be enhanced with concurrent use of aripiprazole with other agents known to cause hypotension, including antihypertensive medications. Contrary to these findings, one case report looking at two patients found that aripiprazole may increase hypertension. The severity of the interaction is minor.

Question: Does Abaloparatide and Aripiprazole lauroxil interact? Information: •Drug A: Abaloparatide •Drug B: Aripiprazole lauroxil •Severity: MINOR •Description: Aripiprazole lauroxil may increase the hypotensive activities of Abaloparatide. •Extended Description: Aripiprazole may cause orthostatic hypotension through antagonism of the α1-adrenergic receptor.3,2,4 Cases of orthostatic hypotension, postural dizziness, and syncope have been reported with the short-term use of aripiprazole in clinical trials. The risk for developing a decrease in blood pressure may be enhanced with concurrent use of aripiprazole with other agents known to cause hypotension, including antihypertensive medications. Contrary to these findings, one case report looking at two patients found that aripiprazole may increase hypertension. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Aripiprazole lauroxil is indicated for the treatment of schizophrenia and related psychotic disorders. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Aripiprazole, which is a major pharmacological metabolite of aripiprazole lauroxil, serves to improve the positive and negative symptoms of schizophrenia by modulating dopaminergic signalling pathways. Aripiprazole lauroxil is reported to have minimal effects on sexual function or prolactin levels. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): The pharmacological activity of aripiprazole lauroxil is thought to be mainly mediated by its metabolite aripiprazole, and to a lesser extent, dehydro-aripiprazole. Aripiprazole functions as a partial agonist at the dopamine D2 and the serotonin 5-HT1A receptors, and as an antagonist at the serotonin 5-HT2A receptor. The desired outcome of antipsuchotic agents in schizophrenia is to inhibit dopaminergic transmission in the limbic system and enhance dopaminergic transmission in the prefrontal cortex. As a partial agonist at D2 receptors in the mesolimbic dopaminergic pathway, aripiprazole acts as a functional antagonist in the mesolimbic dopamine pathway and reduces the extent of dopaminergic pathway activity. This results in reduced positive symptoms in schizophrenia and extrapyramidal motor side effects. In contrast, aripiprazole is thought to act as a functional agonist in the mesocortical pathway, where reduced dopamine activity is seen in association with negative symptoms and cognitive impairment. Antagonism at 5-HT2A receptors by aripiprazole alleviates the negative symptoms and cognitive impairment of schizophrenia. 5-HT2A receptors are Gi/Go-coupled that upon activation, produce neuronal inhibition via decreased neuronal excitability and decreased transmitter release at the nerve terminals. In the nigrostriatal pathway, 5-HT2A regulates the release of dopamine. Through antagonism of 5-HT2A receptors, aripiprazole disinhibits the release of dopamine in the striatum and enhance the levels of the transmitters at the nerve terminals. The combined effects of D2 and 5-HT2A antagonism are thought to counteract the increased dopamine function causing increased extrapyramidal side effects. Blocking 5-HT2A receptors may also lead to the modulation of glutamate release in the mesocortical circuit, which is a transmitter that plays a role in schizophrenia. 5-HT1A receptors are autoreceptors that inhibit 5-HT release upon activation. Aripiprazole is a partial agonist at theses receptors and reduces 5-HT release; this results in potentiated dopamine release in the striatum and prefrontal cortex. It is reported that therapeutic doses of aripiprazole occupies up to 90% of brain D2 receptors in a dose-dependent manner. Apripiprazole targets different receptors that lead to drug-related adverse reactions; for example, the antagonist activity at the alpha-1 adrenergic receptors results in orthostatic hypotension. Aripiprazole's antagonism of histamine H1 receptors may explain the somnolence observed with this drug. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Following a single extended-release intramuscular injection of aripiprazole lauroxil, aripiprazole can be detected in the systemic circulation from 5 to 6 days and is continued to be released for an additional 36 days. The concentrations of aripiprazole increases with consecutive doses of aripiprazole lauroxil and the steady state is reached following the fourth monthly injection. The systemic exposure to aripiprazole was similar when comparing deltoid and gluteal intramuscular injections. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Based on population pharmacokinetic analysis, the apparent volume of distribution of aripiprazole following intramuscular injection of aripiprazole lauroxil was 268 L, indicating extensive extravascular distribution following absorption. Health human volunteer study indicates that aripiprazole crosses the blood-brain barrier. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Serum protein binding of aripiprazole and its major metabolite is >99% at therapeutic concentrations, where they are primarily bound to albumin. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Aripiprazole lauroxil is hydrolyzed to form N-hydroxymethyl-aripiprazole via esterases. N-hydroxymethyl-aripiprazole undergoes a rapid, nonenzymatic spontaneous cleavage, or water-mediated hydrolysis, to form aripiprazole, which mainly contributes to the pharmacological actions of aripiprazole lauroxil. Aripiprazole is further metabolized by hepatic CYP3A4 and CYP2D6 to form dehydro-aripiprazole, which retains some pharmacological activity. Dehydro-aripiprazole displays affinities for D2 receptors similar to aripiprazole and represents 30-40% of the aripiprazole exposure in plasma. Cytochrome P450 2D6 is subject to genetic polymorphism, which results in pharmacokinetic differences among CYP2D6 metabolizer phenotypes and dosage adjustments accordingly. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Based on the pharmacokinetic study for aripiprazole, less than 1% of unchanged aripiprazole was excreted in the urine and approximately 18% of the oral dose was recovered unchanged in the feces. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The mean aripiprazole terminal elimination half-life ranged from 29.2 days to 34.9 days after every 4-week injection of aripiprazole lauroxil 441, 662 and 882 mg. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): In rats, the clearance for aripiprazole lauroxil was 0.32 ± 0.11 L/h/kg following injection of aripiprazole lauroxil molar equivalent to 5 mg aripiprazole/kg. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): LD50 in rat following intramuscular injection was >60 mg aripiprazole equivalents. Oral LD50 of aripiprazole in female rat, male rat, and monkey were 705 mg/kg, 965 mg/kg, and >2000 mg/kg, respectively. Most common adverse reaction of aripiprazole was akathisia. A case of drug overdosage occurred followinga acute ingestion of 1260 mg aripiprazole, which is approximately 42 times the maximum recommended daily dose. Overdose was associated with vomiting, somnolence, and tremor. Other clinically important signs and symptoms observed in one or more patients with aripiprazole overdoses (alone or with other substances) include acidosis, aggression, aspartate aminotransferase increased, atrial fibrillation, bradycardia, coma, confusional state, convulsion, blood creatine phosphokinase increased, depressed level of consciousness, hypertension, hypokalemia, hypotension, lethargy, loss of consciousness, QRS complex prolonged, QT prolonged, pneumonia aspiration, respiratory arrest, status epilepticus, and tachycardia. Aripiprazole is an antipsychotic drug that may develop Neuroleptic Malignant Syndrome (NMS), which is manifested with hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability. In case of NMS, aripiprazole should be discontinued immediately, and intensive symptomatic treatment and medical monitoring should be initiated. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Aristada •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Aripiprazole lauroxil is an antipsychotic used to treat schizophrenia in adults. Output: Aripiprazole may cause orthostatic hypotension through antagonism of the α1-adrenergic receptor.3,2,4 Cases of orthostatic hypotension, postural dizziness, and syncope have been reported with the short-term use of aripiprazole in clinical trials. The risk for developing a decrease in blood pressure may be enhanced with concurrent use of aripiprazole with other agents known to cause hypotension, including antihypertensive medications. Contrary to these findings, one case report looking at two patients found that aripiprazole may increase hypertension. The severity of the interaction is minor.

Does Abaloparatide and Aripiprazole interact?

•Drug A: Abaloparatide •Drug B: Aripiprazole •Severity: MINOR •Description: Aripiprazole may increase the hypotensive activities of Abaloparatide. •Extended Description: Aripiprazole may cause orthostatic hypotension through antagonism of the α1-adrenergic receptor.3,2,4 Cases of orthostatic hypotension, postural dizziness, and syncope have been reported with the short-term use of aripiprazole in clinical trials. The risk for developing a decrease in blood pressure may be enhanced with concurrent use of aripiprazole with other agents known to cause hypotension, including antihypertensive medications. Contrary to these findings, one case report looking at two patients found that aripiprazole may increase hypertension. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Aripiprazole is indicated for the treatment of acute manic and mixed episodes associated with bipolar I disorder, irritability associated with autism spectrum disorder, schizophrenia, and Tourette's disorder. It is also used as an adjunctive treatment of major depressive disorder.[L45859 An injectable formulation of aripiprazole is indicated for agitation associated with schizophrenia or bipolar mania. Finally, an extended-release, bimonthly injection formulation of aripiprazole is indicated for the treatment of adult schizophrenia and maintenance therapy for adult bipolar I disorder. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Aripiprazole exhibits high affinity for dopamine D 2 and D 3, serotonin 5-HT 1a and 5-HT 2a receptors (Ki values of 0.34 nM, 0.8 nM, 1.7 nM, and 3.4 nM, respectively), moderate affinity for dopamine D 4, serotonin 5-HT 2c and 5-HT 7, alpha 1 -adrenergic and histamine H 1 receptors (Ki values of 44 nM, 15 nM, 39 nM, 57 nM, and 61 nM, respectively), and moderate affinity for the serotonin reuptake site (Ki=98 nM). Aripiprazole has no appreciable affinity for cholinergic muscarinic receptors (IC 50 >1000 nM). •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): The antipsychotic action of aripiprazole is likely due to its partial agonist activity on D2 and 5-HT 1A receptors as well as its antagonist activity at 5-HT 2A receptors; however, the exact mechanism has not been fully elucidated. One of the mechanisms that have been proposed is that aripiprazole both stimulates and inhibits dopamine as it engages the D2 receptor. It lowers dopamine neuronal firing at high dopamine concentrations and increases dopamine firing at low concentrations. Its partial agonist activity gives aripiprazole an intermediate level of dopaminergic neuronal tone between full agonist and antagonist of the D2 receptor. In addition, some adverse effects may be due to action on other receptors.[L4620] For example, orthostatic hypotension may be explained by antagonism of the adrenergic alpha-1 receptors. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Tablet: Aripiprazole is well absorbed after administration of the tablet, with peak plasma concentrations occurring within 3 hours to 5 hours; the absolute oral bioavailability of the tablet formulation is 87%. ABILIFY can be administered with or without food. Administration of a 15 mg ABILIFY tablet with a standard high-fat meal did not significantly affect the C max or AUC of aripiprazole or its active metabolite, dehydro-aripiprazole, but delayed T max by 3 hours for aripiprazole and 12 hours for dehydro-aripiprazole. Oral Solution: Aripiprazole is well absorbed when administered orally as the solution. At equivalent doses, the plasma concentrations of aripiprazole from the solution were higher than that from the tablet formulation. In a relative bioavailability study comparing the pharmacokinetics of 30 mg aripiprazole as the oral solution to 30 mg aripiprazole tablets in healthy subjects, the solution-to-tablet ratios of geometric mean C max and AUC values were 122% and 114%, respectively. The single-dose pharmacokinetics of aripiprazole were linear and dose-proportional between the doses of 5 mg to 30 mg. Extended-release injectable suspension, bimonthly injection: Aripiprazole absorption into the systemic circulation is prolonged following gluteal intramuscular injection due to the low solubility of aripiprazole particles. The release profile of aripiprazole from ABILIFY ASIMTUFII results in sustained plasma concentrations over 2 months following gluteal injection(s). Following multiple doses, the median peak:trough ratio for aripiprazole following an ABILIFY ASIMTUFII dose is 1.3, resulting in a flat plasma concentration profile with T max ranging between 1 to 49 days following multiple gluteal administrations of 960 mg. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The steady-state volume of distribution of aripiprazole following intravenous administration is high (404 L or 4.9 L/kg), indicating extensive extravascular distribution. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): At therapeutic concentrations, aripiprazole and its major metabolite are greater than 99% bound to serum proteins, primarily to albumin. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Aripiprazole is metabolized primarily by three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for the dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the predominant drug moiety in systemic circulation. At steady-state, dehydro-aripiprazole, the active metabolite, represents about 40% of aripiprazole AUC in plasma. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Following a single oral dose of [14C]-labeled aripiprazole, approximately 25% and 55% of the administered radioactivity was recovered in the urine and feces, respectively. Less than 1% of unchanged aripiprazole was excreted in the urine and approximately 18% of the oral dose was recovered unchanged in the feces. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The mean elimination half-lives are about 75 hours and 94 hours for aripiprazole and dehydro-aripiprazole, respectively. For populations that are poor CYP2D6 metabolizers, the half-life of aripiprazole is 146 hours and these patients should be treated with half the normal dose. Other studies have reported a half-life of 61.03±19.59 hours for aripiprazole and 279±299 hours for the active metabolite. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The clearance of aripiprazole was estimated to be 0.8mL/min/kg. Other studies have also reported a clearance rate of 3297±1042mL/hr. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Neonates exposed to antipsychotic drugs, including ABILIFY, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Overall available data from published epidemiologic studies of pregnant women exposed to aripiprazole have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks to the mother associated with untreated schizophrenia, bipolar I disorder, or major depressive disorder, and with exposure to antipsychotics, including ABILIFY, during pregnancy. In animal reproduction studies, oral and intravenous aripiprazole administration during organogenesis in rats and/or rabbits at doses 10 and 19 times, respectively, the maximum recommended human dose (MRHD) of 30 mg/day based on mg/m2 body surface area, produced fetal death, decreased fetal weight, undescended testicles, delayed skeletal ossification, skeletal abnormalities, and diaphragmatic hernia. Oral and intravenous aripiprazole administration during the pre- and post-natal period in rats at doses 10 times the MRHD based on mg/m2 body surface area, produced prolonged gestation, stillbirths, decreased pup weight, and decreased pup survival. ABILIFY has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of ABILIFY misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior). In physical dependence studies in monkeys, withdrawal symptoms were observed upon abrupt cessation of dosing. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. In clinical trials and in postmarketing experience, adverse reactions of deliberate or accidental overdosage with oral ABILIFY have been reported worldwide. These include overdoses with oral ABILIFY alone and in combination with other substances. No fatality was reported with ABILIFY alone. The largest known dose with a known outcome involved acute ingestion of 1,260 mg of oral ABILIFY (42 times the maximum recommended daily dose) by a patient who fully recovered. Deliberate or accidental overdosage was also reported in children (age 12 years and younger) involving oral ABILIFY ingestions up to 195 mg with no fatalities. Common adverse reactions (reported in at least 5% of all overdose cases) reported with oral ABILIFY overdosage (alone or in combination with other substances) include vomiting, somnolence, and tremor. Other clinically important signs and symptoms observed in one or more patients with ABILIFY overdoses (alone or with other substances) include acidosis, aggression, aspartate aminotransferase increased, atrial fibrillation, bradycardia, coma, confusional state, convulsion, blood creatine phosphokinase increased, depressed level of consciousness, hypertension, hypokalemia, hypotension, lethargy, loss of consciousness, QRS complex prolonged, QT prolonged, pneumonia aspiration, respiratory arrest, status epilepticus, and tachycardia. No specific information is available on the treatment of overdose with ABILIFY. An electrocardiogram should be obtained in case of overdosage and if QT interval prolongation is present, cardiac monitoring should be instituted. Otherwise, management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. Close medical supervision and monitoring should continue until the patient recovers. Charcoal: In the event of an overdose of ABILIFY, an early charcoal administration may be useful in partially preventing the absorption of aripiprazole. Administration of 50 g of activated charcoal, one hour after a single 15 mg oral dose of ABILIFY, decreased the mean AUC and C max of aripiprazole by 50%. Hemodialysis: Although there is no information on the effect of hemodialysis in treating an overdose with ABILIFY, hemodialysis is unlikely to be useful in overdose management since aripiprazole is highly bound to plasma proteins. Lifetime carcinogenicity studies were conducted in ICR mice, F344 rats, and Sprague-Dawley (SD) rats. Aripiprazole was administered for 2 years in the diet at doses of 1, 3, 10, and 30 mg/kg/day to ICR mice and 1, 3, and 10 mg/kg/day to F344 rats (0.2, 0.5, 2 and 5 times and 0.3, 1 and 3 times the MRHD of 30 mg/day based on mg/m2 body surface area, respectively). In addition, SD rats were dosed orally for 2 years at 10, 20, 40, and 60 mg/kg/day, which are 3, 6, 13 and 19 times the MRHD based on mg/m2 body surface area. Aripiprazole did not induce tumors in male mice or male rats. In female mice, the incidences of pituitary gland adenomas and mammary gland adenocarcinomas and adenoacanthomas were increased at dietary doses of 3 to 30 mg/kg/day (0.5 to 5 times the MRHD). In female rats, the incidence of mammary gland fibroadenomas was increased at a dietary dose of 10 mg/kg/day (3 times the MRHD); and the incidences of adrenocortical carcinomas and combined adrenocortical adenomas/carcinomas were increased at an oral dose of 60 mg/kg/day (19 times the MRHD). An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be mediated by prolonged dopamine D2-receptor antagonism and hyperprolactinemia. Serum prolactin was not measured in the aripiprazole carcinogenicity studies. However, increases in serum prolactin levels were observed in female mice in a 13 week dietary study at the doses associated with mammary gland and pituitary tumors. Serum prolactin was not increased in female rats in 4 week and 13 week dietary studies at the dose associated with mammary gland tumors. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unclear. The mutagenic potential of aripiprazole was tested in the in vitro bacterial reverse-mutation assay, the in vitro bacterial DNA repair assay, the in vitro forward gene mutation assay in mouse lymphoma cells, the in vitro chromosomal aberration assay in Chinese hamster lung (CHL) cells, the in vivo micronucleus assay in mice, and the unscheduled DNA synthesis assay in rats. Aripiprazole and a metabolite (2,3-DCPP) were clastogenic in the in vitro chromosomal aberration assay in CHL cells with and without metabolic activation. The metabolite, 2,3-DCPP, increased numerical aberrations in the in vitro assay in CHL cells in the absence of metabolic activation. A positive response was obtained in the in vivo micronucleus assay in mice; however, the response was due to a mechanism not considered relevant to humans. Female rats were treated orally with aripiprazole from 2 weeks prior to mating through gestation Day 7 at doses of 2, 6, and 20 mg/kg/day, which are 0.6, 2, and 6 times the MRHD of 30 mg/day based on mg/m2 body surface area. Estrus cycle irregularities and increased corpora lutea were seen at all doses, but no impairment of fertility was seen. Increased pre-implantation loss was seen at 2 and 6 times the MRHD, and decreased fetal weight was seen at 6 times the MRHD. Male rats were treated orally with aripiprazole from 9 weeks prior to mating through mating at doses of 20, 40, and 60 mg/kg/day, which are 6, 13, and 19 times the MRHD of 30 mg/day based on mg/m2 body surface area. Disturbances in spermatogenesis were seen at 19 times the MRHD and prostate atrophy was seen at 13 and 19 times the MRHD without impairment of fertility. Pharmacokinetic properties in patients 10-17 years of age are similar to that of adults once body weight has been corrected for. No dosage adjustment is necessary in elderly patients however aripiprazole is not approved for Alzheimer's associated psychosis. Patients classified as CYP2D6 poor metabolizers should be prescribed half the regular dose of aripiprazole. Hepatic and renal function as well as sex, race, and smoking status do not affect dosage requirements for aripiprazole •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Abilify •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Aripiprazole is an atypical antipsychotic used in the treatment of a wide variety of mood and psychotic disorders, such as schizophrenia, bipolar I, major depressive disorder, irritability associated with autism, and Tourette's syndrome.

Aripiprazole may cause orthostatic hypotension through antagonism of the α1-adrenergic receptor.3,2,4 Cases of orthostatic hypotension, postural dizziness, and syncope have been reported with the short-term use of aripiprazole in clinical trials. The risk for developing a decrease in blood pressure may be enhanced with concurrent use of aripiprazole with other agents known to cause hypotension, including antihypertensive medications. Contrary to these findings, one case report looking at two patients found that aripiprazole may increase hypertension. The severity of the interaction is minor.

Question: Does Abaloparatide and Aripiprazole interact? Information: •Drug A: Abaloparatide •Drug B: Aripiprazole •Severity: MINOR •Description: Aripiprazole may increase the hypotensive activities of Abaloparatide. •Extended Description: Aripiprazole may cause orthostatic hypotension through antagonism of the α1-adrenergic receptor.3,2,4 Cases of orthostatic hypotension, postural dizziness, and syncope have been reported with the short-term use of aripiprazole in clinical trials. The risk for developing a decrease in blood pressure may be enhanced with concurrent use of aripiprazole with other agents known to cause hypotension, including antihypertensive medications. Contrary to these findings, one case report looking at two patients found that aripiprazole may increase hypertension. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Aripiprazole is indicated for the treatment of acute manic and mixed episodes associated with bipolar I disorder, irritability associated with autism spectrum disorder, schizophrenia, and Tourette's disorder. It is also used as an adjunctive treatment of major depressive disorder.[L45859 An injectable formulation of aripiprazole is indicated for agitation associated with schizophrenia or bipolar mania. Finally, an extended-release, bimonthly injection formulation of aripiprazole is indicated for the treatment of adult schizophrenia and maintenance therapy for adult bipolar I disorder. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Aripiprazole exhibits high affinity for dopamine D 2 and D 3, serotonin 5-HT 1a and 5-HT 2a receptors (Ki values of 0.34 nM, 0.8 nM, 1.7 nM, and 3.4 nM, respectively), moderate affinity for dopamine D 4, serotonin 5-HT 2c and 5-HT 7, alpha 1 -adrenergic and histamine H 1 receptors (Ki values of 44 nM, 15 nM, 39 nM, 57 nM, and 61 nM, respectively), and moderate affinity for the serotonin reuptake site (Ki=98 nM). Aripiprazole has no appreciable affinity for cholinergic muscarinic receptors (IC 50 >1000 nM). •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): The antipsychotic action of aripiprazole is likely due to its partial agonist activity on D2 and 5-HT 1A receptors as well as its antagonist activity at 5-HT 2A receptors; however, the exact mechanism has not been fully elucidated. One of the mechanisms that have been proposed is that aripiprazole both stimulates and inhibits dopamine as it engages the D2 receptor. It lowers dopamine neuronal firing at high dopamine concentrations and increases dopamine firing at low concentrations. Its partial agonist activity gives aripiprazole an intermediate level of dopaminergic neuronal tone between full agonist and antagonist of the D2 receptor. In addition, some adverse effects may be due to action on other receptors.[L4620] For example, orthostatic hypotension may be explained by antagonism of the adrenergic alpha-1 receptors. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Tablet: Aripiprazole is well absorbed after administration of the tablet, with peak plasma concentrations occurring within 3 hours to 5 hours; the absolute oral bioavailability of the tablet formulation is 87%. ABILIFY can be administered with or without food. Administration of a 15 mg ABILIFY tablet with a standard high-fat meal did not significantly affect the C max or AUC of aripiprazole or its active metabolite, dehydro-aripiprazole, but delayed T max by 3 hours for aripiprazole and 12 hours for dehydro-aripiprazole. Oral Solution: Aripiprazole is well absorbed when administered orally as the solution. At equivalent doses, the plasma concentrations of aripiprazole from the solution were higher than that from the tablet formulation. In a relative bioavailability study comparing the pharmacokinetics of 30 mg aripiprazole as the oral solution to 30 mg aripiprazole tablets in healthy subjects, the solution-to-tablet ratios of geometric mean C max and AUC values were 122% and 114%, respectively. The single-dose pharmacokinetics of aripiprazole were linear and dose-proportional between the doses of 5 mg to 30 mg. Extended-release injectable suspension, bimonthly injection: Aripiprazole absorption into the systemic circulation is prolonged following gluteal intramuscular injection due to the low solubility of aripiprazole particles. The release profile of aripiprazole from ABILIFY ASIMTUFII results in sustained plasma concentrations over 2 months following gluteal injection(s). Following multiple doses, the median peak:trough ratio for aripiprazole following an ABILIFY ASIMTUFII dose is 1.3, resulting in a flat plasma concentration profile with T max ranging between 1 to 49 days following multiple gluteal administrations of 960 mg. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The steady-state volume of distribution of aripiprazole following intravenous administration is high (404 L or 4.9 L/kg), indicating extensive extravascular distribution. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): At therapeutic concentrations, aripiprazole and its major metabolite are greater than 99% bound to serum proteins, primarily to albumin. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Aripiprazole is metabolized primarily by three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for the dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the predominant drug moiety in systemic circulation. At steady-state, dehydro-aripiprazole, the active metabolite, represents about 40% of aripiprazole AUC in plasma. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Following a single oral dose of [14C]-labeled aripiprazole, approximately 25% and 55% of the administered radioactivity was recovered in the urine and feces, respectively. Less than 1% of unchanged aripiprazole was excreted in the urine and approximately 18% of the oral dose was recovered unchanged in the feces. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The mean elimination half-lives are about 75 hours and 94 hours for aripiprazole and dehydro-aripiprazole, respectively. For populations that are poor CYP2D6 metabolizers, the half-life of aripiprazole is 146 hours and these patients should be treated with half the normal dose. Other studies have reported a half-life of 61.03±19.59 hours for aripiprazole and 279±299 hours for the active metabolite. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The clearance of aripiprazole was estimated to be 0.8mL/min/kg. Other studies have also reported a clearance rate of 3297±1042mL/hr. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Neonates exposed to antipsychotic drugs, including ABILIFY, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Overall available data from published epidemiologic studies of pregnant women exposed to aripiprazole have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks to the mother associated with untreated schizophrenia, bipolar I disorder, or major depressive disorder, and with exposure to antipsychotics, including ABILIFY, during pregnancy. In animal reproduction studies, oral and intravenous aripiprazole administration during organogenesis in rats and/or rabbits at doses 10 and 19 times, respectively, the maximum recommended human dose (MRHD) of 30 mg/day based on mg/m2 body surface area, produced fetal death, decreased fetal weight, undescended testicles, delayed skeletal ossification, skeletal abnormalities, and diaphragmatic hernia. Oral and intravenous aripiprazole administration during the pre- and post-natal period in rats at doses 10 times the MRHD based on mg/m2 body surface area, produced prolonged gestation, stillbirths, decreased pup weight, and decreased pup survival. ABILIFY has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of ABILIFY misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior). In physical dependence studies in monkeys, withdrawal symptoms were observed upon abrupt cessation of dosing. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. In clinical trials and in postmarketing experience, adverse reactions of deliberate or accidental overdosage with oral ABILIFY have been reported worldwide. These include overdoses with oral ABILIFY alone and in combination with other substances. No fatality was reported with ABILIFY alone. The largest known dose with a known outcome involved acute ingestion of 1,260 mg of oral ABILIFY (42 times the maximum recommended daily dose) by a patient who fully recovered. Deliberate or accidental overdosage was also reported in children (age 12 years and younger) involving oral ABILIFY ingestions up to 195 mg with no fatalities. Common adverse reactions (reported in at least 5% of all overdose cases) reported with oral ABILIFY overdosage (alone or in combination with other substances) include vomiting, somnolence, and tremor. Other clinically important signs and symptoms observed in one or more patients with ABILIFY overdoses (alone or with other substances) include acidosis, aggression, aspartate aminotransferase increased, atrial fibrillation, bradycardia, coma, confusional state, convulsion, blood creatine phosphokinase increased, depressed level of consciousness, hypertension, hypokalemia, hypotension, lethargy, loss of consciousness, QRS complex prolonged, QT prolonged, pneumonia aspiration, respiratory arrest, status epilepticus, and tachycardia. No specific information is available on the treatment of overdose with ABILIFY. An electrocardiogram should be obtained in case of overdosage and if QT interval prolongation is present, cardiac monitoring should be instituted. Otherwise, management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. Close medical supervision and monitoring should continue until the patient recovers. Charcoal: In the event of an overdose of ABILIFY, an early charcoal administration may be useful in partially preventing the absorption of aripiprazole. Administration of 50 g of activated charcoal, one hour after a single 15 mg oral dose of ABILIFY, decreased the mean AUC and C max of aripiprazole by 50%. Hemodialysis: Although there is no information on the effect of hemodialysis in treating an overdose with ABILIFY, hemodialysis is unlikely to be useful in overdose management since aripiprazole is highly bound to plasma proteins. Lifetime carcinogenicity studies were conducted in ICR mice, F344 rats, and Sprague-Dawley (SD) rats. Aripiprazole was administered for 2 years in the diet at doses of 1, 3, 10, and 30 mg/kg/day to ICR mice and 1, 3, and 10 mg/kg/day to F344 rats (0.2, 0.5, 2 and 5 times and 0.3, 1 and 3 times the MRHD of 30 mg/day based on mg/m2 body surface area, respectively). In addition, SD rats were dosed orally for 2 years at 10, 20, 40, and 60 mg/kg/day, which are 3, 6, 13 and 19 times the MRHD based on mg/m2 body surface area. Aripiprazole did not induce tumors in male mice or male rats. In female mice, the incidences of pituitary gland adenomas and mammary gland adenocarcinomas and adenoacanthomas were increased at dietary doses of 3 to 30 mg/kg/day (0.5 to 5 times the MRHD). In female rats, the incidence of mammary gland fibroadenomas was increased at a dietary dose of 10 mg/kg/day (3 times the MRHD); and the incidences of adrenocortical carcinomas and combined adrenocortical adenomas/carcinomas were increased at an oral dose of 60 mg/kg/day (19 times the MRHD). An increase in mammary, pituitary, and endocrine pancreas neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be mediated by prolonged dopamine D2-receptor antagonism and hyperprolactinemia. Serum prolactin was not measured in the aripiprazole carcinogenicity studies. However, increases in serum prolactin levels were observed in female mice in a 13 week dietary study at the doses associated with mammary gland and pituitary tumors. Serum prolactin was not increased in female rats in 4 week and 13 week dietary studies at the dose associated with mammary gland tumors. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unclear. The mutagenic potential of aripiprazole was tested in the in vitro bacterial reverse-mutation assay, the in vitro bacterial DNA repair assay, the in vitro forward gene mutation assay in mouse lymphoma cells, the in vitro chromosomal aberration assay in Chinese hamster lung (CHL) cells, the in vivo micronucleus assay in mice, and the unscheduled DNA synthesis assay in rats. Aripiprazole and a metabolite (2,3-DCPP) were clastogenic in the in vitro chromosomal aberration assay in CHL cells with and without metabolic activation. The metabolite, 2,3-DCPP, increased numerical aberrations in the in vitro assay in CHL cells in the absence of metabolic activation. A positive response was obtained in the in vivo micronucleus assay in mice; however, the response was due to a mechanism not considered relevant to humans. Female rats were treated orally with aripiprazole from 2 weeks prior to mating through gestation Day 7 at doses of 2, 6, and 20 mg/kg/day, which are 0.6, 2, and 6 times the MRHD of 30 mg/day based on mg/m2 body surface area. Estrus cycle irregularities and increased corpora lutea were seen at all doses, but no impairment of fertility was seen. Increased pre-implantation loss was seen at 2 and 6 times the MRHD, and decreased fetal weight was seen at 6 times the MRHD. Male rats were treated orally with aripiprazole from 9 weeks prior to mating through mating at doses of 20, 40, and 60 mg/kg/day, which are 6, 13, and 19 times the MRHD of 30 mg/day based on mg/m2 body surface area. Disturbances in spermatogenesis were seen at 19 times the MRHD and prostate atrophy was seen at 13 and 19 times the MRHD without impairment of fertility. Pharmacokinetic properties in patients 10-17 years of age are similar to that of adults once body weight has been corrected for. No dosage adjustment is necessary in elderly patients however aripiprazole is not approved for Alzheimer's associated psychosis. Patients classified as CYP2D6 poor metabolizers should be prescribed half the regular dose of aripiprazole. Hepatic and renal function as well as sex, race, and smoking status do not affect dosage requirements for aripiprazole •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Abilify •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Aripiprazole is an atypical antipsychotic used in the treatment of a wide variety of mood and psychotic disorders, such as schizophrenia, bipolar I, major depressive disorder, irritability associated with autism, and Tourette's syndrome. Output: Aripiprazole may cause orthostatic hypotension through antagonism of the α1-adrenergic receptor.3,2,4 Cases of orthostatic hypotension, postural dizziness, and syncope have been reported with the short-term use of aripiprazole in clinical trials. The risk for developing a decrease in blood pressure may be enhanced with concurrent use of aripiprazole with other agents known to cause hypotension, including antihypertensive medications. Contrary to these findings, one case report looking at two patients found that aripiprazole may increase hypertension. The severity of the interaction is minor.

Does Abaloparatide and Arsenic trioxide interact?

•Drug A: Abaloparatide •Drug B: Arsenic trioxide •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Arsenic trioxide is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For induction of remission and consolidation in patients with acute promyelocytic leukemia (APL), and whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Arsenic Trioxide is indicated for induction of remission and consolidation in patients with acute promyelocytic leukemia (APL) who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): The mechanism of action of Arsenic Trioxide is not completely understood. Arsenic trioxide causes morphological changes and DNA fragmentation characteristic of apoptosis in NB4 human promyelocytic leukemia cells in vitro. Arsenic trioxide also causes damage or degradation of the fusion protein PML/RAR-alpha. It is suspected that arsenic trioxide induces cancer cells to undergo apoptosis. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 75% bound •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Inorganic, lyophilized arsenic trioxide, when placed in solution, is immediately hydrolyzed to arsenous acid - this appears to be the pharmacologically active species of arsenic trioxide. Further metabolism involves the oxidation of arsenous acid to arsenic acid, and an oxidative methylation of arsenous acid to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) by methyltransferases in the liver. Both MMA and DMA have relatively long half-lives and can accumulate following multiple doses, the extent of which depends upon the dosing regimen in question. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Trivalent arsenic is mostly methylated in humans and excreted in urine. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): No half-life available •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Symptoms of overdose include convulsions, muscle weakness and confusion. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Trisenox •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Arsenic trioxide is a chemotherapeutic agent used in the treatment of refractory or relapsed acute promyelocytic leukemia in patients with prior retinoid and anthracycline chemotherapy.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Arsenic trioxide interact? Information: •Drug A: Abaloparatide •Drug B: Arsenic trioxide •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Arsenic trioxide is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For induction of remission and consolidation in patients with acute promyelocytic leukemia (APL), and whose APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Arsenic Trioxide is indicated for induction of remission and consolidation in patients with acute promyelocytic leukemia (APL) who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): The mechanism of action of Arsenic Trioxide is not completely understood. Arsenic trioxide causes morphological changes and DNA fragmentation characteristic of apoptosis in NB4 human promyelocytic leukemia cells in vitro. Arsenic trioxide also causes damage or degradation of the fusion protein PML/RAR-alpha. It is suspected that arsenic trioxide induces cancer cells to undergo apoptosis. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 75% bound •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Inorganic, lyophilized arsenic trioxide, when placed in solution, is immediately hydrolyzed to arsenous acid - this appears to be the pharmacologically active species of arsenic trioxide. Further metabolism involves the oxidation of arsenous acid to arsenic acid, and an oxidative methylation of arsenous acid to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) by methyltransferases in the liver. Both MMA and DMA have relatively long half-lives and can accumulate following multiple doses, the extent of which depends upon the dosing regimen in question. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Trivalent arsenic is mostly methylated in humans and excreted in urine. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): No half-life available •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Symptoms of overdose include convulsions, muscle weakness and confusion. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Trisenox •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Arsenic trioxide is a chemotherapeutic agent used in the treatment of refractory or relapsed acute promyelocytic leukemia in patients with prior retinoid and anthracycline chemotherapy. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Atenolol interact?

•Drug A: Abaloparatide •Drug B: Atenolol •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Atenolol is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Indicated for: 1) Management of hypertension alone and in combination with other antihypertensives. 2) Management of angina pectoris associated with coronary atherosclerosis. 3) Management of acute myocardial infarction in hemodynamically stable patients with a heart rate greater than 50 beats per minutes and a systolic blood pressure above 100 mmHg. Off-label uses include: 1) Secondary prevention of myocardial infarction. 2) Management of heart failure. 3) Management of atrial fibrillation. 4) Management of supraventricular tachycardia. 5) Management of ventricular arrythmias such as congenital long-QT and arrhythmogenic right ventricular cardiomyopathy. 6) Management of symptomatic thyrotoxicosis in combination with methimazole. 7) Prophylaxis of migraine headaches. 8) Management of alcohol withdrawal. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Atenolol is a cardio-selective beta-blocker and as such exerts most of its effects on the heart. It acts as an antagonist to sympathetic innervation and prevents increases in heart rate, electrical conductivity, and contractility in the heart due to increased release of norepinephrine from the peripheral nervous system. Together the decreases in contractility and rate produce a reduction in cardiac output resulting in a compensatory increase in peripheral vascular resistance in the short-term. This response later declines to baseline with long-term use of atenolol. More importantly, this reduction in the work demanded of the myocardium also reduces oxygen demand which provides therapeutic benefit by reducing the mismatch of oxygen supply and demand in settings where coronary blood flow is limited, such as in coronary atherosclerosis. Reducing oxygen demand, particularly due to exercise, can reduce the frequency of angina pectoris symptoms and potentially improve survival of the remaining myocardium after myocardial infarction. The decrease in rate of sinoatrial node potentials, electrical conduction, slowing of potentials traveling through the atrioventricular node, and reduced frequency of ectopic potentials due to blockade of adrenergic beta receptors has led to benefit in arrhythmic conditions such as atrial fibrillation by controlling the rate of action potential generation and allowing for more effective coordinated contractions. Since a degree of sympathetic activity is necessary to maintain cardiac function, the reduced contractility induced by atenolol may precipitate or worsen heart failure, especially during volume overload. The effects of atenolol on blood pressure have been established, although it is less effective than alternative beta-blockers, but the mechanism has not yet been characterized. As a β1 selective drug, it does not act via the vasodilation produced by non-selective agents. Despite this there is a sustained reduction in peripheral vascular resistance, and consequently blood pressure, alongside a decrease in cardiac output. It is thought that atenolol's antihypertensive activity may be related to action on the central nervous system (CNS) or it's inhibition of the renin-aldosterone-angiotensin system rather than direct effects on the vasculature. Atenolol produces CNS effects similar to other beta-blockers, but does so to a lesser extent due to reduces ability to cross the blood-brain barrier. It has the potential to produce fatigue, depression, and sleep disturbances such as nightmares or insomnia. The exact mechanisms behind these have not been characterized but their occurrence must be considered as they represent clinically relevant adverse effects. Atenolol exerts some effects on the respiratory system although to a much lesser extent than non-selective beta-blockers. Interaction with β2 receptors in the airways can produce bronchoconstriction by blocking the relaxation of bronchial smooth muscle mediated by the sympathetic nervous system. The same action can interfere with β-agonist therapies used in asthma and chronic obstructive pulmonary disease. Unlike some other beta-blocker drugs, atenolol does not have intrinsic sympathomimetic or membrane stabilizing activity nor does it produce changes in glycemic control. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Atenolol is a cardioselective beta-blocker, called such because it selectively binds to the β1-adrenergic receptor as an antagonist up to a reported 26 fold more than β2 receptors. Selective activity at the β1 receptor produces cardioselectivity due to the higher population of this receptor in cardiac tissue. Some binding to β2 and possibly β3 receptors can still occur at therapeutic dosages but the effects mediated by antagonizing these are significantly reduced from those of non-selective agents. β1 and β2 receptors are G s coupled therefore antagonism of their activation reduces activity of adenylyl cyclase and its downstream signalling via cyclic adenosime monophosphate and protein kinase A (PKA). In cardiomyocytes PKA is thought to mediate activation of L-type calcium channels and ryanodine receptors through their phosphorylation. L-type calcium channels can then provide an initial rise in intracellular calcium and trigger the ryanodine receptors to release calcium stored in the sarcoplasmic reticulum (SR) and increased contractility. PKA also plays a role in the cessation of contraction by phosphorylating phospholamban which in turn increases the affinity of SR Ca ATPase to increase reuptake of calcium into the SR. It also phophorylates troponin I to reduce affinity of the protein for calcium. Both of these events lead to a reduction in contraction which, when coupled with the initial increase in contraction, allows for faster cycling and consequently higher heart rate with increased contractility. L-type calcium channels are also a major contributor to cardiac depolarization and their activation can increase frequency of action potentials and possibly the incidence of ectopic potentials. Similar inihibitory events occur in the bronchial smooth muscle to mediate relaxation including phosphorylation of myosin light-chain kinase, reducing its affinity for calcium. PKA also inhibits the excitatory G q coupled pathway by phosphorylating the inositol trisphosphate receptor and phospholipase C resulting in inhibition of intracellular calcium release. Antagonism of this activity by beta-blocker agents like atenolol can thus cause increased bronchoconstriction. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Approximately 50% of an oral dose is absorbed from the gastrointestinal tract, with the remainder being excreted unchanged in the feces. Administering atenolol with food can decrease the AUC by about 20%. While atenolol can cross the blood-brain barrier, it does so slowly and to a small extent. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Total Vd of 63.8-112.5 L. Atenolol distributes into a central volume of 12.8-17.5 L along with two peripheral compartments with a combined volume of 51-95 L. Distribution takes about 3 hrs for the central compartment, 4 hrs for the shallower peripheral compartment, and 5-6 hrs for the deeper peripheral compartment. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 6-16% bound in plasma. Atenolol binds to two sites on human serum albumin. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Minimal metabolism in the liver. The sole non-conjugated metabolite is the product of a hydroxylation reaction at the carbon between the amide and benzene groups. The only other metabolite to be confirmed is a glucuronide conjugate. These metabolites make up 5-8% and 2% of the renally excreted dose with 87-90% appearing as unchanged drug. The hydroxylated metabolite is exerts 1/10th the beta-blocking activity of atenolol. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): 85% is eliminated by the kidneys following IV administration with 10% appearing in the feces. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 6-7 hrs. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Total clearance is estimated at 97.3-176.3 mL/min with a renal clearance of 95-168 mL/min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): LD 50 Values Mouse: 2 g/kg (Oral), 57 mg/kg (IV), 134 mg/kg (IP), 400 mg/kg (SC) Rat: 2 g/kg (Oral), 77 mg/kg (IV), 600 mg/kg (SC) Rabbit: 50 mg/kg (IV) Carcinogenicity & Mutagenicity Studies in rats and mice at doses of 300 mg/kg/day, equivalent to 150 times maximum recommended human dose, for durations of 18 and 24 months showed no carcinogenicity. One study in rats at doses of 500-1500 mg/kg/day, 250-750 times maximum human dose, resulted in increases benign adrenal medullary tumors in both sexes and increase mammary fibroadenomas in females. Atenolol showed no mutagenicity in the Ames test using S. typhinarium, dominant lethal test in mice, or in vivo cytogenetics test in chinese hamster ovary cells. Reproductive Toxicity No adverse effects on fertility were observed in either male or female mice after receiving doses of 200 mg/kg/day, equivalent to 200 times the maximum human dose. In humans, atenolol is known to cross the placenta and fetuses exposed to the drug have been reported to be smaller than expected considering gestational age. Embryo-fetal resorption has been observed in rats at doses of 50mg/kg/day, 50 times the max human dose, but not in rabbits at doses of 25mg/kg/day. Lactation Atenolol appears in breast milk at a ratio of 1.5-6.8 to plasma concentrations. It has been estimated that infant exposure occurs at 5.7-19.2% maternal weight-adjusted dosage. Effects in infants include bradycardia, hypothermia, and lethargy. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Tenoretic, Tenormin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Atenolol Atenololum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Atenolol is a synthetic beta-1 selective blocker used in the management of hypertension and chronic angina, and to reduce mortality in known or suspected myocardial infarction in hemodynamically stable patients.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Atenolol interact? Information: •Drug A: Abaloparatide •Drug B: Atenolol •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Atenolol is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Indicated for: 1) Management of hypertension alone and in combination with other antihypertensives. 2) Management of angina pectoris associated with coronary atherosclerosis. 3) Management of acute myocardial infarction in hemodynamically stable patients with a heart rate greater than 50 beats per minutes and a systolic blood pressure above 100 mmHg. Off-label uses include: 1) Secondary prevention of myocardial infarction. 2) Management of heart failure. 3) Management of atrial fibrillation. 4) Management of supraventricular tachycardia. 5) Management of ventricular arrythmias such as congenital long-QT and arrhythmogenic right ventricular cardiomyopathy. 6) Management of symptomatic thyrotoxicosis in combination with methimazole. 7) Prophylaxis of migraine headaches. 8) Management of alcohol withdrawal. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Atenolol is a cardio-selective beta-blocker and as such exerts most of its effects on the heart. It acts as an antagonist to sympathetic innervation and prevents increases in heart rate, electrical conductivity, and contractility in the heart due to increased release of norepinephrine from the peripheral nervous system. Together the decreases in contractility and rate produce a reduction in cardiac output resulting in a compensatory increase in peripheral vascular resistance in the short-term. This response later declines to baseline with long-term use of atenolol. More importantly, this reduction in the work demanded of the myocardium also reduces oxygen demand which provides therapeutic benefit by reducing the mismatch of oxygen supply and demand in settings where coronary blood flow is limited, such as in coronary atherosclerosis. Reducing oxygen demand, particularly due to exercise, can reduce the frequency of angina pectoris symptoms and potentially improve survival of the remaining myocardium after myocardial infarction. The decrease in rate of sinoatrial node potentials, electrical conduction, slowing of potentials traveling through the atrioventricular node, and reduced frequency of ectopic potentials due to blockade of adrenergic beta receptors has led to benefit in arrhythmic conditions such as atrial fibrillation by controlling the rate of action potential generation and allowing for more effective coordinated contractions. Since a degree of sympathetic activity is necessary to maintain cardiac function, the reduced contractility induced by atenolol may precipitate or worsen heart failure, especially during volume overload. The effects of atenolol on blood pressure have been established, although it is less effective than alternative beta-blockers, but the mechanism has not yet been characterized. As a β1 selective drug, it does not act via the vasodilation produced by non-selective agents. Despite this there is a sustained reduction in peripheral vascular resistance, and consequently blood pressure, alongside a decrease in cardiac output. It is thought that atenolol's antihypertensive activity may be related to action on the central nervous system (CNS) or it's inhibition of the renin-aldosterone-angiotensin system rather than direct effects on the vasculature. Atenolol produces CNS effects similar to other beta-blockers, but does so to a lesser extent due to reduces ability to cross the blood-brain barrier. It has the potential to produce fatigue, depression, and sleep disturbances such as nightmares or insomnia. The exact mechanisms behind these have not been characterized but their occurrence must be considered as they represent clinically relevant adverse effects. Atenolol exerts some effects on the respiratory system although to a much lesser extent than non-selective beta-blockers. Interaction with β2 receptors in the airways can produce bronchoconstriction by blocking the relaxation of bronchial smooth muscle mediated by the sympathetic nervous system. The same action can interfere with β-agonist therapies used in asthma and chronic obstructive pulmonary disease. Unlike some other beta-blocker drugs, atenolol does not have intrinsic sympathomimetic or membrane stabilizing activity nor does it produce changes in glycemic control. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Atenolol is a cardioselective beta-blocker, called such because it selectively binds to the β1-adrenergic receptor as an antagonist up to a reported 26 fold more than β2 receptors. Selective activity at the β1 receptor produces cardioselectivity due to the higher population of this receptor in cardiac tissue. Some binding to β2 and possibly β3 receptors can still occur at therapeutic dosages but the effects mediated by antagonizing these are significantly reduced from those of non-selective agents. β1 and β2 receptors are G s coupled therefore antagonism of their activation reduces activity of adenylyl cyclase and its downstream signalling via cyclic adenosime monophosphate and protein kinase A (PKA). In cardiomyocytes PKA is thought to mediate activation of L-type calcium channels and ryanodine receptors through their phosphorylation. L-type calcium channels can then provide an initial rise in intracellular calcium and trigger the ryanodine receptors to release calcium stored in the sarcoplasmic reticulum (SR) and increased contractility. PKA also plays a role in the cessation of contraction by phosphorylating phospholamban which in turn increases the affinity of SR Ca ATPase to increase reuptake of calcium into the SR. It also phophorylates troponin I to reduce affinity of the protein for calcium. Both of these events lead to a reduction in contraction which, when coupled with the initial increase in contraction, allows for faster cycling and consequently higher heart rate with increased contractility. L-type calcium channels are also a major contributor to cardiac depolarization and their activation can increase frequency of action potentials and possibly the incidence of ectopic potentials. Similar inihibitory events occur in the bronchial smooth muscle to mediate relaxation including phosphorylation of myosin light-chain kinase, reducing its affinity for calcium. PKA also inhibits the excitatory G q coupled pathway by phosphorylating the inositol trisphosphate receptor and phospholipase C resulting in inhibition of intracellular calcium release. Antagonism of this activity by beta-blocker agents like atenolol can thus cause increased bronchoconstriction. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Approximately 50% of an oral dose is absorbed from the gastrointestinal tract, with the remainder being excreted unchanged in the feces. Administering atenolol with food can decrease the AUC by about 20%. While atenolol can cross the blood-brain barrier, it does so slowly and to a small extent. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Total Vd of 63.8-112.5 L. Atenolol distributes into a central volume of 12.8-17.5 L along with two peripheral compartments with a combined volume of 51-95 L. Distribution takes about 3 hrs for the central compartment, 4 hrs for the shallower peripheral compartment, and 5-6 hrs for the deeper peripheral compartment. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 6-16% bound in plasma. Atenolol binds to two sites on human serum albumin. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Minimal metabolism in the liver. The sole non-conjugated metabolite is the product of a hydroxylation reaction at the carbon between the amide and benzene groups. The only other metabolite to be confirmed is a glucuronide conjugate. These metabolites make up 5-8% and 2% of the renally excreted dose with 87-90% appearing as unchanged drug. The hydroxylated metabolite is exerts 1/10th the beta-blocking activity of atenolol. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): 85% is eliminated by the kidneys following IV administration with 10% appearing in the feces. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 6-7 hrs. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Total clearance is estimated at 97.3-176.3 mL/min with a renal clearance of 95-168 mL/min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): LD 50 Values Mouse: 2 g/kg (Oral), 57 mg/kg (IV), 134 mg/kg (IP), 400 mg/kg (SC) Rat: 2 g/kg (Oral), 77 mg/kg (IV), 600 mg/kg (SC) Rabbit: 50 mg/kg (IV) Carcinogenicity & Mutagenicity Studies in rats and mice at doses of 300 mg/kg/day, equivalent to 150 times maximum recommended human dose, for durations of 18 and 24 months showed no carcinogenicity. One study in rats at doses of 500-1500 mg/kg/day, 250-750 times maximum human dose, resulted in increases benign adrenal medullary tumors in both sexes and increase mammary fibroadenomas in females. Atenolol showed no mutagenicity in the Ames test using S. typhinarium, dominant lethal test in mice, or in vivo cytogenetics test in chinese hamster ovary cells. Reproductive Toxicity No adverse effects on fertility were observed in either male or female mice after receiving doses of 200 mg/kg/day, equivalent to 200 times the maximum human dose. In humans, atenolol is known to cross the placenta and fetuses exposed to the drug have been reported to be smaller than expected considering gestational age. Embryo-fetal resorption has been observed in rats at doses of 50mg/kg/day, 50 times the max human dose, but not in rabbits at doses of 25mg/kg/day. Lactation Atenolol appears in breast milk at a ratio of 1.5-6.8 to plasma concentrations. It has been estimated that infant exposure occurs at 5.7-19.2% maternal weight-adjusted dosage. Effects in infants include bradycardia, hypothermia, and lethargy. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Tenoretic, Tenormin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Atenolol Atenololum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Atenolol is a synthetic beta-1 selective blocker used in the management of hypertension and chronic angina, and to reduce mortality in known or suspected myocardial infarction in hemodynamically stable patients. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Avanafil interact?

•Drug A: Abaloparatide •Drug B: Avanafil •Severity: MINOR •Description: The risk or severity of hypotension can be increased when Avanafil is combined with Abaloparatide. •Extended Description: The subject drug is a phosphodiesterase 5 inhibitor which can lower blood pressure.1 The affected drug can cause hypotension, particularly orthostatic hypotension. Concomitant administration of these medications may lead to an increased risk of hypotension and orthostatic hypotension. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Avanafil is indicated for the treatment of erectile dysfunction. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Avanafil is a strong competitive inhibitor of phosphodiesterase 5 (PDE5) with a demonstrated in vitro IC 50 of 5.2 nM. Its inhibitory effects on PDE5 are 100-fold more potent than on PDE6 and >1000-fold more potent than on other PDE enzymes, meaning it is less likely to cause visual disturbances and cardiovascular adverse effects when compared with less selective PDE5 inhibitors such as sildenafil and vardenafil. It has a relatively quick onset of action allowing for administration as early as 15 minutes prior to sexual activity. PDE5 inhibitors like avanafil can cause significant drug interactions when administered alongside certain antihypertensive agents (e.g. alpha blockers, substantial amounts of alcohol). PDE5 inhibitors have also been associated with the development of non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition that typically presents as sudden loss of vision in one or both eyes and appears to be more common in patients with a "crowded" optic disc. Patients presenting with any degree of vision loss should immediately discontinue use of all PDE5 inhibitors and seek medical attention. In some jurisdictions, a history of NAION or other degenerative retinal disorders is considered a contraindication to avanafil therapy. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Avanafil inhibits the cGMP-specific phosphodiesterase type 5 (PDE5) which is responsible for the degradation of cGMP in the corpus cavernosum located around the penis. Sexual arousal results in the local release of nitric oxide, which in turn stimulates the enzyme guanylate cyclase to produce cGMP. Elevated levels of cGMP result in local smooth muscle relaxation and increased blood flow to the penis (i.e. an erection). As PDE5 inhibitors like avanafil require the endogenous release of nitric oxide in order to exert their pharmacologic effect, they have no effect on the user in the absence of sexual stimulation/arousal. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Avanafil is rapidly absorbed following oral administration (T max of 30-45 minutes) and appears to have low to moderate oral bioavailability, though formal studies have not been conducted. Administration with a meal results in a mean delay in T max of 1.12 to 1.25 hours, a 39% mean reduction in C max, and a negligible effect on AUC. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The apparent volume of distribution of avanafil is 47 to 83 L. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Avanafil and its two major metabolites, M4 and M16, are highly protein-bound in plasma at approximately 99%, 97%, and 81%, respectively. Binding occurs primarily to albumin (99%), with smaller contributions from γ-globulin (43%) and α1-acid glycoprotein (66%). •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Avanafil is extensively metabolized, primarily by CYP3A4 and to a lesser extent by CYP2C9. There are two major metabolites formed, M4 and M16, which exist in the plasma at concentrations 23% and 29% that of the parent compound, respectively. The M16 metabolite lacks pharmacologic effect, but the M4 metabolite has an inhibitory potency for PDE5 18% that of avanafil and accounts for approximately 4% of the observed pharmacologic activity of avanafil. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Following oral administration, avanafil is extensively metabolized. Approximately 62% of a given dose is excreted as metabolites in the feces and approximately 21% as metabolites in the urine. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Studies have demonstrated variability in the terminal elimination half-life of avanafil, with estimates ranging between 5 - 17 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Experience with avanafil overdose is limited. Single doses of up to 800mg and repeat doses of up to 300mg have been administered - these patients experienced adverse effects similar to those seen at therapeutic doses but with increased incidence and severity. Patients experiencing an overdosage of avanafil should be treated with standard symptomatic and supportive measures. Dialysis is unlikely to be of benefit in cases of overdose as avanafil is highly protein-bound in plasma. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Spedra, Stendra •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Avanafil Avanafilo •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Avanafil is a phosphodiesterase-5 (PDE5) inhibitor used to treat erectile dysfunction.

The subject drug is a phosphodiesterase 5 inhibitor which can lower blood pressure.1 The affected drug can cause hypotension, particularly orthostatic hypotension. Concomitant administration of these medications may lead to an increased risk of hypotension and orthostatic hypotension. The severity of the interaction is minor.

Question: Does Abaloparatide and Avanafil interact? Information: •Drug A: Abaloparatide •Drug B: Avanafil •Severity: MINOR •Description: The risk or severity of hypotension can be increased when Avanafil is combined with Abaloparatide. •Extended Description: The subject drug is a phosphodiesterase 5 inhibitor which can lower blood pressure.1 The affected drug can cause hypotension, particularly orthostatic hypotension. Concomitant administration of these medications may lead to an increased risk of hypotension and orthostatic hypotension. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Avanafil is indicated for the treatment of erectile dysfunction. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Avanafil is a strong competitive inhibitor of phosphodiesterase 5 (PDE5) with a demonstrated in vitro IC 50 of 5.2 nM. Its inhibitory effects on PDE5 are 100-fold more potent than on PDE6 and >1000-fold more potent than on other PDE enzymes, meaning it is less likely to cause visual disturbances and cardiovascular adverse effects when compared with less selective PDE5 inhibitors such as sildenafil and vardenafil. It has a relatively quick onset of action allowing for administration as early as 15 minutes prior to sexual activity. PDE5 inhibitors like avanafil can cause significant drug interactions when administered alongside certain antihypertensive agents (e.g. alpha blockers, substantial amounts of alcohol). PDE5 inhibitors have also been associated with the development of non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition that typically presents as sudden loss of vision in one or both eyes and appears to be more common in patients with a "crowded" optic disc. Patients presenting with any degree of vision loss should immediately discontinue use of all PDE5 inhibitors and seek medical attention. In some jurisdictions, a history of NAION or other degenerative retinal disorders is considered a contraindication to avanafil therapy. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Avanafil inhibits the cGMP-specific phosphodiesterase type 5 (PDE5) which is responsible for the degradation of cGMP in the corpus cavernosum located around the penis. Sexual arousal results in the local release of nitric oxide, which in turn stimulates the enzyme guanylate cyclase to produce cGMP. Elevated levels of cGMP result in local smooth muscle relaxation and increased blood flow to the penis (i.e. an erection). As PDE5 inhibitors like avanafil require the endogenous release of nitric oxide in order to exert their pharmacologic effect, they have no effect on the user in the absence of sexual stimulation/arousal. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Avanafil is rapidly absorbed following oral administration (T max of 30-45 minutes) and appears to have low to moderate oral bioavailability, though formal studies have not been conducted. Administration with a meal results in a mean delay in T max of 1.12 to 1.25 hours, a 39% mean reduction in C max, and a negligible effect on AUC. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The apparent volume of distribution of avanafil is 47 to 83 L. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Avanafil and its two major metabolites, M4 and M16, are highly protein-bound in plasma at approximately 99%, 97%, and 81%, respectively. Binding occurs primarily to albumin (99%), with smaller contributions from γ-globulin (43%) and α1-acid glycoprotein (66%). •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Avanafil is extensively metabolized, primarily by CYP3A4 and to a lesser extent by CYP2C9. There are two major metabolites formed, M4 and M16, which exist in the plasma at concentrations 23% and 29% that of the parent compound, respectively. The M16 metabolite lacks pharmacologic effect, but the M4 metabolite has an inhibitory potency for PDE5 18% that of avanafil and accounts for approximately 4% of the observed pharmacologic activity of avanafil. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Following oral administration, avanafil is extensively metabolized. Approximately 62% of a given dose is excreted as metabolites in the feces and approximately 21% as metabolites in the urine. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Studies have demonstrated variability in the terminal elimination half-life of avanafil, with estimates ranging between 5 - 17 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Experience with avanafil overdose is limited. Single doses of up to 800mg and repeat doses of up to 300mg have been administered - these patients experienced adverse effects similar to those seen at therapeutic doses but with increased incidence and severity. Patients experiencing an overdosage of avanafil should be treated with standard symptomatic and supportive measures. Dialysis is unlikely to be of benefit in cases of overdose as avanafil is highly protein-bound in plasma. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Spedra, Stendra •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Avanafil Avanafilo •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Avanafil is a phosphodiesterase-5 (PDE5) inhibitor used to treat erectile dysfunction. Output: The subject drug is a phosphodiesterase 5 inhibitor which can lower blood pressure.1 The affected drug can cause hypotension, particularly orthostatic hypotension. Concomitant administration of these medications may lead to an increased risk of hypotension and orthostatic hypotension. The severity of the interaction is minor.

Does Abaloparatide and Azilsartan medoxomil interact?

•Drug A: Abaloparatide •Drug B: Azilsartan medoxomil •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abaloparatide is combined with Azilsartan medoxomil. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Azilsartan medoxomil is indicated for the treatment of hypertension to lower blood pressure in patients over 18 years of age. It may be used either alone or in combination with other antihypertensive agents. Some antihypertensive drugs have lesser effects on blood pressure in black patients. Azilsartan medoxomil is available as a fixed-dose combination product with chlorthalidone, which is indicated for the treatment of hypertension in patients whose hose blood pressure is not adequately controlled on monotherapy. It may be used as initial therapy if a patient is likely to need multiple drugs to achieve blood pressure goals. Azilsartan medoxomil belongs to the angiotensin-receptor blocking (ARB) class of drugs, which are used to decrease the progression of moderate-to-severe albuminuria and prevent the recurrence of atrial fibrillation as off-label uses in patients with diabetes mellitus and hypertension. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Pharmacodynamic effects of azilsartan medoxomil are mediated by its active metabolite, azilsartan. Azilsartan inhibits the pressor effects of an angiotensin II infusion in a dose-related manner. At a single 32 mg dose, azilsartan inhibited the maximal pressor effect by approximately 90% at peak plasma concentrations and by 60% at 24 hours after administration. In healthy subjects receiving single and repeated doses of azilsartan medoxomil, plasma angiotensin I and II concentrations and plasma renin activity increased, while plasma aldosterone concentrations decreased. Like other ARBs, azilsartan causes dose-dependent decrease in peripheral resistance and decreases smooth muscle vascular tone. As azilsartan blocks the angiotensin II receptor, the negative regulatory feedback of angiotensin II on renin secretion is inhibited; however, the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the blood pressure-lowering effect of azilsartan. Blood pressure-lowering effects of antihypertensive agents can be reduced in patients of African descent. However, there are no recommended dosage adjustment of azilsartan on the basis of a patient’s sex, race, or degree of renal or hepatic impairment. Azilsartan medoxomil has negligible effects on serum potassium or sodium levels. Azilsartan does not affect the biosynthesis of angiotensin II nor bradykinin levels. It also does not bind to any ion channels that are involved in cardiovascular regulation. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): The renin-angiotensin-aldosterone system regulates blood pressure. Angiotensin II is a peptide hormone that is a principal pressor agent in the renin-angiotensin-aldosterone system. It is a potent, direct vasoconstrictor that binds to the angiotensin II type 1 receptor (AT1 receptor) to stimulate the synthesis and release of aldosterone and promote cardiac stimulation. Angiotensin II promotes renal tubular reabsorption of sodium, resulting in water retention. It also inhibits further secretion of renin. AT1 receptors are highly expressed in vascular smooth muscle and the adrenal gland. Azilsartan medoxomil is a prodrug that is hydrolyzed to its active metabolite, azilsartan, in the gastrointestinal tract following oral administration. Azilsartan selectively binds to AT1 receptors as an antagonist, blocking vasoconstrictor and aldosterone-secreting effects of angiotensin II. Azilsartan has more than a 10,000-fold greater affinity for the AT1 receptor than for the AT2 receptor, which is predominantly involved in cardiovascular homeostasis. Azilsartan appears to dissociate from AT1 receptors much more slowly than other ARBs, which explains its longer duration of action when compared to other ARBs. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): During absorption, azilsartan medoxomil is hydrolyzed to azilsartan. The parent drug is not detectable in plasma after oral administration. The absolute bioavailability of azilsartan is estimated to be 60%. T max ranges from 1.5 to three hours. Steady-state levels of azilsartan are achieved within five days, and no accumulation in plasma occurs with repeated once-daily dosing. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The volume of distribution of azilsartan is approximately 16 L. In rats, a minimal amount of radiolabelled drug crossed the blood-brain barrier. Azilsartan crossed the placental barrier in pregnant rats and was distributed to the fetus. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Azilsartan is >99% bound to human plasma proteins, mainly serum albumin. Protein binding is constant at azilsartan plasma concentrations well above the range achieved with recommended doses. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): After azilsartan medoxomil is hydrolyzed into its active metabolite, azilsartan is metabolized to two primary metabolites, which are pharmacologically inactive. The major metabolite in plasma is metabolite M-II, which is formed via O-dealkylation mediated by CYP2C9. The minor metabolite is metabolite M-I, which is formed via decarboxylation mediated by CYP2C8 and CYP2B6. MII has approximately 50% systemic exposure of azilsartan, and MI has less than 1% systemic exposure of azilsartan. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Following oral administration of 14C-labeled azilsartan medoxomil, approximately 55% of radioactivity was recovered in feces and approximately 42% in urine. Of the recovered dose in urine, about 15% was excreted as azilsartan. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The elimination half-life of azilsartan is approximately 11 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Renal clearance of azilsartan is approximately 2.3 mL/min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No maximum toxic doses have been established yet for azilsartan. There is limited human data available related to azilsartan medoxomil overdosage. In clinical trials, healthy subjects tolerated once-daily doses up to 320 mg of azilsartan medoxomil well. In the event of drug overdose, supportive measures should be initiated as azilsartan is not dialyzable. Azilsartan is a teratogenic agent with a risk of congenital abnormalities. Azilsartan and other ARB drugs are considered fetotoxic during the second and third trimesters. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Edarbi, Edarbyclor •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Azilsartan medoxomil is an angiotensin II receptor blocker used to treat hypertension alone or in combination with other antihypertensive agents, such as chlorthalidone.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Azilsartan medoxomil interact? Information: •Drug A: Abaloparatide •Drug B: Azilsartan medoxomil •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abaloparatide is combined with Azilsartan medoxomil. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Azilsartan medoxomil is indicated for the treatment of hypertension to lower blood pressure in patients over 18 years of age. It may be used either alone or in combination with other antihypertensive agents. Some antihypertensive drugs have lesser effects on blood pressure in black patients. Azilsartan medoxomil is available as a fixed-dose combination product with chlorthalidone, which is indicated for the treatment of hypertension in patients whose hose blood pressure is not adequately controlled on monotherapy. It may be used as initial therapy if a patient is likely to need multiple drugs to achieve blood pressure goals. Azilsartan medoxomil belongs to the angiotensin-receptor blocking (ARB) class of drugs, which are used to decrease the progression of moderate-to-severe albuminuria and prevent the recurrence of atrial fibrillation as off-label uses in patients with diabetes mellitus and hypertension. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Pharmacodynamic effects of azilsartan medoxomil are mediated by its active metabolite, azilsartan. Azilsartan inhibits the pressor effects of an angiotensin II infusion in a dose-related manner. At a single 32 mg dose, azilsartan inhibited the maximal pressor effect by approximately 90% at peak plasma concentrations and by 60% at 24 hours after administration. In healthy subjects receiving single and repeated doses of azilsartan medoxomil, plasma angiotensin I and II concentrations and plasma renin activity increased, while plasma aldosterone concentrations decreased. Like other ARBs, azilsartan causes dose-dependent decrease in peripheral resistance and decreases smooth muscle vascular tone. As azilsartan blocks the angiotensin II receptor, the negative regulatory feedback of angiotensin II on renin secretion is inhibited; however, the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the blood pressure-lowering effect of azilsartan. Blood pressure-lowering effects of antihypertensive agents can be reduced in patients of African descent. However, there are no recommended dosage adjustment of azilsartan on the basis of a patient’s sex, race, or degree of renal or hepatic impairment. Azilsartan medoxomil has negligible effects on serum potassium or sodium levels. Azilsartan does not affect the biosynthesis of angiotensin II nor bradykinin levels. It also does not bind to any ion channels that are involved in cardiovascular regulation. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): The renin-angiotensin-aldosterone system regulates blood pressure. Angiotensin II is a peptide hormone that is a principal pressor agent in the renin-angiotensin-aldosterone system. It is a potent, direct vasoconstrictor that binds to the angiotensin II type 1 receptor (AT1 receptor) to stimulate the synthesis and release of aldosterone and promote cardiac stimulation. Angiotensin II promotes renal tubular reabsorption of sodium, resulting in water retention. It also inhibits further secretion of renin. AT1 receptors are highly expressed in vascular smooth muscle and the adrenal gland. Azilsartan medoxomil is a prodrug that is hydrolyzed to its active metabolite, azilsartan, in the gastrointestinal tract following oral administration. Azilsartan selectively binds to AT1 receptors as an antagonist, blocking vasoconstrictor and aldosterone-secreting effects of angiotensin II. Azilsartan has more than a 10,000-fold greater affinity for the AT1 receptor than for the AT2 receptor, which is predominantly involved in cardiovascular homeostasis. Azilsartan appears to dissociate from AT1 receptors much more slowly than other ARBs, which explains its longer duration of action when compared to other ARBs. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): During absorption, azilsartan medoxomil is hydrolyzed to azilsartan. The parent drug is not detectable in plasma after oral administration. The absolute bioavailability of azilsartan is estimated to be 60%. T max ranges from 1.5 to three hours. Steady-state levels of azilsartan are achieved within five days, and no accumulation in plasma occurs with repeated once-daily dosing. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The volume of distribution of azilsartan is approximately 16 L. In rats, a minimal amount of radiolabelled drug crossed the blood-brain barrier. Azilsartan crossed the placental barrier in pregnant rats and was distributed to the fetus. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Azilsartan is >99% bound to human plasma proteins, mainly serum albumin. Protein binding is constant at azilsartan plasma concentrations well above the range achieved with recommended doses. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): After azilsartan medoxomil is hydrolyzed into its active metabolite, azilsartan is metabolized to two primary metabolites, which are pharmacologically inactive. The major metabolite in plasma is metabolite M-II, which is formed via O-dealkylation mediated by CYP2C9. The minor metabolite is metabolite M-I, which is formed via decarboxylation mediated by CYP2C8 and CYP2B6. MII has approximately 50% systemic exposure of azilsartan, and MI has less than 1% systemic exposure of azilsartan. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Following oral administration of 14C-labeled azilsartan medoxomil, approximately 55% of radioactivity was recovered in feces and approximately 42% in urine. Of the recovered dose in urine, about 15% was excreted as azilsartan. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The elimination half-life of azilsartan is approximately 11 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Renal clearance of azilsartan is approximately 2.3 mL/min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No maximum toxic doses have been established yet for azilsartan. There is limited human data available related to azilsartan medoxomil overdosage. In clinical trials, healthy subjects tolerated once-daily doses up to 320 mg of azilsartan medoxomil well. In the event of drug overdose, supportive measures should be initiated as azilsartan is not dialyzable. Azilsartan is a teratogenic agent with a risk of congenital abnormalities. Azilsartan and other ARB drugs are considered fetotoxic during the second and third trimesters. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Edarbi, Edarbyclor •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Azilsartan medoxomil is an angiotensin II receptor blocker used to treat hypertension alone or in combination with other antihypertensive agents, such as chlorthalidone. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Benazepril interact?

•Drug A: Abaloparatide •Drug B: Benazepril •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Benazepril is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Benazepril is indicated for the treatment of hypertension. It may be used alone or in combination with thiazide diuretics. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Benazepril, an angiotensin-converting enzyme (ACE) inhibitor, is a prodrug which, when hydrolyzed by esterases to its active Benazeprilat, is used to treat hypertension and heart failure, to reduce proteinuria and renal disease in patients with nephropathies, and to prevent stroke, myocardial infarction, and cardiac death in high-risk patients. Benazepril and Benazeprilat inhibit angiotensin-converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Benazeprilat, the active metabolite of Benazepril, competes with angiotensin I for binding at the angiotensin-converting enzyme, blocking the conversion of angiotensin I to angiotensin II. Inhibition of ACE results in decreased plasma angiotensin II. As angiotensin II is a vasoconstrictor and a negative-feedback mediator for renin activity, lower concentrations result in a decrease in blood pressure and stimulation of baroreceptor reflex mechanisms, which leads to decreased vasopressor activity and to decreased aldosterone secretion. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Bioavailability of oral dosing is 3% to 4% in horses. In humans at least 37% of oral benazepril is absorbed and reaches peak plasma concentration in 0.5 hours to 1 hour. Other studies have shown a peak plasma concentration at a median of 1.5 hours. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The final population pharmacokinetic model in one study estimated the volume of distribution to be 203±69.9L. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Benazepril is 96.7% protein bound while benazeprilat is 95.3% protein bound. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Cleavage of the ester group (primarily in the liver) converts benazepril to its active metabolite, benazeprilat. Benazepril and benazeprilat are conjugated to glucuronic acid prior to urinary excretion. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Benazepril and benazeprilat are cleared predominantly by renal excretion in healthy subjects with normal renal function. Nonrenal (i.e., biliary) excretion accounts for approximately 11%-12% of benazeprilat excretion in healthy subjects. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The half life of the prodrug benazepril is 2.7±8.5h. The half life of the active metabolite benazeprilat is 22.3±9.2h The accumulation half life of benazepril is 10 to 11 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The final population pharmacokinetic model of one study estimates the clearance to be 129±30.0L. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The most common adverse effects include headache, dizziness, fatigue, somnolence, postural dizziness, nausea, and cough. The most likely symptom of overdosage is severe hypotension. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Amlobenz, Lotensin, Lotensin Hct, Lotrel •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Benazepril is an ACE inhibitor prodrug used to treat hypertension.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Benazepril interact? Information: •Drug A: Abaloparatide •Drug B: Benazepril •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Benazepril is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Benazepril is indicated for the treatment of hypertension. It may be used alone or in combination with thiazide diuretics. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Benazepril, an angiotensin-converting enzyme (ACE) inhibitor, is a prodrug which, when hydrolyzed by esterases to its active Benazeprilat, is used to treat hypertension and heart failure, to reduce proteinuria and renal disease in patients with nephropathies, and to prevent stroke, myocardial infarction, and cardiac death in high-risk patients. Benazepril and Benazeprilat inhibit angiotensin-converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Benazeprilat, the active metabolite of Benazepril, competes with angiotensin I for binding at the angiotensin-converting enzyme, blocking the conversion of angiotensin I to angiotensin II. Inhibition of ACE results in decreased plasma angiotensin II. As angiotensin II is a vasoconstrictor and a negative-feedback mediator for renin activity, lower concentrations result in a decrease in blood pressure and stimulation of baroreceptor reflex mechanisms, which leads to decreased vasopressor activity and to decreased aldosterone secretion. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Bioavailability of oral dosing is 3% to 4% in horses. In humans at least 37% of oral benazepril is absorbed and reaches peak plasma concentration in 0.5 hours to 1 hour. Other studies have shown a peak plasma concentration at a median of 1.5 hours. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The final population pharmacokinetic model in one study estimated the volume of distribution to be 203±69.9L. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Benazepril is 96.7% protein bound while benazeprilat is 95.3% protein bound. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Cleavage of the ester group (primarily in the liver) converts benazepril to its active metabolite, benazeprilat. Benazepril and benazeprilat are conjugated to glucuronic acid prior to urinary excretion. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Benazepril and benazeprilat are cleared predominantly by renal excretion in healthy subjects with normal renal function. Nonrenal (i.e., biliary) excretion accounts for approximately 11%-12% of benazeprilat excretion in healthy subjects. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The half life of the prodrug benazepril is 2.7±8.5h. The half life of the active metabolite benazeprilat is 22.3±9.2h The accumulation half life of benazepril is 10 to 11 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The final population pharmacokinetic model of one study estimates the clearance to be 129±30.0L. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The most common adverse effects include headache, dizziness, fatigue, somnolence, postural dizziness, nausea, and cough. The most likely symptom of overdosage is severe hypotension. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Amlobenz, Lotensin, Lotensin Hct, Lotrel •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Benazepril is an ACE inhibitor prodrug used to treat hypertension. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Betaxolol interact?

•Drug A: Abaloparatide •Drug B: Betaxolol •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Betaxolol is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the management of hypertension. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Betaxolol is a competitive, beta(1)-selective (cardioselective) adrenergic antagonist. Betaxolol is used to treat hypertension, arrhythmias, coronary heart disease, glaucoma, and is also used to reduce non-fatal cardiac events in patients with heart failure. Activation of beta(1)-receptors (located mainly in the heart) by epinephrine increases the heart rate and the blood pressure, and the heart consumes more oxygen. Drugs such as betaxolol that block these receptors therefore have the reverse effect: they lower the heart rate and blood pressure and hence are used in conditions when the heart itself is deprived of oxygen. They are routinely prescribed in patients with ischemic heart disease. In addition, beta(1)-selective blockers prevent the release of renin, which is a hormone produced by the kidneys which leads to constriction of blood vessels. Betaxolol is lipophilic and exhibits no intrinsic sympathomimetic activity (ISA) or membrane stabilizing activity. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Betaxolol selectively blocks catecholamine stimulation of beta(1)-adrenergic receptors in the heart and vascular smooth muscle. This results in a reduction of heart rate, cardiac output, systolic and diastolic blood pressure, and possibly reflex orthostatic hypotension. Betaxolol can also competitively block beta(2)-adrenergic responses in the bronchial and vascular smooth muscles, causing bronchospasm. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Absorption of an oral dose is complete. There is a small and consistent first-pass effect resulting in an absolute bioavailability of 89% ± 5% that is unaffected by the concomitant ingestion of food or alcohol. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 50% •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Primarily hepatic. Approximately 15% of the dose administered is excreted as unchanged drug, the remainder being metabolites whose contribution to the clinical effect is negligible. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 14-22 hours •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Oral LD 50 s are 350 to 400 mg betaxolol/kg in mice and 860 to 980 mg/kg in rats. Predicted symptoms of overdose include bradycardia, congestive heart failure, hypotension, bronchospasm, and hypoglycemia. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Betoptic, Betoptic Pilo, Betoptic S •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Betaxolol Bétaxolol Betaxololum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Betaxolol is a cardioselective beta blocking agent commonly used to treat hypertension and elevated intraocular pressure (when administered ophthalmically).

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Betaxolol interact? Information: •Drug A: Abaloparatide •Drug B: Betaxolol •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Betaxolol is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the management of hypertension. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Betaxolol is a competitive, beta(1)-selective (cardioselective) adrenergic antagonist. Betaxolol is used to treat hypertension, arrhythmias, coronary heart disease, glaucoma, and is also used to reduce non-fatal cardiac events in patients with heart failure. Activation of beta(1)-receptors (located mainly in the heart) by epinephrine increases the heart rate and the blood pressure, and the heart consumes more oxygen. Drugs such as betaxolol that block these receptors therefore have the reverse effect: they lower the heart rate and blood pressure and hence are used in conditions when the heart itself is deprived of oxygen. They are routinely prescribed in patients with ischemic heart disease. In addition, beta(1)-selective blockers prevent the release of renin, which is a hormone produced by the kidneys which leads to constriction of blood vessels. Betaxolol is lipophilic and exhibits no intrinsic sympathomimetic activity (ISA) or membrane stabilizing activity. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Betaxolol selectively blocks catecholamine stimulation of beta(1)-adrenergic receptors in the heart and vascular smooth muscle. This results in a reduction of heart rate, cardiac output, systolic and diastolic blood pressure, and possibly reflex orthostatic hypotension. Betaxolol can also competitively block beta(2)-adrenergic responses in the bronchial and vascular smooth muscles, causing bronchospasm. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Absorption of an oral dose is complete. There is a small and consistent first-pass effect resulting in an absolute bioavailability of 89% ± 5% that is unaffected by the concomitant ingestion of food or alcohol. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 50% •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Primarily hepatic. Approximately 15% of the dose administered is excreted as unchanged drug, the remainder being metabolites whose contribution to the clinical effect is negligible. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 14-22 hours •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Oral LD 50 s are 350 to 400 mg betaxolol/kg in mice and 860 to 980 mg/kg in rats. Predicted symptoms of overdose include bradycardia, congestive heart failure, hypotension, bronchospasm, and hypoglycemia. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Betoptic, Betoptic Pilo, Betoptic S •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Betaxolol Bétaxolol Betaxololum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Betaxolol is a cardioselective beta blocking agent commonly used to treat hypertension and elevated intraocular pressure (when administered ophthalmically). Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Bisoprolol interact?

•Drug A: Abaloparatide •Drug B: Bisoprolol •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Bisoprolol is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Bisoprolol is indicated for the treatment of mild to moderate hypertension. It may be used off-label to treat heart failure, atrial fibrillation, and angina pectoris. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Bisoprolol decreases heart rate (chronotropy), decreases contractility (inotropy), and reduces blood pressure. The results of various clinical studies indicate that bisoprolol reduces cardiovascular mortality and all-cause mortality in patients with heart failure and decreased cardiac ejection fraction (EF). •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Though the mechanism of action of bisoprolol has not been fully elucidated in hypertension, it is thought that therapeutic effects are achieved through the antagonism of β-1adrenoceptors to result in lower cardiac output. Bisoprolol is a competitive, cardioselective β1-adrenergic antagonist. When β1-receptors (located mainly in the heart) are activated by adrenergic neurotransmitters such as epinephrine, both the blood pressure and heart rate increase, leading to greater cardiovascular work, increasing the demand for oxygen. Bisoprolol reduces cardiac workload by decreasing contractility and the need for oxygen through competitive inhibition of β1-adrenergic receptors. Bisoprolol is also thought to reduce the output of renin in the kidneys, which normally increases blood pressure. Additionally, some central nervous system effects of bisoprolol may include diminishing sympathetic nervous system output from the brain, decreasing blood pressure and heart rate. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Bisoprolol is well absorbed in the gastrointestinal tract. The AUC is 642.87 g.hr/mL and bioavailability of bisoprolol is about 90% due to the minimal first pass effects. Absorption is unaffected by food intake. Peak plasma concentrations of bisoprolol are attained within 2-4 hours and steady-state concentrations are achieved within 5 days of administration. In a pharmacokinetic study, the mean peak concentration of bisoprolol was 52 micrograms/L. Cmax at steady state concentrations of bisoprolol is 64±21 ng/ml administered at 10 mg daily. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The volume of distribution of bisoprolol is 3.5 L/kg. The mean volume of distribution was found to be 230 L/kg in heart failure patients, which was similar to the volume of distribution in healthy patients. Bisoprolol is known to cross the placenta. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Binding to serum proteins is approximately 30%. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Approximately 50% of the bisoprolol dose is eliminated by non-renal pathways. Bisoprolol is metabolized through oxidative metabolic pathways with no subsequent conjugation. Bisoprolol metabolites are polar and, therefore, really eliminated. Major metabolites found in plasma and urine are inactive. Bisoprolol is mainly metabolized by CYP3A4 (95%), whereas CYP2D6 plays a minor role. The CYP3A4-mediated metabolism of bisoprolol appears to be non-stereoselective. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Bisoprolol is eliminated equally by both renal and hepatic pathways. About 50% of an oral dose is excreted unchanged in the urine with the remainder of the dose excreted as inactive bisoprolol metabolites. Under 2% of the ingested dose is found to be excreted in the feces. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): A pharmacokinetic study in 12 healthy individuals determined the mean plasma half-life of bisoprolol to be 10-12 hours. Another study comprised of healthy patients determined the elimination half-life to be approximately 10 hours. Renal impairment increased the half-life to 18.5 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Total body clearance in healthy patients was determined to be 14.2 L/h. In patients with renal impairment, clearance was reduced to 7.8 L/h. Hepatic dysfunction also reduced the clearance of bisoprolol. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): LD50 information Oral LD50 of bisoprolol in the mouse was 730 mg/kg. Overdose information Signs of a β-blocker overdose include cardiovascular symptoms such as hypotension, congestive heart failure, and bradycardia. Other symptoms such as bronchospasm, and hypoglycemia may occur. If an overdose occurs with bisoprolol, supportive treatment should be initiated. Glucagon has been shown to be beneficial in bradycardia and hypotension associated with beta-blocker overdosage. Hypoglycemia may be managed by administering IV glucose. Monitor the patient and administer atropine in cases of bradycardia, pressors and fluids in the case of hypotension, and conventional heart failure therapy if heart failure occurs. If heart block occurs, the patient must be closely monitored and isoproterenol infusion or transvenous cardiac pacemaker insertion should take place. For the management of overdose-related bronchospasm, administer bronchodilators with or without IV aminophylline. Limited research suggests that bisoprolol fumarate is not removed adequately by hemodialysis sessions. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Ziac •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Bisoprolol Bisoprololum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Bisoprolol is a beta-1 adrenergic blocking agent used to prevent myocardial infarction and heart failure and to treat mild to moderate hypertension.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Bisoprolol interact? Information: •Drug A: Abaloparatide •Drug B: Bisoprolol •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Bisoprolol is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Bisoprolol is indicated for the treatment of mild to moderate hypertension. It may be used off-label to treat heart failure, atrial fibrillation, and angina pectoris. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Bisoprolol decreases heart rate (chronotropy), decreases contractility (inotropy), and reduces blood pressure. The results of various clinical studies indicate that bisoprolol reduces cardiovascular mortality and all-cause mortality in patients with heart failure and decreased cardiac ejection fraction (EF). •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Though the mechanism of action of bisoprolol has not been fully elucidated in hypertension, it is thought that therapeutic effects are achieved through the antagonism of β-1adrenoceptors to result in lower cardiac output. Bisoprolol is a competitive, cardioselective β1-adrenergic antagonist. When β1-receptors (located mainly in the heart) are activated by adrenergic neurotransmitters such as epinephrine, both the blood pressure and heart rate increase, leading to greater cardiovascular work, increasing the demand for oxygen. Bisoprolol reduces cardiac workload by decreasing contractility and the need for oxygen through competitive inhibition of β1-adrenergic receptors. Bisoprolol is also thought to reduce the output of renin in the kidneys, which normally increases blood pressure. Additionally, some central nervous system effects of bisoprolol may include diminishing sympathetic nervous system output from the brain, decreasing blood pressure and heart rate. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Bisoprolol is well absorbed in the gastrointestinal tract. The AUC is 642.87 g.hr/mL and bioavailability of bisoprolol is about 90% due to the minimal first pass effects. Absorption is unaffected by food intake. Peak plasma concentrations of bisoprolol are attained within 2-4 hours and steady-state concentrations are achieved within 5 days of administration. In a pharmacokinetic study, the mean peak concentration of bisoprolol was 52 micrograms/L. Cmax at steady state concentrations of bisoprolol is 64±21 ng/ml administered at 10 mg daily. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The volume of distribution of bisoprolol is 3.5 L/kg. The mean volume of distribution was found to be 230 L/kg in heart failure patients, which was similar to the volume of distribution in healthy patients. Bisoprolol is known to cross the placenta. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Binding to serum proteins is approximately 30%. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Approximately 50% of the bisoprolol dose is eliminated by non-renal pathways. Bisoprolol is metabolized through oxidative metabolic pathways with no subsequent conjugation. Bisoprolol metabolites are polar and, therefore, really eliminated. Major metabolites found in plasma and urine are inactive. Bisoprolol is mainly metabolized by CYP3A4 (95%), whereas CYP2D6 plays a minor role. The CYP3A4-mediated metabolism of bisoprolol appears to be non-stereoselective. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Bisoprolol is eliminated equally by both renal and hepatic pathways. About 50% of an oral dose is excreted unchanged in the urine with the remainder of the dose excreted as inactive bisoprolol metabolites. Under 2% of the ingested dose is found to be excreted in the feces. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): A pharmacokinetic study in 12 healthy individuals determined the mean plasma half-life of bisoprolol to be 10-12 hours. Another study comprised of healthy patients determined the elimination half-life to be approximately 10 hours. Renal impairment increased the half-life to 18.5 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Total body clearance in healthy patients was determined to be 14.2 L/h. In patients with renal impairment, clearance was reduced to 7.8 L/h. Hepatic dysfunction also reduced the clearance of bisoprolol. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): LD50 information Oral LD50 of bisoprolol in the mouse was 730 mg/kg. Overdose information Signs of a β-blocker overdose include cardiovascular symptoms such as hypotension, congestive heart failure, and bradycardia. Other symptoms such as bronchospasm, and hypoglycemia may occur. If an overdose occurs with bisoprolol, supportive treatment should be initiated. Glucagon has been shown to be beneficial in bradycardia and hypotension associated with beta-blocker overdosage. Hypoglycemia may be managed by administering IV glucose. Monitor the patient and administer atropine in cases of bradycardia, pressors and fluids in the case of hypotension, and conventional heart failure therapy if heart failure occurs. If heart block occurs, the patient must be closely monitored and isoproterenol infusion or transvenous cardiac pacemaker insertion should take place. For the management of overdose-related bronchospasm, administer bronchodilators with or without IV aminophylline. Limited research suggests that bisoprolol fumarate is not removed adequately by hemodialysis sessions. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Ziac •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Bisoprolol Bisoprololum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Bisoprolol is a beta-1 adrenergic blocking agent used to prevent myocardial infarction and heart failure and to treat mild to moderate hypertension. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Bosentan interact?

•Drug A: Abaloparatide •Drug B: Bosentan •Severity: MINOR •Description: Abaloparatide may increase the hypotensive activities of Bosentan. •Extended Description: The use of two drugs that both lower blood pressure may result in a more pronounced hypotensive effect. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Used in the treatment of pulmonary arterial hypertension (PAH), to improve exercise ability and to decrease the rate of clinical worsening (in patients with WHO Class III or IV symptoms). •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Bosentan belongs to a class of drugs known as endothelin receptor antagonists (ERAs). Patients with PAH have elevated levels of endothelin, a potent blood vessel constrictor, in their plasma and lung tissue. Bosentan blocks the binding of endothelin to its receptors, thereby negating endothelin's deleterious effects. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Endothelin-1 (ET-1) is a neurohormone, the effects of which are mediated by binding to ET A and ET B receptors in the endothelium and vascular smooth muscle. It displays a slightly higher affinity towards ET A receptors than ET B receptors. ET-1 concentrations are elevated in plasma and lung tissue of patients with pulmonary arterial hypertension, suggesting a pathogenic role for ET-1 in this disease. Bosentan is a specific and competitive antagonist at endothelin receptor types ET A and ET B. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Absolute bioavailability is approximately 50% and food does not affect absorption. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 18 L •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Greater than 98% to plasma proteins, mainly albumin. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Bosentan is metabolized in the liver by the cytochrome P450 enzymes CYP2C9 and CYP3A4 (and possibly CYP2C19), producing three metabolites, one of which, Ro 48-5033, is pharmacologically active and may contribute 10 to 20% to the total activity of the parent compound. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Bosentan is eliminated by biliary excretion following metabolism in the liver. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Terminal elimination half-life is about 5 hours in healthy adult subjects. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): 4 L/h [patients with pulmonary arterial hypertension] •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Bosentan has been given as a single dose of up to 2400 mg in normal volunteers, or up to 2000 mg/day for 2 months in patients, without any major clinical consequences. The most common side effect was headache of mild to moderate intensity. In the cyclosporine A interaction study, in which doses of 500 and 1000 mg b.i.d. of bosentan were given concomitantly with cyclosporine A, trough plasma concentrations of bosentan increased 30-fold, resulting in severe headache, nausea, and vomiting, but no serious adverse events. Mild decreases in blood pressure and increases in heart rate were observed. There is no specific experience of overdosage with bosentan beyond the doses described above. Massive overdosage may result in pronounced hypotension requiring active cardiovascular support. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Stayveer, Tracleer •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): bosentán Bosentan bosentanum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Bosentan is a dual endothelin receptor antagonist used to treat pulmonary arterial hypertension.

The use of two drugs that both lower blood pressure may result in a more pronounced hypotensive effect. The severity of the interaction is minor.

Question: Does Abaloparatide and Bosentan interact? Information: •Drug A: Abaloparatide •Drug B: Bosentan •Severity: MINOR •Description: Abaloparatide may increase the hypotensive activities of Bosentan. •Extended Description: The use of two drugs that both lower blood pressure may result in a more pronounced hypotensive effect. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Used in the treatment of pulmonary arterial hypertension (PAH), to improve exercise ability and to decrease the rate of clinical worsening (in patients with WHO Class III or IV symptoms). •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Bosentan belongs to a class of drugs known as endothelin receptor antagonists (ERAs). Patients with PAH have elevated levels of endothelin, a potent blood vessel constrictor, in their plasma and lung tissue. Bosentan blocks the binding of endothelin to its receptors, thereby negating endothelin's deleterious effects. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Endothelin-1 (ET-1) is a neurohormone, the effects of which are mediated by binding to ET A and ET B receptors in the endothelium and vascular smooth muscle. It displays a slightly higher affinity towards ET A receptors than ET B receptors. ET-1 concentrations are elevated in plasma and lung tissue of patients with pulmonary arterial hypertension, suggesting a pathogenic role for ET-1 in this disease. Bosentan is a specific and competitive antagonist at endothelin receptor types ET A and ET B. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Absolute bioavailability is approximately 50% and food does not affect absorption. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 18 L •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Greater than 98% to plasma proteins, mainly albumin. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Bosentan is metabolized in the liver by the cytochrome P450 enzymes CYP2C9 and CYP3A4 (and possibly CYP2C19), producing three metabolites, one of which, Ro 48-5033, is pharmacologically active and may contribute 10 to 20% to the total activity of the parent compound. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Bosentan is eliminated by biliary excretion following metabolism in the liver. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Terminal elimination half-life is about 5 hours in healthy adult subjects. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): 4 L/h [patients with pulmonary arterial hypertension] •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Bosentan has been given as a single dose of up to 2400 mg in normal volunteers, or up to 2000 mg/day for 2 months in patients, without any major clinical consequences. The most common side effect was headache of mild to moderate intensity. In the cyclosporine A interaction study, in which doses of 500 and 1000 mg b.i.d. of bosentan were given concomitantly with cyclosporine A, trough plasma concentrations of bosentan increased 30-fold, resulting in severe headache, nausea, and vomiting, but no serious adverse events. Mild decreases in blood pressure and increases in heart rate were observed. There is no specific experience of overdosage with bosentan beyond the doses described above. Massive overdosage may result in pronounced hypotension requiring active cardiovascular support. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Stayveer, Tracleer •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): bosentán Bosentan bosentanum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Bosentan is a dual endothelin receptor antagonist used to treat pulmonary arterial hypertension. Output: The use of two drugs that both lower blood pressure may result in a more pronounced hypotensive effect. The severity of the interaction is minor.

Does Abaloparatide and Bretylium interact?

•Drug A: Abaloparatide •Drug B: Bretylium •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Bretylium is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For use in the prophylaxis and therapy of ventricular fibrillation. Also used in the treatment of life-threatening ventricular arrhythmias, such as ventricular tachycardia, that have failed to respond to adequate doses of a first-line antiarrhythmic agent, such as lidocaine. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Bretylium is a bromobenzyl quaternary ammonium compound which selectively accumulates in sympathetic ganglia and their postganglionic adrenergic neurons where it inhibits norepinephrine release by depressing adrenergic nerve terminal excitability. Bretylium also suppresses ventricular fibrillation and ventricular arrhythmias. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Bretylium inhibits norepinephrine release by depressing adrenergic nerve terminal excitability. The mechanisms of the antifibrillatory and antiarrhythmic actions of bretylium are not established. In efforts to define these mechanisms, the following electrophysiologic actions of bretylium have been demonstrated in animal experiments: increase in ventricular fibrillation threshold, increase in action potential duration and effective refractory period without changes in heart rate, little effect on the rate of rise or amplitude of the cardiac action potential (Phase 0) or in resting membrane potential (Phase 4) in normal myocardium, decrease in the disparity in action potential duration between normal and infarcted regions, and increase in impulse formation and spontaneous firing rate of pacemaker tissue as well as increase ventricular conduction velocity. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): No metabolites have been identified following administration in man and laboratory animals. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The terminal half-life in four normal volunteers averaged 7.8±0.6 hours (range 6.9-8.1). During hemodialysis, this patient's arterial and venous bretylium concentrations declined rapidly, resulting in a half-life of 13 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Oral, mouse: LD 50 = 400 mg/kg. In the presence of life-threatening arrhythmias, underdosing with bretylium probably presents a greater risk to the patient than potential overdosage. However, one case of accidental overdose has been reported in which a rapidly injected intravenous bolus of 30 mg/kg was given instead of an intended 10 mg/kg dose during an episode of ventricular tachycardia. Marked hypertension resulted, followed by protracted refractory hypotension. The patient expired 18 hours later in asystole, complicated by renal failure and aspiration pneumonitis. Bretylium serum levels were 8000 ng/mL. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Bretylium •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Bretylium is a norepinephrine release inhibitor used for the prophylaxis and therapy of ventricular fibrillation, as well as the treatment of life-threatening ventricular arrhythmias.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Bretylium interact? Information: •Drug A: Abaloparatide •Drug B: Bretylium •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Bretylium is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For use in the prophylaxis and therapy of ventricular fibrillation. Also used in the treatment of life-threatening ventricular arrhythmias, such as ventricular tachycardia, that have failed to respond to adequate doses of a first-line antiarrhythmic agent, such as lidocaine. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Bretylium is a bromobenzyl quaternary ammonium compound which selectively accumulates in sympathetic ganglia and their postganglionic adrenergic neurons where it inhibits norepinephrine release by depressing adrenergic nerve terminal excitability. Bretylium also suppresses ventricular fibrillation and ventricular arrhythmias. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Bretylium inhibits norepinephrine release by depressing adrenergic nerve terminal excitability. The mechanisms of the antifibrillatory and antiarrhythmic actions of bretylium are not established. In efforts to define these mechanisms, the following electrophysiologic actions of bretylium have been demonstrated in animal experiments: increase in ventricular fibrillation threshold, increase in action potential duration and effective refractory period without changes in heart rate, little effect on the rate of rise or amplitude of the cardiac action potential (Phase 0) or in resting membrane potential (Phase 4) in normal myocardium, decrease in the disparity in action potential duration between normal and infarcted regions, and increase in impulse formation and spontaneous firing rate of pacemaker tissue as well as increase ventricular conduction velocity. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): No metabolites have been identified following administration in man and laboratory animals. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The terminal half-life in four normal volunteers averaged 7.8±0.6 hours (range 6.9-8.1). During hemodialysis, this patient's arterial and venous bretylium concentrations declined rapidly, resulting in a half-life of 13 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Oral, mouse: LD 50 = 400 mg/kg. In the presence of life-threatening arrhythmias, underdosing with bretylium probably presents a greater risk to the patient than potential overdosage. However, one case of accidental overdose has been reported in which a rapidly injected intravenous bolus of 30 mg/kg was given instead of an intended 10 mg/kg dose during an episode of ventricular tachycardia. Marked hypertension resulted, followed by protracted refractory hypotension. The patient expired 18 hours later in asystole, complicated by renal failure and aspiration pneumonitis. Bretylium serum levels were 8000 ng/mL. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Bretylium •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Bretylium is a norepinephrine release inhibitor used for the prophylaxis and therapy of ventricular fibrillation, as well as the treatment of life-threatening ventricular arrhythmias. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Bromocriptine interact?

•Drug A: Abaloparatide •Drug B: Bromocriptine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Bromocriptine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the treatment of galactorrhea due to hyperprolactinemia, prolactin-dependent menstrual disorders and infertility, prolactin-secreting adenomas, prolactin-dependent male hypogonadism, as adjunct therapy to surgery or radiotherapy for acromegaly or as monotherapy is special cases, as monotherapy in early Parksinsonian Syndrome or as an adjunct with levodopa in advanced cases with motor complications. Bromocriptine has also been used off-label to treat restless legs syndrome and neuroleptic malignant syndrome. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Bromocriptine stimulates centrally-located dopaminergic receptors resulting in a number of pharmacologic effects. Five dopamine receptor types from two dopaminergic subfamilies have been identified. The dopaminergic D1 receptor subfamily consists of D 1 and D 5 subreceptors, which are associated with dyskinesias. The dopaminergic D2 receptor subfamily consists of D 2, D 3 and D 4 subreceptors, which are associated with improvement of symptoms of movement disorders. Thus, agonist activity specific for D2 subfamily receptors, primarily D 2 and D 3 receptor subtypes, are the primary targets of dopaminergic antiparkinsonian agents. It is thought that postsynaptic D 2 stimulation is primarily responsible for the antiparkinsonian effect of dopamine agonists, while presynaptic D 2 stimulation confers neuroprotective effects. This semisynthetic ergot derivative exhibits potent agonist activity on dopamine D 2 -receptors. It also exhibits agonist activity (in order of decreasing binding affinity) on 5-hydroxytryptamine (5-HT) 1D, dopamine D 3, 5-HT 1A, 5-HT 2A, 5-HT 1B, and 5-HT 2C receptors, antagonist activity on α 2A -adrenergic, α 2C, α 2B, and dopamine D 1 receptors, partial agonist activity at receptor 5-HT 2B, and inactivates dopamine D 4 and 5-HT 7 receptors. Parkinsonian Syndrome manifests when approximately 80% of dopaminergic activity in the nigrostriatal pathway of the brain is lost. As this striatum is involved in modulating the intensity of coordinated muscle activity (e.g. movement, balance, walking), loss of activity may result in dystonia (acute muscle contraction), Parkinsonism (including symptoms of bradykinesia, tremor, rigidity, and flattened affect), akathesia (inner restlessness), tardive dyskinesia (involuntary muscle movements usually associated with long-term loss of dopaminergic activity), and neuroleptic malignant syndrome, which manifests when complete blockage of nigrostriatal dopamine occurs. High dopaminergic activity in the mesolimbic pathway of the brain causes hallucinations and delusions; these side effects of dopamine agonists are manifestations seen in patients with schizophrenia who have overractivity in this area of the brain. The hallucinogenic side effects of dopamine agonists may also be due to 5-HT 2A agonism. The tuberoinfundibular pathway of the brain originates in the hypothalamus and terminates in the pituitary gland. In this pathway, dopamine inhibits lactotrophs in anterior pituitary from secreting prolactin. Increased dopaminergic activity in the tuberoinfundibular pathway inhibits prolactin secretion making bromocriptine an effective agent for treating disorders associated with hypersecretion of prolactin. Pulmonary fibrosis may be associated bromocriptine’s agonist activity at 5-HT 1B and 5-HT 2B receptors. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): The dopamine D 2 receptor is a 7-transmembrane G-protein coupled receptor associated with G i proteins. In lactotrophs, stimulation of dopamine D 2 receptor causes inhibition of adenylyl cyclase, which decreases intracellular cAMP concentrations and blocks IP3-dependent release of Ca from intracellular stores. Decreases in intracellular calcium levels may also be brought about via inhibition of calcium influx through voltage-gated calcium channels, rather than via inhibition of adenylyl cyclase. Additionally, receptor activation blocks phosphorylation of p42/p44 MAPK and decreases MAPK/ERK kinase phosphorylation. Inhibition of MAPK appears to be mediated by c-Raf and B-Raf-dependent inhibition of MAPK/ERK kinase. Dopamine-stimulated growth hormone release from the pituitary gland is mediated by a decrease in intracellular calcium influx through voltage-gated calcium channels rather than via adenylyl cyclase inhibition. Stimulation of dopamine D 2 receptors in the nigrostriatal pathway leads to improvements in coordinated muscle activity in those with movement disorders. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Approximately 28% of the oral dose is absorbed; however due to a substantial first pass effect, only 6% of the oral dose reaches the systemic circulation unchanged. Bromocriptine and its metabolites appear in the blood as early as 10 minutes following oral administration and peak plasma concentration are reached within 1-1.5 hours. Serum prolactin may be decreased within 2 hours or oral administration with a maximal effect achieved after 8 hours. Growth hormone concentrations in patients with acromegaly is reduced within 1-2 hours with a single oral dose of 2.5 mg and decreased growth hormone concentrations persist for at least 4-5 hours. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 90-96% bound to serum albumin •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Completely metabolized by the liver, primarily by hydrolysis of the amide bond to produce lysergic acid and a peptide fragment, both inactive and non-toxic. Bromocriptine is metabolized by cytochrome P450 3A4 and excreted primarily in the feces via biliary secretion. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Parent drug and metabolites are almost completely excreted via the liver, and only 6% eliminated via the kidney. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 2-8 hours •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Symptoms of overdosage include nausea, vomiting, and severe hypotension. The most common adverse effects include nausea, headache, vertigo, constipation, light-headedness, abdominal cramps, nasal congestion, diarrhea, and hypotension. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Cycloset, Parlodel •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Bromocriptina Bromocriptine Bromocriptinum Bromocryptine Bromoergocriptine Bromoergocryptine •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Bromocriptine is a dopamine D2 receptor agonist used for the treatment of galactorrhea due to hyperprolactinemia and other prolactin-related conditions, as well as in early Parkinsonian Syndrome.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Bromocriptine interact? Information: •Drug A: Abaloparatide •Drug B: Bromocriptine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Bromocriptine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the treatment of galactorrhea due to hyperprolactinemia, prolactin-dependent menstrual disorders and infertility, prolactin-secreting adenomas, prolactin-dependent male hypogonadism, as adjunct therapy to surgery or radiotherapy for acromegaly or as monotherapy is special cases, as monotherapy in early Parksinsonian Syndrome or as an adjunct with levodopa in advanced cases with motor complications. Bromocriptine has also been used off-label to treat restless legs syndrome and neuroleptic malignant syndrome. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Bromocriptine stimulates centrally-located dopaminergic receptors resulting in a number of pharmacologic effects. Five dopamine receptor types from two dopaminergic subfamilies have been identified. The dopaminergic D1 receptor subfamily consists of D 1 and D 5 subreceptors, which are associated with dyskinesias. The dopaminergic D2 receptor subfamily consists of D 2, D 3 and D 4 subreceptors, which are associated with improvement of symptoms of movement disorders. Thus, agonist activity specific for D2 subfamily receptors, primarily D 2 and D 3 receptor subtypes, are the primary targets of dopaminergic antiparkinsonian agents. It is thought that postsynaptic D 2 stimulation is primarily responsible for the antiparkinsonian effect of dopamine agonists, while presynaptic D 2 stimulation confers neuroprotective effects. This semisynthetic ergot derivative exhibits potent agonist activity on dopamine D 2 -receptors. It also exhibits agonist activity (in order of decreasing binding affinity) on 5-hydroxytryptamine (5-HT) 1D, dopamine D 3, 5-HT 1A, 5-HT 2A, 5-HT 1B, and 5-HT 2C receptors, antagonist activity on α 2A -adrenergic, α 2C, α 2B, and dopamine D 1 receptors, partial agonist activity at receptor 5-HT 2B, and inactivates dopamine D 4 and 5-HT 7 receptors. Parkinsonian Syndrome manifests when approximately 80% of dopaminergic activity in the nigrostriatal pathway of the brain is lost. As this striatum is involved in modulating the intensity of coordinated muscle activity (e.g. movement, balance, walking), loss of activity may result in dystonia (acute muscle contraction), Parkinsonism (including symptoms of bradykinesia, tremor, rigidity, and flattened affect), akathesia (inner restlessness), tardive dyskinesia (involuntary muscle movements usually associated with long-term loss of dopaminergic activity), and neuroleptic malignant syndrome, which manifests when complete blockage of nigrostriatal dopamine occurs. High dopaminergic activity in the mesolimbic pathway of the brain causes hallucinations and delusions; these side effects of dopamine agonists are manifestations seen in patients with schizophrenia who have overractivity in this area of the brain. The hallucinogenic side effects of dopamine agonists may also be due to 5-HT 2A agonism. The tuberoinfundibular pathway of the brain originates in the hypothalamus and terminates in the pituitary gland. In this pathway, dopamine inhibits lactotrophs in anterior pituitary from secreting prolactin. Increased dopaminergic activity in the tuberoinfundibular pathway inhibits prolactin secretion making bromocriptine an effective agent for treating disorders associated with hypersecretion of prolactin. Pulmonary fibrosis may be associated bromocriptine’s agonist activity at 5-HT 1B and 5-HT 2B receptors. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): The dopamine D 2 receptor is a 7-transmembrane G-protein coupled receptor associated with G i proteins. In lactotrophs, stimulation of dopamine D 2 receptor causes inhibition of adenylyl cyclase, which decreases intracellular cAMP concentrations and blocks IP3-dependent release of Ca from intracellular stores. Decreases in intracellular calcium levels may also be brought about via inhibition of calcium influx through voltage-gated calcium channels, rather than via inhibition of adenylyl cyclase. Additionally, receptor activation blocks phosphorylation of p42/p44 MAPK and decreases MAPK/ERK kinase phosphorylation. Inhibition of MAPK appears to be mediated by c-Raf and B-Raf-dependent inhibition of MAPK/ERK kinase. Dopamine-stimulated growth hormone release from the pituitary gland is mediated by a decrease in intracellular calcium influx through voltage-gated calcium channels rather than via adenylyl cyclase inhibition. Stimulation of dopamine D 2 receptors in the nigrostriatal pathway leads to improvements in coordinated muscle activity in those with movement disorders. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Approximately 28% of the oral dose is absorbed; however due to a substantial first pass effect, only 6% of the oral dose reaches the systemic circulation unchanged. Bromocriptine and its metabolites appear in the blood as early as 10 minutes following oral administration and peak plasma concentration are reached within 1-1.5 hours. Serum prolactin may be decreased within 2 hours or oral administration with a maximal effect achieved after 8 hours. Growth hormone concentrations in patients with acromegaly is reduced within 1-2 hours with a single oral dose of 2.5 mg and decreased growth hormone concentrations persist for at least 4-5 hours. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 90-96% bound to serum albumin •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Completely metabolized by the liver, primarily by hydrolysis of the amide bond to produce lysergic acid and a peptide fragment, both inactive and non-toxic. Bromocriptine is metabolized by cytochrome P450 3A4 and excreted primarily in the feces via biliary secretion. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Parent drug and metabolites are almost completely excreted via the liver, and only 6% eliminated via the kidney. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 2-8 hours •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Symptoms of overdosage include nausea, vomiting, and severe hypotension. The most common adverse effects include nausea, headache, vertigo, constipation, light-headedness, abdominal cramps, nasal congestion, diarrhea, and hypotension. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Cycloset, Parlodel •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Bromocriptina Bromocriptine Bromocriptinum Bromocryptine Bromoergocriptine Bromoergocryptine •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Bromocriptine is a dopamine D2 receptor agonist used for the treatment of galactorrhea due to hyperprolactinemia and other prolactin-related conditions, as well as in early Parkinsonian Syndrome. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Bumetanide interact?

•Drug A: Abaloparatide •Drug B: Bumetanide •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Bumetanide is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the treatment of edema associated with congestive heart failure, hepatic and renal disease including the nephrotic syndrome. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Bumetanide is a loop diuretic of the sulfamyl category to treat heart failure. It is often used in patients in whom high doses of furosemide are ineffective. There is however no reason not to use bumetanide as a first choice drug. The main difference between the two substances is in bioavailability. Bumetanide has more predictable pharmacokinetic properties as well as clinical effect. In patients with normal renal function, bumetanide is 40 times more effective than furosemide. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Bumetanide interferes with renal cAMP and/or inhibits the sodium-potassium ATPase pump. Bumetanide appears to block the active reabsorption of chloride and possibly sodium in the ascending loop of Henle, altering electrolyte transfer in the proximal tubule. This results in excretion of sodium, chloride, and water and, hence, diuresis. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Bumetanide is completely absorbed (80%), and the absorption is not altered when taken with food. Bioavailability is almost complete. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 97% •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): 45% is secreted unchanged. Urinary and biliary metabolites are formed by oxidation of the N-butyl side chain. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Oral administration of carbon-14 labeled Bumex to human volunteers revealed that 81% of the administered radioactivity was excreted in the urine, 45% of it as unchanged drug. Biliary excretion of Bumex amounted to only 2% of the administered dose. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 60-90 minutes •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): 0.2 - 1.1 mL/min/kg [preterm and full-term neonates with respiratory disorders] 2.17 mL/min/kg [neonates receiving bumetanide for volume overload] 1.8 +/- 0.3 mL/min/kg [geriatric subjects] 2.9 +/- 0.2 mL/min/kg [younger subjects] •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Overdosage can lead to acute profound water loss, volume and electrolyte depletion, dehydration, reduction of blood volume and circulatory collapse with a possibility of vascular thrombosis and embolism. Electrolyte depletion may be manifested by weakness, dizziness, mental confusion, anorexia, lethargy, vomiting and cramps. Treatment consists of replacement of fluid and electrolyte losses by careful monitoring of the urine and electrolyte output and serum electrolyte levels. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Bumex, Burinex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Bumetanida Bumetanide Bumetanidum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Bumetanide is a sulfamyl diuretic used to treat edema in congestive heart failure, hepatic and renal disease, and nephrotic syndrome.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Bumetanide interact? Information: •Drug A: Abaloparatide •Drug B: Bumetanide •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Bumetanide is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the treatment of edema associated with congestive heart failure, hepatic and renal disease including the nephrotic syndrome. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Bumetanide is a loop diuretic of the sulfamyl category to treat heart failure. It is often used in patients in whom high doses of furosemide are ineffective. There is however no reason not to use bumetanide as a first choice drug. The main difference between the two substances is in bioavailability. Bumetanide has more predictable pharmacokinetic properties as well as clinical effect. In patients with normal renal function, bumetanide is 40 times more effective than furosemide. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Bumetanide interferes with renal cAMP and/or inhibits the sodium-potassium ATPase pump. Bumetanide appears to block the active reabsorption of chloride and possibly sodium in the ascending loop of Henle, altering electrolyte transfer in the proximal tubule. This results in excretion of sodium, chloride, and water and, hence, diuresis. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Bumetanide is completely absorbed (80%), and the absorption is not altered when taken with food. Bioavailability is almost complete. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 97% •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): 45% is secreted unchanged. Urinary and biliary metabolites are formed by oxidation of the N-butyl side chain. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Oral administration of carbon-14 labeled Bumex to human volunteers revealed that 81% of the administered radioactivity was excreted in the urine, 45% of it as unchanged drug. Biliary excretion of Bumex amounted to only 2% of the administered dose. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 60-90 minutes •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): 0.2 - 1.1 mL/min/kg [preterm and full-term neonates with respiratory disorders] 2.17 mL/min/kg [neonates receiving bumetanide for volume overload] 1.8 +/- 0.3 mL/min/kg [geriatric subjects] 2.9 +/- 0.2 mL/min/kg [younger subjects] •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Overdosage can lead to acute profound water loss, volume and electrolyte depletion, dehydration, reduction of blood volume and circulatory collapse with a possibility of vascular thrombosis and embolism. Electrolyte depletion may be manifested by weakness, dizziness, mental confusion, anorexia, lethargy, vomiting and cramps. Treatment consists of replacement of fluid and electrolyte losses by careful monitoring of the urine and electrolyte output and serum electrolyte levels. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Bumex, Burinex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Bumetanida Bumetanide Bumetanidum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Bumetanide is a sulfamyl diuretic used to treat edema in congestive heart failure, hepatic and renal disease, and nephrotic syndrome. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Bupivacaine interact?

•Drug A: Abaloparatide •Drug B: Bupivacaine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Bupivacaine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): As an implant, bupivacaine is indicated in adults for placement into the surgical site to produce postsurgical analgesia for up to 24 hours following open inguinal hernia repair. Bupivacaine, in liposome suspension, is indicated in patients aged 6 years and older for single-dose infiltration to produce postsurgical local analgesia. In adults, it is also indicated to produce regional analgesia via an interscalene brachial plexus nerve block, a sciatic nerve block in the popliteal fossa, or an adductor canal block. Bupivicaine, in combination with meloxicam, is indicated for postsurgical analgesia in adult patients for up to 72 hours following soft tissue surgical procedures, foot and ankle procedures, and other orthopedic procedures in which direct exposure to articular cartilage is avoided. Bupivacaine, alone or in combination with epinephrine, is indicated in adults for the production of local or regional anesthesia or analgesia for surgery, dental and oral surgery procedures, diagnostic and therapeutic procedures, and for obstetrical procedures. Specific concentrations and presentations are recommended for each type of block indicated to produce local or regional anesthesia or analgesia. Finally, its use is not indicated in all blocks given clinically significant risks associated with use. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Bupivacaine is a widely used local anesthetic agent. Bupivacaine is often administered by spinal injection prior to total hip arthroplasty. It is also commonly injected into surgical wound sites to reduce pain for up to 20 hours after surgery. In comparison to other local anesthetics it has a long duration of action. It is also the most toxic to the heart when administered in large doses. This problem has led to the use of other long-acting local anaesthetics:ropivacaine and levobupivacaine. Levobupivacaine is a derivative, specifically an enantiomer, of bupivacaine. Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous systems. At blood concentrations achieved with therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block, ventricular arrhythmias and to cardiac arrest, sometimes resulting in fatalities. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. Following systemic absorption, local anesthetics can produce central nervous system stimulation, depression or both. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Like lidocaine, bupivacaine is an amide local anesthetic that provides local anesthesia through blockade of nerve impulse generation and conduction. These impulses, also known as action potentials, critically depend on membrane depolarization produced by the influx of sodium ions into the neuron through voltage-gated sodium channels. Bupivacaine crosses the neuronal membrane and exerts its anesthetic action through blockade of these channels at the intracellular portion of their pore-forming transmembrane segments. The block is use-dependent, where repetitive or prolonged depolarization increases sodium channel blockade. Without sodium ions passing through the channel’s pore, bupivacaine stabilizes the membrane at rest and therefore prevents neurotransmission. In general, the progression of anesthesia is related to the diameter, myelination and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone. While it is well-established that the main action of bupivacaine is through sodium channel block, additional analgesic effects of bupivacaine are thought to potentially be due to its binding to the prostaglandin E2 receptors, subtype EP1 (PGE2EP1), which inhibits the production of prostaglandins, thereby reducing fever, inflammation, and hyperalgesia. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Systemic absorption of local anesthetics is dose- and concentration-dependendent on the total drug administered. Other factors that affect the rate of systemic absorption include the route of administration, blood flow at the administration site, and the presence or absence of epinephrine in the anesthetic solution. Bupivacaine formulated for instillation with meloxicam produced varied systemic measures following a single dose of varying strength. In patients undergoing bunionectomy, 60 mg of bupivacaine produced a C max of 54 ± 33 ng/mL, a median T max of 3 h, and an AUC ∞ of 1718 ± 1211 ng*h/mL. For a 300 mg dose used in herniorrhaphy, the corresponding values were 271 ± 147 ng/mL, 18 h, and 15,524 ± 8921 ng*h/mL. Lastly, a 400 mg dose used in total knee arthroplasty produced values of 695 ± 411 ng/mL, 21 h, and 38,173 ± 29,400 ng*h/mL. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Bupivacaine is ~95% protein bound. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Amide-type local anesthetics such as bupivacaine are metabolized primarily in the liver via conjugation with glucuronic acid. The major metabolite of bupivacaine is 2,6-pipecoloxylidine, which is mainly catalyzed via cytochrome P450 3A4. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Only 6% of bupivacaine is excreted unchanged in the urine. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 2.7 hours in adults and 8.1 hours in neonates. Bupivacaine applied together with meloxicam for postsurgical analgesia had a median half-life of 15-17 hours, depending on dose and application site. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The mean seizure dosage of bupivacaine in rhesus monkeys was found to be 4.4 mg/kg with mean arterial plasma concentration of 4.5 mcg/mL. The intravenous and subcutaneous LD 50 in mice is 6 to 8 mg/kg and 38 to 54 mg/kg respectively. Recent clinical data from patients experiencing local anesthetic induced convulsions demonstrated rapid development of hypoxia, hypercarbia, and acidosis with bupivacaine within a minute of the onset of convulsions. These observations suggest that oxygen consumption and carbon dioxide production are greatly increased during local anesthetic convulsions and emphasize the importance of immediate and effective ventilation with oxygen which may avoid cardiac arrest. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Exparel, Kenalog, Marbeta, Marcaine, Marcaine With Epinephrine, Marvona Suik, P-Care M, P-Care MG, P-care, Posimir, Readysharp Anesthetics Plus Ketorolac, Readysharp-A, Readysharp-p40, Readysharp-p80, Sensorcaine, Sensorcaine With Epinephrine, Vivacaine, Xaracoll, Zynrelef •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Bupivacaina Bupivacaine Bupivacainum DL-Bupivacaine Racemic bupivacaine •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Bupivacaine is a local anesthetic used in a wide variety of superficial and invasive procedures.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Bupivacaine interact? Information: •Drug A: Abaloparatide •Drug B: Bupivacaine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Bupivacaine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): As an implant, bupivacaine is indicated in adults for placement into the surgical site to produce postsurgical analgesia for up to 24 hours following open inguinal hernia repair. Bupivacaine, in liposome suspension, is indicated in patients aged 6 years and older for single-dose infiltration to produce postsurgical local analgesia. In adults, it is also indicated to produce regional analgesia via an interscalene brachial plexus nerve block, a sciatic nerve block in the popliteal fossa, or an adductor canal block. Bupivicaine, in combination with meloxicam, is indicated for postsurgical analgesia in adult patients for up to 72 hours following soft tissue surgical procedures, foot and ankle procedures, and other orthopedic procedures in which direct exposure to articular cartilage is avoided. Bupivacaine, alone or in combination with epinephrine, is indicated in adults for the production of local or regional anesthesia or analgesia for surgery, dental and oral surgery procedures, diagnostic and therapeutic procedures, and for obstetrical procedures. Specific concentrations and presentations are recommended for each type of block indicated to produce local or regional anesthesia or analgesia. Finally, its use is not indicated in all blocks given clinically significant risks associated with use. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Bupivacaine is a widely used local anesthetic agent. Bupivacaine is often administered by spinal injection prior to total hip arthroplasty. It is also commonly injected into surgical wound sites to reduce pain for up to 20 hours after surgery. In comparison to other local anesthetics it has a long duration of action. It is also the most toxic to the heart when administered in large doses. This problem has led to the use of other long-acting local anaesthetics:ropivacaine and levobupivacaine. Levobupivacaine is a derivative, specifically an enantiomer, of bupivacaine. Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous systems. At blood concentrations achieved with therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block, ventricular arrhythmias and to cardiac arrest, sometimes resulting in fatalities. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. Following systemic absorption, local anesthetics can produce central nervous system stimulation, depression or both. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Like lidocaine, bupivacaine is an amide local anesthetic that provides local anesthesia through blockade of nerve impulse generation and conduction. These impulses, also known as action potentials, critically depend on membrane depolarization produced by the influx of sodium ions into the neuron through voltage-gated sodium channels. Bupivacaine crosses the neuronal membrane and exerts its anesthetic action through blockade of these channels at the intracellular portion of their pore-forming transmembrane segments. The block is use-dependent, where repetitive or prolonged depolarization increases sodium channel blockade. Without sodium ions passing through the channel’s pore, bupivacaine stabilizes the membrane at rest and therefore prevents neurotransmission. In general, the progression of anesthesia is related to the diameter, myelination and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone. While it is well-established that the main action of bupivacaine is through sodium channel block, additional analgesic effects of bupivacaine are thought to potentially be due to its binding to the prostaglandin E2 receptors, subtype EP1 (PGE2EP1), which inhibits the production of prostaglandins, thereby reducing fever, inflammation, and hyperalgesia. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Systemic absorption of local anesthetics is dose- and concentration-dependendent on the total drug administered. Other factors that affect the rate of systemic absorption include the route of administration, blood flow at the administration site, and the presence or absence of epinephrine in the anesthetic solution. Bupivacaine formulated for instillation with meloxicam produced varied systemic measures following a single dose of varying strength. In patients undergoing bunionectomy, 60 mg of bupivacaine produced a C max of 54 ± 33 ng/mL, a median T max of 3 h, and an AUC ∞ of 1718 ± 1211 ng*h/mL. For a 300 mg dose used in herniorrhaphy, the corresponding values were 271 ± 147 ng/mL, 18 h, and 15,524 ± 8921 ng*h/mL. Lastly, a 400 mg dose used in total knee arthroplasty produced values of 695 ± 411 ng/mL, 21 h, and 38,173 ± 29,400 ng*h/mL. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Bupivacaine is ~95% protein bound. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Amide-type local anesthetics such as bupivacaine are metabolized primarily in the liver via conjugation with glucuronic acid. The major metabolite of bupivacaine is 2,6-pipecoloxylidine, which is mainly catalyzed via cytochrome P450 3A4. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Only 6% of bupivacaine is excreted unchanged in the urine. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 2.7 hours in adults and 8.1 hours in neonates. Bupivacaine applied together with meloxicam for postsurgical analgesia had a median half-life of 15-17 hours, depending on dose and application site. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The mean seizure dosage of bupivacaine in rhesus monkeys was found to be 4.4 mg/kg with mean arterial plasma concentration of 4.5 mcg/mL. The intravenous and subcutaneous LD 50 in mice is 6 to 8 mg/kg and 38 to 54 mg/kg respectively. Recent clinical data from patients experiencing local anesthetic induced convulsions demonstrated rapid development of hypoxia, hypercarbia, and acidosis with bupivacaine within a minute of the onset of convulsions. These observations suggest that oxygen consumption and carbon dioxide production are greatly increased during local anesthetic convulsions and emphasize the importance of immediate and effective ventilation with oxygen which may avoid cardiac arrest. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Exparel, Kenalog, Marbeta, Marcaine, Marcaine With Epinephrine, Marvona Suik, P-Care M, P-Care MG, P-care, Posimir, Readysharp Anesthetics Plus Ketorolac, Readysharp-A, Readysharp-p40, Readysharp-p80, Sensorcaine, Sensorcaine With Epinephrine, Vivacaine, Xaracoll, Zynrelef •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Bupivacaina Bupivacaine Bupivacainum DL-Bupivacaine Racemic bupivacaine •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Bupivacaine is a local anesthetic used in a wide variety of superficial and invasive procedures. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Canagliflozin interact?

•Drug A: Abaloparatide •Drug B: Canagliflozin •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abaloparatide is combined with Canagliflozin. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): This drug is used in conjunction with diet and exercise to increase glycemic control in adults diagnosed with type 2 diabetes mellitus. Another indication for canagliflozin is the prevention of major cardiovascular events (myocardial infarction, stroke, or death due to a cardiovascular cause) in patients with type 2 diabetes, as well as hospitalization for heart failure in patients with type 2 diabetes. In addition to the above, canagliflozin can be used to lower the risk of end-stage kidney disease and major increases in serum creatinine and cardiovascular death for patients with a combination of type 2 diabetes mellitus, diabetic nephropathy, and albuminuria. It is important to note that this drug is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): This drug increases urinary glucose excretion and decreases the renal threshold for glucose (RTG) in a dose-dependent manner. The renal threshold is defined as the lowest level of blood glucose associated with the appearance of detectable glucose in the urine. The end result of canagliflozin administration is increased urinary excretion of glucose and less renal absorption of glucose, decreasing glucose concentration in the blood and improving glycemic control. A note on type 2 diabetes and cardiovascular disease The risk of cardiovascular events in diabetes type 2 is increased due to the damaging effects of diabetes on blood vessels and nerves in the cardiovascular system. In particular, there is a tendency for hyperglycemia to create pro-atherogenic (plaque forming) lesions in blood vessels, leading to various fatal and non-fatal events including stroke and myocardial infarction. Long-term glycemic control has been proven to be effective in the prevention of cardiovascular events such as myocardial infarction and stroke in patients with type 2 diabetes. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): The sodium-glucose co-transporter2 (SGLT2), is found in the proximal tubules of the kidney, and reabsorbs filtered glucose from the renal tubular lumen. Canagliflozin inhibits the SGLT2 co-transporter. This inhibition leads to lower reabsorption of filtered glucose into the body and decreases the renal threshold for glucose (RTG), leading to increased glucose excretion in the urine. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Bioavailability and steady-state The absolute oral bioavailability of canagliflozin, on average, is approximately 65%. Steady-state concentrations are achieved after 4 to 5 days of daily dose administration between the range of 100mg to 300mg. Effect of food on absorption Co-administration of a high-fat meal with canagliflozin exerted no appreciable effect on the pharmacokinetic parameters of canagliflozin. This drug may be administered without regard to food. Despite this, because of the potential of canagliflozin to decrease postprandial plasma glucose excretion due to prolonged intestinal glucose absorption, it is advisable to take this drug before the first meal of the day. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): This drug is extensively distributed throughout the body. On average, the volume of distribution of canagliflozin at steady state following a single intravenous dose in healthy patients was measured to be 83.5 L. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Canagliflozin is mainly bound to albumin. The plasma protein binding of this drug is 99%. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Canagliflozin is primarily metabolized by O-glucuronidation. It is mainly glucuronidated by UGT1A9 and UGT2B4 enzymes to two inactive O-glucuronide metabolites. The oxidative metabolism of canagliflozin by hepatic cytochrome enzyme CYP3A4 is negligible (about 7%) in humans. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): After a single oral radiolabeled dose canagliflozin dose to healthy subjects, the following ratios of canagliflozin or metabolites were measured in the feces and urine: Feces 41.5% as the unchanged radiolabeled drug 7.0% as a hydroxylated metabolite 3.2% as an O-glucuronide metabolite Urine About 33% of the ingested radiolabled dose was measured in the urine, generally in the form of O-glucuronide metabolites. Less than 1% of the dose was found excreted as unchanged drug in urine. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): In a clinical study, the terminal half-life of canagliflozin was 10.6 hours for the 100mg dose and 13.1 hours for the 300 mg dose. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): In healthy subjects, canagliflozin clearance was approximately 192 mL/min after intravenous (IV) administration. The renal clearance of 100 mg and 300 mg doses of canagliflozin was measured to be in the range of 1.30 - 1.55 mL/min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Overdose information If an overdose occurs, contact the Poison Control Center. Normal supportive measures should be taken, including the removal unabsorbed drug from the gastrointestinal tract, initiating clinical monitoring of the patient, and providing supportive treatment as deemed necessary. Canagliflozin has been removed in very small quantities after a 4-hour hemodialysis session. This drug is likely not dialyzable by peritoneal dialysis. Pregnancy and lactation Animal data has demonstrated that canagliflozin may cause adverse renal effects in a growing fetus. Data are insufficient at this time in determining a potential canagliflozin related risk for major birth defects or possible miscarriage in humans. There are known risks, however, of uncontrolled diabetes in pregnancy. Inform female patients taking canagliflozin of the potential risk, which is increased during the second and third trimesters. This drug is not recommended during nursing. Mutagenesis and carcinogenicity Canagliflozin was not found to be mutagenic in both metabolically activated and inactivated states in the Ames assay. Canagliflozin showed mutagenicity in laboratory mouse lymphoma assay, but only in the activated state. Canagliflozin was not found to be mutagenic in several in vivo assays performed on rats. The carcinogenic risk of canagliflozin was assessed in 2-year studies completed in both CD1 mice and Sprague-Dawley rats. Canagliflozin was not shown to increase tumor incidence in mouse models given doses less than or equal to 14 times the exposure from a typical 300 mg dose in humans. Despite these negative findings in mice, the incidence of several tumors increased in mice, including Leydig cell tumors, renal tubular adenomas, and adrenal pheochromocytomas. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Invokamet, Invokana •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Canagliflozin Canagliflozina •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Canagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor used to manage hyperglycemia in type 2 diabetes mellitus (DM). Also used to reduce the risk of major cardiovascular events in patients with established cardiovascular disease and type 2 DM.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Canagliflozin interact? Information: •Drug A: Abaloparatide •Drug B: Canagliflozin •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abaloparatide is combined with Canagliflozin. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): This drug is used in conjunction with diet and exercise to increase glycemic control in adults diagnosed with type 2 diabetes mellitus. Another indication for canagliflozin is the prevention of major cardiovascular events (myocardial infarction, stroke, or death due to a cardiovascular cause) in patients with type 2 diabetes, as well as hospitalization for heart failure in patients with type 2 diabetes. In addition to the above, canagliflozin can be used to lower the risk of end-stage kidney disease and major increases in serum creatinine and cardiovascular death for patients with a combination of type 2 diabetes mellitus, diabetic nephropathy, and albuminuria. It is important to note that this drug is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): This drug increases urinary glucose excretion and decreases the renal threshold for glucose (RTG) in a dose-dependent manner. The renal threshold is defined as the lowest level of blood glucose associated with the appearance of detectable glucose in the urine. The end result of canagliflozin administration is increased urinary excretion of glucose and less renal absorption of glucose, decreasing glucose concentration in the blood and improving glycemic control. A note on type 2 diabetes and cardiovascular disease The risk of cardiovascular events in diabetes type 2 is increased due to the damaging effects of diabetes on blood vessels and nerves in the cardiovascular system. In particular, there is a tendency for hyperglycemia to create pro-atherogenic (plaque forming) lesions in blood vessels, leading to various fatal and non-fatal events including stroke and myocardial infarction. Long-term glycemic control has been proven to be effective in the prevention of cardiovascular events such as myocardial infarction and stroke in patients with type 2 diabetes. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): The sodium-glucose co-transporter2 (SGLT2), is found in the proximal tubules of the kidney, and reabsorbs filtered glucose from the renal tubular lumen. Canagliflozin inhibits the SGLT2 co-transporter. This inhibition leads to lower reabsorption of filtered glucose into the body and decreases the renal threshold for glucose (RTG), leading to increased glucose excretion in the urine. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Bioavailability and steady-state The absolute oral bioavailability of canagliflozin, on average, is approximately 65%. Steady-state concentrations are achieved after 4 to 5 days of daily dose administration between the range of 100mg to 300mg. Effect of food on absorption Co-administration of a high-fat meal with canagliflozin exerted no appreciable effect on the pharmacokinetic parameters of canagliflozin. This drug may be administered without regard to food. Despite this, because of the potential of canagliflozin to decrease postprandial plasma glucose excretion due to prolonged intestinal glucose absorption, it is advisable to take this drug before the first meal of the day. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): This drug is extensively distributed throughout the body. On average, the volume of distribution of canagliflozin at steady state following a single intravenous dose in healthy patients was measured to be 83.5 L. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Canagliflozin is mainly bound to albumin. The plasma protein binding of this drug is 99%. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Canagliflozin is primarily metabolized by O-glucuronidation. It is mainly glucuronidated by UGT1A9 and UGT2B4 enzymes to two inactive O-glucuronide metabolites. The oxidative metabolism of canagliflozin by hepatic cytochrome enzyme CYP3A4 is negligible (about 7%) in humans. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): After a single oral radiolabeled dose canagliflozin dose to healthy subjects, the following ratios of canagliflozin or metabolites were measured in the feces and urine: Feces 41.5% as the unchanged radiolabeled drug 7.0% as a hydroxylated metabolite 3.2% as an O-glucuronide metabolite Urine About 33% of the ingested radiolabled dose was measured in the urine, generally in the form of O-glucuronide metabolites. Less than 1% of the dose was found excreted as unchanged drug in urine. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): In a clinical study, the terminal half-life of canagliflozin was 10.6 hours for the 100mg dose and 13.1 hours for the 300 mg dose. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): In healthy subjects, canagliflozin clearance was approximately 192 mL/min after intravenous (IV) administration. The renal clearance of 100 mg and 300 mg doses of canagliflozin was measured to be in the range of 1.30 - 1.55 mL/min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Overdose information If an overdose occurs, contact the Poison Control Center. Normal supportive measures should be taken, including the removal unabsorbed drug from the gastrointestinal tract, initiating clinical monitoring of the patient, and providing supportive treatment as deemed necessary. Canagliflozin has been removed in very small quantities after a 4-hour hemodialysis session. This drug is likely not dialyzable by peritoneal dialysis. Pregnancy and lactation Animal data has demonstrated that canagliflozin may cause adverse renal effects in a growing fetus. Data are insufficient at this time in determining a potential canagliflozin related risk for major birth defects or possible miscarriage in humans. There are known risks, however, of uncontrolled diabetes in pregnancy. Inform female patients taking canagliflozin of the potential risk, which is increased during the second and third trimesters. This drug is not recommended during nursing. Mutagenesis and carcinogenicity Canagliflozin was not found to be mutagenic in both metabolically activated and inactivated states in the Ames assay. Canagliflozin showed mutagenicity in laboratory mouse lymphoma assay, but only in the activated state. Canagliflozin was not found to be mutagenic in several in vivo assays performed on rats. The carcinogenic risk of canagliflozin was assessed in 2-year studies completed in both CD1 mice and Sprague-Dawley rats. Canagliflozin was not shown to increase tumor incidence in mouse models given doses less than or equal to 14 times the exposure from a typical 300 mg dose in humans. Despite these negative findings in mice, the incidence of several tumors increased in mice, including Leydig cell tumors, renal tubular adenomas, and adrenal pheochromocytomas. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Invokamet, Invokana •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Canagliflozin Canagliflozina •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Canagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor used to manage hyperglycemia in type 2 diabetes mellitus (DM). Also used to reduce the risk of major cardiovascular events in patients with established cardiovascular disease and type 2 DM. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Candesartan cilexetil interact?

•Drug A: Abaloparatide •Drug B: Candesartan cilexetil •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Candesartan cilexetil is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): May be used as a first line agent to treat uncomplicated hypertension, isolated systolic hypertension and left ventricular hypertrophy. May be used as a first line agent to delay progression of diabetic nephropathy. Candesartan may be also used as a second line agent in the treatment of congestive heart failure, systolic dysfunction, myocardial infarction and coronary artery disease in those intolerant of ACE inhibitors. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Candesartan cilexetil is an ARB prodrug that is rapidly converted to candesartan, its active metabolite, during absorption from the gastrointestinal tract. Candesartan confers blood pressure lowering effects by antagonizing the hypertensive effects of angiotensin II via the RAAS. RAAS is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from granular cells of the juxtaglomerular apparatus in the kidneys. Renin cleaves circulating angiotensinogen to angiotensin I, which is cleaved by angiotensin converting enzyme (ACE) to angiotensin II. Angiotensin II increases blood pressure by increasing total peripheral resistance, increasing sodium and water reabsorption in the kidneys via aldosterone secretion, and altering cardiovascular structure. Angiotensin II binds to two receptors: type-1 angiotensin II receptor (AT1) and type-2 angiotensin II receptor (AT2). AT1 is a G-protein coupled receptor (GPCR) that mediates the vasoconstrictive and aldosterone-secreting effects of angiotensin II. Studies performed in recent years suggest that AT2 antagonizes AT1-mediated effects and directly affects long-term blood pressure control by inducing vasorelaxation and increasing urinary sodium excretion. Angiotensin receptor blockers (ARBs) are non-peptide competitive inhibitors of AT1. ARBs block the ability of angiotensin II to stimulate pressor and cell proliferative effects. Unlike ACE inhibitors, ARBs do not affect bradykinin-induced vasodilation. The overall effect of ARBs is a decrease in blood pressure. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Candesartan selectively blocks the binding of angiotensin II to AT1 in many tissues including vascular smooth muscle and the adrenal glands. This inhibits the AT1-mediated vasoconstrictive and aldosterone-secreting effects of angiotensin II and results in an overall decrease in blood pressure. Candesartan is greater than 10,000 times more selective for AT1 than AT2. Inhibition of aldosterone secretion may increase sodium and water excretion while decreasing potassium excretion. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Following administration of the candesartan cilexetil prodrug, the absolute bioavailability of candesartan was estimated to be 15%. Food with a high fat content has no effect on the bioavailability of candesartan from candesartan cilexetil. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 0.13 L/kg •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Candesartan is highly bound to plasma proteins (>99%) and does not penetrate red blood cells. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): The prodrug candesartan cilexetil undergoes rapid and complete ester hydrolysis in the intestinal wall to form the active drug, candesartan. Elimination of candesartan is primarily as unchanged drug in the urine and, by the biliary route, in the feces. Minor hepatic metabolism of candesartan (<20%) occurs by O-deethylation via cytochrome P450 2C9 to form an inactive metabolite. Candesartan undergoes N-glucuronidation in the tetrazole ring by uridine diphosphate glucuronosyltransferase 1A3 (UGT1A3). O-glucuronidation may also occur. 75% of candesartan is excreted as unchanged drug in urine and feces. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): When candesartan is administered orally, about 26% of the dose is excreted unchanged in urine. Candesartan is mainly excreted unchanged in urine and feces (via bile). •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Approximately 9 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): 0.37 mL/min/kg •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No lethality was observed in acute toxicity studies in mice, rats and dogs given single oral doses of up to 2000 mg/kg of candesartan cilexetil or in rats given single oral doses of up to 2000 mg/kg of candesartan cilexetil in combination with 1000 mg/kg of hydrochlorothiazide. In mice given single oral doses of the primary metabolite, candesartan, the minimum lethal dose was greater than 1000 mg/kg but less than 2000 mg/kg. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Atacand, Atacand Hct •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Candesartan cilexetil is an angiotensin receptor blocker used to treat hypertension, systolic hypertension, left ventricular hypertrophy, and delay progression of diabetic nephropathy.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Candesartan cilexetil interact? Information: •Drug A: Abaloparatide •Drug B: Candesartan cilexetil •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Candesartan cilexetil is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): May be used as a first line agent to treat uncomplicated hypertension, isolated systolic hypertension and left ventricular hypertrophy. May be used as a first line agent to delay progression of diabetic nephropathy. Candesartan may be also used as a second line agent in the treatment of congestive heart failure, systolic dysfunction, myocardial infarction and coronary artery disease in those intolerant of ACE inhibitors. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Candesartan cilexetil is an ARB prodrug that is rapidly converted to candesartan, its active metabolite, during absorption from the gastrointestinal tract. Candesartan confers blood pressure lowering effects by antagonizing the hypertensive effects of angiotensin II via the RAAS. RAAS is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from granular cells of the juxtaglomerular apparatus in the kidneys. Renin cleaves circulating angiotensinogen to angiotensin I, which is cleaved by angiotensin converting enzyme (ACE) to angiotensin II. Angiotensin II increases blood pressure by increasing total peripheral resistance, increasing sodium and water reabsorption in the kidneys via aldosterone secretion, and altering cardiovascular structure. Angiotensin II binds to two receptors: type-1 angiotensin II receptor (AT1) and type-2 angiotensin II receptor (AT2). AT1 is a G-protein coupled receptor (GPCR) that mediates the vasoconstrictive and aldosterone-secreting effects of angiotensin II. Studies performed in recent years suggest that AT2 antagonizes AT1-mediated effects and directly affects long-term blood pressure control by inducing vasorelaxation and increasing urinary sodium excretion. Angiotensin receptor blockers (ARBs) are non-peptide competitive inhibitors of AT1. ARBs block the ability of angiotensin II to stimulate pressor and cell proliferative effects. Unlike ACE inhibitors, ARBs do not affect bradykinin-induced vasodilation. The overall effect of ARBs is a decrease in blood pressure. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Candesartan selectively blocks the binding of angiotensin II to AT1 in many tissues including vascular smooth muscle and the adrenal glands. This inhibits the AT1-mediated vasoconstrictive and aldosterone-secreting effects of angiotensin II and results in an overall decrease in blood pressure. Candesartan is greater than 10,000 times more selective for AT1 than AT2. Inhibition of aldosterone secretion may increase sodium and water excretion while decreasing potassium excretion. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Following administration of the candesartan cilexetil prodrug, the absolute bioavailability of candesartan was estimated to be 15%. Food with a high fat content has no effect on the bioavailability of candesartan from candesartan cilexetil. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 0.13 L/kg •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Candesartan is highly bound to plasma proteins (>99%) and does not penetrate red blood cells. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): The prodrug candesartan cilexetil undergoes rapid and complete ester hydrolysis in the intestinal wall to form the active drug, candesartan. Elimination of candesartan is primarily as unchanged drug in the urine and, by the biliary route, in the feces. Minor hepatic metabolism of candesartan (<20%) occurs by O-deethylation via cytochrome P450 2C9 to form an inactive metabolite. Candesartan undergoes N-glucuronidation in the tetrazole ring by uridine diphosphate glucuronosyltransferase 1A3 (UGT1A3). O-glucuronidation may also occur. 75% of candesartan is excreted as unchanged drug in urine and feces. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): When candesartan is administered orally, about 26% of the dose is excreted unchanged in urine. Candesartan is mainly excreted unchanged in urine and feces (via bile). •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Approximately 9 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): 0.37 mL/min/kg •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No lethality was observed in acute toxicity studies in mice, rats and dogs given single oral doses of up to 2000 mg/kg of candesartan cilexetil or in rats given single oral doses of up to 2000 mg/kg of candesartan cilexetil in combination with 1000 mg/kg of hydrochlorothiazide. In mice given single oral doses of the primary metabolite, candesartan, the minimum lethal dose was greater than 1000 mg/kg but less than 2000 mg/kg. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Atacand, Atacand Hct •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Candesartan cilexetil is an angiotensin receptor blocker used to treat hypertension, systolic hypertension, left ventricular hypertrophy, and delay progression of diabetic nephropathy. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Captopril interact?

•Drug A: Abaloparatide •Drug B: Captopril •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Captopril is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the treatment of essential or renovascular hypertension (usually administered with other drugs, particularly thiazide diuretics). May be used to treat congestive heart failure in combination with other drugs (e.g. cardiac glycosides, diuretics, β-adrenergic blockers). May improve survival in patients with left ventricular dysfunction following myocardial infarction. May be used to treat nephropathy, including diabetic nephropathy. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Captopril, an ACE inhibitor, antagonizes the effect of the RAAS. The RAAS is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from the granular cells of the juxtaglomerular apparatus in the kidneys. In the blood stream, renin cleaves circulating angiotensinogen to ATI, which is subsequently cleaved to ATII by ACE. ATII increases blood pressure using a number of mechanisms. First, it stimulates the secretion of aldosterone from the adrenal cortex. Aldosterone travels to the distal convoluted tubule (DCT) and collecting tubule of nephrons where it increases sodium and water reabsorption by increasing the number of sodium channels and sodium-potassium ATPases on cell membranes. Second, ATII stimulates the secretion of vasopressin (also known as antidiuretic hormone or ADH) from the posterior pituitary gland. ADH stimulates further water reabsorption from the kidneys via insertion of aquaporin-2 channels on the apical surface of cells of the DCT and collecting tubules. Third, ATII increases blood pressure through direct arterial vasoconstriction. Stimulation of the Type 1 ATII receptor on vascular smooth muscle cells leads to a cascade of events resulting in myocyte contraction and vasoconstriction. In addition to these major effects, ATII induces the thirst response via stimulation of hypothalamic neurons. ACE inhibitors inhibit the rapid conversion of ATI to ATII and antagonize RAAS-induced increases in blood pressure. ACE (also known as kininase II) is also involved in the enzymatic deactivation of bradykinin, a vasodilator. Inhibiting the deactivation of bradykinin increases bradykinin levels and may sustain its effects by causing increased vasodilation and decreased blood pressure. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): There are two isoforms of ACE: the somatic isoform, which exists as a glycoprotein comprised of a single polypeptide chain of 1277; and the testicular isoform, which has a lower molecular mass and is thought to play a role in sperm maturation and binding of sperm to the oviduct epithelium. Somatic ACE has two functionally active domains, N and C, which arise from tandem gene duplication. Although the two domains have high sequence similarity, they play distinct physiological roles. The C-domain is predominantly involved in blood pressure regulation while the N-domain plays a role in hematopoietic stem cell differentiation and proliferation. ACE inhibitors bind to and inhibit the activity of both domains, but have much greater affinity for and inhibitory activity against the C-domain. Captopril, one of the few ACE inhibitors that is not a prodrug, competes with ATI for binding to ACE and inhibits and enzymatic proteolysis of ATI to ATII. Decreasing ATII levels in the body decreases blood pressure by inhibiting the pressor effects of ATII as described in the Pharmacology section above. Captopril also causes an increase in plasma renin activity likely due to a loss of feedback inhibition mediated by ATII on the release of renin and/or stimulation of reflex mechanisms via baroreceptors. Captopril’s affinity for ACE is approximately 30,000 times greater than that of ATI. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): 60-75% in fasting individuals; food decreases absorption by 25-40% (some evidence indicates that this is not clinically significant) •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 25-30% bound to plasma proteins, primarily albumin •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Hepatic. Major metabolites are captopril-cysteine disulfide and the disulfide dimer of captopril. Metabolites may undergo reversible interconversion. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 2 hours •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Symptoms of overdose include emesis and decreased blood pressure. Side effects include dose-dependent rash (usually maculopapular), taste alterations, hypotension, gastric irritation, cough, and angioedema. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Captopril Captoprilum Captopryl L-Captopril •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Captopril is an ACE inhibitor used for the management of essential or renovascular hypertension, congestive heart failure, left ventricular dysfunction following myocardial infarction, and nephropathy.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Captopril interact? Information: •Drug A: Abaloparatide •Drug B: Captopril •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Captopril is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the treatment of essential or renovascular hypertension (usually administered with other drugs, particularly thiazide diuretics). May be used to treat congestive heart failure in combination with other drugs (e.g. cardiac glycosides, diuretics, β-adrenergic blockers). May improve survival in patients with left ventricular dysfunction following myocardial infarction. May be used to treat nephropathy, including diabetic nephropathy. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Captopril, an ACE inhibitor, antagonizes the effect of the RAAS. The RAAS is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from the granular cells of the juxtaglomerular apparatus in the kidneys. In the blood stream, renin cleaves circulating angiotensinogen to ATI, which is subsequently cleaved to ATII by ACE. ATII increases blood pressure using a number of mechanisms. First, it stimulates the secretion of aldosterone from the adrenal cortex. Aldosterone travels to the distal convoluted tubule (DCT) and collecting tubule of nephrons where it increases sodium and water reabsorption by increasing the number of sodium channels and sodium-potassium ATPases on cell membranes. Second, ATII stimulates the secretion of vasopressin (also known as antidiuretic hormone or ADH) from the posterior pituitary gland. ADH stimulates further water reabsorption from the kidneys via insertion of aquaporin-2 channels on the apical surface of cells of the DCT and collecting tubules. Third, ATII increases blood pressure through direct arterial vasoconstriction. Stimulation of the Type 1 ATII receptor on vascular smooth muscle cells leads to a cascade of events resulting in myocyte contraction and vasoconstriction. In addition to these major effects, ATII induces the thirst response via stimulation of hypothalamic neurons. ACE inhibitors inhibit the rapid conversion of ATI to ATII and antagonize RAAS-induced increases in blood pressure. ACE (also known as kininase II) is also involved in the enzymatic deactivation of bradykinin, a vasodilator. Inhibiting the deactivation of bradykinin increases bradykinin levels and may sustain its effects by causing increased vasodilation and decreased blood pressure. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): There are two isoforms of ACE: the somatic isoform, which exists as a glycoprotein comprised of a single polypeptide chain of 1277; and the testicular isoform, which has a lower molecular mass and is thought to play a role in sperm maturation and binding of sperm to the oviduct epithelium. Somatic ACE has two functionally active domains, N and C, which arise from tandem gene duplication. Although the two domains have high sequence similarity, they play distinct physiological roles. The C-domain is predominantly involved in blood pressure regulation while the N-domain plays a role in hematopoietic stem cell differentiation and proliferation. ACE inhibitors bind to and inhibit the activity of both domains, but have much greater affinity for and inhibitory activity against the C-domain. Captopril, one of the few ACE inhibitors that is not a prodrug, competes with ATI for binding to ACE and inhibits and enzymatic proteolysis of ATI to ATII. Decreasing ATII levels in the body decreases blood pressure by inhibiting the pressor effects of ATII as described in the Pharmacology section above. Captopril also causes an increase in plasma renin activity likely due to a loss of feedback inhibition mediated by ATII on the release of renin and/or stimulation of reflex mechanisms via baroreceptors. Captopril’s affinity for ACE is approximately 30,000 times greater than that of ATI. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): 60-75% in fasting individuals; food decreases absorption by 25-40% (some evidence indicates that this is not clinically significant) •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 25-30% bound to plasma proteins, primarily albumin •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Hepatic. Major metabolites are captopril-cysteine disulfide and the disulfide dimer of captopril. Metabolites may undergo reversible interconversion. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 2 hours •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Symptoms of overdose include emesis and decreased blood pressure. Side effects include dose-dependent rash (usually maculopapular), taste alterations, hypotension, gastric irritation, cough, and angioedema. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Captopril Captoprilum Captopryl L-Captopril •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Captopril is an ACE inhibitor used for the management of essential or renovascular hypertension, congestive heart failure, left ventricular dysfunction following myocardial infarction, and nephropathy. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Carbetocin interact?

•Drug A: Abaloparatide •Drug B: Carbetocin •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Carbetocin is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Used to control postpartum hemorrhage and bleeding after giving birth. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Carbetocin is a drug used to control postpartum hemorrhage, bleeding after giving birth. It is sold under the trade name Duratocin. It is an analogue of oxytocin, and its action is similar to that of oxytocin; it causes contraction of the uterus. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Carbetocin binds to oxytocin receptors present on the smooth musculature of the uterus, resulting in rhythmic contractions of the uterus, increased frequency of existing contractions, and increased uterine tone. The oxytocin receptor content of the uterus is very low in the non-pregnant state, and increases during pregnancy, reaching a peak at the time of delivery. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Bioavailability is 80% following intramuscular injection. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 40 minutes •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Duratocin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Carbetocin Carbetocina Carbetocino Carbetocinum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Carbetocin is an oxytocin agent used to control postpartum hemorrhage and bleeding after giving birth.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Carbetocin interact? Information: •Drug A: Abaloparatide •Drug B: Carbetocin •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Carbetocin is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Used to control postpartum hemorrhage and bleeding after giving birth. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Carbetocin is a drug used to control postpartum hemorrhage, bleeding after giving birth. It is sold under the trade name Duratocin. It is an analogue of oxytocin, and its action is similar to that of oxytocin; it causes contraction of the uterus. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Carbetocin binds to oxytocin receptors present on the smooth musculature of the uterus, resulting in rhythmic contractions of the uterus, increased frequency of existing contractions, and increased uterine tone. The oxytocin receptor content of the uterus is very low in the non-pregnant state, and increases during pregnancy, reaching a peak at the time of delivery. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Bioavailability is 80% following intramuscular injection. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 40 minutes •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Duratocin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Carbetocin Carbetocina Carbetocino Carbetocinum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Carbetocin is an oxytocin agent used to control postpartum hemorrhage and bleeding after giving birth. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Carvedilol interact?

•Drug A: Abaloparatide •Drug B: Carvedilol •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Carvedilol is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Carvedilol is indicated to treat mild to severe heart failure, left ventricular dysfunction after myocardial infarction with ventricular ejection fraction ≤40%, or hypertension. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Carvedilol reduces tachycardia through beta adrenergic antagonism and lowers blood pressure through alpha-1 adrenergic antagonism. It has a long duration of action as it is generally taken once daily and has a broad therapeutic index as patients generally take 10-80mg daily. Patients taking carvedilol should not abruptly stop taking this medication as this may exacerbate coronary artery disease. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Carvedilol inhibits exercise induce tachycardia through its inhibition of beta adrenoceptors. Carvedilol's action on alpha-1 adrenergic receptors relaxes smooth muscle in vasculature, leading to reduced peripheral vascular resistance and an overall reduction in blood pressure. At higher doses, calcium channel blocking and antioxidant activity can also be seen. The antioxidant activity of carvedilol prevents oxidation of low density lipoprotein and its uptake into coronary circulation. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Carvedilol has a bioavailability of 25-35%. Carvedilol has a T max of 1 to 2 hours. Taking carvedilol with a meal increases T max without increasing AUC. Carvedilol doses of 50mg lead to a C max of 122-262µg/L and an AUC of 717-1600µg/L*h. Carvedilol doses of 25mg lead to a C max of 24-151µg/L and an AUC of 272-947µg/L*h. Carvedilol doses of 12.5mg lead to a C max of 58-69µg/L and an AUC of 208-225µg/L*h. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Carvedilol has a volume of distribution of 1.5-2L/kg or 115L. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Carvedilol is 98% protein bound in plasma. 95% of carvedilol is bound to serum albumin. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Carvedilol can be hydroxlated at the 1 position by CYP2D6, CYP1A2, or CYP1A1 to form 1-hydroxypheylcarvedilol; at the 4 position by CYP2D6, CYP2E1, CYP2C9, or CYP3A4 to form 4'-hydroxyphenylcarvedilol; at the 5 position by CYP2D6, CYP2C9, or CYP3A4 to form 5'-hydroxyphenylcarvedilol; and at the 8 position by CYP1A2, CYP3A4, and CYP1A1 to form 8-hydroxycarbazolylcarvedilol. Carvedilol can also be demethylated by CYP2C9, CYP2D6, CYP1A2, or CYP2E1 to form O-desmethylcarvedilol. Carvedilol and its metabolites may undergo further sulfate conjugation or glucuronidation before elimination. Carvedilol can be O-glucuronidated by UGT1A1, UGT2B4, and UGT2B7 to form carvedilol glucuronide. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): 16% of carvedilol is excreted in the urine with <2% excreted as unmetabolized drug. Carvedilol is primarily excreted in the bile and feces. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The half life of carvedilol is between 7-10 hours, though significantly shorter half lives have also been reported. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The plasma clearance of carvedilol has been reported as 0.52L/kg or 500-700mL/min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Patients experiencing an overdose may present with hypotension, bradycardia, cardiac insufficiency, cardiogenic shock, and cardiac arrest. Patients should remain in a supine position and may be given atropine for bradycardia and glucagon followed by sympathomimetics to support cardiovascular function. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Coreg •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Carvedilol Carvédilol Carvedilolum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Carvedilol is a non selective beta-adrenergic antagonist used to treat mild to severe chronic heart failure, hypertension, and left ventricular dysfunction following myocardial infarction in clinically stable patients.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Carvedilol interact? Information: •Drug A: Abaloparatide •Drug B: Carvedilol •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Carvedilol is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Carvedilol is indicated to treat mild to severe heart failure, left ventricular dysfunction after myocardial infarction with ventricular ejection fraction ≤40%, or hypertension. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Carvedilol reduces tachycardia through beta adrenergic antagonism and lowers blood pressure through alpha-1 adrenergic antagonism. It has a long duration of action as it is generally taken once daily and has a broad therapeutic index as patients generally take 10-80mg daily. Patients taking carvedilol should not abruptly stop taking this medication as this may exacerbate coronary artery disease. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Carvedilol inhibits exercise induce tachycardia through its inhibition of beta adrenoceptors. Carvedilol's action on alpha-1 adrenergic receptors relaxes smooth muscle in vasculature, leading to reduced peripheral vascular resistance and an overall reduction in blood pressure. At higher doses, calcium channel blocking and antioxidant activity can also be seen. The antioxidant activity of carvedilol prevents oxidation of low density lipoprotein and its uptake into coronary circulation. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Carvedilol has a bioavailability of 25-35%. Carvedilol has a T max of 1 to 2 hours. Taking carvedilol with a meal increases T max without increasing AUC. Carvedilol doses of 50mg lead to a C max of 122-262µg/L and an AUC of 717-1600µg/L*h. Carvedilol doses of 25mg lead to a C max of 24-151µg/L and an AUC of 272-947µg/L*h. Carvedilol doses of 12.5mg lead to a C max of 58-69µg/L and an AUC of 208-225µg/L*h. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Carvedilol has a volume of distribution of 1.5-2L/kg or 115L. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Carvedilol is 98% protein bound in plasma. 95% of carvedilol is bound to serum albumin. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Carvedilol can be hydroxlated at the 1 position by CYP2D6, CYP1A2, or CYP1A1 to form 1-hydroxypheylcarvedilol; at the 4 position by CYP2D6, CYP2E1, CYP2C9, or CYP3A4 to form 4'-hydroxyphenylcarvedilol; at the 5 position by CYP2D6, CYP2C9, or CYP3A4 to form 5'-hydroxyphenylcarvedilol; and at the 8 position by CYP1A2, CYP3A4, and CYP1A1 to form 8-hydroxycarbazolylcarvedilol. Carvedilol can also be demethylated by CYP2C9, CYP2D6, CYP1A2, or CYP2E1 to form O-desmethylcarvedilol. Carvedilol and its metabolites may undergo further sulfate conjugation or glucuronidation before elimination. Carvedilol can be O-glucuronidated by UGT1A1, UGT2B4, and UGT2B7 to form carvedilol glucuronide. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): 16% of carvedilol is excreted in the urine with <2% excreted as unmetabolized drug. Carvedilol is primarily excreted in the bile and feces. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The half life of carvedilol is between 7-10 hours, though significantly shorter half lives have also been reported. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The plasma clearance of carvedilol has been reported as 0.52L/kg or 500-700mL/min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Patients experiencing an overdose may present with hypotension, bradycardia, cardiac insufficiency, cardiogenic shock, and cardiac arrest. Patients should remain in a supine position and may be given atropine for bradycardia and glucagon followed by sympathomimetics to support cardiovascular function. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Coreg •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Carvedilol Carvédilol Carvedilolum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Carvedilol is a non selective beta-adrenergic antagonist used to treat mild to severe chronic heart failure, hypertension, and left ventricular dysfunction following myocardial infarction in clinically stable patients. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Celiprolol interact?

•Drug A: Abaloparatide •Drug B: Celiprolol •Severity: MINOR •Description: Abaloparatide may increase the hypotensive activities of Celiprolol. •Extended Description: The use of two drugs that both lower blood pressure may result in a more pronounced hypotensive effect. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Celiprolol is indicated for the management of mild to moderate hypertension and effort-induced angina pectoris. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Celiprolol is a vasoactive beta-1 selective adrenoceptor antagonist with partial beta-2 agonist activity. The beta-2 agonist activity is thought to account for its mild vasodilating properties. It lowers blood pressure in hypertensive patients at rest and on exercise. The effects on heart rate and cardiac output are dependent on the pre-existing background level of sympathetic tone. Under conditions of stress such as exercise, celiprolol attenuates chronotropic and inotropic responses to sympathetic stimulation. However, at rest minimal impairment of cardiac function is seen. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Absorption of an oral dose is rapid and consistent but incomplete (55% for 200 mg dose and 74% for 400 mg dose) from the gastrointestinal tract. The bioavailability of celiprolol has been shown to be markedly affected by food and one should avoid administration of celiprolol with food. Coadministration of chlorthalidone, hydrochlorothiazide and theophylline also reduces the bioavailability of celiprolol. Following oral dosing, maximal blood concentrations are reached between 2 and 3 hours. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The distribution volume is 4.5L/kg. Celiprolol is hydrophilic and does not cross the blood-brain barrier. The binding to plasma proteins is about 25-30%. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 25-30%. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): A 14C labelled dose was completely recovered within 48 hours. The first-pass effect in the liver is insignificant. Celiprolol is metabolized to a minor extent (1-3%). •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 5 hours •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Cleared by both renal and non-renal excretory pathways. Celiprolol is not recommended for patients with creatinine clearance less than 15 mL per minute. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No data are available regarding celiprolol overdose in humans. The most common symptoms to be expected following overdosage with beta-adrenoceptor blocking agents are bradycardia, hypotension, bronchospasm and acute cardiac insufficiency. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Celiprolol Celiprololum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Celiprolol is a beta-blocker for the management of hypertension and angina pectoris.

The use of two drugs that both lower blood pressure may result in a more pronounced hypotensive effect. The severity of the interaction is minor.

Question: Does Abaloparatide and Celiprolol interact? Information: •Drug A: Abaloparatide •Drug B: Celiprolol •Severity: MINOR •Description: Abaloparatide may increase the hypotensive activities of Celiprolol. •Extended Description: The use of two drugs that both lower blood pressure may result in a more pronounced hypotensive effect. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Celiprolol is indicated for the management of mild to moderate hypertension and effort-induced angina pectoris. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Celiprolol is a vasoactive beta-1 selective adrenoceptor antagonist with partial beta-2 agonist activity. The beta-2 agonist activity is thought to account for its mild vasodilating properties. It lowers blood pressure in hypertensive patients at rest and on exercise. The effects on heart rate and cardiac output are dependent on the pre-existing background level of sympathetic tone. Under conditions of stress such as exercise, celiprolol attenuates chronotropic and inotropic responses to sympathetic stimulation. However, at rest minimal impairment of cardiac function is seen. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Absorption of an oral dose is rapid and consistent but incomplete (55% for 200 mg dose and 74% for 400 mg dose) from the gastrointestinal tract. The bioavailability of celiprolol has been shown to be markedly affected by food and one should avoid administration of celiprolol with food. Coadministration of chlorthalidone, hydrochlorothiazide and theophylline also reduces the bioavailability of celiprolol. Following oral dosing, maximal blood concentrations are reached between 2 and 3 hours. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The distribution volume is 4.5L/kg. Celiprolol is hydrophilic and does not cross the blood-brain barrier. The binding to plasma proteins is about 25-30%. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 25-30%. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): A 14C labelled dose was completely recovered within 48 hours. The first-pass effect in the liver is insignificant. Celiprolol is metabolized to a minor extent (1-3%). •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 5 hours •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Cleared by both renal and non-renal excretory pathways. Celiprolol is not recommended for patients with creatinine clearance less than 15 mL per minute. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No data are available regarding celiprolol overdose in humans. The most common symptoms to be expected following overdosage with beta-adrenoceptor blocking agents are bradycardia, hypotension, bronchospasm and acute cardiac insufficiency. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Celiprolol Celiprololum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Celiprolol is a beta-blocker for the management of hypertension and angina pectoris. Output: The use of two drugs that both lower blood pressure may result in a more pronounced hypotensive effect. The severity of the interaction is minor.

Does Abaloparatide and Chlorothiazide interact?

•Drug A: Abaloparatide •Drug B: Chlorothiazide •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Chlorothiazide is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Chlorothiazide is indicated as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. It is also indicated in the management of hypertension either as the sole therapeutic agent or to enhance the effectiveness of other antihypertensive drugs in the more severe forms of hypertension. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Like other thiazides, chlorothiazide promotes water loss from the body (diuretics). It inhibits Na /Cl reabsorption from the distal convoluted tubules in the kidneys. Thiazides also cause loss of potassium and an increase in serum uric acid. Thiazides are often used to treat hypertension, but their hypotensive effects are not necessarily due to their diuretic activity. Thiazides have been shown to prevent hypertension-related morbidity and mortality although the mechanism is not fully understood. Thiazides cause vasodilation by activating calcium-activated potassium channels (large conductance) in vascular smooth muscles and inhibiting various carbonic anhydrases in vascular tissue. Chlorothiazide affects the distal renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosages, all thiazides are approximately equal in their diuretic efficacy. Chlorothiazide increases excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate. After oral doses, 10-15 percent of the dose is excreted unchanged in the urine. Chlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): As a diuretic, chlorothiazide inhibits active chloride reabsorption at the early distal tubule via the Na-Cl cotransporter, resulting in an increase in the excretion of sodium, chloride, and water. Thiazides like chlorothiazide also inhibit sodium ion transport across the renal tubular epithelium through binding to the thiazide sensitive sodium-chloride transporter. This results in an increase in potassium excretion via the sodium-potassium exchange mechanism. The antihypertensive mechanism of chlorothiazide is less well understood although it may be mediated through its action on carbonic anhydrases in the smooth muscle or through its action on the large-conductance calcium-activated potassium (KCa) channel, also found in the smooth muscle. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Rapidly absorbed following oral administration. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Approximately 40% bound to plasma proteins. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Chlorothiazide is not metabolized but is eliminated rapidly by the kidney. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Chlorothiazide is not metabolized but is eliminated rapidly by the kidney. After oral doses, 10 to 15 percent of the dose is excreted unchanged in the urine. Chlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 45-120 minutes •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Oral, rat LD 50: > 10 g/kg. Signs of overdose include those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered hypokalemia may accentuate cardiac arrhythmias. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Diuril •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Chlorothiazid Chlorothiazide Chlorothiazidum Chlorthiazide Clorotiazida •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Chlorothiazide is a thiazide diuretic used to treat hypertension and edema in congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Chlorothiazide interact? Information: •Drug A: Abaloparatide •Drug B: Chlorothiazide •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Chlorothiazide is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Chlorothiazide is indicated as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. It is also indicated in the management of hypertension either as the sole therapeutic agent or to enhance the effectiveness of other antihypertensive drugs in the more severe forms of hypertension. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Like other thiazides, chlorothiazide promotes water loss from the body (diuretics). It inhibits Na /Cl reabsorption from the distal convoluted tubules in the kidneys. Thiazides also cause loss of potassium and an increase in serum uric acid. Thiazides are often used to treat hypertension, but their hypotensive effects are not necessarily due to their diuretic activity. Thiazides have been shown to prevent hypertension-related morbidity and mortality although the mechanism is not fully understood. Thiazides cause vasodilation by activating calcium-activated potassium channels (large conductance) in vascular smooth muscles and inhibiting various carbonic anhydrases in vascular tissue. Chlorothiazide affects the distal renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosages, all thiazides are approximately equal in their diuretic efficacy. Chlorothiazide increases excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate. After oral doses, 10-15 percent of the dose is excreted unchanged in the urine. Chlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): As a diuretic, chlorothiazide inhibits active chloride reabsorption at the early distal tubule via the Na-Cl cotransporter, resulting in an increase in the excretion of sodium, chloride, and water. Thiazides like chlorothiazide also inhibit sodium ion transport across the renal tubular epithelium through binding to the thiazide sensitive sodium-chloride transporter. This results in an increase in potassium excretion via the sodium-potassium exchange mechanism. The antihypertensive mechanism of chlorothiazide is less well understood although it may be mediated through its action on carbonic anhydrases in the smooth muscle or through its action on the large-conductance calcium-activated potassium (KCa) channel, also found in the smooth muscle. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Rapidly absorbed following oral administration. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Approximately 40% bound to plasma proteins. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Chlorothiazide is not metabolized but is eliminated rapidly by the kidney. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Chlorothiazide is not metabolized but is eliminated rapidly by the kidney. After oral doses, 10 to 15 percent of the dose is excreted unchanged in the urine. Chlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 45-120 minutes •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Oral, rat LD 50: > 10 g/kg. Signs of overdose include those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered hypokalemia may accentuate cardiac arrhythmias. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Diuril •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Chlorothiazid Chlorothiazide Chlorothiazidum Chlorthiazide Clorotiazida •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Chlorothiazide is a thiazide diuretic used to treat hypertension and edema in congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Chlorpromazine interact?

•Drug A: Abaloparatide •Drug B: Chlorpromazine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Chlorpromazine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the treatment of schizophrenia; to control nausea and vomiting; for relief of restlessness and apprehension before surgery; for acute intermittent porphyria; as an adjunct in the treatment of tetanus; to control the manifestations of the manic type of manic-depressive illness; for relief of intractable hiccups; for the treatment of severe behavioral problems in children (1 to 12 years of age) marked by combativeness and/or explosive hyperexcitable behavior (out of proportion to immediate provocations), and in the short-term treatment of hyperactive children who show excessive motor activity with accompanying conduct disorders consisting of some or all of the following symptoms: impulsivity, difficulty sustaining attention, aggressivity, mood lability, and poor frustration tolerance. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Chlorpromazine is a psychotropic agent indicated for the treatment of schizophrenia. It also exerts sedative and antiemetic activity. Chlorpromazine has actions at all levels of the central nervous system-primarily at subcortical levels-as well as on multiple organ systems. Chlorpromazine has strong antiadrenergic and weaker peripheral anticholinergic activity; ganglionic blocking action is relatively slight. It also possesses slight antihistaminic and antiserotonin activity. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Chlorpromazine acts as an antagonist (blocking agent) on different postsysnaptic receptors -on dopaminergic-receptors (subtypes D1, D2, D3 and D4 - different antipsychotic properties on productive and unproductive symptoms), on serotonergic-receptors (5-HT1 and 5-HT2, with anxiolytic, antidepressive and antiaggressive properties as well as an attenuation of extrapypramidal side-effects, but also leading to weight gain, fall in blood pressure, sedation and ejaculation difficulties), on histaminergic-receptors (H1-receptors, sedation, antiemesis, vertigo, fall in blood pressure and weight gain), alpha1/alpha2-receptors (antisympathomimetic properties, lowering of blood pressure, reflex tachycardia, vertigo, sedation, hypersalivation and incontinence as well as sexual dysfunction, but may also attenuate pseudoparkinsonism - controversial) and finally on muscarinic (cholinergic) M1/M2-receptors (causing anticholinergic symptoms like dry mouth, blurred vision, obstipation, difficulty/inability to urinate, sinus tachycardia, ECG-changes and loss of memory, but the anticholinergic action may attenuate extrapyramidal side-effects). Additionally, Chlorpromazine is a weak presynaptic inhibitor of Dopamine reuptake, which may lead to (mild) antidepressive and antiparkinsonian effects. This action could also account for psychomotor agitation and amplification of psychosis (very rarely noted in clinical use). •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Readily absorbed from the GI tract. Bioavailability varies due to first-pass metabolism by the liver. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 20 L/kg •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): > 90% to plasma proteins, primarily albumin •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Extensively metabolized in the liver and kidneys. It is extensively metabolized by cytochrome P450 isozymes CYP2D6 (major pathway), CYP1A2 and CYP3A4. Approximately 10 to 12 major metabolite have been identified. Hydroxylation at positions 3 and 7 of the phenothiazine nucleus and the N-dimethylaminopropyl side chain undergoes demethylation and is also metabolized to an N-oxide. In urine, 20% of chlopromazine and its metabolites are excreted unconjugated in the urine as unchanged drug, demonomethylchlorpromazine, dedimethylchlorpromazine, their sulfoxide metabolites, and chlorpromazine-N-oxide. The remaining 80% consists of conjugated metabolites, principally O-glucuronides and small amounts of ethereal sulfates of the mono- and dihydroxy-derivatives of chlorpromazine and their sulfoxide metabolites. The major metabolites are the monoglucuronide of N-dedimethylchlorpromazine and 7-hydroxychlorpromazine. Approximately 37% of the administered dose of chlorpromazine is excreted in urine. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Kidneys, ~ 37% excreted in urine •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): ~ 30 hours •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Agitation, coma, convulsions, difficulty breathing, difficulty swallowing, dry mouth, extreme sleepiness, fever, intestinal blockage, irregular heart rate, low blood pressure, restlessness •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Chlorpromazine Chlorpromazinum Clorpromazina •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Chlorpromazine is a phenothiazine antipsychotic used to treat nausea, vomiting, preoperative anxiety, schizophrenia, bipolar disorder, and severe behavioral problems in children.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Chlorpromazine interact? Information: •Drug A: Abaloparatide •Drug B: Chlorpromazine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Chlorpromazine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the treatment of schizophrenia; to control nausea and vomiting; for relief of restlessness and apprehension before surgery; for acute intermittent porphyria; as an adjunct in the treatment of tetanus; to control the manifestations of the manic type of manic-depressive illness; for relief of intractable hiccups; for the treatment of severe behavioral problems in children (1 to 12 years of age) marked by combativeness and/or explosive hyperexcitable behavior (out of proportion to immediate provocations), and in the short-term treatment of hyperactive children who show excessive motor activity with accompanying conduct disorders consisting of some or all of the following symptoms: impulsivity, difficulty sustaining attention, aggressivity, mood lability, and poor frustration tolerance. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Chlorpromazine is a psychotropic agent indicated for the treatment of schizophrenia. It also exerts sedative and antiemetic activity. Chlorpromazine has actions at all levels of the central nervous system-primarily at subcortical levels-as well as on multiple organ systems. Chlorpromazine has strong antiadrenergic and weaker peripheral anticholinergic activity; ganglionic blocking action is relatively slight. It also possesses slight antihistaminic and antiserotonin activity. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Chlorpromazine acts as an antagonist (blocking agent) on different postsysnaptic receptors -on dopaminergic-receptors (subtypes D1, D2, D3 and D4 - different antipsychotic properties on productive and unproductive symptoms), on serotonergic-receptors (5-HT1 and 5-HT2, with anxiolytic, antidepressive and antiaggressive properties as well as an attenuation of extrapypramidal side-effects, but also leading to weight gain, fall in blood pressure, sedation and ejaculation difficulties), on histaminergic-receptors (H1-receptors, sedation, antiemesis, vertigo, fall in blood pressure and weight gain), alpha1/alpha2-receptors (antisympathomimetic properties, lowering of blood pressure, reflex tachycardia, vertigo, sedation, hypersalivation and incontinence as well as sexual dysfunction, but may also attenuate pseudoparkinsonism - controversial) and finally on muscarinic (cholinergic) M1/M2-receptors (causing anticholinergic symptoms like dry mouth, blurred vision, obstipation, difficulty/inability to urinate, sinus tachycardia, ECG-changes and loss of memory, but the anticholinergic action may attenuate extrapyramidal side-effects). Additionally, Chlorpromazine is a weak presynaptic inhibitor of Dopamine reuptake, which may lead to (mild) antidepressive and antiparkinsonian effects. This action could also account for psychomotor agitation and amplification of psychosis (very rarely noted in clinical use). •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Readily absorbed from the GI tract. Bioavailability varies due to first-pass metabolism by the liver. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 20 L/kg •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): > 90% to plasma proteins, primarily albumin •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Extensively metabolized in the liver and kidneys. It is extensively metabolized by cytochrome P450 isozymes CYP2D6 (major pathway), CYP1A2 and CYP3A4. Approximately 10 to 12 major metabolite have been identified. Hydroxylation at positions 3 and 7 of the phenothiazine nucleus and the N-dimethylaminopropyl side chain undergoes demethylation and is also metabolized to an N-oxide. In urine, 20% of chlopromazine and its metabolites are excreted unconjugated in the urine as unchanged drug, demonomethylchlorpromazine, dedimethylchlorpromazine, their sulfoxide metabolites, and chlorpromazine-N-oxide. The remaining 80% consists of conjugated metabolites, principally O-glucuronides and small amounts of ethereal sulfates of the mono- and dihydroxy-derivatives of chlorpromazine and their sulfoxide metabolites. The major metabolites are the monoglucuronide of N-dedimethylchlorpromazine and 7-hydroxychlorpromazine. Approximately 37% of the administered dose of chlorpromazine is excreted in urine. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Kidneys, ~ 37% excreted in urine •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): ~ 30 hours •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Agitation, coma, convulsions, difficulty breathing, difficulty swallowing, dry mouth, extreme sleepiness, fever, intestinal blockage, irregular heart rate, low blood pressure, restlessness •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Chlorpromazine Chlorpromazinum Clorpromazina •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Chlorpromazine is a phenothiazine antipsychotic used to treat nausea, vomiting, preoperative anxiety, schizophrenia, bipolar disorder, and severe behavioral problems in children. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Chlorthalidone interact?

•Drug A: Abaloparatide •Drug B: Chlorthalidone •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Chlorthalidone is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Chlorthalidone is indicated in the management of hypertension either as the sole therapeutic agent or to enhance the effect of other antihypertensive drugs in the more severe forms of hypertension. Chlorthalidone is indicated as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. Chlorthalidone has also been found useful in edema due to various forms of renal dysfunction, such as nephrotic syndrome, acute glomerulonephritis, and chronic renal failure. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Chlorthalidone prevents reabsorption of sodium and chloride through inhibition of the Na+/Cl- symporter in the cortical diluting segment of the ascending limb of the loop of Henle. Reduction of sodium reabsorption subsequently reduces extracellular fluid and plasma volume via an osmotic, sodium-driven diuresis. By increasing the delivery of sodium to the distal renal tubule, Chlorthalidone indirectly increases potassium excretion via the sodium-potassium exchange mechanism. The exact mechanism of chlorthalidone's anti-hypertensive effect is under debate, however, it is thought that increased diuresis results in decreased plasma and extracellular fluid volume which therefore requires decreased cardiac output and overall lowers blood pressure. Chlorthalidone has also been shown to decrease platelet aggregation and vascular permeability, as well as promote angiogenesis in vitro, which is thought to be partly the result of reductions in carbonic anhydrase–dependent pathways. These pathways may play a role in chlorthalidone's cardiovascular risk reduction effects. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Chlorthalidone has been shown to rapidly concentrate within erythrocytes and subsequently equilibrate via a slow diffusion back into the serum compartment, resulting in a large volume of distribution. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Approximately 75 percent of the drug is bound to plasma proteins, 58 percent of the drug being bound to albumin. This is caused by an increased affinity of the drug to erythrocyte carbonic anhydrase. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Liver •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Approximately 50% of the administered dose is excreted unmetabolized through the kidney, and excretion is characterized by biphasic elimination with a rapid phase followed by a slow secretory phase. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 40-50 hours •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Edarbyclor, Tenoretic, Thalitone •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Chlorphthalidolone Chlortalidone Chlortalidonum Chlorthalidone Clortalidona Phthalamodine Phthalamudine •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Chlorthalidone is a diuretic used to treat hypertension or edema caused by heart failure, renal failure, hepatic cirrhosis, estrogen therapy, and other conditions.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Chlorthalidone interact? Information: •Drug A: Abaloparatide •Drug B: Chlorthalidone •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Chlorthalidone is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Chlorthalidone is indicated in the management of hypertension either as the sole therapeutic agent or to enhance the effect of other antihypertensive drugs in the more severe forms of hypertension. Chlorthalidone is indicated as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. Chlorthalidone has also been found useful in edema due to various forms of renal dysfunction, such as nephrotic syndrome, acute glomerulonephritis, and chronic renal failure. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Chlorthalidone prevents reabsorption of sodium and chloride through inhibition of the Na+/Cl- symporter in the cortical diluting segment of the ascending limb of the loop of Henle. Reduction of sodium reabsorption subsequently reduces extracellular fluid and plasma volume via an osmotic, sodium-driven diuresis. By increasing the delivery of sodium to the distal renal tubule, Chlorthalidone indirectly increases potassium excretion via the sodium-potassium exchange mechanism. The exact mechanism of chlorthalidone's anti-hypertensive effect is under debate, however, it is thought that increased diuresis results in decreased plasma and extracellular fluid volume which therefore requires decreased cardiac output and overall lowers blood pressure. Chlorthalidone has also been shown to decrease platelet aggregation and vascular permeability, as well as promote angiogenesis in vitro, which is thought to be partly the result of reductions in carbonic anhydrase–dependent pathways. These pathways may play a role in chlorthalidone's cardiovascular risk reduction effects. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Chlorthalidone has been shown to rapidly concentrate within erythrocytes and subsequently equilibrate via a slow diffusion back into the serum compartment, resulting in a large volume of distribution. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Approximately 75 percent of the drug is bound to plasma proteins, 58 percent of the drug being bound to albumin. This is caused by an increased affinity of the drug to erythrocyte carbonic anhydrase. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Liver •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Approximately 50% of the administered dose is excreted unmetabolized through the kidney, and excretion is characterized by biphasic elimination with a rapid phase followed by a slow secretory phase. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 40-50 hours •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Edarbyclor, Tenoretic, Thalitone •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Chlorphthalidolone Chlortalidone Chlortalidonum Chlorthalidone Clortalidona Phthalamodine Phthalamudine •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Chlorthalidone is a diuretic used to treat hypertension or edema caused by heart failure, renal failure, hepatic cirrhosis, estrogen therapy, and other conditions. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Cilazapril interact?

•Drug A: Abaloparatide •Drug B: Cilazapril •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Cilazapril is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Cilazapril is an ACE inhibtor class drug used in the treatment of hypertension and heart failure. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Cilazapril inhibits the production angiotensin II. By doing so, it decreases sodium and water reabsorption (via aldosterone) and it decreases vasoconstriction. The combined effect of this is a decrease in vascular resistance, and therefore, blood pressure. The absolute bioavailability of cilazaprilat after oral administration of cilazapril is 57% based on urinary recovery data. (The absolute bioavailability of cilazaprilat after oral administration of cilazaprilat is 19%.) Ingestion of food immediately before the administration of cilazapril reduces the average peak plasma concentration of cilazaprilat by 29%, delays the peak by one hour and reduces the bioavailability of cilazaprilat by 14%. These pharmacokinetic changes have little influence on plasma ACE inhibition. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Cilazapril is a pyridazine ACE inhibitor. It competes with angiotensin I for binding at the angiotensin-converting enzyme, blocking the conversion of angiotensin I to angiotensin II. As angiotensin II is a vasoconstrictor and a negative feedback mediator for renin activity, lower angiotensin II levels results in a decrease in blood pressure, an increase in renin activity, and stimulation of baroreceptor reflex mechanisms. Kininase II, an enzyme which degrades the vasodilator bradykinin, is identical to ACE and may also be inhibited. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Maximum plasma concentrations of cilazaprilat are reached within two hours after administration of cilazapril. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Maximum ACE inhibition is greater than 90% after 1 to 5 mg cilazapril. Maximum ACE inhibition is 70 to 80% after 0.5 mg cilazapril. Dose proportionality is observed following the administration of 1 to 5 mg cilazapril. Apparent non-proportionality is observed at 0.5 mg reflective of the binding to ACE. The higher doses of cilazapril are associated with longer duration of maximum ACE inhibition. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Cilazaprilat is eliminated unchanged by the kidneys. The total urinary recovery of cilazaprilat after intravenous administration of 2.5 mg is 91%. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Half-lives for the periods 1 to 4 hours and 1 to 7 days after the intravenous administration of 2.5 mg cilazaprilat are 0.90 and 46.2 hours respectively. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Total clearance is 12.3 L/h and renal clearance is 10.8 L/h. The total urinary recovery of cilazaprilat following the oral administration of 2.5 mg cilazapril is 52.6%. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Limited data are available with regard to overdosage in humans. The most likely manifestations are hypotension, which may be severe, hyperkalaemia, hyponatraemia and renal impairment with metabolic acidosis. Treatment should be mainly symptomatic and supportive. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Inhibace •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Cilazapril Cilazaprilum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Cilazapril is an ACE inhibitor used for the management of hypertension and heart failure.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Cilazapril interact? Information: •Drug A: Abaloparatide •Drug B: Cilazapril •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Cilazapril is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Cilazapril is an ACE inhibtor class drug used in the treatment of hypertension and heart failure. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Cilazapril inhibits the production angiotensin II. By doing so, it decreases sodium and water reabsorption (via aldosterone) and it decreases vasoconstriction. The combined effect of this is a decrease in vascular resistance, and therefore, blood pressure. The absolute bioavailability of cilazaprilat after oral administration of cilazapril is 57% based on urinary recovery data. (The absolute bioavailability of cilazaprilat after oral administration of cilazaprilat is 19%.) Ingestion of food immediately before the administration of cilazapril reduces the average peak plasma concentration of cilazaprilat by 29%, delays the peak by one hour and reduces the bioavailability of cilazaprilat by 14%. These pharmacokinetic changes have little influence on plasma ACE inhibition. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Cilazapril is a pyridazine ACE inhibitor. It competes with angiotensin I for binding at the angiotensin-converting enzyme, blocking the conversion of angiotensin I to angiotensin II. As angiotensin II is a vasoconstrictor and a negative feedback mediator for renin activity, lower angiotensin II levels results in a decrease in blood pressure, an increase in renin activity, and stimulation of baroreceptor reflex mechanisms. Kininase II, an enzyme which degrades the vasodilator bradykinin, is identical to ACE and may also be inhibited. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Maximum plasma concentrations of cilazaprilat are reached within two hours after administration of cilazapril. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Maximum ACE inhibition is greater than 90% after 1 to 5 mg cilazapril. Maximum ACE inhibition is 70 to 80% after 0.5 mg cilazapril. Dose proportionality is observed following the administration of 1 to 5 mg cilazapril. Apparent non-proportionality is observed at 0.5 mg reflective of the binding to ACE. The higher doses of cilazapril are associated with longer duration of maximum ACE inhibition. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Cilazaprilat is eliminated unchanged by the kidneys. The total urinary recovery of cilazaprilat after intravenous administration of 2.5 mg is 91%. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Half-lives for the periods 1 to 4 hours and 1 to 7 days after the intravenous administration of 2.5 mg cilazaprilat are 0.90 and 46.2 hours respectively. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Total clearance is 12.3 L/h and renal clearance is 10.8 L/h. The total urinary recovery of cilazaprilat following the oral administration of 2.5 mg cilazapril is 52.6%. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Limited data are available with regard to overdosage in humans. The most likely manifestations are hypotension, which may be severe, hyperkalaemia, hyponatraemia and renal impairment with metabolic acidosis. Treatment should be mainly symptomatic and supportive. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Inhibace •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Cilazapril Cilazaprilum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Cilazapril is an ACE inhibitor used for the management of hypertension and heart failure. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Clevidipine interact?

•Drug A: Abaloparatide •Drug B: Clevidipine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Clevidipine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the reduction of blood pressure when when oral antihypertensive therapy is not feasible or not desirable. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Clevidipine belongs to a well-known class of drugs called dihydropyridine calcium channel antagonists. Clevidpine is the first third generation intravenous dihydropyridine calcium channel blocker. In vitro studies demonstrated that clevidipine acts by selectively relaxing the smooth muscle cells that line small arteries, resulting in arterial dilation, widening of the artery opening, and without reducing central venous pressure or reducing cardiac output. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Possibly by deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum, clevidipine inhibits the influx of extracellular calcium across both the myocardial and vascular smooth muscle cell membranes. The resultant inhibition of the contractile processes of the myocardial smooth muscle cells leads to dilation of the coronary and systemic arteries and improved oxygen delivery to the myocardial tissue. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): >99.5% •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Clevidipine is rapidly hydrolyzed to inactive metabolites by esterases in arterial blood. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): urine 63-74%, feces 7-22% •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 1 minute •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Cleviprex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Clevidipine is a dihydropyridine L-type calcium channel blocker used to lower blood pressure when oral antihypertensive therapy is not feasible or not desirable.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Clevidipine interact? Information: •Drug A: Abaloparatide •Drug B: Clevidipine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Clevidipine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the reduction of blood pressure when when oral antihypertensive therapy is not feasible or not desirable. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Clevidipine belongs to a well-known class of drugs called dihydropyridine calcium channel antagonists. Clevidpine is the first third generation intravenous dihydropyridine calcium channel blocker. In vitro studies demonstrated that clevidipine acts by selectively relaxing the smooth muscle cells that line small arteries, resulting in arterial dilation, widening of the artery opening, and without reducing central venous pressure or reducing cardiac output. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Possibly by deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum, clevidipine inhibits the influx of extracellular calcium across both the myocardial and vascular smooth muscle cell membranes. The resultant inhibition of the contractile processes of the myocardial smooth muscle cells leads to dilation of the coronary and systemic arteries and improved oxygen delivery to the myocardial tissue. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): >99.5% •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Clevidipine is rapidly hydrolyzed to inactive metabolites by esterases in arterial blood. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): urine 63-74%, feces 7-22% •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 1 minute •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Cleviprex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Clevidipine is a dihydropyridine L-type calcium channel blocker used to lower blood pressure when oral antihypertensive therapy is not feasible or not desirable. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Clofarabine interact?

•Drug A: Abaloparatide •Drug B: Clofarabine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Clofarabine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphocytic (lymphoblastic) leukemia after at least two prior regimens. It is designated as an orphan drug by the FDA for this use. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Clofarabine is a purine nucleoside antimetabolite that differs from other puring nucleoside analogs by the presence of a chlorine in the purine ring and a flourine in the ribose moiety. Clofarabine seems to interfere with the growth of cancer cells, which are eventually destroyed. Since the growth of normal body cells may also be affected by clofarabine, other effects also occur. Clofarabine prevents cells from making DNA and RNA by interfering with the synthesis of nucleic acids, thus stopping the growth of cancer cells. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Clofarabine is metabolized intracellularly to the active 5'-monophosphate metabolite by deoxycytidine kinase and 5'-triphosphate metabolite by mono- and di-phospho-kinases. This metabolite inhibits DNA synthesis through an inhibitory action on ribonucleotide reductase, and by terminating DNA chain elongation and inhibiting repair through competitive inhibition of DNA polymerases. This leads to the depletion of the intracellular deoxynucleotide triphosphate pool and the self-potentiation of clofarabine triphosphate incorporation into DNA, thereby intensifying the effectiveness of DNA synthesis inhibition. The affinity of clofarabine triphosphate for these enzymes is similar to or greater than that of deoxyadenosine triphosphate. In preclinical models, clofarabine has demonstrated the ability to inhibit DNA repair by incorporation into the DNA chain during the repair process. Clofarabine 5'-triphosphate also disrupts the integrity of mitochondrial membrane, leading to the release of the pro-apoptotic mitochondrial proteins, cytochrome C and apoptosis-inducing factor, leading to programmed cell death. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 172 L/m2 •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 47% bound to plasma proteins, predominantly to albumin. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Clofarabine is sequentially metabolized intracellularly to the 5’-monophosphate metabolite by deoxycytidine kinase and mono- and di-phosphokinases to the active 5’-triphosphate metabolite. Clofarabine has high affinity for the activating phosphorylating enzyme, deoxycytidine kinase, equal to or greater than that of the natural substrate, deoxycytidine. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Based on 24-hour urine collections in the pediatric studies, 49 - 60% of the dose is excreted in the urine unchanged. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The terminal half-life is estimated to be 5.2 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): 28.8 L/h/m2 [Pediatric patients (2 - 19 years old) with relapsed or refractory acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML) receiving 52 mg/m2 dose] •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): There were no known overdoses of clofarabine. The highest daily dose administered to a human to date (on a mg/m basis) has been 70 mg/m /day × 5 days (2 pediatric ALL patients). The toxicities included in these 2 patients included grade 4 hyperbilirubinemia, grade 2 and 3 vomiting, and grade 3 maculopapular rash. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Clolar, Evoltra •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): CAFdA Clofarabin Clofarabina Clofarabine Clofarabinum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Clofarabine is a purine nucleoside used to treat relapsed or refractory acute lymphoblastic leukemia in patients 1 to 21 years old.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Clofarabine interact? Information: •Drug A: Abaloparatide •Drug B: Clofarabine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Clofarabine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphocytic (lymphoblastic) leukemia after at least two prior regimens. It is designated as an orphan drug by the FDA for this use. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Clofarabine is a purine nucleoside antimetabolite that differs from other puring nucleoside analogs by the presence of a chlorine in the purine ring and a flourine in the ribose moiety. Clofarabine seems to interfere with the growth of cancer cells, which are eventually destroyed. Since the growth of normal body cells may also be affected by clofarabine, other effects also occur. Clofarabine prevents cells from making DNA and RNA by interfering with the synthesis of nucleic acids, thus stopping the growth of cancer cells. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Clofarabine is metabolized intracellularly to the active 5'-monophosphate metabolite by deoxycytidine kinase and 5'-triphosphate metabolite by mono- and di-phospho-kinases. This metabolite inhibits DNA synthesis through an inhibitory action on ribonucleotide reductase, and by terminating DNA chain elongation and inhibiting repair through competitive inhibition of DNA polymerases. This leads to the depletion of the intracellular deoxynucleotide triphosphate pool and the self-potentiation of clofarabine triphosphate incorporation into DNA, thereby intensifying the effectiveness of DNA synthesis inhibition. The affinity of clofarabine triphosphate for these enzymes is similar to or greater than that of deoxyadenosine triphosphate. In preclinical models, clofarabine has demonstrated the ability to inhibit DNA repair by incorporation into the DNA chain during the repair process. Clofarabine 5'-triphosphate also disrupts the integrity of mitochondrial membrane, leading to the release of the pro-apoptotic mitochondrial proteins, cytochrome C and apoptosis-inducing factor, leading to programmed cell death. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 172 L/m2 •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 47% bound to plasma proteins, predominantly to albumin. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Clofarabine is sequentially metabolized intracellularly to the 5’-monophosphate metabolite by deoxycytidine kinase and mono- and di-phosphokinases to the active 5’-triphosphate metabolite. Clofarabine has high affinity for the activating phosphorylating enzyme, deoxycytidine kinase, equal to or greater than that of the natural substrate, deoxycytidine. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Based on 24-hour urine collections in the pediatric studies, 49 - 60% of the dose is excreted in the urine unchanged. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The terminal half-life is estimated to be 5.2 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): 28.8 L/h/m2 [Pediatric patients (2 - 19 years old) with relapsed or refractory acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML) receiving 52 mg/m2 dose] •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): There were no known overdoses of clofarabine. The highest daily dose administered to a human to date (on a mg/m basis) has been 70 mg/m /day × 5 days (2 pediatric ALL patients). The toxicities included in these 2 patients included grade 4 hyperbilirubinemia, grade 2 and 3 vomiting, and grade 3 maculopapular rash. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Clolar, Evoltra •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): CAFdA Clofarabin Clofarabina Clofarabine Clofarabinum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Clofarabine is a purine nucleoside used to treat relapsed or refractory acute lymphoblastic leukemia in patients 1 to 21 years old. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Clomipramine interact?

•Drug A: Abaloparatide •Drug B: Clomipramine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Clomipramine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): May be used to treat obsessive-compulsive disorder and disorders with an obsessive-compulsive component (e.g. depression, schizophrenia, Tourette’s disorder). Unlabeled indications include: depression, panic disorder, chronic pain (e.g. central pain, idiopathic pain disorder, tension headache, diabetic peripheral neuropathy, neuropathic pain), cataplexy and associated narcolepsy (limited evidence), autistic disorder (limited evidence), trichotillomania (limited evidence), onchophagia (limited evidence), stuttering (limited evidence), premature ejaculation, and premenstrual syndrome. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Clomipramine, a tricyclic antidepressant, is the 3-chloro derivative of Imipramine. It was thought that tricyclic antidepressants work exclusively by inhibiting the re-uptake of the neurotransmitters norepinephrine and serotonin by nerve cells. However, this response occurs immediately, yet mood does not lift for around two weeks. It is now thought that changes occur in receptor sensitivity in the cerebral cortex and hippocampus. The hippocampus is part of the limbic system, a part of the brain involved in emotions. Presynaptic receptors are affected: α 1 and β 1 receptors are sensitized, α 2 receptors are desensitized (leading to increased noradrenaline production). Tricyclics are also known as effective analgesics for different types of pain, especially neuropathic or neuralgic pain. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Clomipramine is a strong, but not completely selective serotonin reuptake inhibitor (SRI), as the active main metabolite desmethyclomipramine acts preferably as an inhibitor of noradrenaline reuptake. α 1 -receptor blockage and β-down-regulation have been noted and most likely play a role in the short term effects of clomipramine. A blockade of sodium-channels and NDMA-receptors might, as with other tricyclics, account for its effect in chronic pain, in particular the neuropathic type. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Well absorbed from the GI tract following oral administration. Bioavailability is approximately 50% orally due to extensive first-pass metabolism. Bioavailability is not affected by food. Peak plasma concentrations occurred 2-6 hours following oral administration of a single 50 mg dose. The peak plasma concentration ranged from 56 ng/mL to 154 mg/mL (mean, 92 ng/mL). There are large interindividual variations in plasma concentrations occur, partly due to genetic differences in clomipramine metabolism. On average, steady state plasma concentrations are achieved in 1-2 weeks following multiple dose oral administration. Smoking appears to lower the steady-state plasma concentration of clomipramine, but not its active metabolite desmethylclomipramine. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): ~ 17 L/kg (range: 9-25 L/kg). Clomipramine is capable of distributing into the cerebrospinal fluid, the brain, and into breast milk. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Clomipramine is approximately 97-98% bound to plasma proteins, principally to albumin and possibly to α 1 -acid glycoprotein. Desmethylclomipramine is 97-99% bound to plasma proteins. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Extensively metabolized in the liver. The main active metabolite is desmethylclomipramine, which is formed by N -demethylation of clomipramine via CYP2C19, 3A4 and 1A2. Other metabolites and their glucuronide conjugates are also produced. Other metabolites of clomipramine include 8-hydroxyclomipramine formed via 8-hydroxylation, 2-hydroxyclomipramine formed via 2-hydroxylation, and clomipramine N -oxide formed by N -oxidation. Desmethylclomipramine is further metabolized to 8-hydroxydesmethylclomipramine and didesmethylclomipramine, which are formed by 8-hydroxylation and N -demethylation, respectively. 8-Hydroxyclomipramine and 8-hydroxydesmethylclomipramine are pharmacologically active; however, their clinical relevance remains unknown. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Urine (51-60%) and feces via biliary elimination (24-32%) •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Following oral administration of a single 150 mg dose of clomipramine, the average elimination half-life of clomipramine was 32 hours (range: 19-37 hours) and of desmethylclomipramine was 69 hours (range: 54-77 hours). Elimination half-life may vary substantially with different doses due to saturable kinetics (i.e. metabolism). •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Signs and symptoms vary in severity depending upon factors such as the amount of drug absorbed, the age of the patient, and the time elapsed since drug ingestion. Critical manifestations of overdose include cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic toxicity. In U.S. clinical trials, 2 deaths occurred in 12 reported cases of acute overdosage with Anafranil either alone or in combination with other drugs. One death involved a patient suspected of ingesting a dose of 7000 mg. The second death involved a patient suspected of ingesting a dose of 5750 mg. Side effects include: sedation, hypotension, blurred vision, dry mouth, constipation, urinary retention, postural hypotension, tachycardia, hypertension, ECG changes, heart failure, impaired memory and delirium, and precipitation of hypomanic or manic episodes in bipolar depression. Withdrawal symptoms include gastrointestinal disturbances, anxiety, and insomnia. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Anafranil •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 3-Chloroimipramine Chlorimipramine Clomipramina Clomipramine Clomipraminum Monochlorimipramine •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Clomipramine is a tricyclic antidepressant used in the treatment of obsessive-compulsive disorder and disorders with an obsessive-compulsive component, such as depression, schizophrenia, and Tourette’s disorder.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Clomipramine interact? Information: •Drug A: Abaloparatide •Drug B: Clomipramine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Clomipramine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): May be used to treat obsessive-compulsive disorder and disorders with an obsessive-compulsive component (e.g. depression, schizophrenia, Tourette’s disorder). Unlabeled indications include: depression, panic disorder, chronic pain (e.g. central pain, idiopathic pain disorder, tension headache, diabetic peripheral neuropathy, neuropathic pain), cataplexy and associated narcolepsy (limited evidence), autistic disorder (limited evidence), trichotillomania (limited evidence), onchophagia (limited evidence), stuttering (limited evidence), premature ejaculation, and premenstrual syndrome. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Clomipramine, a tricyclic antidepressant, is the 3-chloro derivative of Imipramine. It was thought that tricyclic antidepressants work exclusively by inhibiting the re-uptake of the neurotransmitters norepinephrine and serotonin by nerve cells. However, this response occurs immediately, yet mood does not lift for around two weeks. It is now thought that changes occur in receptor sensitivity in the cerebral cortex and hippocampus. The hippocampus is part of the limbic system, a part of the brain involved in emotions. Presynaptic receptors are affected: α 1 and β 1 receptors are sensitized, α 2 receptors are desensitized (leading to increased noradrenaline production). Tricyclics are also known as effective analgesics for different types of pain, especially neuropathic or neuralgic pain. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Clomipramine is a strong, but not completely selective serotonin reuptake inhibitor (SRI), as the active main metabolite desmethyclomipramine acts preferably as an inhibitor of noradrenaline reuptake. α 1 -receptor blockage and β-down-regulation have been noted and most likely play a role in the short term effects of clomipramine. A blockade of sodium-channels and NDMA-receptors might, as with other tricyclics, account for its effect in chronic pain, in particular the neuropathic type. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Well absorbed from the GI tract following oral administration. Bioavailability is approximately 50% orally due to extensive first-pass metabolism. Bioavailability is not affected by food. Peak plasma concentrations occurred 2-6 hours following oral administration of a single 50 mg dose. The peak plasma concentration ranged from 56 ng/mL to 154 mg/mL (mean, 92 ng/mL). There are large interindividual variations in plasma concentrations occur, partly due to genetic differences in clomipramine metabolism. On average, steady state plasma concentrations are achieved in 1-2 weeks following multiple dose oral administration. Smoking appears to lower the steady-state plasma concentration of clomipramine, but not its active metabolite desmethylclomipramine. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): ~ 17 L/kg (range: 9-25 L/kg). Clomipramine is capable of distributing into the cerebrospinal fluid, the brain, and into breast milk. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Clomipramine is approximately 97-98% bound to plasma proteins, principally to albumin and possibly to α 1 -acid glycoprotein. Desmethylclomipramine is 97-99% bound to plasma proteins. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Extensively metabolized in the liver. The main active metabolite is desmethylclomipramine, which is formed by N -demethylation of clomipramine via CYP2C19, 3A4 and 1A2. Other metabolites and their glucuronide conjugates are also produced. Other metabolites of clomipramine include 8-hydroxyclomipramine formed via 8-hydroxylation, 2-hydroxyclomipramine formed via 2-hydroxylation, and clomipramine N -oxide formed by N -oxidation. Desmethylclomipramine is further metabolized to 8-hydroxydesmethylclomipramine and didesmethylclomipramine, which are formed by 8-hydroxylation and N -demethylation, respectively. 8-Hydroxyclomipramine and 8-hydroxydesmethylclomipramine are pharmacologically active; however, their clinical relevance remains unknown. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Urine (51-60%) and feces via biliary elimination (24-32%) •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Following oral administration of a single 150 mg dose of clomipramine, the average elimination half-life of clomipramine was 32 hours (range: 19-37 hours) and of desmethylclomipramine was 69 hours (range: 54-77 hours). Elimination half-life may vary substantially with different doses due to saturable kinetics (i.e. metabolism). •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Signs and symptoms vary in severity depending upon factors such as the amount of drug absorbed, the age of the patient, and the time elapsed since drug ingestion. Critical manifestations of overdose include cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic toxicity. In U.S. clinical trials, 2 deaths occurred in 12 reported cases of acute overdosage with Anafranil either alone or in combination with other drugs. One death involved a patient suspected of ingesting a dose of 7000 mg. The second death involved a patient suspected of ingesting a dose of 5750 mg. Side effects include: sedation, hypotension, blurred vision, dry mouth, constipation, urinary retention, postural hypotension, tachycardia, hypertension, ECG changes, heart failure, impaired memory and delirium, and precipitation of hypomanic or manic episodes in bipolar depression. Withdrawal symptoms include gastrointestinal disturbances, anxiety, and insomnia. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Anafranil •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 3-Chloroimipramine Chlorimipramine Clomipramina Clomipramine Clomipraminum Monochlorimipramine •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Clomipramine is a tricyclic antidepressant used in the treatment of obsessive-compulsive disorder and disorders with an obsessive-compulsive component, such as depression, schizophrenia, and Tourette’s disorder. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Clonidine interact?

•Drug A: Abaloparatide •Drug B: Clonidine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Clonidine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Clonidine tablets and transdermal systems are indicated for the treatment of hypertension alone or in combination with other medications. A clonidine injection is indicated for use with opiates in the treatment of severe cancer pain where opiates alone are insufficient. An extended release tablet of clonidine is indicated for the treatment of ADHD either alone or in combination with other medications. Clonidine is also used for the diagnosis of pheochromocytoma, treatment of nicotine dependance, and opiate withdrawal. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Clonidine functions through agonism of alpha-2 adrenoceptors which have effects such as lowering blood pressure, sedation, and hyperpolarization of nerves. It has a long duration of action as it is given twice daily and the therapeutic window is between 0.1mg and 2.4mg daily. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Clonidine is primarily an alpha-2 adrenoceptor agonist which causes central hypotensive and anti-arrhythmogenic effects. The alpha-2 adrenoceptor is coupled to the G-proteins G o and G i. G i inhibits adenylyl cyclase and activates opening of a potassium channel that causes hyperpolarization. Clonidine binding to the alpha-2 adrenoceptor causes structural changes in the alpha subunit of the G-protein, reducing its affinity for GDP. Magnesium catalyzes the replacement of GDP with GTP. The alpha subunit dissociates from the other subunits and associates with an effector. The stimulation of alpha-2 adrenoceptors in the locus coeruleus may be responsible for the hypnotic effects of clonidine as this region of the brain helps regulate wakefulness. Clonidine can also decrease transmission of pain signals at the spine. Finally clonidine can affect regulators of blood pressure in the ventromedial and rostral-ventrolateral areas of the medulla. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Clonidine reaches maximum concentration in 60-90 minutes after oral administration. Race and fasting status do not influence pharmacokinetics of clonidine. A 100µg oral clonidine tablet reaches a C max of 400.72pg/mL with an AUC of 5606.78h*pg/mL and a bioavailability of 55-87%. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The volume of distribution of clonidine has been reported as 1.7-2.5L/kg, 2.9L/kg, or 2.1±0.4L/kg depending on the source. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Clonidine is 20-40% bound to plasma proteins, especially albumin. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): The metabolism of clonidine is poorly understood. The main reaction in clonidine metabolism is the 4-hydroxylation of clonidine by CYP2D6, CYP1A2, CYP3A4, CYP1A1, and CYP3A5. Clonidine is <50% metabolized in the liver to inactive metabolites. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Approximately 50% of a clonidine dose is excreted in the urine as the unchanged drug and 20% is eliminated in the feces. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The elimination half life after epidural administration is 30 minutes but otherwise can range from 6-23h. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The clearance of clonidine is 1.9-4.3mL/min/kg. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Oral LD 50 is 126 mg/kg in rats. The TDLO is 70µg/kg in children, 126µg/kg in women, and 69µg/kg in men. Symptoms of overdose include hypertension followed by hypotension, bradycardia, respiratory depression, hypothermia, drowsiness, decreased reflexes, weakness, irritability, and miosis. Severe overdoses can cause reversible cardiac conduction defects or dysrhythmias, apnea, coma, and seizures. Induction of vomiting is not recommended due to CNS depression but gastric lavage or activated charcoal may be useful in recent ingestion. Dialysis is also unlikely to be beneficial. Overdose can be treated with supportive measures such as atropine sulfate for bradycardia, intravenous fluids or vasopressors for hypotension, vasodilators for hypertension, naloxone for respiratory depression, and blood pressure monitoring. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Catapres, Catapres-TTS, Catapres-tts-1, Duraclon, Kapvay, Nexiclon XR •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Chlofazoline Clonidin Clonidina Clonidine Clonidinum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Clonidine is an alpha-2 adrenergic agonist used to treat hypertension and severe cancer pain, among other conditions, and to treat withdrawal symptoms from various substances. It is also used to aid in the diagnosis of pheochromocytoma and to prevent migraines.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Clonidine interact? Information: •Drug A: Abaloparatide •Drug B: Clonidine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Clonidine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Clonidine tablets and transdermal systems are indicated for the treatment of hypertension alone or in combination with other medications. A clonidine injection is indicated for use with opiates in the treatment of severe cancer pain where opiates alone are insufficient. An extended release tablet of clonidine is indicated for the treatment of ADHD either alone or in combination with other medications. Clonidine is also used for the diagnosis of pheochromocytoma, treatment of nicotine dependance, and opiate withdrawal. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Clonidine functions through agonism of alpha-2 adrenoceptors which have effects such as lowering blood pressure, sedation, and hyperpolarization of nerves. It has a long duration of action as it is given twice daily and the therapeutic window is between 0.1mg and 2.4mg daily. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Clonidine is primarily an alpha-2 adrenoceptor agonist which causes central hypotensive and anti-arrhythmogenic effects. The alpha-2 adrenoceptor is coupled to the G-proteins G o and G i. G i inhibits adenylyl cyclase and activates opening of a potassium channel that causes hyperpolarization. Clonidine binding to the alpha-2 adrenoceptor causes structural changes in the alpha subunit of the G-protein, reducing its affinity for GDP. Magnesium catalyzes the replacement of GDP with GTP. The alpha subunit dissociates from the other subunits and associates with an effector. The stimulation of alpha-2 adrenoceptors in the locus coeruleus may be responsible for the hypnotic effects of clonidine as this region of the brain helps regulate wakefulness. Clonidine can also decrease transmission of pain signals at the spine. Finally clonidine can affect regulators of blood pressure in the ventromedial and rostral-ventrolateral areas of the medulla. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Clonidine reaches maximum concentration in 60-90 minutes after oral administration. Race and fasting status do not influence pharmacokinetics of clonidine. A 100µg oral clonidine tablet reaches a C max of 400.72pg/mL with an AUC of 5606.78h*pg/mL and a bioavailability of 55-87%. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The volume of distribution of clonidine has been reported as 1.7-2.5L/kg, 2.9L/kg, or 2.1±0.4L/kg depending on the source. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Clonidine is 20-40% bound to plasma proteins, especially albumin. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): The metabolism of clonidine is poorly understood. The main reaction in clonidine metabolism is the 4-hydroxylation of clonidine by CYP2D6, CYP1A2, CYP3A4, CYP1A1, and CYP3A5. Clonidine is <50% metabolized in the liver to inactive metabolites. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Approximately 50% of a clonidine dose is excreted in the urine as the unchanged drug and 20% is eliminated in the feces. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The elimination half life after epidural administration is 30 minutes but otherwise can range from 6-23h. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The clearance of clonidine is 1.9-4.3mL/min/kg. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Oral LD 50 is 126 mg/kg in rats. The TDLO is 70µg/kg in children, 126µg/kg in women, and 69µg/kg in men. Symptoms of overdose include hypertension followed by hypotension, bradycardia, respiratory depression, hypothermia, drowsiness, decreased reflexes, weakness, irritability, and miosis. Severe overdoses can cause reversible cardiac conduction defects or dysrhythmias, apnea, coma, and seizures. Induction of vomiting is not recommended due to CNS depression but gastric lavage or activated charcoal may be useful in recent ingestion. Dialysis is also unlikely to be beneficial. Overdose can be treated with supportive measures such as atropine sulfate for bradycardia, intravenous fluids or vasopressors for hypotension, vasodilators for hypertension, naloxone for respiratory depression, and blood pressure monitoring. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Catapres, Catapres-TTS, Catapres-tts-1, Duraclon, Kapvay, Nexiclon XR •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Chlofazoline Clonidin Clonidina Clonidine Clonidinum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Clonidine is an alpha-2 adrenergic agonist used to treat hypertension and severe cancer pain, among other conditions, and to treat withdrawal symptoms from various substances. It is also used to aid in the diagnosis of pheochromocytoma and to prevent migraines. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Clozapine interact?

•Drug A: Abaloparatide •Drug B: Clozapine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Clozapine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Clozapine is indicated for the treatment of severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment. Because of the risks of severe neutropenia and of seizure associated with its use, Clozapine should be used only in patients who have failed to respond adequately to standard antipsychotic treatment. Clozapine is also indicated for reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for re-experiencing suicidal behavior, based on history and recent clinical state. Suicidal behavior refers to actions by a patient that put him/herself at risk for death. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Clozapine is a psychotropic agent belonging to the chemical class of benzisoxazole derivatives that is universally regarded as the treatment of choice for treatment-resistant schizophrenia. Although it is thought to mediate its pharmacological effect through antagonism of the dopamine type 2 (D 2 ) and the serotonin type 2A (5-HT 2A ) receptors, research have shown that clozapine can act on various types of receptors. Patients should be counseled regarding the risk of hypersensitivity reactions such as agranulocytosis and myocarditis with clozapine use. Clozapine-induced agranulocytosis, which is a reduction in the absolute neutrophil count or white blood cell count, places the patient at an increased risk for infection. Agranulocytosis is most likely to occur in the first 3-6 months of therapy, but it can still occur after years of treatment. The mechanism is thought to be a dose-independent and immune-mediated reaction against neutrophils. Patients are strictly monitored by lab testing (complete blood count with differential) to ensure agranulocytosis is detected and treated if it occurs. Testing is initially completed at one-week intervals but is expanded to two-week intervals at six months, and then four-week intervals at twelve months if lab results have been within an appropriate range. Monitoring parameters may change if there is any break in therapy. In Canada, the patient's lab values are reported to the manufacturer for hematological monitoring, and in the USA, the patient's lab values are reported to the REMS (Risk Evaluation and Mitigation Strategy) program. These programs function to notify the care provider of any significant drop in WBC/neutrophil count, or if there is a drop below a threshold level. Patients who enter the "Red" zone (WBC<2x109/L or ANC<1.5x109/L) should normally not be re-challenged. Clozapine-induced myocarditis is a hypersensitivity reaction that usually occurs in the third week of clozapine therapy and about 2% of clozapine patients. Monitor the patient's troponin, CRP, and ECG at baseline, and 28 days into treatment. Follow guidelines for appropriate next steps according to the patient's lab results. If myocarditis occurs, the patient should not be re-challenged with clozapine. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): The mechanism of action of clozapine is unknown. However, it has been proposed that the therapeutic efficacy of clozapine in schizophrenia is mediated through antagonism of the dopamine type 2 (D 2 ) and the serotonin type 2A (5-HT 2A ) receptors. Clozapine also acts as an antagonist at adrenergic, cholinergic, histaminergic, and other dopaminergic and serotonergic receptors. Clozapine demonstrated binding affinity to the following receptors: histamine H1 (Ki 1.1 nM), adrenergic α1A (Ki 1.6 nM), serotonin 5-HT6 (Ki 4 nM), serotonin 5-HT2A (Ki 5.4 nM), muscarinic M1 (Ki 6.2 nM), serotonin 5-HT7 (Ki 6.3 nM), serotonin 5-HT2C (Ki 9.4 nM), dopamine D4 (Ki 24 nM), adrenergic α2A (Ki 90 nM), serotonin 5-HT3 (Ki 95 nM), serotonin 5-HT1A (Ki 120 nM), dopamine D2 (Ki 160 nM), dopamine D1 (Ki 270 nM), dopamine D5 (Ki 454 nM), and dopamine D3 (Ki 555 nM). Clozapine acts as an antagonist at other receptors, but with lower potency. Antagonism at receptors other than dopamine and 5HT 2 with similar receptor affinities may explain some of the other therapeutic and side effects of clozapine. Clozapine's antagonism of muscarinic M1-5 receptors may explain its anticholinergic effects. Clozapine's antagonism of histamine H1 receptors may explain the somnolence observed with this drug. Clozapine's antagonism of adrenergic α1 receptors may explain the orthostatic hypotension observed with this drug. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): In humans, clozapine tablets (25 mg and 100 mg) are equally bioavailable relative to a CLOZARIL solution. Following oral administration of clozapine 100 mg twice daily, the average steady-state peak plasma concentration was 319 ng/mL (range: 102 to 771 ng/mL), occurring at the average of 2.5 hours (range: 1 to 6 hours) after dosing. The average minimum concentration at steady state was 122 ng/mL (range: 41 to 343 ng/mL), after 100 mg twice daily dosing. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The median volume of distribution of clozapine was calculated to be 508 L (272–1290 L). •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Clozapine is approximately 97% bound to serum proteins. The interaction between clozapine and other highly protein-bound drugs has not been fully evaluated but may be important. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Clozapine is almost completely metabolized prior to excretion, and only trace amounts of unchanged drug are detected in the urine and feces. Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP2D6, and CYP3A4.The unmethylated, hydroxylated, and N-oxide derivatives are components in both urine and feces. Pharmacological testing has shown the desmethyl metabolite (norclozapine) to have only limited activity, while the hydroxylated and N-oxide derivatives were inactive. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Approximately 50% of the administered dose is excreted in the urine and 30% in the feces. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The mean elimination half-life of clozapine after a single 75 mg dose was 8 hours (range: 4 to 12 hours), compared to a mean elimination half-life of 12 hours (range: 4 to 66 hours), after achieving a steady state with 100 mg twice daily dosing. A comparison of single-dose and multiple-dose administration of clozapine demonstrated that the elimination half-life increased significantly after multiple dosing relative to that after single-dose administration, suggesting the possibility of concentration-dependent pharmacokinetics. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The median clearance of clozapine is calculated to be 30.3 L/h (14.4–45.2 L/h). •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): There are no adequate or well-controlled studies of clozapine in pregnant women. Reproduction studies have been performed in rats and rabbits at doses up to 0.4 and 0.9 times, respectively, the maximum recommended human dose (MRHD) of 900 mg/day on a mg/m2 body surface area basis. The studies revealed no evidence of impaired fertility or harm to the fetus due to clozapine. Because animal reproduction studies are not always predictive of human response, CLOZARIL should be used during pregnancy only if clearly needed. Consider the risk of exacerbation of psychosis when discontinuing or changing treatment with antipsychotic medications during pregnancy and postpartum. Consider early screening for gestational diabetes for patients treated with antipsychotic medications [see Warnings and Precautions (5.11)]. Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Monitor neonates for symptoms of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding difficulties. The severity of complications can vary from self-limited symptoms to some neonates requiring intensive care unit support and prolonged hospitalization. The most commonly reported signs and symptoms associated with clozapine overdose are: sedation, delirium, coma, tachycardia, hypotension, respiratory depression or failure; and hypersalivation. There are reports of aspiration pneumonia, cardiac arrhythmias, and seizure. Fatal overdoses have been reported with clozapine, generally at doses above 2500 mg. There have also been reports of patients recovering from overdoses well in excess of 4 g. There is no available specific antidote to an overdose of CLOZARIL. Establish and maintain an airway; ensure adequate oxygenation and ventilation. Monitor cardiac status and vital signs. Use general symptomatic and supportive measures. Consider the possibility of multiple-drug involvement. No carcinogenic potential was demonstrated in long-term studies in mice and rats at doses up to 0.3 times and 0.4 times, respectively, the maximum recommended human dose (MRHD) of 900 mg/day on an mg/m2 body surface area basis. Clozapine was not genotoxic when tested in the following gene mutation and chromosomal aberration tests: the bacterial Ames test, the in vitro mammalian V79 in Chinese hamster cells, the in vitro unscheduled DNA synthesis in rat hepatocytes or the in vivo micronucleus assay in mice. Clozapine had no effect on any parameters of fertility, pregnancy, fetal weight, or postnatal development when administered orally to male rats 70 days before mating and to female rats for 14 days before mating at doses up to 0.4 times the MRHD of 900 mg/day on an mg/m2 body surface area basis. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Clozaril, Fazaclo, Versacloz •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Clozapine is an atypical or second-generation antipsychotic drug used in treatment-resistant schizophrenia and to decrease suicide risk in schizophrenic patients.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Clozapine interact? Information: •Drug A: Abaloparatide •Drug B: Clozapine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Clozapine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Clozapine is indicated for the treatment of severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment. Because of the risks of severe neutropenia and of seizure associated with its use, Clozapine should be used only in patients who have failed to respond adequately to standard antipsychotic treatment. Clozapine is also indicated for reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for re-experiencing suicidal behavior, based on history and recent clinical state. Suicidal behavior refers to actions by a patient that put him/herself at risk for death. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Clozapine is a psychotropic agent belonging to the chemical class of benzisoxazole derivatives that is universally regarded as the treatment of choice for treatment-resistant schizophrenia. Although it is thought to mediate its pharmacological effect through antagonism of the dopamine type 2 (D 2 ) and the serotonin type 2A (5-HT 2A ) receptors, research have shown that clozapine can act on various types of receptors. Patients should be counseled regarding the risk of hypersensitivity reactions such as agranulocytosis and myocarditis with clozapine use. Clozapine-induced agranulocytosis, which is a reduction in the absolute neutrophil count or white blood cell count, places the patient at an increased risk for infection. Agranulocytosis is most likely to occur in the first 3-6 months of therapy, but it can still occur after years of treatment. The mechanism is thought to be a dose-independent and immune-mediated reaction against neutrophils. Patients are strictly monitored by lab testing (complete blood count with differential) to ensure agranulocytosis is detected and treated if it occurs. Testing is initially completed at one-week intervals but is expanded to two-week intervals at six months, and then four-week intervals at twelve months if lab results have been within an appropriate range. Monitoring parameters may change if there is any break in therapy. In Canada, the patient's lab values are reported to the manufacturer for hematological monitoring, and in the USA, the patient's lab values are reported to the REMS (Risk Evaluation and Mitigation Strategy) program. These programs function to notify the care provider of any significant drop in WBC/neutrophil count, or if there is a drop below a threshold level. Patients who enter the "Red" zone (WBC<2x109/L or ANC<1.5x109/L) should normally not be re-challenged. Clozapine-induced myocarditis is a hypersensitivity reaction that usually occurs in the third week of clozapine therapy and about 2% of clozapine patients. Monitor the patient's troponin, CRP, and ECG at baseline, and 28 days into treatment. Follow guidelines for appropriate next steps according to the patient's lab results. If myocarditis occurs, the patient should not be re-challenged with clozapine. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): The mechanism of action of clozapine is unknown. However, it has been proposed that the therapeutic efficacy of clozapine in schizophrenia is mediated through antagonism of the dopamine type 2 (D 2 ) and the serotonin type 2A (5-HT 2A ) receptors. Clozapine also acts as an antagonist at adrenergic, cholinergic, histaminergic, and other dopaminergic and serotonergic receptors. Clozapine demonstrated binding affinity to the following receptors: histamine H1 (Ki 1.1 nM), adrenergic α1A (Ki 1.6 nM), serotonin 5-HT6 (Ki 4 nM), serotonin 5-HT2A (Ki 5.4 nM), muscarinic M1 (Ki 6.2 nM), serotonin 5-HT7 (Ki 6.3 nM), serotonin 5-HT2C (Ki 9.4 nM), dopamine D4 (Ki 24 nM), adrenergic α2A (Ki 90 nM), serotonin 5-HT3 (Ki 95 nM), serotonin 5-HT1A (Ki 120 nM), dopamine D2 (Ki 160 nM), dopamine D1 (Ki 270 nM), dopamine D5 (Ki 454 nM), and dopamine D3 (Ki 555 nM). Clozapine acts as an antagonist at other receptors, but with lower potency. Antagonism at receptors other than dopamine and 5HT 2 with similar receptor affinities may explain some of the other therapeutic and side effects of clozapine. Clozapine's antagonism of muscarinic M1-5 receptors may explain its anticholinergic effects. Clozapine's antagonism of histamine H1 receptors may explain the somnolence observed with this drug. Clozapine's antagonism of adrenergic α1 receptors may explain the orthostatic hypotension observed with this drug. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): In humans, clozapine tablets (25 mg and 100 mg) are equally bioavailable relative to a CLOZARIL solution. Following oral administration of clozapine 100 mg twice daily, the average steady-state peak plasma concentration was 319 ng/mL (range: 102 to 771 ng/mL), occurring at the average of 2.5 hours (range: 1 to 6 hours) after dosing. The average minimum concentration at steady state was 122 ng/mL (range: 41 to 343 ng/mL), after 100 mg twice daily dosing. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The median volume of distribution of clozapine was calculated to be 508 L (272–1290 L). •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Clozapine is approximately 97% bound to serum proteins. The interaction between clozapine and other highly protein-bound drugs has not been fully evaluated but may be important. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Clozapine is almost completely metabolized prior to excretion, and only trace amounts of unchanged drug are detected in the urine and feces. Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP2D6, and CYP3A4.The unmethylated, hydroxylated, and N-oxide derivatives are components in both urine and feces. Pharmacological testing has shown the desmethyl metabolite (norclozapine) to have only limited activity, while the hydroxylated and N-oxide derivatives were inactive. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Approximately 50% of the administered dose is excreted in the urine and 30% in the feces. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The mean elimination half-life of clozapine after a single 75 mg dose was 8 hours (range: 4 to 12 hours), compared to a mean elimination half-life of 12 hours (range: 4 to 66 hours), after achieving a steady state with 100 mg twice daily dosing. A comparison of single-dose and multiple-dose administration of clozapine demonstrated that the elimination half-life increased significantly after multiple dosing relative to that after single-dose administration, suggesting the possibility of concentration-dependent pharmacokinetics. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The median clearance of clozapine is calculated to be 30.3 L/h (14.4–45.2 L/h). •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): There are no adequate or well-controlled studies of clozapine in pregnant women. Reproduction studies have been performed in rats and rabbits at doses up to 0.4 and 0.9 times, respectively, the maximum recommended human dose (MRHD) of 900 mg/day on a mg/m2 body surface area basis. The studies revealed no evidence of impaired fertility or harm to the fetus due to clozapine. Because animal reproduction studies are not always predictive of human response, CLOZARIL should be used during pregnancy only if clearly needed. Consider the risk of exacerbation of psychosis when discontinuing or changing treatment with antipsychotic medications during pregnancy and postpartum. Consider early screening for gestational diabetes for patients treated with antipsychotic medications [see Warnings and Precautions (5.11)]. Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Monitor neonates for symptoms of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding difficulties. The severity of complications can vary from self-limited symptoms to some neonates requiring intensive care unit support and prolonged hospitalization. The most commonly reported signs and symptoms associated with clozapine overdose are: sedation, delirium, coma, tachycardia, hypotension, respiratory depression or failure; and hypersalivation. There are reports of aspiration pneumonia, cardiac arrhythmias, and seizure. Fatal overdoses have been reported with clozapine, generally at doses above 2500 mg. There have also been reports of patients recovering from overdoses well in excess of 4 g. There is no available specific antidote to an overdose of CLOZARIL. Establish and maintain an airway; ensure adequate oxygenation and ventilation. Monitor cardiac status and vital signs. Use general symptomatic and supportive measures. Consider the possibility of multiple-drug involvement. No carcinogenic potential was demonstrated in long-term studies in mice and rats at doses up to 0.3 times and 0.4 times, respectively, the maximum recommended human dose (MRHD) of 900 mg/day on an mg/m2 body surface area basis. Clozapine was not genotoxic when tested in the following gene mutation and chromosomal aberration tests: the bacterial Ames test, the in vitro mammalian V79 in Chinese hamster cells, the in vitro unscheduled DNA synthesis in rat hepatocytes or the in vivo micronucleus assay in mice. Clozapine had no effect on any parameters of fertility, pregnancy, fetal weight, or postnatal development when administered orally to male rats 70 days before mating and to female rats for 14 days before mating at doses up to 0.4 times the MRHD of 900 mg/day on an mg/m2 body surface area basis. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Clozaril, Fazaclo, Versacloz •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Clozapine is an atypical or second-generation antipsychotic drug used in treatment-resistant schizophrenia and to decrease suicide risk in schizophrenic patients. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Conivaptan interact?

•Drug A: Abaloparatide •Drug B: Conivaptan •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Conivaptan is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the treatment of euvolemic or hypervolemic hyponatremia (e.g. the syndrome of inappropriate secretion of antidiuretic hormone, or in the setting of hypothyroidism, adrenal insufficiency, pulmonary disorders, etc.) in hospitalized patients. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Conivaptan is a nonpeptide, dual antagonist of arginine vasopressin (AVP) V 1A and V 2 receptors. The level of AVP in circulating blood is critical for the regulation of water and electrolyte balance and is usually elevated in both euvolemic and hypervolemic hyponatremia. The AVP effect is mediated through V 2 receptors, which are functionally coupled to aquaporin channels in the apical membrane of the collecting ducts of the kidney. These receptors help to maintain plasma osmolality within the normal range by increasing permeability of the renal collecting ducts to water. Vasopressin also causes vasoconstriction through its actions on vascular 1A receptors. The predominant pharmacodynamic effect of conivaptan in the treatment of hyponatremia is through its V 2 antagonism of AVP in the renal collecting ducts, an effect that results in aquaresis, or excretion of free water. Conivaptan's antagonist activity on V 1A receptors may also cause splanchnic vasodilation, resulting in possible hypotension or variceal bleeding in patients with cirrhosis. The pharmacodynamic effects of conivaptan include increased free water excretion (i.e., effective water clearance [EWC]) generally accompanied by increased net fluid loss, increased urine output, and decreased urine osmolality. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Conivaptan is a dual AVP antagonist with nanomolar affinity for human arginine vasopressin V 1A and V 2 receptors in vitro. This antagonism occurs in the renal collecting ducts, resulting in aquaresis, or excretion of free water. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 99% •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): CYP3A4 is the sole cytochrome P450 isozyme responsible for the metabolism of conivaptan. Four metabolites have been identified. The pharmacological activity of the metabolites at V 1a and V 2 receptors ranged from approximately 3-50% and 50-100% that of conivaptan, respectively. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 5 hours •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Although no data on overdosage in humans are available, conivaptan has been administered as a 20 mg loading dose on Day 1 followed by continuous infusion of 80 mg/day for 4 days in hyponatremia patients and up to 120 mg/day for 2 days in CHF patients. No new toxicities were identified at these higher doses, but adverse events related to the pharmacologic activity of conivaptan, e.g. hypotension and thirst, occurred more frequently at these higher doses. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Vaprisol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Conivaptan •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Conivaptan is an antidiuretic hormone inhibitor used to raise serum sodium levels.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Conivaptan interact? Information: •Drug A: Abaloparatide •Drug B: Conivaptan •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Conivaptan is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the treatment of euvolemic or hypervolemic hyponatremia (e.g. the syndrome of inappropriate secretion of antidiuretic hormone, or in the setting of hypothyroidism, adrenal insufficiency, pulmonary disorders, etc.) in hospitalized patients. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Conivaptan is a nonpeptide, dual antagonist of arginine vasopressin (AVP) V 1A and V 2 receptors. The level of AVP in circulating blood is critical for the regulation of water and electrolyte balance and is usually elevated in both euvolemic and hypervolemic hyponatremia. The AVP effect is mediated through V 2 receptors, which are functionally coupled to aquaporin channels in the apical membrane of the collecting ducts of the kidney. These receptors help to maintain plasma osmolality within the normal range by increasing permeability of the renal collecting ducts to water. Vasopressin also causes vasoconstriction through its actions on vascular 1A receptors. The predominant pharmacodynamic effect of conivaptan in the treatment of hyponatremia is through its V 2 antagonism of AVP in the renal collecting ducts, an effect that results in aquaresis, or excretion of free water. Conivaptan's antagonist activity on V 1A receptors may also cause splanchnic vasodilation, resulting in possible hypotension or variceal bleeding in patients with cirrhosis. The pharmacodynamic effects of conivaptan include increased free water excretion (i.e., effective water clearance [EWC]) generally accompanied by increased net fluid loss, increased urine output, and decreased urine osmolality. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Conivaptan is a dual AVP antagonist with nanomolar affinity for human arginine vasopressin V 1A and V 2 receptors in vitro. This antagonism occurs in the renal collecting ducts, resulting in aquaresis, or excretion of free water. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 99% •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): CYP3A4 is the sole cytochrome P450 isozyme responsible for the metabolism of conivaptan. Four metabolites have been identified. The pharmacological activity of the metabolites at V 1a and V 2 receptors ranged from approximately 3-50% and 50-100% that of conivaptan, respectively. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 5 hours •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Although no data on overdosage in humans are available, conivaptan has been administered as a 20 mg loading dose on Day 1 followed by continuous infusion of 80 mg/day for 4 days in hyponatremia patients and up to 120 mg/day for 2 days in CHF patients. No new toxicities were identified at these higher doses, but adverse events related to the pharmacologic activity of conivaptan, e.g. hypotension and thirst, occurred more frequently at these higher doses. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Vaprisol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Conivaptan •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Conivaptan is an antidiuretic hormone inhibitor used to raise serum sodium levels. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Dapagliflozin interact?

•Drug A: Abaloparatide •Drug B: Dapagliflozin •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abaloparatide is combined with Dapagliflozin. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Dapagliflozin is indicated as an adjunct treatment to improve glycemic control in adult patients with type 2 diabetes mellitus along with diet and exercise. For patients with chronic kidney disease at risk of progression, dapagliflozin in used to reduce the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure. Dapagliflozin is also indicated to either reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in adults with heart failure or reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and either established cardiovascular disease or multiple cardiovascular risk factors. Combination products with dapagliflozin also exist, either as a dapagliflozin-saxagliptin or dapagliflozin-metformin hydrochloride formulation. Both are used as an adjunct treatment to diet and exercise to improve glycemic control in adults with type 2 diabetes. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Dapagliflozin also reduces sodium reabsorption and increases the delivery of sodium to the distal tubule. This may influence several physiological functions including, but not restricted to, lowering both pre- and afterload of the heart and downregulation of sympathetic activity, and decreased intraglomerular pressure which is believed to be mediated by increased tubuloglomerular feedback. Increases in the amount of glucose excreted in the urine were observed in healthy subjects and in patients with type 2 diabetes mellitus following the administration of dapagliflozin. Dapagliflozin doses of 5 or 10 mg per day in patients with type 2 diabetes mellitus for 12 weeks resulted in excretion of approximately 70 grams of glucose in the urine per day at Week 12. A near-maximum glucose excretion was observed at the dapagliflozin daily dose of 20 mg. This urinary glucose excretion with dapagliflozin also results in increases in urinary volume. After discontinuation of dapagliflozin, on average, the elevation in urinary glucose excretion approaches baseline by about 3 days for the 10 mg dose. Dapagliflozin was not associated with clinically meaningful prolongation of QTc interval at daily doses up to 150 mg (15 times the recommended maximum dose) in a study of healthy subjects. In addition, no clinically meaningful effect on QTc interval was observed following single doses of up to 500 mg (50 times the recommended maximum dose) of dapagliflozin in healthy subjects. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Dapagliflozin inhibits the sodium-glucose cotransporter 2(SGLT2) which is primarily located in the proximal tubule of the nephron. SGLT2 facilitates 90% of glucose reabsorption in the kidneys and so its inhibition allows for glucose to be excreted in the urine. This excretion allows for better glycemic control and potentially weight loss in patients with type 2 diabetes mellitus. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Oral dapagliflozin reaches a maximum concentration within 1 hour of administration when patients have been fasting. Following oral administration of dapagliflozin, the maximum plasma concentration (C max ) is usually attained within 2 hours under fasting state. The C max and AUC values increase dose proportionally with an increase in dapagliflozin dose in the therapeutic dose range. The absolute oral bioavailability of dapagliflozin following the administration of a 10 mg dose is 78%. Administration of dapagliflozin with a high-fat meal decreases its C max by up to 50% and prolongs T max by approximately 1 hour but does not alter AUC as compared with the fasted state. These changes are not considered to be clinically meaningful and dapagliflozin can be administered with or without food. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The volume of distribution was estimated to be 118L. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Dapagliflozin is approximately 91% protein bound. Protein binding is not altered in patients with renal or hepatic impairment. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Dapagliflozin is primarily glucuronidated to become the inactive 3-O-glucuronide metabolite(60.7%). Dapagliflozin also produces another minor glucuronidated metabolite(5.4%), a de-ethylated metabolite(<5%), and a hydroxylated metabolite(<5%). Metabolism of dapagliflozin is mediated by cytochrome p-450(CYP)1A1, CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP3A4, uridine diphosphate glucuronyltransferase(UGT)1A9, UGT2B4, and UGT2B7. Glucuronidation to the major metabolite is mediated by UGT1A9. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Dapagliflozin and related metabolites are primarily eliminated via the renal pathway. Following a single 50 mg dose of [ C]-dapagliflozin, 75% and 21% of total radioactivity is excreted in urine and feces, respectively. In urine, less than 2% of the dose is excreted as the parent drug. In feces, approximately 15% of the dose is excreted as the parent drug. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The mean plasma terminal half-life (t 1/2 ) for dapagliflozin is approximately 12.9 hours following a single oral dose of 10 mg. In healthy subjects given a single oral dose of 50 mg of dapagliflozin, the mean terminal half-life was 13.8 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Oral plasma clearance was 4.9 mL/min/kg, and renal clearance was 5.6 mL/min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Age, gender, race, and body weight do not affect dapagliflozin dosing requirements. Although age does not affect dosing requirements, safety has not been established in pediatric populations and patients at an especially advanced age may be more susceptible to adverse effects. Animal studies in pregnancy showed no fetal toxicity in the first trimester but exposure later in pregnancy was associated with renal pelvic dilatation and maternal toxicity at much higher doses than the maximum recommended human dose. Due to this data, dapagliflozin is not recommended in the second and third trimester of pregnancy. Dapagliflozin is excreted in milk from rats, though this may not necessarily be the case in humans. Children under 2 years old who are exposed to dapagliflozin may be at risk of improper kidney development. Dapagliflozin is not recommended in patients with a creatinine clearance below 45mL/min and is contraindicated in patients with creatinine clearance below 30mL/min. Dose adjustments are not necessary in patients with hepatic impairment at any stage, although the risk and benefit to the patient must be assessed as there is limited data on dapagliflozin use in this population. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Edistride, Farxiga, Forxiga, Qtern, Qternmet, Xigduo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Dapagliflozin Dapagliflozina •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Dapagliflozin is a sodium-glucose cotransporter 2 inhibitor used in the management of type 2 diabetes mellitus.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Dapagliflozin interact? Information: •Drug A: Abaloparatide •Drug B: Dapagliflozin •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abaloparatide is combined with Dapagliflozin. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Dapagliflozin is indicated as an adjunct treatment to improve glycemic control in adult patients with type 2 diabetes mellitus along with diet and exercise. For patients with chronic kidney disease at risk of progression, dapagliflozin in used to reduce the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure. Dapagliflozin is also indicated to either reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in adults with heart failure or reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and either established cardiovascular disease or multiple cardiovascular risk factors. Combination products with dapagliflozin also exist, either as a dapagliflozin-saxagliptin or dapagliflozin-metformin hydrochloride formulation. Both are used as an adjunct treatment to diet and exercise to improve glycemic control in adults with type 2 diabetes. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Dapagliflozin also reduces sodium reabsorption and increases the delivery of sodium to the distal tubule. This may influence several physiological functions including, but not restricted to, lowering both pre- and afterload of the heart and downregulation of sympathetic activity, and decreased intraglomerular pressure which is believed to be mediated by increased tubuloglomerular feedback. Increases in the amount of glucose excreted in the urine were observed in healthy subjects and in patients with type 2 diabetes mellitus following the administration of dapagliflozin. Dapagliflozin doses of 5 or 10 mg per day in patients with type 2 diabetes mellitus for 12 weeks resulted in excretion of approximately 70 grams of glucose in the urine per day at Week 12. A near-maximum glucose excretion was observed at the dapagliflozin daily dose of 20 mg. This urinary glucose excretion with dapagliflozin also results in increases in urinary volume. After discontinuation of dapagliflozin, on average, the elevation in urinary glucose excretion approaches baseline by about 3 days for the 10 mg dose. Dapagliflozin was not associated with clinically meaningful prolongation of QTc interval at daily doses up to 150 mg (15 times the recommended maximum dose) in a study of healthy subjects. In addition, no clinically meaningful effect on QTc interval was observed following single doses of up to 500 mg (50 times the recommended maximum dose) of dapagliflozin in healthy subjects. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Dapagliflozin inhibits the sodium-glucose cotransporter 2(SGLT2) which is primarily located in the proximal tubule of the nephron. SGLT2 facilitates 90% of glucose reabsorption in the kidneys and so its inhibition allows for glucose to be excreted in the urine. This excretion allows for better glycemic control and potentially weight loss in patients with type 2 diabetes mellitus. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Oral dapagliflozin reaches a maximum concentration within 1 hour of administration when patients have been fasting. Following oral administration of dapagliflozin, the maximum plasma concentration (C max ) is usually attained within 2 hours under fasting state. The C max and AUC values increase dose proportionally with an increase in dapagliflozin dose in the therapeutic dose range. The absolute oral bioavailability of dapagliflozin following the administration of a 10 mg dose is 78%. Administration of dapagliflozin with a high-fat meal decreases its C max by up to 50% and prolongs T max by approximately 1 hour but does not alter AUC as compared with the fasted state. These changes are not considered to be clinically meaningful and dapagliflozin can be administered with or without food. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The volume of distribution was estimated to be 118L. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Dapagliflozin is approximately 91% protein bound. Protein binding is not altered in patients with renal or hepatic impairment. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Dapagliflozin is primarily glucuronidated to become the inactive 3-O-glucuronide metabolite(60.7%). Dapagliflozin also produces another minor glucuronidated metabolite(5.4%), a de-ethylated metabolite(<5%), and a hydroxylated metabolite(<5%). Metabolism of dapagliflozin is mediated by cytochrome p-450(CYP)1A1, CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP3A4, uridine diphosphate glucuronyltransferase(UGT)1A9, UGT2B4, and UGT2B7. Glucuronidation to the major metabolite is mediated by UGT1A9. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Dapagliflozin and related metabolites are primarily eliminated via the renal pathway. Following a single 50 mg dose of [ C]-dapagliflozin, 75% and 21% of total radioactivity is excreted in urine and feces, respectively. In urine, less than 2% of the dose is excreted as the parent drug. In feces, approximately 15% of the dose is excreted as the parent drug. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The mean plasma terminal half-life (t 1/2 ) for dapagliflozin is approximately 12.9 hours following a single oral dose of 10 mg. In healthy subjects given a single oral dose of 50 mg of dapagliflozin, the mean terminal half-life was 13.8 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Oral plasma clearance was 4.9 mL/min/kg, and renal clearance was 5.6 mL/min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Age, gender, race, and body weight do not affect dapagliflozin dosing requirements. Although age does not affect dosing requirements, safety has not been established in pediatric populations and patients at an especially advanced age may be more susceptible to adverse effects. Animal studies in pregnancy showed no fetal toxicity in the first trimester but exposure later in pregnancy was associated with renal pelvic dilatation and maternal toxicity at much higher doses than the maximum recommended human dose. Due to this data, dapagliflozin is not recommended in the second and third trimester of pregnancy. Dapagliflozin is excreted in milk from rats, though this may not necessarily be the case in humans. Children under 2 years old who are exposed to dapagliflozin may be at risk of improper kidney development. Dapagliflozin is not recommended in patients with a creatinine clearance below 45mL/min and is contraindicated in patients with creatinine clearance below 30mL/min. Dose adjustments are not necessary in patients with hepatic impairment at any stage, although the risk and benefit to the patient must be assessed as there is limited data on dapagliflozin use in this population. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Edistride, Farxiga, Forxiga, Qtern, Qternmet, Xigduo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Dapagliflozin Dapagliflozina •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Dapagliflozin is a sodium-glucose cotransporter 2 inhibitor used in the management of type 2 diabetes mellitus. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Dasiglucagon interact?

•Drug A: Abaloparatide •Drug B: Dasiglucagon •Severity: MINOR •Description: Abaloparatide may increase the hypotensive activities of Dasiglucagon. •Extended Description: The use of two drugs that both lower blood pressure may result in a more pronounced hypotensive effect. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Dasiglucagon is an antihypoglycemic agent indicated for the treatment of severe hypoglycemia in pediatric and adult patients with diabetes aged 6 years and above. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Dasiglucagon works to increase blood glucose levels under normal and hypoglycemic conditions. After administration of dasiglucagon in adult patients with type 1 diabetes, the mean glucose increase from baseline at 90 minutes was 168 mg/dL. In pediatric patients with type 1 diabetes aged seven to 17 years, the mean glucose increase at 60 minutes after administration of dasiglucagon was 162 mg/dL. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Dasiglucagon is an analog of glucagon, which is a peptide hormone responsible for increasing blood glucose levels. It has the same mechanism of action as endogenous glucagon by acting as an agonist at glucagon receptors, which are G-coupled receptors expressed throughout the body. Dasiglucagon binds to glucagon receptors in the liver, which activates Gsα and Gq, and consequently, adenylate cyclase. Adenyl cyclase increases intracellular cyclic AMP, which stimulates glycogenolysis and glucogenesis in the liver. As glucose is primarily released from liver glycogen stores, hepatic stores of glycogen are crucial for dasiglucagon to exert its antihypoglycemic effects. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Following subcutaneous administration of 0.6 mg dasiglucagon, the mean peak plasma concentration was 5110 pg/mL (1510 pmol/L). T max was 35 minutes. In pediatric patients with type 1 diabetes, the mean peak plasma concentration of 3920 pg/mL occurred at around 21 minutes. Dasiglucagon has a higher absorption rate than traditional reconstituted glucagon. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The mean apparent volume of distribution ranged from 47 L to 57 L after subcutaneous administration. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Like endogenous glucagon, dasiglucagon undergoes proteolytic degradation pathways in blood, liver, and kidney. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The half-life was approximately 30 minutes following subcutaneous administration. Dasiglucagon has a longer plasma elimination half-life than traditional reconstituted glucagon. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Overdose may be characterized by nausea, vomiting, inhibition of gastrointestinal tract motility, increased blood pressure, and elevated heart rate. In case of a suspected overdose, serum potassium may decrease so monitoring and correcting of potassium levels may be warranted. A marked increase in blood pressure may be managed by the short-term use of phentolamine mesylate. Appropriate supportive treatment should be initiated. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Zegalogue •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Dasiglucagon is a glucagon analog used to treat severe hypoglycemia in pediatric and adult patients with diabetes.

The use of two drugs that both lower blood pressure may result in a more pronounced hypotensive effect. The severity of the interaction is minor.

Question: Does Abaloparatide and Dasiglucagon interact? Information: •Drug A: Abaloparatide •Drug B: Dasiglucagon •Severity: MINOR •Description: Abaloparatide may increase the hypotensive activities of Dasiglucagon. •Extended Description: The use of two drugs that both lower blood pressure may result in a more pronounced hypotensive effect. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Dasiglucagon is an antihypoglycemic agent indicated for the treatment of severe hypoglycemia in pediatric and adult patients with diabetes aged 6 years and above. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Dasiglucagon works to increase blood glucose levels under normal and hypoglycemic conditions. After administration of dasiglucagon in adult patients with type 1 diabetes, the mean glucose increase from baseline at 90 minutes was 168 mg/dL. In pediatric patients with type 1 diabetes aged seven to 17 years, the mean glucose increase at 60 minutes after administration of dasiglucagon was 162 mg/dL. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Dasiglucagon is an analog of glucagon, which is a peptide hormone responsible for increasing blood glucose levels. It has the same mechanism of action as endogenous glucagon by acting as an agonist at glucagon receptors, which are G-coupled receptors expressed throughout the body. Dasiglucagon binds to glucagon receptors in the liver, which activates Gsα and Gq, and consequently, adenylate cyclase. Adenyl cyclase increases intracellular cyclic AMP, which stimulates glycogenolysis and glucogenesis in the liver. As glucose is primarily released from liver glycogen stores, hepatic stores of glycogen are crucial for dasiglucagon to exert its antihypoglycemic effects. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Following subcutaneous administration of 0.6 mg dasiglucagon, the mean peak plasma concentration was 5110 pg/mL (1510 pmol/L). T max was 35 minutes. In pediatric patients with type 1 diabetes, the mean peak plasma concentration of 3920 pg/mL occurred at around 21 minutes. Dasiglucagon has a higher absorption rate than traditional reconstituted glucagon. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The mean apparent volume of distribution ranged from 47 L to 57 L after subcutaneous administration. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Like endogenous glucagon, dasiglucagon undergoes proteolytic degradation pathways in blood, liver, and kidney. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The half-life was approximately 30 minutes following subcutaneous administration. Dasiglucagon has a longer plasma elimination half-life than traditional reconstituted glucagon. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Overdose may be characterized by nausea, vomiting, inhibition of gastrointestinal tract motility, increased blood pressure, and elevated heart rate. In case of a suspected overdose, serum potassium may decrease so monitoring and correcting of potassium levels may be warranted. A marked increase in blood pressure may be managed by the short-term use of phentolamine mesylate. Appropriate supportive treatment should be initiated. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Zegalogue •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Dasiglucagon is a glucagon analog used to treat severe hypoglycemia in pediatric and adult patients with diabetes. Output: The use of two drugs that both lower blood pressure may result in a more pronounced hypotensive effect. The severity of the interaction is minor.

Does Abaloparatide and Desflurane interact?

•Drug A: Abaloparatide •Drug B: Desflurane •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Desflurane is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Desflurane is indicated for the induction and maintenance of anesthesia in adults, as well as the maintenance of anesthesia in pediatric patients. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Desflurane is a general inhalation anesthetic. It has a short duration of action as it is rapidly cleared. Patients should be counselled regarding the risks of malignant hyperthermia, perioperative hyperkalemia, respiratory adverse reactions in pediatric patients, QTc prolongation, hepatobiliary disorders, pediatric neurotoxicity, and postoperative agitation in children. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): The mechanism of inhalational anesthetics is still not fully understood. They can block excitatory ion channels and increase the activity of inhibitory ion channels. The most notable agonism is at the GABA A channel. Desflurane is also an agonist of glycine receptors, antagonist of glutamate receptors, inducer of potassium voltage gated channels, and inhibits both NADH-ubiquinone oxioreductase chain 1 and calcium transporting ATPases. An older school of thought is the unitary theory of general anesthetic action, suggesting that desflurane affects the lipid bilayer of cells. Studies of other halogenated inhalational anesthetics have shown that the lipid bilayer spreads out more thinly as the anesthetic incorporates into the bilayer. However, the anesthetic does not bind to lipid heads or acyl chains of hydrocarbons in the bilayer. The effect of incorporating into the lipid bilayer is not well described. By incorporating into the lipid bilayer, anesthetics may introduce disorder in the lipids, leading to some indirect effect on ion channels. However, this theory remains controversial. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Data regarding the C max, T max, and AUC of desflurane are not readily available. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Desflurane has a median volume of distribution of 612 mL/kg. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Desflurane is bound to human serum albumin in plasma. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Desflurane is minimally defluorinated by CYP2E1, to the extent that serum fluoride levels do not increase above baseline levels. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Initially, desflurane is rapidly eliminated from the lungs. A small amount of the metabolite trifluoroacetic acid is eliminated in the urine and only 0.02% of an inhaled dose is recovered as urinary metabolites. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Desflurane has a terminal elimination half life of 8.16 ± 3.15 minutes. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): A 26 g dose of desflurane is 90% eliminated from the brain after 33 hours. The metabolite trifluoroacetic acid has a urinary clearance rate of 0.169 ± 0.107 µmol/L. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Patients experiencing a desflurane overdose may experience deepening anesthesia, cardiac or respiratory depression. In the event of an overdose, patients may require symptomatic and supportive treatment to maintain airway, breathing, and circulation. Discontinue desflurane. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Suprane •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Desflurane Desflurano Desfluranum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Desflurane is a general inhalation anesthetic for inpatient and outpatient surgery in adults.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Desflurane interact? Information: •Drug A: Abaloparatide •Drug B: Desflurane •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Desflurane is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Desflurane is indicated for the induction and maintenance of anesthesia in adults, as well as the maintenance of anesthesia in pediatric patients. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Desflurane is a general inhalation anesthetic. It has a short duration of action as it is rapidly cleared. Patients should be counselled regarding the risks of malignant hyperthermia, perioperative hyperkalemia, respiratory adverse reactions in pediatric patients, QTc prolongation, hepatobiliary disorders, pediatric neurotoxicity, and postoperative agitation in children. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): The mechanism of inhalational anesthetics is still not fully understood. They can block excitatory ion channels and increase the activity of inhibitory ion channels. The most notable agonism is at the GABA A channel. Desflurane is also an agonist of glycine receptors, antagonist of glutamate receptors, inducer of potassium voltage gated channels, and inhibits both NADH-ubiquinone oxioreductase chain 1 and calcium transporting ATPases. An older school of thought is the unitary theory of general anesthetic action, suggesting that desflurane affects the lipid bilayer of cells. Studies of other halogenated inhalational anesthetics have shown that the lipid bilayer spreads out more thinly as the anesthetic incorporates into the bilayer. However, the anesthetic does not bind to lipid heads or acyl chains of hydrocarbons in the bilayer. The effect of incorporating into the lipid bilayer is not well described. By incorporating into the lipid bilayer, anesthetics may introduce disorder in the lipids, leading to some indirect effect on ion channels. However, this theory remains controversial. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Data regarding the C max, T max, and AUC of desflurane are not readily available. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Desflurane has a median volume of distribution of 612 mL/kg. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Desflurane is bound to human serum albumin in plasma. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Desflurane is minimally defluorinated by CYP2E1, to the extent that serum fluoride levels do not increase above baseline levels. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Initially, desflurane is rapidly eliminated from the lungs. A small amount of the metabolite trifluoroacetic acid is eliminated in the urine and only 0.02% of an inhaled dose is recovered as urinary metabolites. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Desflurane has a terminal elimination half life of 8.16 ± 3.15 minutes. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): A 26 g dose of desflurane is 90% eliminated from the brain after 33 hours. The metabolite trifluoroacetic acid has a urinary clearance rate of 0.169 ± 0.107 µmol/L. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Patients experiencing a desflurane overdose may experience deepening anesthesia, cardiac or respiratory depression. In the event of an overdose, patients may require symptomatic and supportive treatment to maintain airway, breathing, and circulation. Discontinue desflurane. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Suprane •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Desflurane Desflurano Desfluranum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Desflurane is a general inhalation anesthetic for inpatient and outpatient surgery in adults. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Dexmedetomidine interact?

•Drug A: Abaloparatide •Drug B: Dexmedetomidine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Dexmedetomidine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Administered intravenously, dexmedetomidine is indicated for the sedation of initially intubated and mechanically ventilated patients during treatment in intensive care settings, and for the sedation of non-intubated patients prior to and/or during surgery and other procedures. It is also available as a buccally- or sublingually-administered dissolvable film for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Dexmedetomidine activates 2-adrenoceptors, and causes the decrease of sympathetic tone, with attenuation of the neuroendocrine and hemodynamic responses to anesthesia and surgery; it reduces anesthetic and opioid requirements; and causes sedation and analgesia. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Dexmedetomidine is a specific and selective alpha-2 adrenoceptor agonist. By binding to the presynaptic alpha-2 adrenoceptors, it inhibits the release if norepinephrine, therefore, terminate the propagation of pain signals. Activation of the postsynaptic alpha-2 adrenoceptors inhibits the sympathetic activity decreases blood pressure and heart rate. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 118 L •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 94% •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Hepatic •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): A mass balance study demonstrated that after nine days an average of 95% of the radioactivity, following intravenous administration of radiolabeled dexmedetomidine, was recovered in the urine and 4% in the feces. Fractionation of the radioactivity excreted in urine demonstrated that products of N-glucuronidation accounted for approximately 34% of the cumulative urinary excretion. The majority of metabolites are excreted in the urine. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 2 hours •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): 39 L/h [Healthy volunteers receiving IV infusion (0.2-0.7 mcg/kg/hr)] •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Dexdor, Igalmi, Precedex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Dexmedetomidin Dexmedetomidina Dexmédétomidine Dexmedetomidine Dexmedetomidinum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Dexmedetomidine is an alpha-2 agonist used for sedation during various procedures.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Dexmedetomidine interact? Information: •Drug A: Abaloparatide •Drug B: Dexmedetomidine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Dexmedetomidine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Administered intravenously, dexmedetomidine is indicated for the sedation of initially intubated and mechanically ventilated patients during treatment in intensive care settings, and for the sedation of non-intubated patients prior to and/or during surgery and other procedures. It is also available as a buccally- or sublingually-administered dissolvable film for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Dexmedetomidine activates 2-adrenoceptors, and causes the decrease of sympathetic tone, with attenuation of the neuroendocrine and hemodynamic responses to anesthesia and surgery; it reduces anesthetic and opioid requirements; and causes sedation and analgesia. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Dexmedetomidine is a specific and selective alpha-2 adrenoceptor agonist. By binding to the presynaptic alpha-2 adrenoceptors, it inhibits the release if norepinephrine, therefore, terminate the propagation of pain signals. Activation of the postsynaptic alpha-2 adrenoceptors inhibits the sympathetic activity decreases blood pressure and heart rate. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 118 L •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 94% •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Hepatic •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): A mass balance study demonstrated that after nine days an average of 95% of the radioactivity, following intravenous administration of radiolabeled dexmedetomidine, was recovered in the urine and 4% in the feces. Fractionation of the radioactivity excreted in urine demonstrated that products of N-glucuronidation accounted for approximately 34% of the cumulative urinary excretion. The majority of metabolites are excreted in the urine. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 2 hours •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): 39 L/h [Healthy volunteers receiving IV infusion (0.2-0.7 mcg/kg/hr)] •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Dexdor, Igalmi, Precedex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Dexmedetomidin Dexmedetomidina Dexmédétomidine Dexmedetomidine Dexmedetomidinum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Dexmedetomidine is an alpha-2 agonist used for sedation during various procedures. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Diazoxide interact?

•Drug A: Abaloparatide •Drug B: Diazoxide •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Diazoxide is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Oral diazoxide is indicated to manage hypoglycemia due to hyperinsulinism associated with conditions such as inoperable islet cell adenoma or carcinoma, and extrapancreatic malignancy in adults, or leucine sensitivity, islet cell hyperplasia, nesidioblastosis, extrapancreatic malignancy, islet cell adenoma, and adenomatosis in infants and children. In infants and children oral diazoxide may be used preoperatively as a temporary measure, and postoperatively, if hypoglycemia persists. Diazoxide may also be used parentally or intravenously to treat hypertensive emergencies. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Diazoxide is a potassium channel activator that enhances cell membrane permeability to potassium ions. By promoting a vasodilatory effect on the smooth muscle in peripheral arterioles, diazoxide lowers blood pressure and peripheral vascular resistance. Diazoxide-induced decreases in blood pressure lead to reflex increases in heart rate and cardiac output. The oral administration of diazoxide increases blood glucose in a dose-dependent manner. In patients with normal renal function, this effect is observed within an hour and lasts no more than eight hours. The hypotensive effects of diazoxide are usually not detected when administered orally. Diazoxide administered intravenously may lead to sodium and water retention, severe hypotension, transient myocardial or cerebral ischaemia and gastrointestinal upsets such as nausea, vomiting and abdominal discomfort. Diazoxide administered orally may cause ketoacidosis and nonketotic hyperosmolar coma, especially in patients with other concurrent conditions. The use of intravenous or oral diazoxide may lead to the development of pulmonary hypertension in infants and neonates. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Diazoxide is a nondiuretic benzothiadiazine derivative used for the management of symptomatic hypoglycemia. By binding to the sulfonylurea receptor (SUR) subunit of the ATP-sensitive potassium channel (K ATP ) channel on the membrane of pancreatic beta‐cells, diazoxide promotes a potassium efflux from beta-cells. This hyperpolarizes the cell membrane and prevents the influx of calcium to the pancreatic beta‐cells. Without a sufficient amount of calcium in the cell, insulin release is inhibited. Therefore, the use of diazoxide produces an increase in glucose levels. Diazoxide is chemically related to thiazide diuretics but does not inhibit carbonic anhydrase and does not have chloriuretic or natriuretic activity. It also exhibits hypotensive activity by reducing arteriolar smooth muscle and vascular resistance. The mechanism of action of its hypotensive effect has not been fully elucidated; however, it is possible that it involves the antagonism of calcium. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Diazoxide is readily absorbed following oral administration; however, its absorption depends on the dissolution rate of the dosage form. Diazoxide has a bioavailability of 91%. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The apparent volume of distribution of diazoxide in adults with normal renal function is 13 L (21% of body weight), while in children with normal renal function, it is 2 L (33% of body weight). Other sources show that the volume of distribution of diazoxide is 0.21 L/kg. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): The protein binding of diazoxide in normal adults can range from 77% to 94%, depending on the administered dose. In patients with renal failure, protein binding ranges between 77% and 87%. This reduction can be related to the lower levels of albumin in patients with renal failure. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Diazoxide is metabolized in the liver through oxidation of the 3-methyl group, producing hydroxymethyl (MI) and carboxy (M2) derivatives. The MI derivatives undergo subsequent sulphate conjugation. It is estimated that, in subjects with normal renal function, 54-60% of diazoxide is metabolized. Diazoxide metabolites are inactive and do not contribute to its cardiovascular activity. Additionally, diazoxide metabolites do not displace diazoxide from protein binding sites. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Diazoxide and its metabolites are mainly eliminated through urine. Since diazoxide is extensively protein-bond, it has a slow excretion and a prolonged half-life. In subjects with normal renal function, the urinary excretion rates of diazoxide peak on the first day after oral administration. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Following oral administration, the plasma half-life of diazoxide varies from 9.5 to 24 hours in children with normal renal function and from 20 to 72 hours in adults with normal renal function. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): In subjects with normal renal function given 300 mg of diazoxide intravenously, renal clearance was 4 ml/min. Other sources show that the clearance of diazoxide is 0.06 ml/min/kg. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The oral LD 50 of diazoxide in rats and mice are 980 mg/kg and 444 mg/kg, respectively. In the mouse, rat, rabbit, dog, pig, and monkey, the oral administration of diazoxide leads to a rapid and transient rise in blood glucose levels. In rats given 400 mg/kg of diazoxide orally during subacute toxicity studies, growth retardation, edema, increases in liver and kidney weights, and adrenal hypertrophy were observed. Rats given doses up to 1080 mg/kg for three months developed hyperglycemia, an increase in liver weight and an increase in mortality. Toxicity is increased when diazoxide was administered at high dosages concomitantly with either chlorothiazide to rats or trichlormethiazide to dogs. Reproduction and teratology studies in different animal species suggest that diazoxide may interfere with normal fetal development, possibly due to the alteration of glucose metabolism. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Proglycem •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Diazossido Diazoxide Diazoxido Diazoxidum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Diazoxide is a non diuretic benzothiadiazine indicated for the management of hypoglycemia in patients who produce an excess of insulin caused by a variety of conditions.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Diazoxide interact? Information: •Drug A: Abaloparatide •Drug B: Diazoxide •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Diazoxide is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Oral diazoxide is indicated to manage hypoglycemia due to hyperinsulinism associated with conditions such as inoperable islet cell adenoma or carcinoma, and extrapancreatic malignancy in adults, or leucine sensitivity, islet cell hyperplasia, nesidioblastosis, extrapancreatic malignancy, islet cell adenoma, and adenomatosis in infants and children. In infants and children oral diazoxide may be used preoperatively as a temporary measure, and postoperatively, if hypoglycemia persists. Diazoxide may also be used parentally or intravenously to treat hypertensive emergencies. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Diazoxide is a potassium channel activator that enhances cell membrane permeability to potassium ions. By promoting a vasodilatory effect on the smooth muscle in peripheral arterioles, diazoxide lowers blood pressure and peripheral vascular resistance. Diazoxide-induced decreases in blood pressure lead to reflex increases in heart rate and cardiac output. The oral administration of diazoxide increases blood glucose in a dose-dependent manner. In patients with normal renal function, this effect is observed within an hour and lasts no more than eight hours. The hypotensive effects of diazoxide are usually not detected when administered orally. Diazoxide administered intravenously may lead to sodium and water retention, severe hypotension, transient myocardial or cerebral ischaemia and gastrointestinal upsets such as nausea, vomiting and abdominal discomfort. Diazoxide administered orally may cause ketoacidosis and nonketotic hyperosmolar coma, especially in patients with other concurrent conditions. The use of intravenous or oral diazoxide may lead to the development of pulmonary hypertension in infants and neonates. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Diazoxide is a nondiuretic benzothiadiazine derivative used for the management of symptomatic hypoglycemia. By binding to the sulfonylurea receptor (SUR) subunit of the ATP-sensitive potassium channel (K ATP ) channel on the membrane of pancreatic beta‐cells, diazoxide promotes a potassium efflux from beta-cells. This hyperpolarizes the cell membrane and prevents the influx of calcium to the pancreatic beta‐cells. Without a sufficient amount of calcium in the cell, insulin release is inhibited. Therefore, the use of diazoxide produces an increase in glucose levels. Diazoxide is chemically related to thiazide diuretics but does not inhibit carbonic anhydrase and does not have chloriuretic or natriuretic activity. It also exhibits hypotensive activity by reducing arteriolar smooth muscle and vascular resistance. The mechanism of action of its hypotensive effect has not been fully elucidated; however, it is possible that it involves the antagonism of calcium. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Diazoxide is readily absorbed following oral administration; however, its absorption depends on the dissolution rate of the dosage form. Diazoxide has a bioavailability of 91%. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The apparent volume of distribution of diazoxide in adults with normal renal function is 13 L (21% of body weight), while in children with normal renal function, it is 2 L (33% of body weight). Other sources show that the volume of distribution of diazoxide is 0.21 L/kg. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): The protein binding of diazoxide in normal adults can range from 77% to 94%, depending on the administered dose. In patients with renal failure, protein binding ranges between 77% and 87%. This reduction can be related to the lower levels of albumin in patients with renal failure. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Diazoxide is metabolized in the liver through oxidation of the 3-methyl group, producing hydroxymethyl (MI) and carboxy (M2) derivatives. The MI derivatives undergo subsequent sulphate conjugation. It is estimated that, in subjects with normal renal function, 54-60% of diazoxide is metabolized. Diazoxide metabolites are inactive and do not contribute to its cardiovascular activity. Additionally, diazoxide metabolites do not displace diazoxide from protein binding sites. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Diazoxide and its metabolites are mainly eliminated through urine. Since diazoxide is extensively protein-bond, it has a slow excretion and a prolonged half-life. In subjects with normal renal function, the urinary excretion rates of diazoxide peak on the first day after oral administration. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Following oral administration, the plasma half-life of diazoxide varies from 9.5 to 24 hours in children with normal renal function and from 20 to 72 hours in adults with normal renal function. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): In subjects with normal renal function given 300 mg of diazoxide intravenously, renal clearance was 4 ml/min. Other sources show that the clearance of diazoxide is 0.06 ml/min/kg. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The oral LD 50 of diazoxide in rats and mice are 980 mg/kg and 444 mg/kg, respectively. In the mouse, rat, rabbit, dog, pig, and monkey, the oral administration of diazoxide leads to a rapid and transient rise in blood glucose levels. In rats given 400 mg/kg of diazoxide orally during subacute toxicity studies, growth retardation, edema, increases in liver and kidney weights, and adrenal hypertrophy were observed. Rats given doses up to 1080 mg/kg for three months developed hyperglycemia, an increase in liver weight and an increase in mortality. Toxicity is increased when diazoxide was administered at high dosages concomitantly with either chlorothiazide to rats or trichlormethiazide to dogs. Reproduction and teratology studies in different animal species suggest that diazoxide may interfere with normal fetal development, possibly due to the alteration of glucose metabolism. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Proglycem •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Diazossido Diazoxide Diazoxido Diazoxidum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Diazoxide is a non diuretic benzothiadiazine indicated for the management of hypoglycemia in patients who produce an excess of insulin caused by a variety of conditions. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Diclofenamide interact?

•Drug A: Abaloparatide •Drug B: Diclofenamide •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Diclofenamide is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For adjunctive treatment of: chronic simple (open-angle) glaucoma, secondary glaucoma, and preoperatively in acute angle-closure glaucoma where delay of surgery is desired in order to lower intraocular pressure •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Dichlorphenamide is an oral carbonic anhydrase inhibitor indicated for adjunctive treatment of: chronic simple (open-angle) glaucoma, secondary glaucoma, and preoperatively in acute angle-closure glaucoma where delay of surgery is desired in order to lower intraocular pressure. Carbonic anhydrase inhibitors reduce intraocular pressure by partially suppressing the secretion of aqueous humor (inflow). •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Carbonic anhydrase inhibitors reduce intraocular pressure by partially suppressing the secretion of aqueous humor (inflow), although the mechanism by which they do this is not fully understood. Evidence suggests that HCO ions are produced in the ciliary body by hydration of carbon dioxide under the influence of carbonic anhydrase and diffuse into the posterior chamber which contains more Na and HCO ions than does plasma and consequently is hypertonic. Water is then attracted to the posterior chamber by osmosis, resulting in a drop in pressure. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 55% •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): No half-life available •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Keveyis, Ormalvi •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Dichlofenamide Dichlorophenamide Dichlorphenamide Diclofenamida Diclofenamide Diclofenamidum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Diclofenamide is a carbonic anhydrase inhibitor used for the management of open-angle and secondary glaucoma, as well as acute angle-closure glaucoma in delayed pre-operative setting requiring a reduction in intraocular pressure.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Diclofenamide interact? Information: •Drug A: Abaloparatide •Drug B: Diclofenamide •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Diclofenamide is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For adjunctive treatment of: chronic simple (open-angle) glaucoma, secondary glaucoma, and preoperatively in acute angle-closure glaucoma where delay of surgery is desired in order to lower intraocular pressure •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Dichlorphenamide is an oral carbonic anhydrase inhibitor indicated for adjunctive treatment of: chronic simple (open-angle) glaucoma, secondary glaucoma, and preoperatively in acute angle-closure glaucoma where delay of surgery is desired in order to lower intraocular pressure. Carbonic anhydrase inhibitors reduce intraocular pressure by partially suppressing the secretion of aqueous humor (inflow). •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Carbonic anhydrase inhibitors reduce intraocular pressure by partially suppressing the secretion of aqueous humor (inflow), although the mechanism by which they do this is not fully understood. Evidence suggests that HCO ions are produced in the ciliary body by hydration of carbon dioxide under the influence of carbonic anhydrase and diffuse into the posterior chamber which contains more Na and HCO ions than does plasma and consequently is hypertonic. Water is then attracted to the posterior chamber by osmosis, resulting in a drop in pressure. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 55% •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): No half-life available •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Keveyis, Ormalvi •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Dichlofenamide Dichlorophenamide Dichlorphenamide Diclofenamida Diclofenamide Diclofenamidum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Diclofenamide is a carbonic anhydrase inhibitor used for the management of open-angle and secondary glaucoma, as well as acute angle-closure glaucoma in delayed pre-operative setting requiring a reduction in intraocular pressure. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Digoxin interact?

•Drug A: Abaloparatide •Drug B: Digoxin •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abaloparatide is combined with Digoxin. •Extended Description: Cases of clinical toxicity have been documented with digoxin levels in the therapeutic range.2 Some studies report that electrolyte imbalances, such as hypercalcemia, can alter the effects of digoxin on the myocardium and increase sensitivity to digoxin, elevating the risk for digoxin toxicity even with a lower serum digoxin concentration. Because abaloparatide has been shown to cause transient increases in serum calcium, it may predispose patients to digitalis toxicity. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Digoxin is indicated in the following conditions: 1) For the treatment of mild to moderate heart failure in adult patients. 2) To increase myocardial contraction in children diagnosed with heart failure. 3) To maintain control ventricular rate in adult patients diagnosed with chronic atrial fibrillation. In adults with heart failure, when it is clinically possible, digoxin should be administered in conjunction with a diuretic and an angiotensin-converting enzyme (ACE) inhibitor for optimum effects. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Digoxin is a positive inotropic and negative chronotropic drug, meaning that it increases the force of the heartbeat and decreases the heart rate. The decrease in heart rate is particularly useful in cases of atrial fibrillation, a condition characterized by a fast and irregular heartbeat. The relief of heart failure symptoms during digoxin therapy has been demonstrated in clinical studies by increased exercise capacity and reduced hospitalization due to heart failure and reduced heart failure-related emergency medical visits. Digoxin has a narrow therapeutic window. A note on cardiovascular risk Digoxin poses a risk of rapid ventricular response that can cause ventricular fibrillation in patients with an accessory atrioventricular (AV) pathway. Cardiac arrest as a result of ventricular fibrillation is fatal. An increased risk of fatal severe or complete heart block is present in individuals with pre-existing sinus node disease and AV block who take digoxin. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Digoxin exerts hemodynamic, electrophysiologic, and neurohormonal effects on the cardiovascular system. It reversibly inhibits the Na-K ATPase enzyme, leading to various beneficial effects. The Na-K ATPase enzyme functions to maintain the intracellular environment by regulating the entry and exit of sodium, potassium, and calcium (indirectly). Na-K ATPase is also known as the sodium pump. The inhibition of the sodium pump by digoxin increases intracellular sodium and increases the calcium level in the myocardial cells, causing an increased contractile force of the heart. This improves the left ventricular ejection fraction (EF), an important measure of cardiac function. Digoxin also stimulates the parasympathetic nervous system via the vagus nerve leading to sinoatrial (SA) and atrioventricular (AV) node effects, decreasing the heart rate. Part of the pathophysiology of heart failure includes neurohormonal activation, leading to an increase in norepinephrine. Digoxin helps to decrease norepinephrine levels through activation of the parasympathetic nervous system. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Digoxin is approximately 70-80% absorbed in the first part of the small bowel. The bioavailability of an oral dose varies from 50-90%, however, oral gelatinized capsules of digoxin are reported to have a bioavailability of 100%. Tmax, or the time to reach the maximum concentration of digoxin was measured to be 1.0 h in one clinical study of healthy patients taking 0.25 mg of digoxin with a placebo. Cmax, or maximum concentration, was 1.32 ± 0.18 ng/ml−1 in the same study, and AUC (area under the curve) was 12.5 ± 2.38 ng/ml−1. If digoxin is ingested after a meal, absorption is slowed but this does not change the total amount of absorbed drug. If digoxin is taken with meals that are in fiber, absorption may be decreased. A note on gut bacteria An oral dose of digoxin may be transformed into pharmacologically inactive products by bacteria in the colon. Studies have indicated that 10% of patients receiving digoxin tablets will experience the degradation of at least 40% of an ingested dose of digoxin by gut bacteria. Several antibiotics may increase the absorption of digoxin in these patients, due to the elimination of gut bacteria, which normally cause digoxin degradation. A note on malabsorption Patients with malabsorption due to a variety of causes may have a decreased ability to absorb digoxin. P-glycoprotein, located on cells in the intestine, may interfere with digoxin pharmacokinetics, as it is a substrate of this efflux transporter. P-glycoprotein can be induced by other drugs, therefore reducing the effects of digoxin by increasing its efflux in the intestine. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): This drug is widely distributed in the body, and is known to cross the blood-brain barrier and the placenta. The apparent volume of distribution of digoxin is 475-500 L. A large portion of digoxin is distributed in the skeletal muscle followed by the heart and kidneys. It is important to note that the elderly population, generally having a decreased muscle mass, may show a lower volume of digoxin distribution. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Digoxin protein binding is approximately 25%. It is mainly bound to albumin. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): About 13% of a digoxin dose is found to be metabolized in healthy subjects. Several urinary metabolites of digoxin exist, including dihydrodigoxin and digoxigenin bisdigitoxoside. Their glucuronidated and sulfated conjugates are thought to be produced through the process of hydrolysis, oxidation, and additionally, conjugation. The cytochrome P-450 system does not play a major role in digoxin metabolism, nor does this drug induce or inhibit the enzymes in this system. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): The elimination of digoxin is proportional to the total dose, following first order kinetics. After intravenous (IV) administration to healthy subjects, 50-70% of the dose is measured excreted as unchanged digoxin in the urine. Approximately 25 to 28% of digoxin is eliminated outside of the kidney. Biliary excretion appears to be of much less importance than renal excretion. Digoxin is not effectively removed from the body by dialysis, exchange transfusion, or during cardiopulmonary bypass because most of the drug is bound to extravascular tissues. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Digoxin has a half-life of 1.5-2 days in healthy subjects. The half-life in patients who do not pass urine, usually due to renal failure, is prolonged to 3.5-5 days. Since most of the drug is distributed extravascularly, dialysis and exchange transfusion are not optimal methods for the removal of digoxin. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The clearance of digoxin closely correlates to creatinine clearance, and does not depend on urinary flow. Individuals with renal impairment or failure may exhibit extensively prolonged half-lives. It is therefore important to titrate the dose accordingly and regularly monitor serum digoxin levels. One pharmacokinetic study measured the mean body clearance of intravenous digoxin to be 88 ± 44ml/min/l.73 m². Another study provided mean clearance values of 53 ml/min/1.73 m² in men aged 73-81 and 83 ml/min/1.73 m² in men aged 20-33 years old after an intravenous digoxin dose. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Oral TDLO (human female): 100 ug/kg, Oral TDLO (human male): 75 ug/kg, Oral LD50 (rat): 28270 ug/kg Digoxin toxicity can occur in cases of supratherapeutic dose ingestion or as a result of chronic overexposure. Digoxin toxicity may be manifested by symptoms of nausea, vomiting, visual changes, in addition to arrhythmia. Older age, lower body weight, and decreased renal function or electrolyte abnormalities lead to an increased risk of digoxin toxicity. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Digox, Lanoxin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Digossina Digoxin Digoxina Digoxine Digoxinum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Digoxin is a cardiac glycoside used in the treatment of mild to moderate heart failure and for ventricular response rate control in chronic atrial fibrillation.

Cases of clinical toxicity have been documented with digoxin levels in the therapeutic range.2 Some studies report that electrolyte imbalances, such as hypercalcemia, can alter the effects of digoxin on the myocardium and increase sensitivity to digoxin, elevating the risk for digoxin toxicity even with a lower serum digoxin concentration. Because abaloparatide has been shown to cause transient increases in serum calcium, it may predispose patients to digitalis toxicity. The severity of the interaction is minor.

Question: Does Abaloparatide and Digoxin interact? Information: •Drug A: Abaloparatide •Drug B: Digoxin •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abaloparatide is combined with Digoxin. •Extended Description: Cases of clinical toxicity have been documented with digoxin levels in the therapeutic range.2 Some studies report that electrolyte imbalances, such as hypercalcemia, can alter the effects of digoxin on the myocardium and increase sensitivity to digoxin, elevating the risk for digoxin toxicity even with a lower serum digoxin concentration. Because abaloparatide has been shown to cause transient increases in serum calcium, it may predispose patients to digitalis toxicity. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Digoxin is indicated in the following conditions: 1) For the treatment of mild to moderate heart failure in adult patients. 2) To increase myocardial contraction in children diagnosed with heart failure. 3) To maintain control ventricular rate in adult patients diagnosed with chronic atrial fibrillation. In adults with heart failure, when it is clinically possible, digoxin should be administered in conjunction with a diuretic and an angiotensin-converting enzyme (ACE) inhibitor for optimum effects. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Digoxin is a positive inotropic and negative chronotropic drug, meaning that it increases the force of the heartbeat and decreases the heart rate. The decrease in heart rate is particularly useful in cases of atrial fibrillation, a condition characterized by a fast and irregular heartbeat. The relief of heart failure symptoms during digoxin therapy has been demonstrated in clinical studies by increased exercise capacity and reduced hospitalization due to heart failure and reduced heart failure-related emergency medical visits. Digoxin has a narrow therapeutic window. A note on cardiovascular risk Digoxin poses a risk of rapid ventricular response that can cause ventricular fibrillation in patients with an accessory atrioventricular (AV) pathway. Cardiac arrest as a result of ventricular fibrillation is fatal. An increased risk of fatal severe or complete heart block is present in individuals with pre-existing sinus node disease and AV block who take digoxin. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Digoxin exerts hemodynamic, electrophysiologic, and neurohormonal effects on the cardiovascular system. It reversibly inhibits the Na-K ATPase enzyme, leading to various beneficial effects. The Na-K ATPase enzyme functions to maintain the intracellular environment by regulating the entry and exit of sodium, potassium, and calcium (indirectly). Na-K ATPase is also known as the sodium pump. The inhibition of the sodium pump by digoxin increases intracellular sodium and increases the calcium level in the myocardial cells, causing an increased contractile force of the heart. This improves the left ventricular ejection fraction (EF), an important measure of cardiac function. Digoxin also stimulates the parasympathetic nervous system via the vagus nerve leading to sinoatrial (SA) and atrioventricular (AV) node effects, decreasing the heart rate. Part of the pathophysiology of heart failure includes neurohormonal activation, leading to an increase in norepinephrine. Digoxin helps to decrease norepinephrine levels through activation of the parasympathetic nervous system. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Digoxin is approximately 70-80% absorbed in the first part of the small bowel. The bioavailability of an oral dose varies from 50-90%, however, oral gelatinized capsules of digoxin are reported to have a bioavailability of 100%. Tmax, or the time to reach the maximum concentration of digoxin was measured to be 1.0 h in one clinical study of healthy patients taking 0.25 mg of digoxin with a placebo. Cmax, or maximum concentration, was 1.32 ± 0.18 ng/ml−1 in the same study, and AUC (area under the curve) was 12.5 ± 2.38 ng/ml−1. If digoxin is ingested after a meal, absorption is slowed but this does not change the total amount of absorbed drug. If digoxin is taken with meals that are in fiber, absorption may be decreased. A note on gut bacteria An oral dose of digoxin may be transformed into pharmacologically inactive products by bacteria in the colon. Studies have indicated that 10% of patients receiving digoxin tablets will experience the degradation of at least 40% of an ingested dose of digoxin by gut bacteria. Several antibiotics may increase the absorption of digoxin in these patients, due to the elimination of gut bacteria, which normally cause digoxin degradation. A note on malabsorption Patients with malabsorption due to a variety of causes may have a decreased ability to absorb digoxin. P-glycoprotein, located on cells in the intestine, may interfere with digoxin pharmacokinetics, as it is a substrate of this efflux transporter. P-glycoprotein can be induced by other drugs, therefore reducing the effects of digoxin by increasing its efflux in the intestine. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): This drug is widely distributed in the body, and is known to cross the blood-brain barrier and the placenta. The apparent volume of distribution of digoxin is 475-500 L. A large portion of digoxin is distributed in the skeletal muscle followed by the heart and kidneys. It is important to note that the elderly population, generally having a decreased muscle mass, may show a lower volume of digoxin distribution. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Digoxin protein binding is approximately 25%. It is mainly bound to albumin. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): About 13% of a digoxin dose is found to be metabolized in healthy subjects. Several urinary metabolites of digoxin exist, including dihydrodigoxin and digoxigenin bisdigitoxoside. Their glucuronidated and sulfated conjugates are thought to be produced through the process of hydrolysis, oxidation, and additionally, conjugation. The cytochrome P-450 system does not play a major role in digoxin metabolism, nor does this drug induce or inhibit the enzymes in this system. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): The elimination of digoxin is proportional to the total dose, following first order kinetics. After intravenous (IV) administration to healthy subjects, 50-70% of the dose is measured excreted as unchanged digoxin in the urine. Approximately 25 to 28% of digoxin is eliminated outside of the kidney. Biliary excretion appears to be of much less importance than renal excretion. Digoxin is not effectively removed from the body by dialysis, exchange transfusion, or during cardiopulmonary bypass because most of the drug is bound to extravascular tissues. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Digoxin has a half-life of 1.5-2 days in healthy subjects. The half-life in patients who do not pass urine, usually due to renal failure, is prolonged to 3.5-5 days. Since most of the drug is distributed extravascularly, dialysis and exchange transfusion are not optimal methods for the removal of digoxin. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The clearance of digoxin closely correlates to creatinine clearance, and does not depend on urinary flow. Individuals with renal impairment or failure may exhibit extensively prolonged half-lives. It is therefore important to titrate the dose accordingly and regularly monitor serum digoxin levels. One pharmacokinetic study measured the mean body clearance of intravenous digoxin to be 88 ± 44ml/min/l.73 m². Another study provided mean clearance values of 53 ml/min/1.73 m² in men aged 73-81 and 83 ml/min/1.73 m² in men aged 20-33 years old after an intravenous digoxin dose. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Oral TDLO (human female): 100 ug/kg, Oral TDLO (human male): 75 ug/kg, Oral LD50 (rat): 28270 ug/kg Digoxin toxicity can occur in cases of supratherapeutic dose ingestion or as a result of chronic overexposure. Digoxin toxicity may be manifested by symptoms of nausea, vomiting, visual changes, in addition to arrhythmia. Older age, lower body weight, and decreased renal function or electrolyte abnormalities lead to an increased risk of digoxin toxicity. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Digox, Lanoxin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Digossina Digoxin Digoxina Digoxine Digoxinum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Digoxin is a cardiac glycoside used in the treatment of mild to moderate heart failure and for ventricular response rate control in chronic atrial fibrillation. Output: Cases of clinical toxicity have been documented with digoxin levels in the therapeutic range.2 Some studies report that electrolyte imbalances, such as hypercalcemia, can alter the effects of digoxin on the myocardium and increase sensitivity to digoxin, elevating the risk for digoxin toxicity even with a lower serum digoxin concentration. Because abaloparatide has been shown to cause transient increases in serum calcium, it may predispose patients to digitalis toxicity. The severity of the interaction is minor.

Does Abaloparatide and Diltiazem interact?

•Drug A: Abaloparatide •Drug B: Diltiazem •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Diltiazem is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Oral Indicated for the management of hypertension, to lower blood pressure, alone or in combination with other antihypertensive agents. Indicated for use to improve exercise tolerance in patients with chronic stable angina. Indicated for the management of variant angina (Prinzmetal's angina). Intravenous Indicated for the short-term management of atrial fibrillation or atrial flutter for temporary control of rapid ventricular rate. Indicated for the rapid conversion of paroxysmal supraventricular tachycardias (PSVT) to sinus rhythm. This includes AV nodal reentrant tachycardias and reciprocating tachycardias associated with an extranodal accessory pathway such as the WPW syndrome or short PR syndrome. Off-label Indicated for off-label uses in anal fissures (as topical formulation), migraine prophylaxis, cramps in lower leg related to rest, pulmonary hypertension, idiopathic dilated cardiomyopathy, and proteinuria associated with diabetic nephropathy. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Diltiazem is an antihypertensive and vasodilating agent that works by relaxing the vascular muscle and reducing blood pressure. This is related to the long-term therapeutic effects, as lowering the blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. Diltiazem inhibits the influx of extracellular calcium ions across the myocardial and vascular smooth muscle cell membranes during depolarization. Diltiazem is classified as a negative inotrope (decreased force) and negative chronotrope (decreased rate). It is also considered a rate-control drug as it reduces heart rate. Diltiazem is exerts hemodynamic actions by reducing blood pressure, systemic vascular resistance, the rate-pressure product, and coronary vascular resistance while increasing coronary blood flow. Diltiazem decreases sinoatrial and atrioventricular conduction in isolated tissues and has a negative inotropic effect in isolated preparations. In supraventricular tachycardia, diltiazem prolongs AV nodal refractories. As the magnitude of blood pressure reduction is related to the degree of hypertension, the antihypertensive effect of diltiazem is most pronounced in individuals with hypertension. In a randomized, double-blind, parallel-group, dose-response study involving patients with essential hypertension, there was a reduction in the diastolic blood pressure by 1.9, 5.4, 6.1, and 8.6 mmHg in the patients receiving diltiazem at doses of 120, 240, 360, and 540 mg, respectively. In patients receiving placebo, there was a reduction in the diastolic blood pressure by 2.6 mmHg.In a randomized, double-blind study involving patients with chronic stable angina, variable doses of diltiazem administered at night all caused an increased exercise tolerance in the after 21 hours, compared to placebo. In the NORDIL study of patients with hypertension, the therapeutic effectiveness of diltiazem in reducing cardiovascular morbidity and mortality was assessed. When using the combined primary endpoint as fatal and non-fatal stroke, myocardial infarction, and other cardiovascular death, fatal and non-fatal stroke was shown to be reduced by 25% in the diltiazem group. Although the clinical significance to this effect remains unclear, it is suggested that diltiazem may exert a protective role against cerebral stroke in hypertensive patients. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Excitation of cardiac muscle involves the activation of a slow calcium inward current that is induced by L-type slow calcium channels, which are voltage-sensitive, ion-selective channels associated with a high activation threshold and slow inactivation profile. L-type calcium channels are the main current responsible for the late phase of the pacemaker potential. Acting as the main Ca2+ source for contraction in smooth and cardiac muscle, activation of L-type calcium channels allows the influx of calcium ions into the muscles upon depolarization and excitation of the channel. It is proposed that this cation influx may also trigger the release of additional calcium ions from intracellular storage sites. Diltiazem is a slow calcium channel blocker that binds to the extracellular site of the alpha-1C subunit of the channel, which is thought to be the S5-6 linker region of the transmembrane domain IV and/or S6 segment of domain III. Diltiazem can get access to this binding site from either the intracellular or extracellular side, but it requires a voltage-induced conformational changes in the membrane. Diltiazem inhibits the influx of extracellular calcium across the myocardial and vascular smooth muscle cell membranes. In isolated human atrial and ventricular myocardium, diltiazem suppressed tension over the range of membrane potentials associated with calcium channel activity but had little effect on the tension-voltage relations at more positive potentials. This effect is thought to be mediated by the voltage-dependent block of the L-type calcium channels and inhibition of calcium ion release from the ER stores, without altering the sodium-calcium coupled transport or calcium sensitivity of myofilaments. Through inhibition of inward calcium current, diltiazem exerts a direct ionotropic and energy sparing effect on the myocardium. Diltiazem fslows atrioventricular nodal conduction, which is due to its ability to impede slow channel function. Reduced intracellular calcium concentrations equate to increased smooth muscle relaxation resulting in arterial vasodilation and therefore, decreased blood pressure. The decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload. Through its actions on reducing calcium levels in cardiac and vascular smooth muscles, diltiazem causes a reduction in the contractile processes of the myocardial smooth muscle cells and vasodilation of the coronary and systemic arteries, including epicardial and subendocardial. This subsequently leads to increased oxygen delivery to the myocardial tissue, improved cardiac output due to increased stroke volume, decreased total peripheral resistance, decreased systemic blood pressure and heart rate, and decreased afterload. Diltiazem lowers myocardial oxygen demand through a reduction in heart rate, blood pressure, and cardiac contractility; this leads to a therapeutic effect in improving exercise tolerance in chronic stable angina. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Diltiazem is readily absorbed from the gastrointestinal tract. Minimum therapeutic plasma diltiazem concentrations appear to be in the range of 50 to 200 ng/mL. Following oral administration of extended formulations of 360 mg diltiazem, the drug in plasma was detectable within 3 to 4 hours and the peak plasma concentrations were reached between 11 and 18 hours post-dose. Diltiazem peak and systemic exposures were not affected by concurrent food intake. Due to hepatic first-pass metabolism, the absolute bioavailability following oral administration is about 40%, with the value ranging from 24 to 74% due to high interindividual variation in the first pass effect. The bioavailability may increase in patients with hepatic impairment. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The apparent volume of distribution of diltiazem was approximately 305 L following a single intravenous injection in healthy male volunteers. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Diltiazem is about 70-80% bound to plasma proteins, according to in vitro binding studies. About 40% of the drug is thought to bind to alpha-1-glycoprotein at clinically significant concentrations while about 30% of the drug is bound to albumin. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Diltiazem is subject to extensive first-pass metabolism, which explains its relatively low absolute oral bioavailability. It undergoes N-demethylation primarily mediated by CYP3A4. CYP2D6 is responsible for O-demethylation and esterases mediate deacetylation. There was large inter-individual variability in the circulating plasma levels of metabolites in healthy volunteers. In healthy volunteers, the major circulating metabolites in the plasma are N-monodesmethyl diltilazem, deacetyl diltiazem, and deacetyl N-monodesmethyl diltiazem, which are all pharmacologically active. Deacetyl diltiazem retains about 25-50% of the pharmacological activity to that of the parent compound. Deacetyl diltiazem can be further transformed into deacetyl diltiazem N-oxide or deacetyl O-desmethyl diltiazem. N-monodesmethyl diltilazem can be further metabolized to N,O-didesmethyl diltiazem. Deacetyl N-monodesmethyl diltiazem can be further metabolized to deacetyl N,O-didesmethyl diltiazem, which can be glucuronidated or sulphated. Diltiazem can be O-demethylated by CYP2D6 to form O-desmethyl diltiazem. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Due to its extensive metabolism, only 2% to 4% of the unchanged drug can be detected in the urine. The major urinary metabolite in healthy volunnteers was N-monodesmethyl diltiazem, followed by deacetyl N,O-didesmethyl diltiazem, deacetyl N-monodesmethyl diltiazem, and deacetyl diltiazem; however, there seems to be large inter-individual variability in the urinary excretion of DTZ and its metabolites. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The plasma elimination half-life is approximately 3.0 to 4.5 hours following single and multiple oral doses. The half-life may slightly increase with dose and the extent of hepatic impairment. The apparent elimination half-life for diltiazem as extended-release tablets after single or multiple dosing is 6 to 9 hours. The plasma elimination half-life is approximately 3.4 hours following administration of a single intravenous injection. The elimination half-lives of pharmacologically active metabolites are longer than that of diltiazem. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Following a single intravenous injection in healthy male volunteers, the systemic clearance of diltiazem was approximately 65 L/h. After constant rate intravenous infusion, the systemic clearance decreased to 48 L/h. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Clinical Toxicity and Overdose The oral LD 50 ranges from 415 to 740mg/kg in mice and 560 to 810 mg/kg in rats. The oral LD 50 in dogs is considered to be in excess of 50 mg/kg. A dose of 360 mg/kg resulted in lethality in monkeys. The intravenous LD 50 is 60 mg/kg in mice and 38 mg/kg in rats. Cases of overdose from doses ranging from less than 1 g to 18 g have been reported with diltiazem, with several cases involving multiple drug ingestions resulting in death. Overdoses were associated with bradycardia, hypotension, heart block, and cardiac failure that may manifest as dizziness, lightheadedness, and fatigue. Actual treatment and dosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician. Diltiazem overdose should be responded with appropriate supportive measures and gastrointestinal decontamination. Bradycardia and heart block can be treated with atropine at doses ranging from 0.60 to 1.0 mg. In the case of bradycardia, if there is no response to vagal blockage, cautious administration of isoproterenol should be considered. Cardiac pacing can also be used to treat fixed high-degree AV block. In the case of heart failure, blood pressure may be maintained with the use of fluids and vasopressors, as well as inotropic agents such as isoproterenol, dopamine, or dobutamine. Other appropriate measures include ventilatory support, gastric lavage, activated charcoal, and/or intravenous calcium. Diltiazem does not appear to be removed by peritoneal or hemodialysis. Non-clinical toxicity In a 24-month study in rats receiving oral doses of up to 100 mg/kg/day, there was no evidence of carcinogenicity. There was also no mutagenic response in vitro or in vivo in mammalian cell assays or in vitro bacterial assays. No evidence of impaired fertility was observed in a study performed in male and female rats receiving oral doses of up to 100 mg/kg/day. Pregnancy and Lactation In reproduction studies in animals, administration of diltiazem at doses ranging from five to twenty times the daily recommended human therapeutic dose resulted in cases of the embryo and fetal lethality and skeletal abnormalities, and an increase in the risk of stillbirths. There have been no up-to-date controlled studies that investigated the use of diltiazem in pregnant women. The use of diltiazem in pregnant women should be undertaken only if the potential benefit justifies the risk to the fetus. Diltiazem is excreted in human milk, where one report suggests that the concentrations in breast milk may approximate serum levels; therefore, the decision should be made to either discontinue nursing or the use of the drug after careful consideration of the clinical necessity of diltiazem therapy in the nursing mother. Use in special populations As there is limited information on the variable effects of diltiazem in geriatric patients, the initial therapy of diltiazem should involve the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Currently, there are no specific dosing guidelines for patients with renal or hepatic impairment. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Cardizem, Cartia, Matzim, Taztia, Tiadylt, Tiazac •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): d-cis-diltiazem Diltiazem Diltiazemum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Diltiazem is a calcium channel blocker used to treat hypertension and to manage chronic stable angina.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Diltiazem interact? Information: •Drug A: Abaloparatide •Drug B: Diltiazem •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Diltiazem is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Oral Indicated for the management of hypertension, to lower blood pressure, alone or in combination with other antihypertensive agents. Indicated for use to improve exercise tolerance in patients with chronic stable angina. Indicated for the management of variant angina (Prinzmetal's angina). Intravenous Indicated for the short-term management of atrial fibrillation or atrial flutter for temporary control of rapid ventricular rate. Indicated for the rapid conversion of paroxysmal supraventricular tachycardias (PSVT) to sinus rhythm. This includes AV nodal reentrant tachycardias and reciprocating tachycardias associated with an extranodal accessory pathway such as the WPW syndrome or short PR syndrome. Off-label Indicated for off-label uses in anal fissures (as topical formulation), migraine prophylaxis, cramps in lower leg related to rest, pulmonary hypertension, idiopathic dilated cardiomyopathy, and proteinuria associated with diabetic nephropathy. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Diltiazem is an antihypertensive and vasodilating agent that works by relaxing the vascular muscle and reducing blood pressure. This is related to the long-term therapeutic effects, as lowering the blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. Diltiazem inhibits the influx of extracellular calcium ions across the myocardial and vascular smooth muscle cell membranes during depolarization. Diltiazem is classified as a negative inotrope (decreased force) and negative chronotrope (decreased rate). It is also considered a rate-control drug as it reduces heart rate. Diltiazem is exerts hemodynamic actions by reducing blood pressure, systemic vascular resistance, the rate-pressure product, and coronary vascular resistance while increasing coronary blood flow. Diltiazem decreases sinoatrial and atrioventricular conduction in isolated tissues and has a negative inotropic effect in isolated preparations. In supraventricular tachycardia, diltiazem prolongs AV nodal refractories. As the magnitude of blood pressure reduction is related to the degree of hypertension, the antihypertensive effect of diltiazem is most pronounced in individuals with hypertension. In a randomized, double-blind, parallel-group, dose-response study involving patients with essential hypertension, there was a reduction in the diastolic blood pressure by 1.9, 5.4, 6.1, and 8.6 mmHg in the patients receiving diltiazem at doses of 120, 240, 360, and 540 mg, respectively. In patients receiving placebo, there was a reduction in the diastolic blood pressure by 2.6 mmHg.In a randomized, double-blind study involving patients with chronic stable angina, variable doses of diltiazem administered at night all caused an increased exercise tolerance in the after 21 hours, compared to placebo. In the NORDIL study of patients with hypertension, the therapeutic effectiveness of diltiazem in reducing cardiovascular morbidity and mortality was assessed. When using the combined primary endpoint as fatal and non-fatal stroke, myocardial infarction, and other cardiovascular death, fatal and non-fatal stroke was shown to be reduced by 25% in the diltiazem group. Although the clinical significance to this effect remains unclear, it is suggested that diltiazem may exert a protective role against cerebral stroke in hypertensive patients. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Excitation of cardiac muscle involves the activation of a slow calcium inward current that is induced by L-type slow calcium channels, which are voltage-sensitive, ion-selective channels associated with a high activation threshold and slow inactivation profile. L-type calcium channels are the main current responsible for the late phase of the pacemaker potential. Acting as the main Ca2+ source for contraction in smooth and cardiac muscle, activation of L-type calcium channels allows the influx of calcium ions into the muscles upon depolarization and excitation of the channel. It is proposed that this cation influx may also trigger the release of additional calcium ions from intracellular storage sites. Diltiazem is a slow calcium channel blocker that binds to the extracellular site of the alpha-1C subunit of the channel, which is thought to be the S5-6 linker region of the transmembrane domain IV and/or S6 segment of domain III. Diltiazem can get access to this binding site from either the intracellular or extracellular side, but it requires a voltage-induced conformational changes in the membrane. Diltiazem inhibits the influx of extracellular calcium across the myocardial and vascular smooth muscle cell membranes. In isolated human atrial and ventricular myocardium, diltiazem suppressed tension over the range of membrane potentials associated with calcium channel activity but had little effect on the tension-voltage relations at more positive potentials. This effect is thought to be mediated by the voltage-dependent block of the L-type calcium channels and inhibition of calcium ion release from the ER stores, without altering the sodium-calcium coupled transport or calcium sensitivity of myofilaments. Through inhibition of inward calcium current, diltiazem exerts a direct ionotropic and energy sparing effect on the myocardium. Diltiazem fslows atrioventricular nodal conduction, which is due to its ability to impede slow channel function. Reduced intracellular calcium concentrations equate to increased smooth muscle relaxation resulting in arterial vasodilation and therefore, decreased blood pressure. The decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload. Through its actions on reducing calcium levels in cardiac and vascular smooth muscles, diltiazem causes a reduction in the contractile processes of the myocardial smooth muscle cells and vasodilation of the coronary and systemic arteries, including epicardial and subendocardial. This subsequently leads to increased oxygen delivery to the myocardial tissue, improved cardiac output due to increased stroke volume, decreased total peripheral resistance, decreased systemic blood pressure and heart rate, and decreased afterload. Diltiazem lowers myocardial oxygen demand through a reduction in heart rate, blood pressure, and cardiac contractility; this leads to a therapeutic effect in improving exercise tolerance in chronic stable angina. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Diltiazem is readily absorbed from the gastrointestinal tract. Minimum therapeutic plasma diltiazem concentrations appear to be in the range of 50 to 200 ng/mL. Following oral administration of extended formulations of 360 mg diltiazem, the drug in plasma was detectable within 3 to 4 hours and the peak plasma concentrations were reached between 11 and 18 hours post-dose. Diltiazem peak and systemic exposures were not affected by concurrent food intake. Due to hepatic first-pass metabolism, the absolute bioavailability following oral administration is about 40%, with the value ranging from 24 to 74% due to high interindividual variation in the first pass effect. The bioavailability may increase in patients with hepatic impairment. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The apparent volume of distribution of diltiazem was approximately 305 L following a single intravenous injection in healthy male volunteers. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Diltiazem is about 70-80% bound to plasma proteins, according to in vitro binding studies. About 40% of the drug is thought to bind to alpha-1-glycoprotein at clinically significant concentrations while about 30% of the drug is bound to albumin. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Diltiazem is subject to extensive first-pass metabolism, which explains its relatively low absolute oral bioavailability. It undergoes N-demethylation primarily mediated by CYP3A4. CYP2D6 is responsible for O-demethylation and esterases mediate deacetylation. There was large inter-individual variability in the circulating plasma levels of metabolites in healthy volunteers. In healthy volunteers, the major circulating metabolites in the plasma are N-monodesmethyl diltilazem, deacetyl diltiazem, and deacetyl N-monodesmethyl diltiazem, which are all pharmacologically active. Deacetyl diltiazem retains about 25-50% of the pharmacological activity to that of the parent compound. Deacetyl diltiazem can be further transformed into deacetyl diltiazem N-oxide or deacetyl O-desmethyl diltiazem. N-monodesmethyl diltilazem can be further metabolized to N,O-didesmethyl diltiazem. Deacetyl N-monodesmethyl diltiazem can be further metabolized to deacetyl N,O-didesmethyl diltiazem, which can be glucuronidated or sulphated. Diltiazem can be O-demethylated by CYP2D6 to form O-desmethyl diltiazem. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Due to its extensive metabolism, only 2% to 4% of the unchanged drug can be detected in the urine. The major urinary metabolite in healthy volunnteers was N-monodesmethyl diltiazem, followed by deacetyl N,O-didesmethyl diltiazem, deacetyl N-monodesmethyl diltiazem, and deacetyl diltiazem; however, there seems to be large inter-individual variability in the urinary excretion of DTZ and its metabolites. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The plasma elimination half-life is approximately 3.0 to 4.5 hours following single and multiple oral doses. The half-life may slightly increase with dose and the extent of hepatic impairment. The apparent elimination half-life for diltiazem as extended-release tablets after single or multiple dosing is 6 to 9 hours. The plasma elimination half-life is approximately 3.4 hours following administration of a single intravenous injection. The elimination half-lives of pharmacologically active metabolites are longer than that of diltiazem. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Following a single intravenous injection in healthy male volunteers, the systemic clearance of diltiazem was approximately 65 L/h. After constant rate intravenous infusion, the systemic clearance decreased to 48 L/h. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Clinical Toxicity and Overdose The oral LD 50 ranges from 415 to 740mg/kg in mice and 560 to 810 mg/kg in rats. The oral LD 50 in dogs is considered to be in excess of 50 mg/kg. A dose of 360 mg/kg resulted in lethality in monkeys. The intravenous LD 50 is 60 mg/kg in mice and 38 mg/kg in rats. Cases of overdose from doses ranging from less than 1 g to 18 g have been reported with diltiazem, with several cases involving multiple drug ingestions resulting in death. Overdoses were associated with bradycardia, hypotension, heart block, and cardiac failure that may manifest as dizziness, lightheadedness, and fatigue. Actual treatment and dosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician. Diltiazem overdose should be responded with appropriate supportive measures and gastrointestinal decontamination. Bradycardia and heart block can be treated with atropine at doses ranging from 0.60 to 1.0 mg. In the case of bradycardia, if there is no response to vagal blockage, cautious administration of isoproterenol should be considered. Cardiac pacing can also be used to treat fixed high-degree AV block. In the case of heart failure, blood pressure may be maintained with the use of fluids and vasopressors, as well as inotropic agents such as isoproterenol, dopamine, or dobutamine. Other appropriate measures include ventilatory support, gastric lavage, activated charcoal, and/or intravenous calcium. Diltiazem does not appear to be removed by peritoneal or hemodialysis. Non-clinical toxicity In a 24-month study in rats receiving oral doses of up to 100 mg/kg/day, there was no evidence of carcinogenicity. There was also no mutagenic response in vitro or in vivo in mammalian cell assays or in vitro bacterial assays. No evidence of impaired fertility was observed in a study performed in male and female rats receiving oral doses of up to 100 mg/kg/day. Pregnancy and Lactation In reproduction studies in animals, administration of diltiazem at doses ranging from five to twenty times the daily recommended human therapeutic dose resulted in cases of the embryo and fetal lethality and skeletal abnormalities, and an increase in the risk of stillbirths. There have been no up-to-date controlled studies that investigated the use of diltiazem in pregnant women. The use of diltiazem in pregnant women should be undertaken only if the potential benefit justifies the risk to the fetus. Diltiazem is excreted in human milk, where one report suggests that the concentrations in breast milk may approximate serum levels; therefore, the decision should be made to either discontinue nursing or the use of the drug after careful consideration of the clinical necessity of diltiazem therapy in the nursing mother. Use in special populations As there is limited information on the variable effects of diltiazem in geriatric patients, the initial therapy of diltiazem should involve the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Currently, there are no specific dosing guidelines for patients with renal or hepatic impairment. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Cardizem, Cartia, Matzim, Taztia, Tiadylt, Tiazac •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): d-cis-diltiazem Diltiazem Diltiazemum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Diltiazem is a calcium channel blocker used to treat hypertension and to manage chronic stable angina. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Dinutuximab interact?

•Drug A: Abaloparatide •Drug B: Dinutuximab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abaloparatide is combined with Dinutuximab. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Dinutuximab is indicated, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and 13-cis-retinoic acid (RA), for the treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response to prior first-line multiagent, multimodality therapy. Despite a high clinical response seen after first-line treatment, the complete eradication of neuroblastoma is rarely achieved and the majority of patients with advanced disease suffer a relapse. Current strategies for treatment include immunotherapy with drugs such as dinutuximab to target surviving neuroblastoma cells and to prevent relapse. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): In vitro dinutuximab binds to neuroblastoma tumour cells and mediates the lysis of tumour cells via cell-mediated and complement-mediated cytotoxicity. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Dinutuximab is an IgG1 monoclonal human/mouse chimeric antibody against GD2, a disialoganglioside expressed on tumors of neuroectodermal origin, including human neuroblastoma and melanoma, with highly restricted expression on normal tissues. It is composed of the variable heavy- and light-chain regions of the murine anti-GD2 mAb 14.18 and the constant regions of human IgG1 heavy-chain and kappa light-chain. By binding to GD2, dinutiximab induces antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity of tumor cells thereby leading to apoptosis and inhibiting proliferation of the tumour. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The mean volume of distribution at steady state (Vdss) is 5.4 L •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The terminal half-life is 10 days •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The clearance is 0.21 L/day and increases with body size •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The most common (incidence 15 %) grade 3 or 4 treatment-related adverse events in dinutuximab compared with standard therapy recipients were neuropathic pain (52 vs. 6 %), fever without neutropenia (39 vs. 6 %), any in-fection (39 vs. 22 %), hypokalaemia (35 vs. 2 %), hypersensitivity reactions (25 vs. 1 %), hyponatraemia (23 vs. 4 %), elevation of alanine transferase levels (23 vs. 3 %) and hypotension (18 vs. 0 %). Based on its mechanism of action, dinutuximab may cause fetal harm when administered to a pregnant woman however, there are no studies in pregnant women and no reproductive studies in animals to inform the drug-associated risk. Non-clinical studies suggest that dinutuximab-induced neuropathic pain is mediated by binding of the antibody to the GD2 antigen located on the surface of peripheral nerve fibers and myelin and subsequent induction of cell- and complement-mediated cytotoxicity. In clinical trials, 114 (85%) patients treated in the dinutuximab/RA group experienced pain despite pre­-treatment with analgesics including morphine sulfate infusion. Severe (Grade 3) pain occurred in 68 (51%) patients in the dinutuximab/RA group compared to 5 (5%) patients in the RA group. Pain typically occurred during the dinutuximab infusion and was most commonly reported as abdominal pain, generalized pain, extremity pain, back pain, neuralgia, musculoskeletal chest pain, and arthralgia. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Unituxin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Dinutuximab is an immunotherapeutic agent used in combination with other immunomodulating agents to treat high-risk neuroblastoma in pediatric patients who achieve at least a partial response to prior first-line multiagent, multimodality therapy.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Dinutuximab interact? Information: •Drug A: Abaloparatide •Drug B: Dinutuximab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abaloparatide is combined with Dinutuximab. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Dinutuximab is indicated, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and 13-cis-retinoic acid (RA), for the treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response to prior first-line multiagent, multimodality therapy. Despite a high clinical response seen after first-line treatment, the complete eradication of neuroblastoma is rarely achieved and the majority of patients with advanced disease suffer a relapse. Current strategies for treatment include immunotherapy with drugs such as dinutuximab to target surviving neuroblastoma cells and to prevent relapse. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): In vitro dinutuximab binds to neuroblastoma tumour cells and mediates the lysis of tumour cells via cell-mediated and complement-mediated cytotoxicity. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Dinutuximab is an IgG1 monoclonal human/mouse chimeric antibody against GD2, a disialoganglioside expressed on tumors of neuroectodermal origin, including human neuroblastoma and melanoma, with highly restricted expression on normal tissues. It is composed of the variable heavy- and light-chain regions of the murine anti-GD2 mAb 14.18 and the constant regions of human IgG1 heavy-chain and kappa light-chain. By binding to GD2, dinutiximab induces antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity of tumor cells thereby leading to apoptosis and inhibiting proliferation of the tumour. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The mean volume of distribution at steady state (Vdss) is 5.4 L •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The terminal half-life is 10 days •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The clearance is 0.21 L/day and increases with body size •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The most common (incidence 15 %) grade 3 or 4 treatment-related adverse events in dinutuximab compared with standard therapy recipients were neuropathic pain (52 vs. 6 %), fever without neutropenia (39 vs. 6 %), any in-fection (39 vs. 22 %), hypokalaemia (35 vs. 2 %), hypersensitivity reactions (25 vs. 1 %), hyponatraemia (23 vs. 4 %), elevation of alanine transferase levels (23 vs. 3 %) and hypotension (18 vs. 0 %). Based on its mechanism of action, dinutuximab may cause fetal harm when administered to a pregnant woman however, there are no studies in pregnant women and no reproductive studies in animals to inform the drug-associated risk. Non-clinical studies suggest that dinutuximab-induced neuropathic pain is mediated by binding of the antibody to the GD2 antigen located on the surface of peripheral nerve fibers and myelin and subsequent induction of cell- and complement-mediated cytotoxicity. In clinical trials, 114 (85%) patients treated in the dinutuximab/RA group experienced pain despite pre­-treatment with analgesics including morphine sulfate infusion. Severe (Grade 3) pain occurred in 68 (51%) patients in the dinutuximab/RA group compared to 5 (5%) patients in the RA group. Pain typically occurred during the dinutuximab infusion and was most commonly reported as abdominal pain, generalized pain, extremity pain, back pain, neuralgia, musculoskeletal chest pain, and arthralgia. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Unituxin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Dinutuximab is an immunotherapeutic agent used in combination with other immunomodulating agents to treat high-risk neuroblastoma in pediatric patients who achieve at least a partial response to prior first-line multiagent, multimodality therapy. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Dipyridamole interact?

•Drug A: Abaloparatide •Drug B: Dipyridamole •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Dipyridamole is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For as an adjunct to coumarin anticoagulants in the prevention of postoperative thromboembolic complications of cardiac valve replacement and also used in prevention of angina. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Dipyridamole, a non-nitrate coronary vasodilator that also inhibits platelet aggregation, is combined with other anticoagulant drugs, such as warfarin, to prevent thrombosis in patients with valvular or vascular disorders. Dipyridamole is also used in myocardial perfusion imaging, as an antiplatelet agent, and in combination with aspirin for stroke prophylaxis. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Dipyridamole likely inhibits both adenosine deaminase and phosphodiesterase, preventing the degradation of cAMP, an inhibitor of platelet function. This elevation in cAMP blocks the release of arachidonic acid from membrane phospholipids and reduces thromboxane A2 activity. Dipyridamole also directly stimulates the release of prostacyclin, which induces adenylate cyclase activity, thereby raising the intraplatelet concentration of cAMP and further inhibiting platelet aggregation. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): 70% •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 1 to 2.5 L/kg •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 99% •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): hepatic •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Dipyridamole is metabolized in the liver to the glucuronic acid conjugate and excreted with the bile. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 40 minutes •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): 2.3-3.5 mL/min/kg •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Hypotension, if it occurs, is likely to be of short duration, but a vasopressor drug may be used if necessary. The oral LD 50 in rats is greater than 6,000 mg/kg while in the dogs, the oral LD 50 is approximately 400 mg/kg. LD 50 =8.4g/kg (orally in rat) •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Aggrenox, Persantine •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Dipyridamole is a phosphodiesterase inhibitor used to prevent postoperative thromboembolic events.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Dipyridamole interact? Information: •Drug A: Abaloparatide •Drug B: Dipyridamole •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Dipyridamole is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For as an adjunct to coumarin anticoagulants in the prevention of postoperative thromboembolic complications of cardiac valve replacement and also used in prevention of angina. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Dipyridamole, a non-nitrate coronary vasodilator that also inhibits platelet aggregation, is combined with other anticoagulant drugs, such as warfarin, to prevent thrombosis in patients with valvular or vascular disorders. Dipyridamole is also used in myocardial perfusion imaging, as an antiplatelet agent, and in combination with aspirin for stroke prophylaxis. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Dipyridamole likely inhibits both adenosine deaminase and phosphodiesterase, preventing the degradation of cAMP, an inhibitor of platelet function. This elevation in cAMP blocks the release of arachidonic acid from membrane phospholipids and reduces thromboxane A2 activity. Dipyridamole also directly stimulates the release of prostacyclin, which induces adenylate cyclase activity, thereby raising the intraplatelet concentration of cAMP and further inhibiting platelet aggregation. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): 70% •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 1 to 2.5 L/kg •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 99% •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): hepatic •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Dipyridamole is metabolized in the liver to the glucuronic acid conjugate and excreted with the bile. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 40 minutes •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): 2.3-3.5 mL/min/kg •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Hypotension, if it occurs, is likely to be of short duration, but a vasopressor drug may be used if necessary. The oral LD 50 in rats is greater than 6,000 mg/kg while in the dogs, the oral LD 50 is approximately 400 mg/kg. LD 50 =8.4g/kg (orally in rat) •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Aggrenox, Persantine •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Dipyridamole is a phosphodiesterase inhibitor used to prevent postoperative thromboembolic events. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Doxazosin interact?

•Drug A: Abaloparatide •Drug B: Doxazosin •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Doxazosin is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Doxazosin is indicated to treat the symptoms of benign prostatic hypertrophy, which may include urinary frequency, urgency, and nocturia, among other symptoms. In addition, doxazosin is indicated alone or in combination with various antihypertensive agents for the management of hypertension. Off-label uses of doxazosin include the treatment of pediatric hypertension and the treatment of ureteric calculi. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Doxazosin decreases standing and supine blood pressure and relieves the symptoms of benign prostatic hypertrophy through the inhibition of alpha-1 receptors. Doxazosin may cause hypotension due to its pharmacological actions. This frequently occurs in the upright position, leading to a feeling of dizziness or lightheadedness. The first dose of doxazosin may lead to such effects, however, subsequent doses may also cause them. The risk of these effects is particularly high when dose adjustments occur or there are long intervals between doxazosin doses. Treatment should be started with the 1 mg dose of doxazosin, followed by slow titration to the appropriate dose. Patients must be advised of this risk and to avoid situations in which syncope and dizziness could be hazardous following the ingestion of doxazosin. Interestingly doxazosin exerts beneficial effects on plasma lipids. It reduces LDL (low-density lipoprotein) cholesterol and triglyceride levels and increases HDL (high-density lipoprotein) cholesterol levels. A note on priapism risk In rare cases, doxazosin and other alpha-1 blockers may cause priapism, a painful occurrence of persistent and unrelievable penile erection that can lead to impotence if medical attention is not sought as soon as possible. Patients must be advised of the priapism risk associated with doxazosin and to seek medical attention immediately if it is suspected. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Doxazosin selectively inhibits the postsynaptic alpha-1 receptors on vascular smooth muscle by nonselectively blocking the alpha-1a, alpha-1b, and alpha-1d subtypes. This action on blood vessels decreases systemic peripheral vascular resistance, reducing blood pressure, exerting minimal effects on the heart rate due to its receptor selectivity. Norepinephrine-activated alpha-1 receptors located on the prostate gland and bladder neck normally cause contraction of regional muscular tissue, obstructing urinary flow and contributing to the symptoms of benign prostatic hypertrophy. Alpha-1 antagonism causes smooth muscle relaxation in the prostate and bladder, effectively relieving urinary frequency, urgency, weak urinary stream, and other unpleasant effects of BPH. Recently, doxazosin was found to cause apoptosis of hERG potassium channels in an in vitro setting, possibly contributing to a risk of heart failure with doxazosin use. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Doxazosin is rapidly absorbed in the gastrointestinal tract and peak concentrations are achieved within 2-3 hours after administration. The bioavailability is about 60%-70%. The intake of food with doxazosin is not expected to cause clinically significant effects. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The volume of distribution of doxazosin is 1.0-1.9 L/kg. In a study of radiolabeled doxazosin administered to pregnant rats, doxazosin was found to cross the placenta. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): The plasma protein binding of doxazosin is estimated at 98%.. It has also been shown to be bound to the alpha-1 acid glycoprotein. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Hepatic metabolism of doxazosin produces inactive O-demethylated and C-hydroxylated metabolites. Metabolism occurs via O-demethylation of the quinazoline nucleus of doxazosin or via hydroxylation of its benzodioxan portion. The enzymes involved in the metabolism of doxazosin include CYP2C19, CYP2D6, CYP2C19, and CYP3A4, which is the primary metabolizing enzyme. Doxazosin itself is considered to be mainly responsible for its pharmacological action, however, some active metabolites have been identified whose pharmacokinetics have not been adequately characterized. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): In a pharmacokinetic study using a 1 mg IV radiolabeled dose and a 2 mg oral dose, 63% of the ingested doxazosin was found to be excreted in the feces and about 9% of the dose was found to be excreted in the urine. Traces of radiolabeled unchanged drug were found in the urine and about 5% of the administered drug was found as unchanged drug excreted in the feces. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The terminal elimination half-life of doxazosin has been estimated at 9-12 hours according to some resources. The FDA label indicates the elimination half-life of doxazosin is 22 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The clearance of doxazosin is low and ranges from approximately 1-2 ml/min/kg. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): LD50 information The oral LD50 of doxazosin in mice is >1000 mg/kg. Overdose information Symptoms of overdose include hypotension, changes in heart rate, and drowsiness. Administer supportive treatment in case of an overdose with doxazosin. Remove unabsorbed doxazosin from the gastrointestinal tract, correct hypotension, and closely monitor vital signs. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Cardura •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Doxazosin Doxazosina Doxazosine Doxazosinum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Doxazosin is an alpha-1 adrenergic receptor used to treat mild to moderate hypertension and urinary obstruction due to benign prostatic hyperplasia.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Doxazosin interact? Information: •Drug A: Abaloparatide •Drug B: Doxazosin •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Doxazosin is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Doxazosin is indicated to treat the symptoms of benign prostatic hypertrophy, which may include urinary frequency, urgency, and nocturia, among other symptoms. In addition, doxazosin is indicated alone or in combination with various antihypertensive agents for the management of hypertension. Off-label uses of doxazosin include the treatment of pediatric hypertension and the treatment of ureteric calculi. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Doxazosin decreases standing and supine blood pressure and relieves the symptoms of benign prostatic hypertrophy through the inhibition of alpha-1 receptors. Doxazosin may cause hypotension due to its pharmacological actions. This frequently occurs in the upright position, leading to a feeling of dizziness or lightheadedness. The first dose of doxazosin may lead to such effects, however, subsequent doses may also cause them. The risk of these effects is particularly high when dose adjustments occur or there are long intervals between doxazosin doses. Treatment should be started with the 1 mg dose of doxazosin, followed by slow titration to the appropriate dose. Patients must be advised of this risk and to avoid situations in which syncope and dizziness could be hazardous following the ingestion of doxazosin. Interestingly doxazosin exerts beneficial effects on plasma lipids. It reduces LDL (low-density lipoprotein) cholesterol and triglyceride levels and increases HDL (high-density lipoprotein) cholesterol levels. A note on priapism risk In rare cases, doxazosin and other alpha-1 blockers may cause priapism, a painful occurrence of persistent and unrelievable penile erection that can lead to impotence if medical attention is not sought as soon as possible. Patients must be advised of the priapism risk associated with doxazosin and to seek medical attention immediately if it is suspected. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Doxazosin selectively inhibits the postsynaptic alpha-1 receptors on vascular smooth muscle by nonselectively blocking the alpha-1a, alpha-1b, and alpha-1d subtypes. This action on blood vessels decreases systemic peripheral vascular resistance, reducing blood pressure, exerting minimal effects on the heart rate due to its receptor selectivity. Norepinephrine-activated alpha-1 receptors located on the prostate gland and bladder neck normally cause contraction of regional muscular tissue, obstructing urinary flow and contributing to the symptoms of benign prostatic hypertrophy. Alpha-1 antagonism causes smooth muscle relaxation in the prostate and bladder, effectively relieving urinary frequency, urgency, weak urinary stream, and other unpleasant effects of BPH. Recently, doxazosin was found to cause apoptosis of hERG potassium channels in an in vitro setting, possibly contributing to a risk of heart failure with doxazosin use. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Doxazosin is rapidly absorbed in the gastrointestinal tract and peak concentrations are achieved within 2-3 hours after administration. The bioavailability is about 60%-70%. The intake of food with doxazosin is not expected to cause clinically significant effects. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The volume of distribution of doxazosin is 1.0-1.9 L/kg. In a study of radiolabeled doxazosin administered to pregnant rats, doxazosin was found to cross the placenta. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): The plasma protein binding of doxazosin is estimated at 98%.. It has also been shown to be bound to the alpha-1 acid glycoprotein. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Hepatic metabolism of doxazosin produces inactive O-demethylated and C-hydroxylated metabolites. Metabolism occurs via O-demethylation of the quinazoline nucleus of doxazosin or via hydroxylation of its benzodioxan portion. The enzymes involved in the metabolism of doxazosin include CYP2C19, CYP2D6, CYP2C19, and CYP3A4, which is the primary metabolizing enzyme. Doxazosin itself is considered to be mainly responsible for its pharmacological action, however, some active metabolites have been identified whose pharmacokinetics have not been adequately characterized. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): In a pharmacokinetic study using a 1 mg IV radiolabeled dose and a 2 mg oral dose, 63% of the ingested doxazosin was found to be excreted in the feces and about 9% of the dose was found to be excreted in the urine. Traces of radiolabeled unchanged drug were found in the urine and about 5% of the administered drug was found as unchanged drug excreted in the feces. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The terminal elimination half-life of doxazosin has been estimated at 9-12 hours according to some resources. The FDA label indicates the elimination half-life of doxazosin is 22 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The clearance of doxazosin is low and ranges from approximately 1-2 ml/min/kg. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): LD50 information The oral LD50 of doxazosin in mice is >1000 mg/kg. Overdose information Symptoms of overdose include hypotension, changes in heart rate, and drowsiness. Administer supportive treatment in case of an overdose with doxazosin. Remove unabsorbed doxazosin from the gastrointestinal tract, correct hypotension, and closely monitor vital signs. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Cardura •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Doxazosin Doxazosina Doxazosine Doxazosinum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Doxazosin is an alpha-1 adrenergic receptor used to treat mild to moderate hypertension and urinary obstruction due to benign prostatic hyperplasia. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Duloxetine interact?

•Drug A: Abaloparatide •Drug B: Duloxetine •Severity: MINOR •Description: The risk or severity of orthostatic hypotension and syncope can be increased when Abaloparatide is combined with Duloxetine. •Extended Description: Cases of orthostatic hypotension and syncope have been reported with therapeutic doses of duloxetine, which may occur anytime during therapy, particularly within the first week of therapy. The risk of developing decreased blood pressure may increase with the concomitant use of other agents known to cause hypotension. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Indicated for: 1) Management of Major Depressive Disorder. 2) Management of Generalized Anxiety Disorder. 3) Management of diabetic peripheral neuropathy. 4) Management of fibromyalgia. 5) Management of chronic musculoskeletal pain. 6) Management of osteoarthritis of the knee in adults. 7) Management of chronic lower back pain in adults. 8) Management of stress urinary incontinence in adult women. Off-label uses include: 1) Management of chemotherapy-induced peripheral neuropathy. 2) Management of stress urinary incontinence in adult men after prostatectomy until recovery is complete. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Duloxetine, through increasing serotonin and norepinephrine concentrations in Onuf's nucleus, enhances glutamatergic activation of the pudendal motor nerve which innervates the external urethral sphinter. This enhanced signaling allows for stronger contraction. Increased contraction of this sphincter increases the pressure needed to produce an incontinence episode in stress urinary incontinence. Duloxetine has been shown to improve Patient Global Impression of Improvement and Incontinence Quality of Life scores. It has also been shown to reduce the median incontinence episode frequency at doses of 40 and 80 mg. Action at the dorsal horn of the spinal cord allows duloxetine to strengthen the the serotonergic and adrenergic pathways involved in descending inhibition of pain. This results in an increased threshold of activation necessary to transmit painful stimuli to the brain and effective relief of pain, particularly in neuropathic pain. Pain relief has been noted in a variety of painful conditions including diabetic peripheral neuropathy, fibromyalgia, and osteoarthritis using a range of pain assessment surveys. While duloxetine has been shown to be effective in both animal models of mood disorders and in clinical trials for the treatment of these disorders in humans, the broad scope of its pharmacodynamic effects on mood regulation in the brain has yet to be explained. Increased blood pressure is a common side effect with duloxetine due to vasoconstriction mediated by the intended increase in norepinephrine signaling. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors. Action on the external urinary sphincter is mediated via duloxetine's CNS effects. Increased serotonin and norepinephrine concentrations in Onuf's nucleus leads to increased activation of 5-HT 2, 5-HT 3, and α 1 adrenergic receptors. 5-HT 2 and α 1 are both G q coupled and their activation increases the activity of the inositol trisphosphate/phospholipase C (IP 3 /PLC) pathway. This pathway leads to release of intracellular calcium stores, increasing intracellular calcium concentrations, and facilitating neuronal excitability. 5-HT 3 functions as a ligand-gated sodium channel which allows sodium to flow into the neuron when activated. Increased flow of sodium into the neuron contributes to depolarization and activation of voltage gated channels involved in action potential generation. The combined action of these three receptors contributes to increased excitability of the pudendal motor nerve in response to glutamate. Also related to duloxetine's action at the spinal cord is its modulation of pain. Increasing the concentration of serotonin and norepinephrine in the dorsal horn of the spinal cord increases descending inhibition of pain through activation of 5-HT 1A, 5-HT 1B, 5-HT 1D, 5-HT 2, 5-HT 3, α 1 -adrenergic, and α 2 -adrenergic receptors. 5-HT 2, 5-HT 3, and α 1 -adrenergic mediate neuronal activation as described above. The activated neuron in this case is the GABAergic inhibitory interneuron which synapses onto the nociceptive projection neuron to inhibit the transmission of painful stimuli to the brain. The 5-HT 1 and α 2 receptors are G i /G o coupled and their activation leads to increased potassium current through inward rectifier channels and decreased adenylyl cyclase/protein kinase A signaling which contributes to neuronal inhibition. These inhibitory receptors are present on the projection neuron itself as well as the dorsal root ganglion which precedes it and serves to directly suppress the transmission of painful stimuli. The mechanisms involved in duloxetine's benefits in depression and anxiety have not been fully elucidated. Dysfunctional serotonin and norepinephrine signaling are thought to be involved and increases in the availability of these neurotransmitters at the synaptic cleft thought to mediate a therapeutic effect. It is postulated that the involvement of serotonin and norepinephrine in area responsible for emotional modulation such as the limbic system contributes to the effects in mood disorders specifically but this has yet to be confirmed. Duloxetine's hypertensive effect is related to its intended pharmacological effect. Increased availability of norepinephrine leads to activation of adrenergic receptors on the vascular endothelium. Since the action of α 1 receptors predominates, vasoconstriction results as the G q coupled receptor mediates calcium release from the sarcoplasmic reticulum to facilitate smooth muscle contraction. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Duloxetine is incompletely absorbed with a mean bioavailability of 50% although there is wide variability in the range of 30-80%. The population absorption constant (ka) is 0.168 h.The molecule is susceptible to hydrolysis in acidic environments necessitating the use of an enteric coating to protect it during transit through the stomach. This creates a 2 hour lag time from administration to the start of absorption. The Tmax is 6 hours including the lag time. Administering duloxetine with food 3 hour delay in Tmax along with an 10% decrease in AUC. Similarly, administering the dose at bedtime produces a 4 hour delay and 18% decrease in AUC with a 29% reduction in Cmax. These are attributed to delayed gastric emptying in both cases but are not expected to impact therapy to a clinically significant degree. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Apparent Vd of 1620-1800 L. Duloxetine crosses the blood-brain barrier and collects in the cerebral cortex at a higher concentration than the plasma. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Over 90% bound to plasma proteins, primarily albumin and α1 acid-glycoprotein. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Duloxetine is extensively metabolized primarily by CYP1A2 and CYP2D6 with the former being the greater contributor. It is hydroxylated at the 4, 5, or 6 positions on the naphthalene ring with the 4-hydroxy metabolite proceeding directly to a glucuronide conjugate while the 5 and 6-hydroxy metabolites proceed through a catechol and a 5-hydroxy, 6-methoxy intermediate before undergoing glucuronide or sulfate conjugation. CYP2C9 is known to be a minor contributor to the 5-hydroxy metabolite. Another uncharacterized metabolite is known to be excreted in the feces but comprises <5% of the total excreted drug. Many other metabolites exist but have not been identified due their low contribution to the overall profile of duloxetine and lack of clinical significance. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): About 70% of duloxetine is excreted in the urine mainly as conjugated metabolites. Another 20% is present in the feces as the parent drug, 4-hydroxy metabolite, and an uncharacterized metabolite. Biliary secretion is thought to play a role due to timeline of fecal excretion exceeding the time expected of normal GI transit. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Mean of 12 h with a range of 8-17. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): There is a large degree of interindividual variation reported in the clearance of duloxetine with values ranging from 57-114 L/h. Steady state concentrations have still been shown to be dose proportional with a doubling of dose from 30 to 60 mg and from 60 to 120 mg producing 2.3 and 2.6 times the Css respectively. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Overdose Fatalities have been reported with doses of 1000mg involving both mixed drugs as well as duloxetine alone. Signs and symptoms of overdose include: somnolence, coma, serotonin syndrome, seizure, syncope, hypo- or hypertension, tachycardia, and vomiting. No antidote exists and the drug is unlikely to be cleared by hemodialysis. Supportive care is recommended along with activated charcoal and gastric lavage to reduce absorption. If serotonin syndrome occurs specific treatment such as temperature control or cyproheptadine may be initiated. Carcinogenicity & Mutagenicity Increased incidence of hepatocellular carcinomas and adenomas were reported in female mice fed 140 mg/kg/day duloxetine for 2 years, equivalent to 6 times the maximum recommended human dose (MRHD). No effect was reported with doses of 50mg/kg/day (2 time MRHD) in females or 100 mg/kg/day in males (4 times MRHD). Similar investigation in rats produced no carcinogenicity at doses of 27 mg/kg/day (2 times MRHD)in females and 36 mg/kg/day in males (4 times MRHD). No mutagenicity, clastogenicity, induction of sister chromatid exchange, or genotoxicity has been observed in toxicology investigations. Reproductive Toxicity Neither male or female rats displayed adverse reproductive effects at doses up to 45 mg/kg/day (4 times MRHD). Lactation An estimated 25% of plasma duloxetine appears in breast milk with the estimated daily infant dose being 0.14% of the maternal dose. Breast milk concentrations have been observed to peak 3 hours after administration. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Cymbalta, Drizalma, Irenka, Yentreve •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-duloxetine Duloxetina Duloxetine •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Duloxetine is a serotonin norepinephrine reuptake inhibitor used to treat generalized anxiety disorder, neuropathic pain, osteoarthritis, and stress incontinence.

Cases of orthostatic hypotension and syncope have been reported with therapeutic doses of duloxetine, which may occur anytime during therapy, particularly within the first week of therapy. The risk of developing decreased blood pressure may increase with the concomitant use of other agents known to cause hypotension. The severity of the interaction is minor.

Question: Does Abaloparatide and Duloxetine interact? Information: •Drug A: Abaloparatide •Drug B: Duloxetine •Severity: MINOR •Description: The risk or severity of orthostatic hypotension and syncope can be increased when Abaloparatide is combined with Duloxetine. •Extended Description: Cases of orthostatic hypotension and syncope have been reported with therapeutic doses of duloxetine, which may occur anytime during therapy, particularly within the first week of therapy. The risk of developing decreased blood pressure may increase with the concomitant use of other agents known to cause hypotension. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Indicated for: 1) Management of Major Depressive Disorder. 2) Management of Generalized Anxiety Disorder. 3) Management of diabetic peripheral neuropathy. 4) Management of fibromyalgia. 5) Management of chronic musculoskeletal pain. 6) Management of osteoarthritis of the knee in adults. 7) Management of chronic lower back pain in adults. 8) Management of stress urinary incontinence in adult women. Off-label uses include: 1) Management of chemotherapy-induced peripheral neuropathy. 2) Management of stress urinary incontinence in adult men after prostatectomy until recovery is complete. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Duloxetine, through increasing serotonin and norepinephrine concentrations in Onuf's nucleus, enhances glutamatergic activation of the pudendal motor nerve which innervates the external urethral sphinter. This enhanced signaling allows for stronger contraction. Increased contraction of this sphincter increases the pressure needed to produce an incontinence episode in stress urinary incontinence. Duloxetine has been shown to improve Patient Global Impression of Improvement and Incontinence Quality of Life scores. It has also been shown to reduce the median incontinence episode frequency at doses of 40 and 80 mg. Action at the dorsal horn of the spinal cord allows duloxetine to strengthen the the serotonergic and adrenergic pathways involved in descending inhibition of pain. This results in an increased threshold of activation necessary to transmit painful stimuli to the brain and effective relief of pain, particularly in neuropathic pain. Pain relief has been noted in a variety of painful conditions including diabetic peripheral neuropathy, fibromyalgia, and osteoarthritis using a range of pain assessment surveys. While duloxetine has been shown to be effective in both animal models of mood disorders and in clinical trials for the treatment of these disorders in humans, the broad scope of its pharmacodynamic effects on mood regulation in the brain has yet to be explained. Increased blood pressure is a common side effect with duloxetine due to vasoconstriction mediated by the intended increase in norepinephrine signaling. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors. Action on the external urinary sphincter is mediated via duloxetine's CNS effects. Increased serotonin and norepinephrine concentrations in Onuf's nucleus leads to increased activation of 5-HT 2, 5-HT 3, and α 1 adrenergic receptors. 5-HT 2 and α 1 are both G q coupled and their activation increases the activity of the inositol trisphosphate/phospholipase C (IP 3 /PLC) pathway. This pathway leads to release of intracellular calcium stores, increasing intracellular calcium concentrations, and facilitating neuronal excitability. 5-HT 3 functions as a ligand-gated sodium channel which allows sodium to flow into the neuron when activated. Increased flow of sodium into the neuron contributes to depolarization and activation of voltage gated channels involved in action potential generation. The combined action of these three receptors contributes to increased excitability of the pudendal motor nerve in response to glutamate. Also related to duloxetine's action at the spinal cord is its modulation of pain. Increasing the concentration of serotonin and norepinephrine in the dorsal horn of the spinal cord increases descending inhibition of pain through activation of 5-HT 1A, 5-HT 1B, 5-HT 1D, 5-HT 2, 5-HT 3, α 1 -adrenergic, and α 2 -adrenergic receptors. 5-HT 2, 5-HT 3, and α 1 -adrenergic mediate neuronal activation as described above. The activated neuron in this case is the GABAergic inhibitory interneuron which synapses onto the nociceptive projection neuron to inhibit the transmission of painful stimuli to the brain. The 5-HT 1 and α 2 receptors are G i /G o coupled and their activation leads to increased potassium current through inward rectifier channels and decreased adenylyl cyclase/protein kinase A signaling which contributes to neuronal inhibition. These inhibitory receptors are present on the projection neuron itself as well as the dorsal root ganglion which precedes it and serves to directly suppress the transmission of painful stimuli. The mechanisms involved in duloxetine's benefits in depression and anxiety have not been fully elucidated. Dysfunctional serotonin and norepinephrine signaling are thought to be involved and increases in the availability of these neurotransmitters at the synaptic cleft thought to mediate a therapeutic effect. It is postulated that the involvement of serotonin and norepinephrine in area responsible for emotional modulation such as the limbic system contributes to the effects in mood disorders specifically but this has yet to be confirmed. Duloxetine's hypertensive effect is related to its intended pharmacological effect. Increased availability of norepinephrine leads to activation of adrenergic receptors on the vascular endothelium. Since the action of α 1 receptors predominates, vasoconstriction results as the G q coupled receptor mediates calcium release from the sarcoplasmic reticulum to facilitate smooth muscle contraction. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Duloxetine is incompletely absorbed with a mean bioavailability of 50% although there is wide variability in the range of 30-80%. The population absorption constant (ka) is 0.168 h.The molecule is susceptible to hydrolysis in acidic environments necessitating the use of an enteric coating to protect it during transit through the stomach. This creates a 2 hour lag time from administration to the start of absorption. The Tmax is 6 hours including the lag time. Administering duloxetine with food 3 hour delay in Tmax along with an 10% decrease in AUC. Similarly, administering the dose at bedtime produces a 4 hour delay and 18% decrease in AUC with a 29% reduction in Cmax. These are attributed to delayed gastric emptying in both cases but are not expected to impact therapy to a clinically significant degree. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Apparent Vd of 1620-1800 L. Duloxetine crosses the blood-brain barrier and collects in the cerebral cortex at a higher concentration than the plasma. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Over 90% bound to plasma proteins, primarily albumin and α1 acid-glycoprotein. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Duloxetine is extensively metabolized primarily by CYP1A2 and CYP2D6 with the former being the greater contributor. It is hydroxylated at the 4, 5, or 6 positions on the naphthalene ring with the 4-hydroxy metabolite proceeding directly to a glucuronide conjugate while the 5 and 6-hydroxy metabolites proceed through a catechol and a 5-hydroxy, 6-methoxy intermediate before undergoing glucuronide or sulfate conjugation. CYP2C9 is known to be a minor contributor to the 5-hydroxy metabolite. Another uncharacterized metabolite is known to be excreted in the feces but comprises <5% of the total excreted drug. Many other metabolites exist but have not been identified due their low contribution to the overall profile of duloxetine and lack of clinical significance. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): About 70% of duloxetine is excreted in the urine mainly as conjugated metabolites. Another 20% is present in the feces as the parent drug, 4-hydroxy metabolite, and an uncharacterized metabolite. Biliary secretion is thought to play a role due to timeline of fecal excretion exceeding the time expected of normal GI transit. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Mean of 12 h with a range of 8-17. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): There is a large degree of interindividual variation reported in the clearance of duloxetine with values ranging from 57-114 L/h. Steady state concentrations have still been shown to be dose proportional with a doubling of dose from 30 to 60 mg and from 60 to 120 mg producing 2.3 and 2.6 times the Css respectively. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Overdose Fatalities have been reported with doses of 1000mg involving both mixed drugs as well as duloxetine alone. Signs and symptoms of overdose include: somnolence, coma, serotonin syndrome, seizure, syncope, hypo- or hypertension, tachycardia, and vomiting. No antidote exists and the drug is unlikely to be cleared by hemodialysis. Supportive care is recommended along with activated charcoal and gastric lavage to reduce absorption. If serotonin syndrome occurs specific treatment such as temperature control or cyproheptadine may be initiated. Carcinogenicity & Mutagenicity Increased incidence of hepatocellular carcinomas and adenomas were reported in female mice fed 140 mg/kg/day duloxetine for 2 years, equivalent to 6 times the maximum recommended human dose (MRHD). No effect was reported with doses of 50mg/kg/day (2 time MRHD) in females or 100 mg/kg/day in males (4 times MRHD). Similar investigation in rats produced no carcinogenicity at doses of 27 mg/kg/day (2 times MRHD)in females and 36 mg/kg/day in males (4 times MRHD). No mutagenicity, clastogenicity, induction of sister chromatid exchange, or genotoxicity has been observed in toxicology investigations. Reproductive Toxicity Neither male or female rats displayed adverse reproductive effects at doses up to 45 mg/kg/day (4 times MRHD). Lactation An estimated 25% of plasma duloxetine appears in breast milk with the estimated daily infant dose being 0.14% of the maternal dose. Breast milk concentrations have been observed to peak 3 hours after administration. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Cymbalta, Drizalma, Irenka, Yentreve •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-duloxetine Duloxetina Duloxetine •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Duloxetine is a serotonin norepinephrine reuptake inhibitor used to treat generalized anxiety disorder, neuropathic pain, osteoarthritis, and stress incontinence. Output: Cases of orthostatic hypotension and syncope have been reported with therapeutic doses of duloxetine, which may occur anytime during therapy, particularly within the first week of therapy. The risk of developing decreased blood pressure may increase with the concomitant use of other agents known to cause hypotension. The severity of the interaction is minor.

Does Abaloparatide and Empagliflozin interact?

•Drug A: Abaloparatide •Drug B: Empagliflozin •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abaloparatide is combined with Empagliflozin. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Empagliflozin is indicated as an adjunct to diet and exercise to improve glycemic control in patients aged 10 years and older with type 2 diabetes. It is used either alone or in combination with metformin or linagliptin. It is also indicated to reduce the risk of cardiovascular death in adult patients with both type 2 diabetes mellitus and established cardiovascular disease, either alone or as a combination product with metformin. An extended-release combination product containing empagliflozin, metformin, and linagliptin was approved by the FDA in January 2020 for the improvement of glycemic control in adults with type 2 diabetes mellitus when used adjunctively with diet and exercise. Empagliflozin is also approved to reduce the risk of cardiovascular mortality and hospitalization due to heart failure in adult patients with heart failure, either alone or in combination with metformin. It is also indicated in adults to reduce the risk of sustained decline in eGFR, end-stage kidney disease, cardiovascular death, and hospitalization in adults with chronic kidney disease at risk of progression. Empagliflozin is not approved for use in patients with type 1 diabetes. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Empagliflozin lowers blood glucose levels by preventing glucose reabsorption in the kidneys, thereby increasing the amount of glucose excreted in the urine. It has a relatively long duration of action requiring only once-daily dosing. Patients should be monitored closely for signs and symptoms of ketoacidosis regardless of blood glucose level as empagliflozin may precipitate diabetic ketoacidosis in the absence of hyperglycemia. As its mechanism of action is contingent on the renal excretion of glucose, empagliflozin may be held in cases of acute kidney injury and/or discontinued in patients who develop chronic renal disease. The overexcretion of glucose creates a sugar-rich urogenital environment which increases the risk of urogenital infections in both male and female patients - monitor closely for signs and symptoms of developing infection. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): The vast majority of glucose filtered through the glomerulus is reabsorbed within the proximal tubule, primarily via SGLT2 (sodium-glucose linked co-transporter-2) which is responsible for ~90% of the total glucose reabsorption within the kidneys. Na /K -ATPase on the basolateral membrane of proximal tubular cells utilize ATP to actively pump Na+ ions into the interstitium surrounding the tubule, establishing a Na gradient within the tubular cell. SGLT2 on the apical membrane of these cells then utilize this gradient to facilitate secondary active co-transport of both Na+ and glucose out of the filtrate, thereby reabsorbing glucose back into the blood – inhibiting this co-transport, then, allows for a marked increase in glucosuria and decrease in blood glucose levels. Empagliflozin is a potent inhibitor of renal SGLT2 transporters located in the proximal tubules of the kidneys and works to lower blood glucose levels via an increase in glucosuria. Empagliflozin also appears to exert cardiovascular benefits - specifically in the prevention of heart failure - independent of its blood glucose-lowering effects, though the exact mechanism of this benefit is not precisely understood. Several theories have been posited, including the potential inhibition of Na /H exchanger (NHE) 1 in the myocardium and NHE3 in the proximal tubule, reduction of pre-load via diuretic/natriuretic effects and reduction of blood pressure, prevention of cardiac fibrosis via suppression of pro-fibrotic markers, and reduction of pro-inflammatory adipokines. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Following oral administration, peak plasma concentrations are reached in approximately 1.5 hours (T max ). At steady-state, plasma AUC and C max were 1870 nmol·h/L and 259 nmol/L, respectively, following therapy with empagliflozin 10mg daily and 4740 nmol·h/L and 687 nmol/L, respectively, following therapy with empagliflozin 25mg daily. Administration with food does not significantly affect the absorption of empagliflozin. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The estimated apparent steady-state volume of distribution is 73.8 L. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Empagliflozin is approximately 86.2% protein-bound in plasma. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Empagliflozin undergoes minimal metabolism. It is primarily metabolized via glucuronidation by 5'-diphospho-glucuronosyltransferases 2B7, 1A3, 1A8, and 1A9 to yield three glucuronide metabolites: 2-O-, 3-O-, and 6-O-glucuronide. No metabolite represented more than 10% of total drug-related material. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): After oral administration of radiolabeled empagliflozin approximately 41.2% of the administered dose was found eliminated in feces and 54.4% eliminated in urine. The majority of radioactivity in the feces was due to unchanged parent drug while approximately half of the radioactivity in urine was due to unchanged parent drug. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The apparent terminal elimination half-life was found to be 12.4 h based on population pharmacokinetic analysis. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Apparent oral clearance was found to be 10.6 L/h based on a population pharmacokinetic analysis. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Experience with empagliflozin overdose is limited - employ standard symptomatic and supportive measures, as well as gastric decontamination when appropriate. The use of hemodialysis in empagliflozin overdose has not been studied but is unlikely to be of benefit given the drug's relatively high protein-binding. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Glyxambi, Jardiance, Synjardy, Trijardy •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Empagliflozin Empagliflozina Empagliflozine Empagliflozinum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Empagliflozin is an SGLT2 inhibitor used to manage type 2 diabetes mellitus.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Empagliflozin interact? Information: •Drug A: Abaloparatide •Drug B: Empagliflozin •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abaloparatide is combined with Empagliflozin. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Empagliflozin is indicated as an adjunct to diet and exercise to improve glycemic control in patients aged 10 years and older with type 2 diabetes. It is used either alone or in combination with metformin or linagliptin. It is also indicated to reduce the risk of cardiovascular death in adult patients with both type 2 diabetes mellitus and established cardiovascular disease, either alone or as a combination product with metformin. An extended-release combination product containing empagliflozin, metformin, and linagliptin was approved by the FDA in January 2020 for the improvement of glycemic control in adults with type 2 diabetes mellitus when used adjunctively with diet and exercise. Empagliflozin is also approved to reduce the risk of cardiovascular mortality and hospitalization due to heart failure in adult patients with heart failure, either alone or in combination with metformin. It is also indicated in adults to reduce the risk of sustained decline in eGFR, end-stage kidney disease, cardiovascular death, and hospitalization in adults with chronic kidney disease at risk of progression. Empagliflozin is not approved for use in patients with type 1 diabetes. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Empagliflozin lowers blood glucose levels by preventing glucose reabsorption in the kidneys, thereby increasing the amount of glucose excreted in the urine. It has a relatively long duration of action requiring only once-daily dosing. Patients should be monitored closely for signs and symptoms of ketoacidosis regardless of blood glucose level as empagliflozin may precipitate diabetic ketoacidosis in the absence of hyperglycemia. As its mechanism of action is contingent on the renal excretion of glucose, empagliflozin may be held in cases of acute kidney injury and/or discontinued in patients who develop chronic renal disease. The overexcretion of glucose creates a sugar-rich urogenital environment which increases the risk of urogenital infections in both male and female patients - monitor closely for signs and symptoms of developing infection. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): The vast majority of glucose filtered through the glomerulus is reabsorbed within the proximal tubule, primarily via SGLT2 (sodium-glucose linked co-transporter-2) which is responsible for ~90% of the total glucose reabsorption within the kidneys. Na /K -ATPase on the basolateral membrane of proximal tubular cells utilize ATP to actively pump Na+ ions into the interstitium surrounding the tubule, establishing a Na gradient within the tubular cell. SGLT2 on the apical membrane of these cells then utilize this gradient to facilitate secondary active co-transport of both Na+ and glucose out of the filtrate, thereby reabsorbing glucose back into the blood – inhibiting this co-transport, then, allows for a marked increase in glucosuria and decrease in blood glucose levels. Empagliflozin is a potent inhibitor of renal SGLT2 transporters located in the proximal tubules of the kidneys and works to lower blood glucose levels via an increase in glucosuria. Empagliflozin also appears to exert cardiovascular benefits - specifically in the prevention of heart failure - independent of its blood glucose-lowering effects, though the exact mechanism of this benefit is not precisely understood. Several theories have been posited, including the potential inhibition of Na /H exchanger (NHE) 1 in the myocardium and NHE3 in the proximal tubule, reduction of pre-load via diuretic/natriuretic effects and reduction of blood pressure, prevention of cardiac fibrosis via suppression of pro-fibrotic markers, and reduction of pro-inflammatory adipokines. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Following oral administration, peak plasma concentrations are reached in approximately 1.5 hours (T max ). At steady-state, plasma AUC and C max were 1870 nmol·h/L and 259 nmol/L, respectively, following therapy with empagliflozin 10mg daily and 4740 nmol·h/L and 687 nmol/L, respectively, following therapy with empagliflozin 25mg daily. Administration with food does not significantly affect the absorption of empagliflozin. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The estimated apparent steady-state volume of distribution is 73.8 L. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Empagliflozin is approximately 86.2% protein-bound in plasma. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Empagliflozin undergoes minimal metabolism. It is primarily metabolized via glucuronidation by 5'-diphospho-glucuronosyltransferases 2B7, 1A3, 1A8, and 1A9 to yield three glucuronide metabolites: 2-O-, 3-O-, and 6-O-glucuronide. No metabolite represented more than 10% of total drug-related material. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): After oral administration of radiolabeled empagliflozin approximately 41.2% of the administered dose was found eliminated in feces and 54.4% eliminated in urine. The majority of radioactivity in the feces was due to unchanged parent drug while approximately half of the radioactivity in urine was due to unchanged parent drug. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The apparent terminal elimination half-life was found to be 12.4 h based on population pharmacokinetic analysis. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Apparent oral clearance was found to be 10.6 L/h based on a population pharmacokinetic analysis. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Experience with empagliflozin overdose is limited - employ standard symptomatic and supportive measures, as well as gastric decontamination when appropriate. The use of hemodialysis in empagliflozin overdose has not been studied but is unlikely to be of benefit given the drug's relatively high protein-binding. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Glyxambi, Jardiance, Synjardy, Trijardy •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Empagliflozin Empagliflozina Empagliflozine Empagliflozinum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Empagliflozin is an SGLT2 inhibitor used to manage type 2 diabetes mellitus. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Enalapril interact?

•Drug A: Abaloparatide •Drug B: Enalapril •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Enalapril is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Indicated for the management of essential or renovascular hypertension as monotherapy or in combination with other antihypertensive agents, such as thiazide diuretics, for an additive effect. Indicated for the treatment of symptomatic congestive heart failure, usually in combination with diuretics and digitalis. Indicated for the management of asymptomatic left ventricular dysfunction in patients with an ejection fraction of ≤ to 35 percent to decrease the rate of development of overt heart failure and the incidence of hospitalization for heart failure. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Enalapril is an antihypertensive agent that exhibits natriuretic and uricosuric properties. Enalapril lowers blood pressure in all grades of essential and renovascular hypertension, and peripheral vascular resistance without causing an increase in heart rate. Individuals with low-renin hypertensive population were still responsive to enalapril. The duration of hypertensive effect in the systolic and diastolic blood pressure persists for at least 24 hours following initial administration of a single oral dose, and repeated daily administration of enalapril confers an additional reduction in blood pressure and a steady-state antihypertensive response may take several weeks. In patients with severe congestive heart failure and inadequate clinical response to conventional antihypertensive therapies, treatment with enalapril resulted in improvements in cardiac performance as observed by a reduction in both preload and afterload, and improved clinical status long-term. Furthermore, enalapril was shown to increase cardiac output and stroke volume while decreasing pulmonary capillary wedge pressure in patients with congestive heart failure refractory to conventional treatment with digitalis and diuretics. In clinical studies, enalapril reduced left ventricular mass, and did not affect cardiac function or myocardial perfusion during exercise. Enalapril is not highly associated with the risk of bradycardia unlike most diuretics and beta-blockers and it does not produce rebound hypertension upon discontinuation of therapy. Enalapril is not reported to produce hypokalaemia, hyperglycaemia, hyperuricaemia or hypercholesterolaemia. In the kidneys, enalapril was shown to increase renal blood flow and decrease renal vascular resistance. It also augmented the glomerular filtration rate in patients with a glomerular filtration rate less than 80 mL/min. When used in combination, enalapril was shown to attenuate the extent of drug-induced hypokalemia caused by hydrochlorothiazide and the antihypertensive effects of both drugs were potentiated. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): The renin-angiotensin-aldosterone system (RAAS) is a signaling pathway that works in synergism with the sympathetic system to regulate blood pressure and fluid and electrolyte homeostasis. Activation of this system upon stimulation by different factors, such as low blood pressure and nerve impulses, leads to increased release of norepinephrine (NE) from sympathetic nerve terminals and effects on the vascular growth, vasoconstriction, and salt retention in the kidneys. Renin is released from Renin acts on the precursor prottein angiotensinogen, which is a plasma globulin synthesized from the liver, to produce cleaved peptide hormone angiotensin I. Angiotensin I then can be further cleaved by ACE to produce angiotensin II, a vasoconstrictive peptide hormone. Present in different isoforms, angiotensin converting enzyme (ACE) is peptidyl dipeptidase enzyme expressed in various tissues, including the vascular tissues, such as the heart, brain, and kidneys. ACE also plays a role in inactivation of bradykinin, a potent vasodepressor peptide. Angiotensin II mediates various actions on the body by working on its G-protein coupled receptors, AT1 and AT2. It causes direct vasoconstriction of precapillary arterioles and postcapillary venules, inhibits the reuptake of NE thereby increasing available levels, stimulates the release of catecholamines from the adrenal medulla, reduces urinary excretion of sodium ions and water by promoting proximal tubular reabsorption, stimulates synthesis and release of aldosterone from the adrenal cortex, and stimulates hypertrophy of both vascular smooth muscle cells and cardiac myocytes. Enalapril is a pharmacologically inactive prodrug that requires hepatic biotransformation to form enalaprilat, its active metabolite that works on the RAAS to inhibit ACE. Biotransformation is critial for the therapeutic actions of the drug, as enalapril itself is only a weak inhibitor of ACE. ACE inhibition results in reduced production and plasma levels of angiotensin II, increased plasma renin activity due to the loss of feedback inhibition by angiotensin II, and decreased aldosterone secretion. However, plasma aldosterone levels usually return to normal during long-term administration of enalapril. Decreased levels of angiotensin II subsequently leads to the dilatation of peripheral vessles and reduced vascular resistance which in turn lower blood pressure. While inhibition of ACE leading to suppression of RAAS is thought to be the primary mechanism of action of enalapril, the drug was shown to still exert antihypertensive effects on individuals with low-renin hypertension. It is suggested that enalapril may mediate its pharmacological actions via other modes of action that are not fully understood. As ACE is structurally similar to kininase I, which is a carboxypeptidase that degrades bradykinin, whether increased levels of bradykinin play a role in the therapeutic effects of enalapril remains to be elucidated. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Following oral administration, the peak plasma concentrations (Cmax) of enalapril is achieved within 1 hour post dosing while the Cmax of enalaprilat occurs at three to four hours post dosing. The steady-state is achieved by the fourth daily dose and there is no accumulation with repeated dosing. However, accumulation of enalaprilat may occur in patients with creatinine clearance less than 30 mL/min. Food intake is reported to have a minimal effect on drug absorption. Following oral administration, about 60% of enalapril was absorbed. Bioavailability of enalapril averaged about 40% when intravenous enalaprilat was used as a reference standard. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The volume of distribution of enalapril has not been established. Enalaprilat is shown to penetrate into most tissuesm, in particular the kidneys and vascular tissuem, although penetration of the blood-brain barrier has not been demonstrated after administration at therapeutic doses. In dog studies, enalapril and enalaprilat cross the blood-brain barrier poorly. Minimal penetration occurs into breast milk but significant fetal transfer occurs. The drug crosses the placental barrier in rats and hamsters. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): It is reported that less than 50% of enalaprilat is bound to human plasma proteins, based on limited data from binding studies of enalaprilat in human plasma both by equilibrium dialysis and by ultrafiltration. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): About 60% of the absorbed dose is extensively hydrolyzed to enalaprilat via de-esterification mediated by hepatic esterases. In humans, metabolism beyond bioactivation to enalaprilat is not observed. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Enalapril is mainly eliminated through renal excretion, where approximately 94% of the total dose is excreted via urine or feces as either enalaprilat or unchanged parent compound. About 61% and 33% of the total dose can be recovered in the urine and feces, respectively. In the urine, about 40% of the recovered dose is in the form of enalaprilat. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The average terminal half life of enalaprilat is 35-38 hours. The effective half life following multiple doses is 11-14 hours. The prolonged terminal half-life is due to the binding of enalaprilat to ACE. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Following oral administration in healthy male volunteers, the renal clearance was approximately 158 ± 47 mL/min. It is reported that enalapril and enalaprilat are undetectable in the plasma by 4 hours post-dosing. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): LD 50 and Overdose Oral LD 50 in rats is 2973 mg/kg. Lethality was observed with single oral doses of enalapril above 1000 mg/kg in mice and greater than or equal to 1775 mg/kg in rats. Serum enalaprilat levels 100- and 200-fold higher than usually seen after therapeutic doses have been reported after ingestion of 300 mg and 440 mg of enalapril, respectively. While there is limited data about enalapril overdose in humans, overdosage may result in marked hypotension and stupor based on the pharmacological properties of the drug. Most common adverse effects of enalapril include cough, hypotension, stupor, headache, dizziness and fatigue. If hypotension is seen, usual treatment of intravenous infusion of normal saline solution is recommended. Enalaprilat may be removed from systemic circulation with the use of hemodialysis. It has been removed from neonatal circulation by peritoneal dialysis. Nonclinical toxicology Maternal and fetal toxicity occudred in some rabbits treated with enalapril at doses of 1 mg/kg/day or more. There was no fetotoxicity, expressed as a decrease in average fetal weight, or teratogenicity in rats treated with enalapril at doses up to 200 mg/kg/day, which is about 333 times the maximum human dose. In mice and rats receiving enalapril at doses ranging from 90 to 180 mg/kg/day, there was no evidence of a tumorigenic effect. Neither enalapril or its active metabolite were shown to be mutagenic or genotoxic in in vitro and in vivo studies. There were no adverse effects on reproductive performance of male and female rats treated with up to 90 mg/kg/day of enalapril. Use in special populations Caution is warranted in patients who are concurrently using another ACE inhibitors with enalapril, as there have been incidences of agranulocytosis with the use of captopril, which is another ACE inhibitor. This adverse event may be particularly significant in patients with renal impairment or collagen vascular disease. As enalapril and enalaprilat were shown to be secreted in human milk in trace amounts, the use of enalaprilat in nursing women is not recommended. Significant fetal transfer occurs with enalapril and enalaprilat thus the use of the drug in pregnant women should be strongly avoided. Caution is advised when enalapril is used in patients who are elderly or with renal impairment, as dosage adjustments may be appropriate. The antihypertensive effect of angiotensin converting enzyme inhibitors is generally lower in individuals of African descent, usually a low-renin hypertensive population. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Epaned, Vaseretic, Vasotec •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): ánalapril Enalapril Enalaprila Enalaprilum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Enalapril is a prodrug of an ACE inhibitor used to treat hypertension and congestive heart failure.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Enalapril interact? Information: •Drug A: Abaloparatide •Drug B: Enalapril •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Enalapril is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Indicated for the management of essential or renovascular hypertension as monotherapy or in combination with other antihypertensive agents, such as thiazide diuretics, for an additive effect. Indicated for the treatment of symptomatic congestive heart failure, usually in combination with diuretics and digitalis. Indicated for the management of asymptomatic left ventricular dysfunction in patients with an ejection fraction of ≤ to 35 percent to decrease the rate of development of overt heart failure and the incidence of hospitalization for heart failure. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Enalapril is an antihypertensive agent that exhibits natriuretic and uricosuric properties. Enalapril lowers blood pressure in all grades of essential and renovascular hypertension, and peripheral vascular resistance without causing an increase in heart rate. Individuals with low-renin hypertensive population were still responsive to enalapril. The duration of hypertensive effect in the systolic and diastolic blood pressure persists for at least 24 hours following initial administration of a single oral dose, and repeated daily administration of enalapril confers an additional reduction in blood pressure and a steady-state antihypertensive response may take several weeks. In patients with severe congestive heart failure and inadequate clinical response to conventional antihypertensive therapies, treatment with enalapril resulted in improvements in cardiac performance as observed by a reduction in both preload and afterload, and improved clinical status long-term. Furthermore, enalapril was shown to increase cardiac output and stroke volume while decreasing pulmonary capillary wedge pressure in patients with congestive heart failure refractory to conventional treatment with digitalis and diuretics. In clinical studies, enalapril reduced left ventricular mass, and did not affect cardiac function or myocardial perfusion during exercise. Enalapril is not highly associated with the risk of bradycardia unlike most diuretics and beta-blockers and it does not produce rebound hypertension upon discontinuation of therapy. Enalapril is not reported to produce hypokalaemia, hyperglycaemia, hyperuricaemia or hypercholesterolaemia. In the kidneys, enalapril was shown to increase renal blood flow and decrease renal vascular resistance. It also augmented the glomerular filtration rate in patients with a glomerular filtration rate less than 80 mL/min. When used in combination, enalapril was shown to attenuate the extent of drug-induced hypokalemia caused by hydrochlorothiazide and the antihypertensive effects of both drugs were potentiated. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): The renin-angiotensin-aldosterone system (RAAS) is a signaling pathway that works in synergism with the sympathetic system to regulate blood pressure and fluid and electrolyte homeostasis. Activation of this system upon stimulation by different factors, such as low blood pressure and nerve impulses, leads to increased release of norepinephrine (NE) from sympathetic nerve terminals and effects on the vascular growth, vasoconstriction, and salt retention in the kidneys. Renin is released from Renin acts on the precursor prottein angiotensinogen, which is a plasma globulin synthesized from the liver, to produce cleaved peptide hormone angiotensin I. Angiotensin I then can be further cleaved by ACE to produce angiotensin II, a vasoconstrictive peptide hormone. Present in different isoforms, angiotensin converting enzyme (ACE) is peptidyl dipeptidase enzyme expressed in various tissues, including the vascular tissues, such as the heart, brain, and kidneys. ACE also plays a role in inactivation of bradykinin, a potent vasodepressor peptide. Angiotensin II mediates various actions on the body by working on its G-protein coupled receptors, AT1 and AT2. It causes direct vasoconstriction of precapillary arterioles and postcapillary venules, inhibits the reuptake of NE thereby increasing available levels, stimulates the release of catecholamines from the adrenal medulla, reduces urinary excretion of sodium ions and water by promoting proximal tubular reabsorption, stimulates synthesis and release of aldosterone from the adrenal cortex, and stimulates hypertrophy of both vascular smooth muscle cells and cardiac myocytes. Enalapril is a pharmacologically inactive prodrug that requires hepatic biotransformation to form enalaprilat, its active metabolite that works on the RAAS to inhibit ACE. Biotransformation is critial for the therapeutic actions of the drug, as enalapril itself is only a weak inhibitor of ACE. ACE inhibition results in reduced production and plasma levels of angiotensin II, increased plasma renin activity due to the loss of feedback inhibition by angiotensin II, and decreased aldosterone secretion. However, plasma aldosterone levels usually return to normal during long-term administration of enalapril. Decreased levels of angiotensin II subsequently leads to the dilatation of peripheral vessles and reduced vascular resistance which in turn lower blood pressure. While inhibition of ACE leading to suppression of RAAS is thought to be the primary mechanism of action of enalapril, the drug was shown to still exert antihypertensive effects on individuals with low-renin hypertension. It is suggested that enalapril may mediate its pharmacological actions via other modes of action that are not fully understood. As ACE is structurally similar to kininase I, which is a carboxypeptidase that degrades bradykinin, whether increased levels of bradykinin play a role in the therapeutic effects of enalapril remains to be elucidated. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Following oral administration, the peak plasma concentrations (Cmax) of enalapril is achieved within 1 hour post dosing while the Cmax of enalaprilat occurs at three to four hours post dosing. The steady-state is achieved by the fourth daily dose and there is no accumulation with repeated dosing. However, accumulation of enalaprilat may occur in patients with creatinine clearance less than 30 mL/min. Food intake is reported to have a minimal effect on drug absorption. Following oral administration, about 60% of enalapril was absorbed. Bioavailability of enalapril averaged about 40% when intravenous enalaprilat was used as a reference standard. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The volume of distribution of enalapril has not been established. Enalaprilat is shown to penetrate into most tissuesm, in particular the kidneys and vascular tissuem, although penetration of the blood-brain barrier has not been demonstrated after administration at therapeutic doses. In dog studies, enalapril and enalaprilat cross the blood-brain barrier poorly. Minimal penetration occurs into breast milk but significant fetal transfer occurs. The drug crosses the placental barrier in rats and hamsters. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): It is reported that less than 50% of enalaprilat is bound to human plasma proteins, based on limited data from binding studies of enalaprilat in human plasma both by equilibrium dialysis and by ultrafiltration. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): About 60% of the absorbed dose is extensively hydrolyzed to enalaprilat via de-esterification mediated by hepatic esterases. In humans, metabolism beyond bioactivation to enalaprilat is not observed. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Enalapril is mainly eliminated through renal excretion, where approximately 94% of the total dose is excreted via urine or feces as either enalaprilat or unchanged parent compound. About 61% and 33% of the total dose can be recovered in the urine and feces, respectively. In the urine, about 40% of the recovered dose is in the form of enalaprilat. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The average terminal half life of enalaprilat is 35-38 hours. The effective half life following multiple doses is 11-14 hours. The prolonged terminal half-life is due to the binding of enalaprilat to ACE. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Following oral administration in healthy male volunteers, the renal clearance was approximately 158 ± 47 mL/min. It is reported that enalapril and enalaprilat are undetectable in the plasma by 4 hours post-dosing. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): LD 50 and Overdose Oral LD 50 in rats is 2973 mg/kg. Lethality was observed with single oral doses of enalapril above 1000 mg/kg in mice and greater than or equal to 1775 mg/kg in rats. Serum enalaprilat levels 100- and 200-fold higher than usually seen after therapeutic doses have been reported after ingestion of 300 mg and 440 mg of enalapril, respectively. While there is limited data about enalapril overdose in humans, overdosage may result in marked hypotension and stupor based on the pharmacological properties of the drug. Most common adverse effects of enalapril include cough, hypotension, stupor, headache, dizziness and fatigue. If hypotension is seen, usual treatment of intravenous infusion of normal saline solution is recommended. Enalaprilat may be removed from systemic circulation with the use of hemodialysis. It has been removed from neonatal circulation by peritoneal dialysis. Nonclinical toxicology Maternal and fetal toxicity occudred in some rabbits treated with enalapril at doses of 1 mg/kg/day or more. There was no fetotoxicity, expressed as a decrease in average fetal weight, or teratogenicity in rats treated with enalapril at doses up to 200 mg/kg/day, which is about 333 times the maximum human dose. In mice and rats receiving enalapril at doses ranging from 90 to 180 mg/kg/day, there was no evidence of a tumorigenic effect. Neither enalapril or its active metabolite were shown to be mutagenic or genotoxic in in vitro and in vivo studies. There were no adverse effects on reproductive performance of male and female rats treated with up to 90 mg/kg/day of enalapril. Use in special populations Caution is warranted in patients who are concurrently using another ACE inhibitors with enalapril, as there have been incidences of agranulocytosis with the use of captopril, which is another ACE inhibitor. This adverse event may be particularly significant in patients with renal impairment or collagen vascular disease. As enalapril and enalaprilat were shown to be secreted in human milk in trace amounts, the use of enalaprilat in nursing women is not recommended. Significant fetal transfer occurs with enalapril and enalaprilat thus the use of the drug in pregnant women should be strongly avoided. Caution is advised when enalapril is used in patients who are elderly or with renal impairment, as dosage adjustments may be appropriate. The antihypertensive effect of angiotensin converting enzyme inhibitors is generally lower in individuals of African descent, usually a low-renin hypertensive population. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Epaned, Vaseretic, Vasotec •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): ánalapril Enalapril Enalaprila Enalaprilum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Enalapril is a prodrug of an ACE inhibitor used to treat hypertension and congestive heart failure. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Enalaprilat interact?

•Drug A: Abaloparatide •Drug B: Enalaprilat •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abaloparatide is combined with Enalaprilat. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Enalaprilat injection is indicated for the treatment of hypertension when oral therapy is not practical. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Enalaprilat injection results in the reduction of both supine and standing systolic and diastolic blood pressure, usually with no orthostatic component. Symptomatic postural hypotension is therefore infrequent, although it might be anticipated in volume-depleted patients. The onset of action usually occurs within fifteen minutes of administration with the maximum effect occurring within one to four hours. The abrupt withdrawal of enalaprilat has not been associated with a rapid increase in blood pressure. The duration of hemodynamic effects appears to be dose-related. However, for the recommended dose, the duration of action in most patients is approximately six hours. Following administration of enalapril, there is an increase in renal blood flow; glomerular filtration rate is usually unchanged. The effects appear to be similar in patients with renovascular hypertension. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Enalaprilat is the active metabolite of the orally available pro-drug, enalapril. Used in the treatment of hypertension, enalapril is an ACE inhibitor that prevents Angiotensin Converting Enzyme (ACE) from transforming angiotensin I into angiotensin II. As angiotensin II is responsible for vasoconstriction and sodium reabsorption in the proximal tubule of the kidney, down-regulation of this protein results in reduced blood pressure and blood fluid volume •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Enalaprilat is poorly absorbed following oral administration, and is therefore only available as an intravenous injection. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Enalaprilat is approximately 50% bound to plasma proteins. (Davies, et al. 1984) •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Both enalapril and enalaprilat undergo renal excretion without further metabolism. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Excretion of enalaprilat is primarily renal with more than 90 percent of an administered dose recovered in the urine as unchanged drug within 24 hours. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 11 hr •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The disposition of enalaprilat in patients with renal insufficiency is similar to that in patients with normal renal function until the glomerular filtration rate is 30 mL/min or less. Renal clearance was 158 ± 47 ml/min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Adverse experiences occurring in 0.5 to 1.0 percent of patients in controlled clinical trials included: myocardial infarction, fatigue, dizziness, fever, rash and constipation. Angioedema has also been reported in patients receiving enalaprilat, with an incidence higher in black than in non-black patients. Angioedema associated with laryngeal edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis and/or larynx occurs, treatment with enalaprilat should be discontinued and appropriate therapy instituted immediately. Rarer adverse effects that are less likely, but should be monitored for, include development of anaphylaxis, hypotension, agranulocytosis, hepatic failure, hyperkalemia, and persistent cough. Furthermore, ACE inhibitors should be avoided during pregnancy as they can cause fetal and neonatal morbidity and death. When pregnancy is detected, ACE inhibitors should be discontinued as soon as possible. Use during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Enalaprilat •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Enalaprilat is an antihypertensive agent used for the management of hypertension when oral therapy is not practical.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Enalaprilat interact? Information: •Drug A: Abaloparatide •Drug B: Enalaprilat •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abaloparatide is combined with Enalaprilat. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Enalaprilat injection is indicated for the treatment of hypertension when oral therapy is not practical. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Enalaprilat injection results in the reduction of both supine and standing systolic and diastolic blood pressure, usually with no orthostatic component. Symptomatic postural hypotension is therefore infrequent, although it might be anticipated in volume-depleted patients. The onset of action usually occurs within fifteen minutes of administration with the maximum effect occurring within one to four hours. The abrupt withdrawal of enalaprilat has not been associated with a rapid increase in blood pressure. The duration of hemodynamic effects appears to be dose-related. However, for the recommended dose, the duration of action in most patients is approximately six hours. Following administration of enalapril, there is an increase in renal blood flow; glomerular filtration rate is usually unchanged. The effects appear to be similar in patients with renovascular hypertension. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Enalaprilat is the active metabolite of the orally available pro-drug, enalapril. Used in the treatment of hypertension, enalapril is an ACE inhibitor that prevents Angiotensin Converting Enzyme (ACE) from transforming angiotensin I into angiotensin II. As angiotensin II is responsible for vasoconstriction and sodium reabsorption in the proximal tubule of the kidney, down-regulation of this protein results in reduced blood pressure and blood fluid volume •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Enalaprilat is poorly absorbed following oral administration, and is therefore only available as an intravenous injection. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Enalaprilat is approximately 50% bound to plasma proteins. (Davies, et al. 1984) •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Both enalapril and enalaprilat undergo renal excretion without further metabolism. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Excretion of enalaprilat is primarily renal with more than 90 percent of an administered dose recovered in the urine as unchanged drug within 24 hours. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 11 hr •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The disposition of enalaprilat in patients with renal insufficiency is similar to that in patients with normal renal function until the glomerular filtration rate is 30 mL/min or less. Renal clearance was 158 ± 47 ml/min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Adverse experiences occurring in 0.5 to 1.0 percent of patients in controlled clinical trials included: myocardial infarction, fatigue, dizziness, fever, rash and constipation. Angioedema has also been reported in patients receiving enalaprilat, with an incidence higher in black than in non-black patients. Angioedema associated with laryngeal edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis and/or larynx occurs, treatment with enalaprilat should be discontinued and appropriate therapy instituted immediately. Rarer adverse effects that are less likely, but should be monitored for, include development of anaphylaxis, hypotension, agranulocytosis, hepatic failure, hyperkalemia, and persistent cough. Furthermore, ACE inhibitors should be avoided during pregnancy as they can cause fetal and neonatal morbidity and death. When pregnancy is detected, ACE inhibitors should be discontinued as soon as possible. Use during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Enalaprilat •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Enalaprilat is an antihypertensive agent used for the management of hypertension when oral therapy is not practical. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Eplerenone interact?

•Drug A: Abaloparatide •Drug B: Eplerenone •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Eplerenone is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For improvement of survival of stable patients with left ventricular systolic dysfunction (ejection fraction <40%) and clinical evidence of congestive heart failure after an acute myocardial infarction. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Eplerenone, an aldosterone receptor antagonist similar to spironolactone, has been shown to produce sustained increases in plasma renin and serum aldosterone, consistent with inhibition of the negative regulatory feedback of aldosterone on renin secretion. The resulting increased plasma renin activity and aldosterone circulating levels do not overcome the effects of eplerenone. Eplerenone selectively binds to recombinant human mineralocorticoid receptors relative to its binding to recombinant human glucocorticoid, progesterone and androgen receptors. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Eplerenone binds to the mineralocorticoid receptor and thereby blocks the binding of aldosterone (component of the renin-angiotensin-aldosterone-system, or RAAS). Aldosterone synthesis, which occurs primarily in the adrenal gland, is modulated by multiple factors, including angiotensin II and non-RAAS mediators such as adrenocorticotropic hormone (ACTH) and potassium. Aldosterone binds to mineralocorticoid receptors in both epithelial (e.g., kidney) and nonepithelial (e.g., heart, blood vessels, and brain) tissues and increases blood pressure through induction of sodium reabsorption and possibly other mechanisms. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): The absolute bioavailability of eplerenone is unknown. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 43 to 90 L •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 50% •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Eplerenone is metabolized primarily by CYP3A4, however, no active metabolites have been identified in human plasma. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 4-6 hours •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Apparent plasma cl=10 L/hr •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The most likely symptoms of human overdosage would be anticipated to be hypotension or hyperkalemia. However, no cases of human overdosage with eplerenone have been reported. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Inspra •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Eplerenone is an aldosterone receptor antagonist used to improve survival of patients with symptomatic heart failure and to reduce blood pressure.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Eplerenone interact? Information: •Drug A: Abaloparatide •Drug B: Eplerenone •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Eplerenone is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For improvement of survival of stable patients with left ventricular systolic dysfunction (ejection fraction <40%) and clinical evidence of congestive heart failure after an acute myocardial infarction. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Eplerenone, an aldosterone receptor antagonist similar to spironolactone, has been shown to produce sustained increases in plasma renin and serum aldosterone, consistent with inhibition of the negative regulatory feedback of aldosterone on renin secretion. The resulting increased plasma renin activity and aldosterone circulating levels do not overcome the effects of eplerenone. Eplerenone selectively binds to recombinant human mineralocorticoid receptors relative to its binding to recombinant human glucocorticoid, progesterone and androgen receptors. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Eplerenone binds to the mineralocorticoid receptor and thereby blocks the binding of aldosterone (component of the renin-angiotensin-aldosterone-system, or RAAS). Aldosterone synthesis, which occurs primarily in the adrenal gland, is modulated by multiple factors, including angiotensin II and non-RAAS mediators such as adrenocorticotropic hormone (ACTH) and potassium. Aldosterone binds to mineralocorticoid receptors in both epithelial (e.g., kidney) and nonepithelial (e.g., heart, blood vessels, and brain) tissues and increases blood pressure through induction of sodium reabsorption and possibly other mechanisms. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): The absolute bioavailability of eplerenone is unknown. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 43 to 90 L •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 50% •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Eplerenone is metabolized primarily by CYP3A4, however, no active metabolites have been identified in human plasma. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 4-6 hours •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Apparent plasma cl=10 L/hr •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The most likely symptoms of human overdosage would be anticipated to be hypotension or hyperkalemia. However, no cases of human overdosage with eplerenone have been reported. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Inspra •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Eplerenone is an aldosterone receptor antagonist used to improve survival of patients with symptomatic heart failure and to reduce blood pressure. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Epoprostenol interact?

•Drug A: Abaloparatide •Drug B: Epoprostenol •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Epoprostenol is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the long-term intravenous treatment of primary pulmonary hypertension and pulmonary hypertension associated with the scleroderma spectrum of disease in NYHA Class III and Class IV patients who do not respond adequately to conventional therapy. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Epoprostenol has two major pharmacological actions: (1) direct vasodilation of pulmonary and systemic arterial vascular beds, and (2) inhibition of platelet aggregation. In animals, the vasodilatory effects reduce right and left ventricular afterload and increase cardiac output and stroke volume. The effect of epoprostenol on heart rate in animals varies with dose. At low doses, there is vagally mediated brudycardia, but at higher doses, epoprostenol causes reflex tachycardia in response to direct vasodilation and hypotension. No major effects on cardiac conduction have been observed. Additional pharmacologic effects of epoprostenol in animals include bronchodilation, inhibition of gastric acid secretion, and decreased gastric emptying. No available chemical assay is sufficiently sensitive and specific to assess the in vivo human pharmacokinetics of epoprostenol. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Prostaglandins are present in most body tissues and fluids and mediate many biological functions. Epoprostenol (PGI2) is a member of the family of prostaglandins that is derived from arachidonic acid. The major pharmacological actions of epoprostenol is ultimately inhibition of platelet aggregation. Prostacycline (PGI2) from endothelial cells activate G protein-coupled receptors on platelets and endothelial cells. This activation causes adenylate cyclase to produce cyclic AMP which inhibits further platelet activation and activates protein kinase A. Cyclic AMP also prevents coagulation by preventing an increase in intracellular calcium from thromboxane A2 binding. PKA then continues the cascade by phosphorylating and inhibiting myosin light-chain kinase which leads to smooth muscle relaxation and vasodilation. Notably, PGI2 and TXA2 work as physiological antagonists. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 357 mL/kg •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Epoprostenol is metabolized to 2 primary metabolites: 6-keto-PGF1α (formed by spontaneous degradation) and 6,15-diketo-13,14-dihydro-PGF1α (enzymatically formed), both of which have pharmacological activity orders of magnitude less than epoprostenol in animal test systems. Fourteen additional minor metabolites have been isolated from urine, indicating that epoprostenol is extensively metabolized in humans. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Epoprostenol is metabolized to 2 primary metabolites: 6-keto-PGF1α (formed by spontaneous degradation) and 6,15-diketo-13,14-dihydro-PGF1α (enzymatically formed), both of which have pharmacological activity orders of magnitude less than epoprostenol in animal test systems. Fourteen additional minor metabolites have been isolated from urine, indicating that epoprostenol is extensively metabolized in humans. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The in vitro half-life of epoprostenol in human blood at 37°C and pH 7.4 is approximately 6 minutes; the in vivo half-life of epoprostenol in humans is therefore expected to be no greater than 6 minutes. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Symptoms of overdose are extensions of its dose-limiting pharmacologic effects and include flushing, headache, hypotension, nausea, vomiting, and diarrhea. Most events were self-limiting and resolved with reduction or withholding of epoprostenol. Single intravenous doses at 10 and 50 mg/kg (2703 and 27,027 times the recommended acute phase human dose based on body surface area) were lethal to mice and rats, respectively. Symptoms of acute toxicity were hypoactivity, ataxia, loss of righting reflex, deep slow breathing, and hypothermia. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Flolan, Veletri •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Epoprostenol Prostacyclin Prostaglandin I2 Prostaglandin X Vasocyclin •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Epoprostenol is a vasodilator and platelet aggregation inhibitor used for the management of primary pulmonary hypertension and pulmonary hypertension in patients with heart failure.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Epoprostenol interact? Information: •Drug A: Abaloparatide •Drug B: Epoprostenol •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Epoprostenol is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the long-term intravenous treatment of primary pulmonary hypertension and pulmonary hypertension associated with the scleroderma spectrum of disease in NYHA Class III and Class IV patients who do not respond adequately to conventional therapy. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Epoprostenol has two major pharmacological actions: (1) direct vasodilation of pulmonary and systemic arterial vascular beds, and (2) inhibition of platelet aggregation. In animals, the vasodilatory effects reduce right and left ventricular afterload and increase cardiac output and stroke volume. The effect of epoprostenol on heart rate in animals varies with dose. At low doses, there is vagally mediated brudycardia, but at higher doses, epoprostenol causes reflex tachycardia in response to direct vasodilation and hypotension. No major effects on cardiac conduction have been observed. Additional pharmacologic effects of epoprostenol in animals include bronchodilation, inhibition of gastric acid secretion, and decreased gastric emptying. No available chemical assay is sufficiently sensitive and specific to assess the in vivo human pharmacokinetics of epoprostenol. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Prostaglandins are present in most body tissues and fluids and mediate many biological functions. Epoprostenol (PGI2) is a member of the family of prostaglandins that is derived from arachidonic acid. The major pharmacological actions of epoprostenol is ultimately inhibition of platelet aggregation. Prostacycline (PGI2) from endothelial cells activate G protein-coupled receptors on platelets and endothelial cells. This activation causes adenylate cyclase to produce cyclic AMP which inhibits further platelet activation and activates protein kinase A. Cyclic AMP also prevents coagulation by preventing an increase in intracellular calcium from thromboxane A2 binding. PKA then continues the cascade by phosphorylating and inhibiting myosin light-chain kinase which leads to smooth muscle relaxation and vasodilation. Notably, PGI2 and TXA2 work as physiological antagonists. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 357 mL/kg •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Epoprostenol is metabolized to 2 primary metabolites: 6-keto-PGF1α (formed by spontaneous degradation) and 6,15-diketo-13,14-dihydro-PGF1α (enzymatically formed), both of which have pharmacological activity orders of magnitude less than epoprostenol in animal test systems. Fourteen additional minor metabolites have been isolated from urine, indicating that epoprostenol is extensively metabolized in humans. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Epoprostenol is metabolized to 2 primary metabolites: 6-keto-PGF1α (formed by spontaneous degradation) and 6,15-diketo-13,14-dihydro-PGF1α (enzymatically formed), both of which have pharmacological activity orders of magnitude less than epoprostenol in animal test systems. Fourteen additional minor metabolites have been isolated from urine, indicating that epoprostenol is extensively metabolized in humans. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The in vitro half-life of epoprostenol in human blood at 37°C and pH 7.4 is approximately 6 minutes; the in vivo half-life of epoprostenol in humans is therefore expected to be no greater than 6 minutes. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Symptoms of overdose are extensions of its dose-limiting pharmacologic effects and include flushing, headache, hypotension, nausea, vomiting, and diarrhea. Most events were self-limiting and resolved with reduction or withholding of epoprostenol. Single intravenous doses at 10 and 50 mg/kg (2703 and 27,027 times the recommended acute phase human dose based on body surface area) were lethal to mice and rats, respectively. Symptoms of acute toxicity were hypoactivity, ataxia, loss of righting reflex, deep slow breathing, and hypothermia. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Flolan, Veletri •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Epoprostenol Prostacyclin Prostaglandin I2 Prostaglandin X Vasocyclin •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Epoprostenol is a vasodilator and platelet aggregation inhibitor used for the management of primary pulmonary hypertension and pulmonary hypertension in patients with heart failure. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Eprosartan interact?

•Drug A: Abaloparatide •Drug B: Eprosartan •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Eprosartan is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the management of hypertension alone or in combination with other classes of antihypertensive agents. Also used as a first-line agent in the treatment of diabetic nephropathy, as well as a second-line agent in the treatment of congestive heart failure (only in those intolerant of ACE inhibitors). •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Angiotensin II, the principal pressor agent of the renin-angiotensin system, is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme [kininase II]. It is responsible for effects such as vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Eprosartan selectively blocks the binding of angiotensin II to the AT 1 receptor, which in turn leads to multiple effects including vasodilation, a reduction in the secretion of vasopressin, and reduction in the production and secretion of aldosterone. The resulting effect is a decrease in blood pressure. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Eprosartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT 1 receptor found in many tissues (e.g., vascular smooth muscle, adrenal gland). There is also an AT 2 receptor found in many tissues but it is not known to be associated with cardiovascular homeostasis. Eprosartan does not exhibit any partial agonist activity at the AT 1 receptor. Its affinity for the AT 1 receptor is 1,000 times greater than for the AT 2 receptor. In vitro binding studies indicate that eprosartan is a reversible, competitive inhibitor of the AT 1 receptor. Eprosartan has also been shown to bind to AT 1 receptors both presynaptically and synaptically. Its action on presynaptic AT 1 receptors results in the inhibition of sympathetically stimulated noradrenaline release. Unlike ACE inhibitors, eprosartan and other ARBs do not interfere with response to bradykinins and substance P, which allows for the absence of adverse effects that are present in ACE inhibitors (eg. dry cough). •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Absolute bioavailability following a single 300 mg oral dose of eprosartan is approximately 13%. Administering eprosartan with food delays absorption. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Plasma protein binding of eprosartan is high (approximately 98%) and constant over the concentration range achieved with therapeutic doses. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Eprosartan is not metabolized by the cytochrome P450 system. It is mainly eliminated as unchanged drug. Less than 2% of an oral dose is excreted in the urine as a glucuronide. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The terminal elimination half-life of eprosartan following oral administration is typically 5 to 9 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): There was no mortality in rats and mice receiving oral doses of up to 3000 mg eprosartan/kg and in dogs receiving oral doses of up to 1000 mg eprosartan/kg. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Teveten HCT •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Éprosartan Eprosartan Eprosartanum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Eprosartan is an ARB used to treat hypertension, diabetic nephropathy, and congestive heart failure.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Eprosartan interact? Information: •Drug A: Abaloparatide •Drug B: Eprosartan •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Eprosartan is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the management of hypertension alone or in combination with other classes of antihypertensive agents. Also used as a first-line agent in the treatment of diabetic nephropathy, as well as a second-line agent in the treatment of congestive heart failure (only in those intolerant of ACE inhibitors). •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Angiotensin II, the principal pressor agent of the renin-angiotensin system, is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme [kininase II]. It is responsible for effects such as vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Eprosartan selectively blocks the binding of angiotensin II to the AT 1 receptor, which in turn leads to multiple effects including vasodilation, a reduction in the secretion of vasopressin, and reduction in the production and secretion of aldosterone. The resulting effect is a decrease in blood pressure. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Eprosartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT 1 receptor found in many tissues (e.g., vascular smooth muscle, adrenal gland). There is also an AT 2 receptor found in many tissues but it is not known to be associated with cardiovascular homeostasis. Eprosartan does not exhibit any partial agonist activity at the AT 1 receptor. Its affinity for the AT 1 receptor is 1,000 times greater than for the AT 2 receptor. In vitro binding studies indicate that eprosartan is a reversible, competitive inhibitor of the AT 1 receptor. Eprosartan has also been shown to bind to AT 1 receptors both presynaptically and synaptically. Its action on presynaptic AT 1 receptors results in the inhibition of sympathetically stimulated noradrenaline release. Unlike ACE inhibitors, eprosartan and other ARBs do not interfere with response to bradykinins and substance P, which allows for the absence of adverse effects that are present in ACE inhibitors (eg. dry cough). •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Absolute bioavailability following a single 300 mg oral dose of eprosartan is approximately 13%. Administering eprosartan with food delays absorption. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Plasma protein binding of eprosartan is high (approximately 98%) and constant over the concentration range achieved with therapeutic doses. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Eprosartan is not metabolized by the cytochrome P450 system. It is mainly eliminated as unchanged drug. Less than 2% of an oral dose is excreted in the urine as a glucuronide. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The terminal elimination half-life of eprosartan following oral administration is typically 5 to 9 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): There was no mortality in rats and mice receiving oral doses of up to 3000 mg eprosartan/kg and in dogs receiving oral doses of up to 1000 mg eprosartan/kg. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Teveten HCT •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Éprosartan Eprosartan Eprosartanum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Eprosartan is an ARB used to treat hypertension, diabetic nephropathy, and congestive heart failure. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Esmolol interact?

•Drug A: Abaloparatide •Drug B: Esmolol •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Esmolol is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the rapid control of ventricular rate in patients with atrial fibrillation or atrial flutter in perioperative, postoperative, or other emergent circumstances where short term control of ventricular rate with a short-acting agent is desirable. Also used in noncompensatory sinus tachycardia where the rapid heart rate requires specific intervention. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Similar to other beta-blockers, esmolol blocks the agonistic effect of the sympathetic neurotransmitters by competing for receptor binding sites. Because it predominantly blocks the beta-1 receptors in cardiac tissue, it is said to be cardioselective. In general, so-called cardioselective beta-blockers are relatively cardioselective; at lower doses they block beta-1 receptors only but begin to block beta-2 receptors as the dose increases. At therapeutic dosages, esmolol does not have intrinsic sympathomimetic activity (ISA) or membrane-stabilizing (quinidine-like) activity. Antiarrhythmic activity is due to blockade of adrenergic stimulation of cardiac pacemaker potentials. In the Vaughan Williams classification of antiarrhythmics, beta-blockers are considered to be class II agents. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Rapidly absorbed, steady-state blood levels for dosages from 50-300 µg/kg/min (0.05-0.3 mg/kg/mm) are obtained within five minutes. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 55% bound to human plasma protein, while the acid metabolite is 10% bound. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Esmolol undergoes rapid hydrolysis of ester linkage which is catalyzed by esterases found in the cytosol of red blood cells (RBCs). The plasma cholinersterases or RBC membrane acetylcholinesterases are not involved in this metabolic reaction. Metabolism of the drug occurs mainly in RBCs to form a free acid metabolite (with 1/1500 the activity of esmolol) and methanol. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Consistent with the high rate of blood-based metabolism of esmolol hydrochloride, less than 2% of the drug is excreted unchanged in the urine. The acid metabolite has an elimination half-life of about 3.7 hours and is excreted in the urine with a clearance approximately equivalent to the glomerular filtration rate. Excretion of the acid metabolite is significantly decreased in patients with renal disease, with the elimination half-life increased to about ten-fold that of normals, and plasma levels considerably elevated. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Rapid distribution half-life of about 2 minutes and an elimination half-life of about 9 minutes. The acid metabolite has an elimination half-life of about 3.7 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): 20 L/kg/hr [Men] •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Symptoms of overdose include cardiac arrest, bradycardia, hypotension, electromechanical dissociation and loss of consciousness. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Brevibloc •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Esmolol •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Esmolol is a cardioselective beta-adrenergic blocker used for the short-term control of ventricular rate and heart rate in various types of tachycardia, including perioperative tachycardia and hypertension.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Esmolol interact? Information: •Drug A: Abaloparatide •Drug B: Esmolol •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Esmolol is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the rapid control of ventricular rate in patients with atrial fibrillation or atrial flutter in perioperative, postoperative, or other emergent circumstances where short term control of ventricular rate with a short-acting agent is desirable. Also used in noncompensatory sinus tachycardia where the rapid heart rate requires specific intervention. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Similar to other beta-blockers, esmolol blocks the agonistic effect of the sympathetic neurotransmitters by competing for receptor binding sites. Because it predominantly blocks the beta-1 receptors in cardiac tissue, it is said to be cardioselective. In general, so-called cardioselective beta-blockers are relatively cardioselective; at lower doses they block beta-1 receptors only but begin to block beta-2 receptors as the dose increases. At therapeutic dosages, esmolol does not have intrinsic sympathomimetic activity (ISA) or membrane-stabilizing (quinidine-like) activity. Antiarrhythmic activity is due to blockade of adrenergic stimulation of cardiac pacemaker potentials. In the Vaughan Williams classification of antiarrhythmics, beta-blockers are considered to be class II agents. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Rapidly absorbed, steady-state blood levels for dosages from 50-300 µg/kg/min (0.05-0.3 mg/kg/mm) are obtained within five minutes. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 55% bound to human plasma protein, while the acid metabolite is 10% bound. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Esmolol undergoes rapid hydrolysis of ester linkage which is catalyzed by esterases found in the cytosol of red blood cells (RBCs). The plasma cholinersterases or RBC membrane acetylcholinesterases are not involved in this metabolic reaction. Metabolism of the drug occurs mainly in RBCs to form a free acid metabolite (with 1/1500 the activity of esmolol) and methanol. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Consistent with the high rate of blood-based metabolism of esmolol hydrochloride, less than 2% of the drug is excreted unchanged in the urine. The acid metabolite has an elimination half-life of about 3.7 hours and is excreted in the urine with a clearance approximately equivalent to the glomerular filtration rate. Excretion of the acid metabolite is significantly decreased in patients with renal disease, with the elimination half-life increased to about ten-fold that of normals, and plasma levels considerably elevated. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Rapid distribution half-life of about 2 minutes and an elimination half-life of about 9 minutes. The acid metabolite has an elimination half-life of about 3.7 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): 20 L/kg/hr [Men] •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Symptoms of overdose include cardiac arrest, bradycardia, hypotension, electromechanical dissociation and loss of consciousness. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Brevibloc •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Esmolol •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Esmolol is a cardioselective beta-adrenergic blocker used for the short-term control of ventricular rate and heart rate in various types of tachycardia, including perioperative tachycardia and hypertension. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Etacrynic acid interact?

•Drug A: Abaloparatide •Drug B: Etacrynic acid •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Etacrynic acid is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the treatment of high blood pressure and edema caused by diseases like congestive heart failure, liver failure, and kidney failure. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Ethacrynic acid is a monosulfonamyl loop or high ceiling diuretic. Ethacrynic acid acts on the ascending limb of the loop of Henle and on the proximal and distal tubules. Urinary output is usually dose dependent and related to the magnitude of fluid accumulation. Water and electrolyte excretion may be increased several times over that observed with thiazide diuretics, since ethacrynic acid inhibits reabsorption of a much greater proportion of filtered sodium than most other diuretic agents. Therefore, ethacrynic acid is effective in many patients who have significant degrees of renal insufficiency. Ethacrynic acid has little or no effect on glomerular filtration or on renal blood flow, except following pronounced reductions in plasma volume when associated with rapid diuresis. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Ethacrynic acid inhibits symport of sodium, potassium, and chloride primarily in the ascending limb of Henle, but also in the proximal and distal tubules. This pharmacological action results in excretion of these ions, increased urinary output, and reduction in extracellular fluid. Diuretics also lower blood pressure initially by reducing plasma and extracellular fluid volume; cardiac output also decreases, explaining its antihypertensive action. Eventually, cardiac output returns to normal with an accompanying decrease in peripheral resistance. Its mode of action does not involve carbonic anhydrase inhibition. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Onset of action is rapid, usually within 30 minutes after an oral dose of ethacrynic acid or within 5 minutes after an intravenous injection of ethacrynic acid. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): > 98% •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Hepatic. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): No half-life available •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Overdosage may lead to excessive diuresis with electrolyte depletion. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Edecrin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Acide étacrynique ácido etacrínico Acidum etacrynicum Etacrinic acid Etacrynic acid Ethacrynate Ethacrynic acid Methylenebutyrylphenoxyacetic acid •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Etacrynic acid is a diuretic used to treat ascites and edema in congestive heart failure, liver cirrhosis, and renal disease.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Etacrynic acid interact? Information: •Drug A: Abaloparatide •Drug B: Etacrynic acid •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Etacrynic acid is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the treatment of high blood pressure and edema caused by diseases like congestive heart failure, liver failure, and kidney failure. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Ethacrynic acid is a monosulfonamyl loop or high ceiling diuretic. Ethacrynic acid acts on the ascending limb of the loop of Henle and on the proximal and distal tubules. Urinary output is usually dose dependent and related to the magnitude of fluid accumulation. Water and electrolyte excretion may be increased several times over that observed with thiazide diuretics, since ethacrynic acid inhibits reabsorption of a much greater proportion of filtered sodium than most other diuretic agents. Therefore, ethacrynic acid is effective in many patients who have significant degrees of renal insufficiency. Ethacrynic acid has little or no effect on glomerular filtration or on renal blood flow, except following pronounced reductions in plasma volume when associated with rapid diuresis. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Ethacrynic acid inhibits symport of sodium, potassium, and chloride primarily in the ascending limb of Henle, but also in the proximal and distal tubules. This pharmacological action results in excretion of these ions, increased urinary output, and reduction in extracellular fluid. Diuretics also lower blood pressure initially by reducing plasma and extracellular fluid volume; cardiac output also decreases, explaining its antihypertensive action. Eventually, cardiac output returns to normal with an accompanying decrease in peripheral resistance. Its mode of action does not involve carbonic anhydrase inhibition. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Onset of action is rapid, usually within 30 minutes after an oral dose of ethacrynic acid or within 5 minutes after an intravenous injection of ethacrynic acid. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): > 98% •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Hepatic. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): No half-life available •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Overdosage may lead to excessive diuresis with electrolyte depletion. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Edecrin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Acide étacrynique ácido etacrínico Acidum etacrynicum Etacrinic acid Etacrynic acid Ethacrynate Ethacrynic acid Methylenebutyrylphenoxyacetic acid •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Etacrynic acid is a diuretic used to treat ascites and edema in congestive heart failure, liver cirrhosis, and renal disease. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Ethanol interact?

•Drug A: Abaloparatide •Drug B: Ethanol •Severity: MODERATE •Description: Ethanol may increase the hypotensive activities of Abaloparatide. •Extended Description: Coadministration of alcohol with hypotensive agents may result in profound or unpredictable hypotensive effects. This may be due to the accumulation of vasodilatory alcohol metabolite acetaldehyde or the acute increase in heart rate and cardiac output with a decrease in systemic vascular resistance following the ingestion of alcohol . Some studies suggest, however, that alcohol may interfere with antihypertensive therapy and increase blood pressure and/or heart rate , , . Data supporting this interaction are conflicting. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For therapeutic neurolysis of nerves or ganglia for the relief of intractable chronic pain in such conditions as inoperable cancer and trigeminal neuralgia (tic douloureux), in patients for whom neurosurgical procedures are contraindicated. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Alcohol produces injury to cells by dehydration and precipitation of the cytoplasm or protoplasm. This accounts for its bacteriocidal and antifungal action. When alcohol is injected in close proximity to nerve tissues, it produces neuritis and nerve degeneration (neurolysis). Ninety to 98% of ethanol that enters the body is completely oxidized. Ethanol is also used as a cosolvent to dissolve many insoluble drugs and to serve as a mild sedative in some medicinal formulations. Ethanol also binds to GABA, glycine, NMDA receptors and modulates their effects. Ethanol is also metabolised by the hepatic enzyme alcohol dehydrogenase. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Ethanol affects the brain’s neurons in several ways. It alters their membranes as well as their ion channels, enzymes, and receptors. Alcohol also binds directly to the receptors for acetylcholine, serotonin, GABA, and the NMDA receptors for glutamate. The sedative effects of ethanol are mediated through binding to GABA receptors and glycine receptors (alpha 1 and alpha 2 subunits). It also inhibits NMDA receptor functioning. In its role as an anti-infective, ethanol acts as an osmolyte or dehydrating agent that disrupts the osmotic balance across cell membranes. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Rapidly absorbed. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Hepatic. Metabolized by cytochrome P450 enzyme CYP2E1. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): No half-life available •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Oral, rat LD 50: 5628 mg/kg. Symptoms and effects of overdose include nausea, vomiting, CNS depression, acute respiratory failure or death and with chronic use, severe health problems, such as liver and brain damage. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Dalmacol, Gattex, Healing Waters Aloe Cucumber Hand Sanitizer, Healing Waters Cotton Blossom Hand Sanitizer, Healing Waters Lemon Verbena Hand Sanitizer, Healing Waters Peach Nectarine Hand Sanitizer, Lupaneta Pack 1-month, Viva-drops Lubricating Eye Drops •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 1-Hydroxyethane Alcohol Alcohol (ethyl) Alcohol denatured Alcohol etílico Alcohol, denatured Alcool éthylique Alkohol Äthanol Äthylalkohol Dehydrated alcohol Dehydrated ethanol etanol éthanol Ethyl Alcohol Grain alcohol Hydroxyethane Methylcarbinol Spiritus vini •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): No summary available

Coadministration of alcohol with hypotensive agents may result in profound or unpredictable hypotensive effects. This may be due to the accumulation of vasodilatory alcohol metabolite acetaldehyde or the acute increase in heart rate and cardiac output with a decrease in systemic vascular resistance following the ingestion of alcohol . Some studies suggest, however, that alcohol may interfere with antihypertensive therapy and increase blood pressure and/or heart rate , , . Data supporting this interaction are conflicting. The severity of the interaction is moderate.

Question: Does Abaloparatide and Ethanol interact? Information: •Drug A: Abaloparatide •Drug B: Ethanol •Severity: MODERATE •Description: Ethanol may increase the hypotensive activities of Abaloparatide. •Extended Description: Coadministration of alcohol with hypotensive agents may result in profound or unpredictable hypotensive effects. This may be due to the accumulation of vasodilatory alcohol metabolite acetaldehyde or the acute increase in heart rate and cardiac output with a decrease in systemic vascular resistance following the ingestion of alcohol . Some studies suggest, however, that alcohol may interfere with antihypertensive therapy and increase blood pressure and/or heart rate , , . Data supporting this interaction are conflicting. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For therapeutic neurolysis of nerves or ganglia for the relief of intractable chronic pain in such conditions as inoperable cancer and trigeminal neuralgia (tic douloureux), in patients for whom neurosurgical procedures are contraindicated. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Alcohol produces injury to cells by dehydration and precipitation of the cytoplasm or protoplasm. This accounts for its bacteriocidal and antifungal action. When alcohol is injected in close proximity to nerve tissues, it produces neuritis and nerve degeneration (neurolysis). Ninety to 98% of ethanol that enters the body is completely oxidized. Ethanol is also used as a cosolvent to dissolve many insoluble drugs and to serve as a mild sedative in some medicinal formulations. Ethanol also binds to GABA, glycine, NMDA receptors and modulates their effects. Ethanol is also metabolised by the hepatic enzyme alcohol dehydrogenase. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Ethanol affects the brain’s neurons in several ways. It alters their membranes as well as their ion channels, enzymes, and receptors. Alcohol also binds directly to the receptors for acetylcholine, serotonin, GABA, and the NMDA receptors for glutamate. The sedative effects of ethanol are mediated through binding to GABA receptors and glycine receptors (alpha 1 and alpha 2 subunits). It also inhibits NMDA receptor functioning. In its role as an anti-infective, ethanol acts as an osmolyte or dehydrating agent that disrupts the osmotic balance across cell membranes. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Rapidly absorbed. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Hepatic. Metabolized by cytochrome P450 enzyme CYP2E1. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): No half-life available •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Oral, rat LD 50: 5628 mg/kg. Symptoms and effects of overdose include nausea, vomiting, CNS depression, acute respiratory failure or death and with chronic use, severe health problems, such as liver and brain damage. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Dalmacol, Gattex, Healing Waters Aloe Cucumber Hand Sanitizer, Healing Waters Cotton Blossom Hand Sanitizer, Healing Waters Lemon Verbena Hand Sanitizer, Healing Waters Peach Nectarine Hand Sanitizer, Lupaneta Pack 1-month, Viva-drops Lubricating Eye Drops •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 1-Hydroxyethane Alcohol Alcohol (ethyl) Alcohol denatured Alcohol etílico Alcohol, denatured Alcool éthylique Alkohol Äthanol Äthylalkohol Dehydrated alcohol Dehydrated ethanol etanol éthanol Ethyl Alcohol Grain alcohol Hydroxyethane Methylcarbinol Spiritus vini •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): No summary available Output: Coadministration of alcohol with hypotensive agents may result in profound or unpredictable hypotensive effects. This may be due to the accumulation of vasodilatory alcohol metabolite acetaldehyde or the acute increase in heart rate and cardiac output with a decrease in systemic vascular resistance following the ingestion of alcohol . Some studies suggest, however, that alcohol may interfere with antihypertensive therapy and increase blood pressure and/or heart rate , , . Data supporting this interaction are conflicting. The severity of the interaction is moderate.

Does Abaloparatide and Felodipine interact?

•Drug A: Abaloparatide •Drug B: Felodipine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Felodipine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the treatment of mild to moderate essential hypertension. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Felodipine belongs to the dihydropyridine (DHP) class of calcium channel blockers (CCBs), the most widely used class of CCBs. There are at least five different types of calcium channels in Homo sapiens: L-, N-, P/Q-, R- and T-type. It was widely accepted that CCBs target L-type calcium channels, the major channel in muscle cells that mediates contraction; however, some studies have shown that felodipine also binds to and inhibits T-type calcium channels. T-type calcium channels are most commonly found on neurons, cells with pacemaker activity and on osteocytes. The pharmacologic significance of T-type calcium channel blockade is unknown. Felodipine also binds to calmodulin and inhibits calmodulin-dependent calcium release from the sarcoplasmic reticulum. The effect of this interaction appears to be minor. Another study demonstrated that felodipine attenuates the activity of calmodulin-dependent cyclic nucleotide phosphodiesterase (CaMPDE) by binding to the PDE-1B1 and PDE-1A2 enzyme subunits. CaMPDE is one of the key enzymes involved in cyclic nucleotides and calcium second messenger systems. Felodipine also acts as an antagonist to the mineralcorticoid receptor by competing with aldosterone for binding and blocking aldosterone-induced coactivator recruitment of the mineralcorticoid receptor. Felodipine is able to bind to skeletal and cardiac muscle isoforms of troponin C, one of the key regulatory proteins in muscle contraction. Though felodipine exhibits binding to many endogenous molecules, its vasodilatory effects are still thought to be brought about primarily through inhibition of voltage-gated L-type calcium channels. Similar to other DHP CCBs, felodipine binds directly to inactive calcium channels stabilizing their inactive conformation. Since arterial smooth muscle depolarizations are longer in duration than cardiac muscle depolarizations, inactive channels are more prevalent in smooth muscle cells. Alternative splicing of the alpha-1 subunit of the channel gives felodipine additional arterial selectivity. At therapeutic sub-toxic concentrations, felodipine has little effect on cardiac myocytes and conduction cells. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Felodipine decreases arterial smooth muscle contractility and subsequent vasoconstriction by inhibiting the influx of calcium ions through voltage-gated L-type calcium channels. It reversibly competes against nitrendipine and other DHP CCBs for DHP binding sites in vascular smooth muscle and cultured rabbit atrial cells. Calcium ions entering the cell through these channels bind to calmodulin. Calcium-bound calmodulin then binds to and activates myosin light chain kinase (MLCK). Activated MLCK catalyzes the phosphorylation of the regulatory light chain subunit of myosin, a key step in muscle contraction. Signal amplification is achieved by calcium-induced calcium release from the sarcoplasmic reticulum through ryanodine receptors. Inhibition of the initial influx of calcium decreases the contractile activity of arterial smooth muscle cells and results in vasodilation. The vasodilatory effects of felodipine result in an overall decrease in blood pressure. Felodipine may be used to treat mild to moderate essential hypertension. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Is completely absorbed from the gastrointestinal tract; however, extensive first-pass metabolism through the portal circulation results in a low systemic availability of 15%. Bioavailability is unaffected by food. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 10 L/kg •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 99%, primarily to the albumin fraction. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Hepatic metabolism primarily via cytochrome P450 3A4. Six metabolites with no appreciable vasodilatory effects have been identified. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Although higher concentrations of the metabolites are present in the plasma due to decreased urinary excretion, these are inactive. Animal studies have demonstrated that felodipine crosses the blood-brain barrier and the placenta. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 17.5-31.5 hours in hypertensive patients; 19.1-35.9 hours in elderly hypertensive patients; 8.5-19.7 in healthy volunteers. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): 0.8 L/min [Young healthy subjects] •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Symptoms of overdose include excessive peripheral vasodilation with marked hypotension and possibly bradycardia. Oral rat LD 50 is 1050 mg/kg. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Plendil •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Felodipina Felodipine Felodipino Felodipinum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Felodipine is a calcium channel blocker used to treat hypertension.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Felodipine interact? Information: •Drug A: Abaloparatide •Drug B: Felodipine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Felodipine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the treatment of mild to moderate essential hypertension. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Felodipine belongs to the dihydropyridine (DHP) class of calcium channel blockers (CCBs), the most widely used class of CCBs. There are at least five different types of calcium channels in Homo sapiens: L-, N-, P/Q-, R- and T-type. It was widely accepted that CCBs target L-type calcium channels, the major channel in muscle cells that mediates contraction; however, some studies have shown that felodipine also binds to and inhibits T-type calcium channels. T-type calcium channels are most commonly found on neurons, cells with pacemaker activity and on osteocytes. The pharmacologic significance of T-type calcium channel blockade is unknown. Felodipine also binds to calmodulin and inhibits calmodulin-dependent calcium release from the sarcoplasmic reticulum. The effect of this interaction appears to be minor. Another study demonstrated that felodipine attenuates the activity of calmodulin-dependent cyclic nucleotide phosphodiesterase (CaMPDE) by binding to the PDE-1B1 and PDE-1A2 enzyme subunits. CaMPDE is one of the key enzymes involved in cyclic nucleotides and calcium second messenger systems. Felodipine also acts as an antagonist to the mineralcorticoid receptor by competing with aldosterone for binding and blocking aldosterone-induced coactivator recruitment of the mineralcorticoid receptor. Felodipine is able to bind to skeletal and cardiac muscle isoforms of troponin C, one of the key regulatory proteins in muscle contraction. Though felodipine exhibits binding to many endogenous molecules, its vasodilatory effects are still thought to be brought about primarily through inhibition of voltage-gated L-type calcium channels. Similar to other DHP CCBs, felodipine binds directly to inactive calcium channels stabilizing their inactive conformation. Since arterial smooth muscle depolarizations are longer in duration than cardiac muscle depolarizations, inactive channels are more prevalent in smooth muscle cells. Alternative splicing of the alpha-1 subunit of the channel gives felodipine additional arterial selectivity. At therapeutic sub-toxic concentrations, felodipine has little effect on cardiac myocytes and conduction cells. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Felodipine decreases arterial smooth muscle contractility and subsequent vasoconstriction by inhibiting the influx of calcium ions through voltage-gated L-type calcium channels. It reversibly competes against nitrendipine and other DHP CCBs for DHP binding sites in vascular smooth muscle and cultured rabbit atrial cells. Calcium ions entering the cell through these channels bind to calmodulin. Calcium-bound calmodulin then binds to and activates myosin light chain kinase (MLCK). Activated MLCK catalyzes the phosphorylation of the regulatory light chain subunit of myosin, a key step in muscle contraction. Signal amplification is achieved by calcium-induced calcium release from the sarcoplasmic reticulum through ryanodine receptors. Inhibition of the initial influx of calcium decreases the contractile activity of arterial smooth muscle cells and results in vasodilation. The vasodilatory effects of felodipine result in an overall decrease in blood pressure. Felodipine may be used to treat mild to moderate essential hypertension. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Is completely absorbed from the gastrointestinal tract; however, extensive first-pass metabolism through the portal circulation results in a low systemic availability of 15%. Bioavailability is unaffected by food. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 10 L/kg •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 99%, primarily to the albumin fraction. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Hepatic metabolism primarily via cytochrome P450 3A4. Six metabolites with no appreciable vasodilatory effects have been identified. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Although higher concentrations of the metabolites are present in the plasma due to decreased urinary excretion, these are inactive. Animal studies have demonstrated that felodipine crosses the blood-brain barrier and the placenta. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 17.5-31.5 hours in hypertensive patients; 19.1-35.9 hours in elderly hypertensive patients; 8.5-19.7 in healthy volunteers. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): 0.8 L/min [Young healthy subjects] •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Symptoms of overdose include excessive peripheral vasodilation with marked hypotension and possibly bradycardia. Oral rat LD 50 is 1050 mg/kg. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Plendil •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Felodipina Felodipine Felodipino Felodipinum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Felodipine is a calcium channel blocker used to treat hypertension. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Fenoldopam interact?

•Drug A: Abaloparatide •Drug B: Fenoldopam •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Fenoldopam is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the in-hospital, short-term (up to 48 hours) management of severe hypertension when rapid, but quickly reversible, emergency reduction of blood pressure is clinically indicated, including malignant hypertension with deteriorating end-organ function. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Fenoldopam is an agonist at D 1 -like dopamine receptors, binds to α 2 -adrenoceptors, increasing renal blood flow. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Fenoldopam is a rapid-acting vasodilator. It is an agonist for D 1 -like dopamine receptors and binds with moderate affinity to α 2 -adrenoceptors. It has no significant affinity for D 2 -like receptors, α 1 and β-adrenoceptors, 5 HT1 and 5 HT2 receptors, or muscarinic receptors. Fenoldopam is a racemic mixture with the R-isomer responsible for the biological activity. The R-isomer has approximately 250-fold higher affinity for D 1 -like receptors than does the S-isomer. In non-clinical studies, fenoldopam had no agonist effect on presynaptic D 2 -like dopamine receptors, or α or β -adrenoceptors, nor did it affect angiotensin-converting enzyme activity. Fenoldopam may increase norepinephrine plasma concentration. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Elimination is largely by conjugation, without participation of cytochrome P-450 enzymes. Methylation, glucuronidation, and sulfation are the main routes of conjugation. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Radiolabeled studies show that about 90% of infused fenoldopam is eliminated in urine, 10% in feces. Elimination is largely by conjugation, without participation of cytochrome P-450 enzymes. Only 4% of the administered dose is excreted unchanged. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The elimination half-life is about 5 minutes in mild to moderate hypertensives, with little difference between the R (active) and S isomers. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The most likely reaction of overdose would be excessive hypotension which should be treated with drug discontinuation and appropriate supportive measures. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Corlopam •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Fenoldopam is a dopamine D1 receptor agonist used for the short term management of hypertension.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Fenoldopam interact? Information: •Drug A: Abaloparatide •Drug B: Fenoldopam •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Fenoldopam is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the in-hospital, short-term (up to 48 hours) management of severe hypertension when rapid, but quickly reversible, emergency reduction of blood pressure is clinically indicated, including malignant hypertension with deteriorating end-organ function. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Fenoldopam is an agonist at D 1 -like dopamine receptors, binds to α 2 -adrenoceptors, increasing renal blood flow. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Fenoldopam is a rapid-acting vasodilator. It is an agonist for D 1 -like dopamine receptors and binds with moderate affinity to α 2 -adrenoceptors. It has no significant affinity for D 2 -like receptors, α 1 and β-adrenoceptors, 5 HT1 and 5 HT2 receptors, or muscarinic receptors. Fenoldopam is a racemic mixture with the R-isomer responsible for the biological activity. The R-isomer has approximately 250-fold higher affinity for D 1 -like receptors than does the S-isomer. In non-clinical studies, fenoldopam had no agonist effect on presynaptic D 2 -like dopamine receptors, or α or β -adrenoceptors, nor did it affect angiotensin-converting enzyme activity. Fenoldopam may increase norepinephrine plasma concentration. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Elimination is largely by conjugation, without participation of cytochrome P-450 enzymes. Methylation, glucuronidation, and sulfation are the main routes of conjugation. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Radiolabeled studies show that about 90% of infused fenoldopam is eliminated in urine, 10% in feces. Elimination is largely by conjugation, without participation of cytochrome P-450 enzymes. Only 4% of the administered dose is excreted unchanged. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The elimination half-life is about 5 minutes in mild to moderate hypertensives, with little difference between the R (active) and S isomers. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The most likely reaction of overdose would be excessive hypotension which should be treated with drug discontinuation and appropriate supportive measures. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Corlopam •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Fenoldopam is a dopamine D1 receptor agonist used for the short term management of hypertension. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Fosinopril interact?

•Drug A: Abaloparatide •Drug B: Fosinopril •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Fosinopril is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For treating mild to moderate hypertension, use as an adjunct in treating congestive heart failure, and may be used to slow the rate of progression of renal disease in hypertensive individuals with diabetes mellitus and microalbuminuria or overt nephropathy. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Following oral administration, fosinopril is rapidly and completely hydrolyzed to its principle active metabolite, fosinoprilat. Hydrolysis is thought to occur in the gastrointestinal mucosa and liver. Fosinoprilat is a competitive inhibitor of ACE, a peptidyl dipeptidase that is part of the RAAS. The RAAS is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from the granular cells of the juxtaglomerular apparatus in the kidneys. In the blood stream, renin cleaves circulating angiotensinogen to ATI, which is subsequently cleaved to ATII by ACE. ATII increases blood pressure using a number of mechanisms. First, it stimulates the secretion of aldosterone from the adrenal cortex. Aldosterone travels to the distal convoluted tubule (DCT) and collecting tubule of nephrons where it increases sodium and water reabsorption by increasing the number of sodium channels and sodium-potassium ATPases on cell membranes. Second, ATII stimulates the secretion of vasopressin (also known as antidiuretic hormone or ADH) from the posterior pituitary gland. ADH stimulates further water reabsorption from the kidneys via insertion of aquaporin-2 channels on the apical surface of cells of the DCT and collecting tubules. Third, ATII increases blood pressure through direct arterial vasoconstriction. Stimulation of the Type 1 ATII receptor on vascular smooth muscle cells leads to a cascade of events resulting in myocyte contraction and vasoconstriction. In addition to these major effects, ATII induces the thirst response via stimulation of hypothalamic neurons. ACE inhibitors inhibit the rapid conversion of ATI to ATII and antagonize RAAS-induced increases in blood pressure. ACE (also known as kininase II) is also involved in the enzymatic deactivation of bradykinin, a vasodilator. Inhibiting the deactivation of bradykinin increases bradykinin levels and may further sustain the effects of fosinoprilat by causing increased vasodilation and decreased blood pressure. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): There are two isoforms of ACE: the somatic isoform, which exists as a glycoprotein comprised of a single polypeptide chain of 1277; and the testicular isoform, which has a lower molecular mass and is thought to play a role in sperm maturation and binding of sperm to the oviduct epithelium. Somatic ACE has two functionally active domains, N and C, which arise from tandem gene duplication. Although the two domains have high sequence similarity, they play distinct physiological roles. The C-domain is predominantly involved in blood pressure regulation while the N-domain plays a role in hematopoietic stem cell differentiation and proliferation. ACE inhibitors bind to and inhibit the activity of both domains, but have much greater affinity for and inhibitory activity against the C-domain. Fosinoprilat, the active metabolite of fosinopril, competes with ATI for binding to ACE and inhibits and enzymatic proteolysis of ATI to ATII. Decreasing ATII levels in the body decreases blood pressure by inhibiting the pressor effects of ATII as described in the Pharmacology section above. Fosinoprilat also causes an increase in plasma renin activity likely due to a loss of feedback inhibition mediated by ATII on the release of renin and/or stimulation of reflex mechanisms via baroreceptors. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Average absolute absorption is 36%. The primary site of absorption is the proximal small intestine (duodenum/jejunum). Food slows the rate of absorption with no effect on the extent of absorption. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Fosinoprilat is ≥95% protein bound •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Since fosinoprilat is not biotransformed after intravenous administration, fosinopril, not fosinoprilat, appears to be the precursor for the glucuronide and p-hydroxy metabolites. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): After oral administration of radiolabeled fosinopril, approximately half of the absorbed dose is excreted in the urine and the remainder is excreted in the feces. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 12 hours •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): 26 - 39 mL/min [healthy] •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Human overdoses of fosinopril have not been reported, but the most common manifestation of human fosinopril overdosage is likely to be hypotension. Oral doses of fosinopril at 2600 mg/kg in rats were associated with significant lethality. The most common adverse effects include dizzines, cough, fatigue, and headache. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Fosinopril is an ACE inhibitor used to treat mild to moderate hypertension, congestive heart failure, and to slow the progression of renal disease in hypertensive diabetics.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Fosinopril interact? Information: •Drug A: Abaloparatide •Drug B: Fosinopril •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Fosinopril is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For treating mild to moderate hypertension, use as an adjunct in treating congestive heart failure, and may be used to slow the rate of progression of renal disease in hypertensive individuals with diabetes mellitus and microalbuminuria or overt nephropathy. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Following oral administration, fosinopril is rapidly and completely hydrolyzed to its principle active metabolite, fosinoprilat. Hydrolysis is thought to occur in the gastrointestinal mucosa and liver. Fosinoprilat is a competitive inhibitor of ACE, a peptidyl dipeptidase that is part of the RAAS. The RAAS is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from the granular cells of the juxtaglomerular apparatus in the kidneys. In the blood stream, renin cleaves circulating angiotensinogen to ATI, which is subsequently cleaved to ATII by ACE. ATII increases blood pressure using a number of mechanisms. First, it stimulates the secretion of aldosterone from the adrenal cortex. Aldosterone travels to the distal convoluted tubule (DCT) and collecting tubule of nephrons where it increases sodium and water reabsorption by increasing the number of sodium channels and sodium-potassium ATPases on cell membranes. Second, ATII stimulates the secretion of vasopressin (also known as antidiuretic hormone or ADH) from the posterior pituitary gland. ADH stimulates further water reabsorption from the kidneys via insertion of aquaporin-2 channels on the apical surface of cells of the DCT and collecting tubules. Third, ATII increases blood pressure through direct arterial vasoconstriction. Stimulation of the Type 1 ATII receptor on vascular smooth muscle cells leads to a cascade of events resulting in myocyte contraction and vasoconstriction. In addition to these major effects, ATII induces the thirst response via stimulation of hypothalamic neurons. ACE inhibitors inhibit the rapid conversion of ATI to ATII and antagonize RAAS-induced increases in blood pressure. ACE (also known as kininase II) is also involved in the enzymatic deactivation of bradykinin, a vasodilator. Inhibiting the deactivation of bradykinin increases bradykinin levels and may further sustain the effects of fosinoprilat by causing increased vasodilation and decreased blood pressure. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): There are two isoforms of ACE: the somatic isoform, which exists as a glycoprotein comprised of a single polypeptide chain of 1277; and the testicular isoform, which has a lower molecular mass and is thought to play a role in sperm maturation and binding of sperm to the oviduct epithelium. Somatic ACE has two functionally active domains, N and C, which arise from tandem gene duplication. Although the two domains have high sequence similarity, they play distinct physiological roles. The C-domain is predominantly involved in blood pressure regulation while the N-domain plays a role in hematopoietic stem cell differentiation and proliferation. ACE inhibitors bind to and inhibit the activity of both domains, but have much greater affinity for and inhibitory activity against the C-domain. Fosinoprilat, the active metabolite of fosinopril, competes with ATI for binding to ACE and inhibits and enzymatic proteolysis of ATI to ATII. Decreasing ATII levels in the body decreases blood pressure by inhibiting the pressor effects of ATII as described in the Pharmacology section above. Fosinoprilat also causes an increase in plasma renin activity likely due to a loss of feedback inhibition mediated by ATII on the release of renin and/or stimulation of reflex mechanisms via baroreceptors. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Average absolute absorption is 36%. The primary site of absorption is the proximal small intestine (duodenum/jejunum). Food slows the rate of absorption with no effect on the extent of absorption. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Fosinoprilat is ≥95% protein bound •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Since fosinoprilat is not biotransformed after intravenous administration, fosinopril, not fosinoprilat, appears to be the precursor for the glucuronide and p-hydroxy metabolites. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): After oral administration of radiolabeled fosinopril, approximately half of the absorbed dose is excreted in the urine and the remainder is excreted in the feces. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 12 hours •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): 26 - 39 mL/min [healthy] •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Human overdoses of fosinopril have not been reported, but the most common manifestation of human fosinopril overdosage is likely to be hypotension. Oral doses of fosinopril at 2600 mg/kg in rats were associated with significant lethality. The most common adverse effects include dizzines, cough, fatigue, and headache. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Fosinopril is an ACE inhibitor used to treat mild to moderate hypertension, congestive heart failure, and to slow the progression of renal disease in hypertensive diabetics. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Fostamatinib interact?

•Drug A: Abaloparatide •Drug B: Fostamatinib •Severity: MINOR •Description: The risk or severity of hypotension can be increased when Fostamatinib is combined with Abaloparatide. •Extended Description: The subject drug is a phosphodiesterase 5 inhibitor which can lower blood pressure.1 The affected drug can cause hypotension, particularly orthostatic hypotension. Concomitant administration of these medications may lead to an increased risk of hypotension and orthostatic hypotension. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Fostamatinib is indicated for use in the treatment of chronic immune thrombocytopenia (ITP) in patients who have had insufficient response to previous therapy. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): The active metabolite of fostamatinib, R406, inhibits signal transduction by Fcγ receptors involved in the antibody-mediated destruction of platelets by immune cells in chronic ITP. This results in increased platelet counts in this population. R406 produces inhibition of T and B lymphocyte activation by T-cell receptors (TCRs) and B-cell receptors (BCRs) respectively. It can also inhibit signalling via Fcε receptors which could have applications in treating allergic symptoms through prevention of mast cell degranulation. Inhibition of Fc receptor signalling system also affected by R406 suppresses both dendritic cell maturation and antigen presentation and may contribute to the effects of fostamatinib. As a knock-on effect of disabling signal transduction from Fc receptors, TCRs, and BCRs, the production of inflammatory mediators and cytokines like tumour necrosis factor α, leukotriene C4, interleukin-8, and granulocyte-macrophage colony-stimulating factor. Fostamatinib can produce hypertension through off-target effects •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): The active metabolite of fostamatinib, R406, is an inhibitor of spleen tyrosine kinase (Syk). It binds reversibly to the ATP binding pocket with high affinity (Ki = 30nM), inhibiting the kinase activity with an IC50 of 41nM. Syk is a cytosolic protein kinase and part of the signalling cascade which occurs with Fc receptors, TCRs, and BCRs. It contains two src homology 2 (SH2) domains separated by a linker domain. These SH2 domains bind to tyrosine residues on the immunoreceptor tyrosine-based activating motif phosphorylated by Lyn, another kinase in the cascade. This motif is located on the cytoplasmic regions of several immune receptors including Fc receptors, TCRs, BCRs, and natural killer cell receptors. The flexibility provided by the linker enables the protein to bind to many receptor types. Inhibition of Syk suppresses downstream signal transduction. While Syk plays a role in some pathways involved in the generation of the oxidative burst by neutrophils or phagocytosis by macrophages, R406 does not have a significant effect on these processes. This is likely due to redundant pathways which do not involve Syk. Similarly Syk does not produce significant effects on platelet activation despite its involvement in glycoprotein IV and integrin based signalling. Activation of antibody-dependent cell-mediated toxicity by natural killer cells is also unaffected despite the involvement of Syk in Fc receptor signalling. R406 binds to the adenosine A3 receptor as an antagonist as well as the adenosine and monoamine uptake transporters as an inhibitor. It has also been found to be an inhibitor of UDP glucuronosyltransferase UGT1A1, phosphodiesterase PDE5, fatty acid amide hydrolase, 5-lipoxygenase, cathepsin L, and cathepsin S. R406 appears to inhibit a wide range of kinases at higher concentrations. It is thought that inhibition of some of these targets may be responsible for the increase in blood pressure seen with fostamatinib. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Fostmatinib is the methylene phosphate prodrug of R406, the active metabolite. It is extensively hydrolyzed by intestinal alkaline phosphatase. Only negligible amounts of fostamatinib enter systemic circulation. R406 has an absolute bioavailability of 55% and reaches peak plasma concentrations in approximately 1.5 h. Administration with a high calorie, high fat meal increases exposure by 23% and the maximum plasma concentration by 15%. This may lengthen time to peak plasma concentration to approximately 3 h. Exposure to R406 is known to be dose proportional up to 200 mg twice daily. R406 accumulates 2-3 fold with twice daily dosing at 100-160 mg. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): R406 has an apparent oral volume of distribution of approximately 400 L. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): R406 is 98.3% bound to plasma proteins. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Fostamatinib is metabolized in the gut by alkaline phosphatase to the active metabolite R406. R406 is further oxidized by CYP3A4 and glucuronidated by UGT1A9. Plasma metabolites found include an O-glucuronide conjugate, an N-glucuronide conjugate, an O-desmethyl metabolite, and a sulfate conjugate. A 3,5 benzene diol metabolite forms in the feces via processing of the O-desmethyl metabolite by gut bacteria. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): About 80% of R406 is excreted in the feces, primarily as the O-glucuronide conjugate and the O-desmethyl metabolite produced by gut bacteria. The remaining 20% is excreted in the urine as the N-glucuronide conjugate. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): R406 has a half-life of elimination of approximately 15 h. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): R406 has an apparent oral clearance of approximately 300 mL/min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Neither fostamatinib or R406 were found to be carcinogenic or mutagenic. Fostamatinib can cause embryo-fetal mortality or developmental abnormalities at exposures of 0.3-10 times the maximum recommended human dose. Serious adverse effects include hypertension, neutropenia, diarrhea, and hepatotoxicity •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Tavalisse •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Fostamatinib is a spleen tyrosine kinase inhibitor used to treat chronic immune thrombocytopenia after attempting one other treatment.

The subject drug is a phosphodiesterase 5 inhibitor which can lower blood pressure.1 The affected drug can cause hypotension, particularly orthostatic hypotension. Concomitant administration of these medications may lead to an increased risk of hypotension and orthostatic hypotension. The severity of the interaction is minor.

Question: Does Abaloparatide and Fostamatinib interact? Information: •Drug A: Abaloparatide •Drug B: Fostamatinib •Severity: MINOR •Description: The risk or severity of hypotension can be increased when Fostamatinib is combined with Abaloparatide. •Extended Description: The subject drug is a phosphodiesterase 5 inhibitor which can lower blood pressure.1 The affected drug can cause hypotension, particularly orthostatic hypotension. Concomitant administration of these medications may lead to an increased risk of hypotension and orthostatic hypotension. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Fostamatinib is indicated for use in the treatment of chronic immune thrombocytopenia (ITP) in patients who have had insufficient response to previous therapy. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): The active metabolite of fostamatinib, R406, inhibits signal transduction by Fcγ receptors involved in the antibody-mediated destruction of platelets by immune cells in chronic ITP. This results in increased platelet counts in this population. R406 produces inhibition of T and B lymphocyte activation by T-cell receptors (TCRs) and B-cell receptors (BCRs) respectively. It can also inhibit signalling via Fcε receptors which could have applications in treating allergic symptoms through prevention of mast cell degranulation. Inhibition of Fc receptor signalling system also affected by R406 suppresses both dendritic cell maturation and antigen presentation and may contribute to the effects of fostamatinib. As a knock-on effect of disabling signal transduction from Fc receptors, TCRs, and BCRs, the production of inflammatory mediators and cytokines like tumour necrosis factor α, leukotriene C4, interleukin-8, and granulocyte-macrophage colony-stimulating factor. Fostamatinib can produce hypertension through off-target effects •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): The active metabolite of fostamatinib, R406, is an inhibitor of spleen tyrosine kinase (Syk). It binds reversibly to the ATP binding pocket with high affinity (Ki = 30nM), inhibiting the kinase activity with an IC50 of 41nM. Syk is a cytosolic protein kinase and part of the signalling cascade which occurs with Fc receptors, TCRs, and BCRs. It contains two src homology 2 (SH2) domains separated by a linker domain. These SH2 domains bind to tyrosine residues on the immunoreceptor tyrosine-based activating motif phosphorylated by Lyn, another kinase in the cascade. This motif is located on the cytoplasmic regions of several immune receptors including Fc receptors, TCRs, BCRs, and natural killer cell receptors. The flexibility provided by the linker enables the protein to bind to many receptor types. Inhibition of Syk suppresses downstream signal transduction. While Syk plays a role in some pathways involved in the generation of the oxidative burst by neutrophils or phagocytosis by macrophages, R406 does not have a significant effect on these processes. This is likely due to redundant pathways which do not involve Syk. Similarly Syk does not produce significant effects on platelet activation despite its involvement in glycoprotein IV and integrin based signalling. Activation of antibody-dependent cell-mediated toxicity by natural killer cells is also unaffected despite the involvement of Syk in Fc receptor signalling. R406 binds to the adenosine A3 receptor as an antagonist as well as the adenosine and monoamine uptake transporters as an inhibitor. It has also been found to be an inhibitor of UDP glucuronosyltransferase UGT1A1, phosphodiesterase PDE5, fatty acid amide hydrolase, 5-lipoxygenase, cathepsin L, and cathepsin S. R406 appears to inhibit a wide range of kinases at higher concentrations. It is thought that inhibition of some of these targets may be responsible for the increase in blood pressure seen with fostamatinib. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Fostmatinib is the methylene phosphate prodrug of R406, the active metabolite. It is extensively hydrolyzed by intestinal alkaline phosphatase. Only negligible amounts of fostamatinib enter systemic circulation. R406 has an absolute bioavailability of 55% and reaches peak plasma concentrations in approximately 1.5 h. Administration with a high calorie, high fat meal increases exposure by 23% and the maximum plasma concentration by 15%. This may lengthen time to peak plasma concentration to approximately 3 h. Exposure to R406 is known to be dose proportional up to 200 mg twice daily. R406 accumulates 2-3 fold with twice daily dosing at 100-160 mg. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): R406 has an apparent oral volume of distribution of approximately 400 L. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): R406 is 98.3% bound to plasma proteins. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Fostamatinib is metabolized in the gut by alkaline phosphatase to the active metabolite R406. R406 is further oxidized by CYP3A4 and glucuronidated by UGT1A9. Plasma metabolites found include an O-glucuronide conjugate, an N-glucuronide conjugate, an O-desmethyl metabolite, and a sulfate conjugate. A 3,5 benzene diol metabolite forms in the feces via processing of the O-desmethyl metabolite by gut bacteria. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): About 80% of R406 is excreted in the feces, primarily as the O-glucuronide conjugate and the O-desmethyl metabolite produced by gut bacteria. The remaining 20% is excreted in the urine as the N-glucuronide conjugate. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): R406 has a half-life of elimination of approximately 15 h. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): R406 has an apparent oral clearance of approximately 300 mL/min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Neither fostamatinib or R406 were found to be carcinogenic or mutagenic. Fostamatinib can cause embryo-fetal mortality or developmental abnormalities at exposures of 0.3-10 times the maximum recommended human dose. Serious adverse effects include hypertension, neutropenia, diarrhea, and hepatotoxicity •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Tavalisse •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Fostamatinib is a spleen tyrosine kinase inhibitor used to treat chronic immune thrombocytopenia after attempting one other treatment. Output: The subject drug is a phosphodiesterase 5 inhibitor which can lower blood pressure.1 The affected drug can cause hypotension, particularly orthostatic hypotension. Concomitant administration of these medications may lead to an increased risk of hypotension and orthostatic hypotension. The severity of the interaction is minor.

Does Abaloparatide and Furosemide interact?

•Drug A: Abaloparatide •Drug B: Furosemide •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Furosemide is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Furosemide is indicated for the treatment of edema associated with congestive heart failure, cirrhosis of the liver, and renal disease, including the nephrotic syndrome, in adults and pediatric patients. Oral furosemide is indicated alone for the management of mild to moderate hypertension or severe hypertension in combination with other antihypertensive medications. Intravenous furosemide is indicated as adjunctive therapy in acute pulmonary edema when a rapid onset of diuresis is desired. Subcutaneous furosemide is indicated for the treatment of congestion due to fluid overload in adults with NYHA Class II/III chronic heart failure. This drug formulation is not indicated for emergency situations or in patients with acute pulmonary edema. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Furosemide manages hypertension and edema associated with congestive heart failure, cirrhosis, and renal disease, including the nephrotic syndrome. Furosemide is a potent loop diuretic that works to increase the excretion of Na+ and water by the kidneys by inhibiting their reabsorption from the proximal and distal tubules, as well as the loop of Henle. It works directly acts on the cells of the nephron and indirectly modifies the content of the renal filtrate. Ultimately, furosemide increases the urine output by the kidney. Protein-bound furosemide is delivered to its site of action in the kidneys and secreted via active secretion by nonspecific organic transporters expressed at the luminal site of action. Following oral administration, the onset of the diuretic effect is about 1 and 1.5 hours, and the peak effect is reached within the first 2 hours. The duration of effect following oral administration is about 4-6 hours but may last up to 8 hours. Following intravenous administration, the onset of effect is within 5 minutes, and the peak effect is reached within 30 minutes. The duration of action following intravenous administration is approximately 2 hours. Following intramuscular administration, the onset of action is somewhat delayed. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Furosemide promotes diuresis by blocking tubular reabsorption of sodium and chloride in the proximal and distal tubules, as well as in the thick ascending loop of Henle. This diuretic effect is achieved through the competitive inhibition of sodium-potassium-chloride cotransporters (NKCC2) expressed along these tubules in the nephron, preventing the transport of sodium ions from the lumenal side into the basolateral side for reabsorption. This inhibition results in increased excretion of water along with sodium, chloride, magnesium, calcium, hydrogen, and potassium ions. As with other loop diuretics, furosemide decreases the excretion of uric acid. Furosemide exerts direct vasodilatory effects, which results in its therapeutic effectiveness in the treatment of acute pulmonary edema. Vasodilation leads to reduced responsiveness to vasoconstrictors, such as angiotensin II and noradrenaline, and decreased production of endogenous natriuretic hormones with vasoconstricting properties. It also leads to increased production of prostaglandins with vasodilating properties. Furosemide may also open potassium channels in resistance arteries. The main mechanism of action of furosemide is independent of its inhibitory effect on carbonic anhydrase and aldosterone. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Following oral administration, furosemide is absorbed from the gastrointestinal tract. It displays variable bioavailability from oral dosage forms, ranging from 10 to 90%. The oral bioavailability of furosemide from oral tablets or oral solution is about 64% and 60%, respectively, of that from an intravenous injection of the drug. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The volume of distribution following intravenous administration of 40 mg furosemide were 0.181 L/kg in healthy subjects and 0.140 L/kg in patients with heart failure. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Plasma concentrations ranging from 1 to 400 mcg/mL are about 91-99% bound in healthy individuals. The unbound fraction is about 2.3-4.1% at therapeutic concentrations. Furosemide mainly binds to serum albumin. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): The metabolism of furosemide occurs mainly in the kidneys and the liver, to a smaller extent. The kidneys are responsible for about 85% of total furosemide total clearance, where about 40% involves biotransformation. Two major metabolites of furosemide are furosemide glucuronide, which is pharmacologically active, and saluamine (CSA) or 4-chloro-5-sulfamoylanthranilic acid. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): The kidneys are responsible for 85% of total furosemide total clearance, where about 43% of the drug undergoes renal excretion. Significantly more furosemide is excreted in urine following the I.V. injection than after the tablet or oral solution. Approximately 50% of the furosemide load is excreted unchanged in urine, and the rest is metabolized into glucuronide in the kidney. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The half-life from the dose of 40 mg furosemide was 4 hours following oral administration and 4.5 hours following intravenous administration. The terminal half-life of furosemide is approximately 2 hours following parenteral administration. The terminal half-life may be increased up to 24 hours in patients with severe renal failure. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Following intravenous administration of 400 mg furosemide, the plasma clearance was 1.23 mL/kg/min in patients with heart failure and 2.34 mL/kg/min in healthy subjects, respectively. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Clinical consequences from overdose depend on the extent of electrolyte and fluid loss and include dehydration, blood volume reduction, hypotension, electrolyte imbalance, hypokalemia, hypochloremic alkalosis, hemoconcentration, cardiac arrhythmias (including A-V block and ventricular fibrillation). Symptoms of overdose include acute renal failure, thrombosis, delirious states, flaccid paralysis, apathy and confusion. In cirrhotic patients, overdosage might precipitate hepatic coma. In rats, the oral LD 50, intraperitoneal LD 50, and subcutaneous LD 50 is 2600 mg/kg, 800 mg/kg, and 4600 mg/kg, respectively. The Lowest published toxic dose (TDLo) in a female is 6250 μg/kg. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Furoscix, Lasix •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Frusemide Furosemid Furosemida Furosemide Furosemidu Furosemidum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Furosemide is a loop diuretic used to treat hypertension and edema in congestive heart failure, liver cirrhosis, renal disease, and hypertension.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Furosemide interact? Information: •Drug A: Abaloparatide •Drug B: Furosemide •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Furosemide is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Furosemide is indicated for the treatment of edema associated with congestive heart failure, cirrhosis of the liver, and renal disease, including the nephrotic syndrome, in adults and pediatric patients. Oral furosemide is indicated alone for the management of mild to moderate hypertension or severe hypertension in combination with other antihypertensive medications. Intravenous furosemide is indicated as adjunctive therapy in acute pulmonary edema when a rapid onset of diuresis is desired. Subcutaneous furosemide is indicated for the treatment of congestion due to fluid overload in adults with NYHA Class II/III chronic heart failure. This drug formulation is not indicated for emergency situations or in patients with acute pulmonary edema. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Furosemide manages hypertension and edema associated with congestive heart failure, cirrhosis, and renal disease, including the nephrotic syndrome. Furosemide is a potent loop diuretic that works to increase the excretion of Na+ and water by the kidneys by inhibiting their reabsorption from the proximal and distal tubules, as well as the loop of Henle. It works directly acts on the cells of the nephron and indirectly modifies the content of the renal filtrate. Ultimately, furosemide increases the urine output by the kidney. Protein-bound furosemide is delivered to its site of action in the kidneys and secreted via active secretion by nonspecific organic transporters expressed at the luminal site of action. Following oral administration, the onset of the diuretic effect is about 1 and 1.5 hours, and the peak effect is reached within the first 2 hours. The duration of effect following oral administration is about 4-6 hours but may last up to 8 hours. Following intravenous administration, the onset of effect is within 5 minutes, and the peak effect is reached within 30 minutes. The duration of action following intravenous administration is approximately 2 hours. Following intramuscular administration, the onset of action is somewhat delayed. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Furosemide promotes diuresis by blocking tubular reabsorption of sodium and chloride in the proximal and distal tubules, as well as in the thick ascending loop of Henle. This diuretic effect is achieved through the competitive inhibition of sodium-potassium-chloride cotransporters (NKCC2) expressed along these tubules in the nephron, preventing the transport of sodium ions from the lumenal side into the basolateral side for reabsorption. This inhibition results in increased excretion of water along with sodium, chloride, magnesium, calcium, hydrogen, and potassium ions. As with other loop diuretics, furosemide decreases the excretion of uric acid. Furosemide exerts direct vasodilatory effects, which results in its therapeutic effectiveness in the treatment of acute pulmonary edema. Vasodilation leads to reduced responsiveness to vasoconstrictors, such as angiotensin II and noradrenaline, and decreased production of endogenous natriuretic hormones with vasoconstricting properties. It also leads to increased production of prostaglandins with vasodilating properties. Furosemide may also open potassium channels in resistance arteries. The main mechanism of action of furosemide is independent of its inhibitory effect on carbonic anhydrase and aldosterone. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Following oral administration, furosemide is absorbed from the gastrointestinal tract. It displays variable bioavailability from oral dosage forms, ranging from 10 to 90%. The oral bioavailability of furosemide from oral tablets or oral solution is about 64% and 60%, respectively, of that from an intravenous injection of the drug. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The volume of distribution following intravenous administration of 40 mg furosemide were 0.181 L/kg in healthy subjects and 0.140 L/kg in patients with heart failure. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Plasma concentrations ranging from 1 to 400 mcg/mL are about 91-99% bound in healthy individuals. The unbound fraction is about 2.3-4.1% at therapeutic concentrations. Furosemide mainly binds to serum albumin. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): The metabolism of furosemide occurs mainly in the kidneys and the liver, to a smaller extent. The kidneys are responsible for about 85% of total furosemide total clearance, where about 40% involves biotransformation. Two major metabolites of furosemide are furosemide glucuronide, which is pharmacologically active, and saluamine (CSA) or 4-chloro-5-sulfamoylanthranilic acid. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): The kidneys are responsible for 85% of total furosemide total clearance, where about 43% of the drug undergoes renal excretion. Significantly more furosemide is excreted in urine following the I.V. injection than after the tablet or oral solution. Approximately 50% of the furosemide load is excreted unchanged in urine, and the rest is metabolized into glucuronide in the kidney. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The half-life from the dose of 40 mg furosemide was 4 hours following oral administration and 4.5 hours following intravenous administration. The terminal half-life of furosemide is approximately 2 hours following parenteral administration. The terminal half-life may be increased up to 24 hours in patients with severe renal failure. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Following intravenous administration of 400 mg furosemide, the plasma clearance was 1.23 mL/kg/min in patients with heart failure and 2.34 mL/kg/min in healthy subjects, respectively. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Clinical consequences from overdose depend on the extent of electrolyte and fluid loss and include dehydration, blood volume reduction, hypotension, electrolyte imbalance, hypokalemia, hypochloremic alkalosis, hemoconcentration, cardiac arrhythmias (including A-V block and ventricular fibrillation). Symptoms of overdose include acute renal failure, thrombosis, delirious states, flaccid paralysis, apathy and confusion. In cirrhotic patients, overdosage might precipitate hepatic coma. In rats, the oral LD 50, intraperitoneal LD 50, and subcutaneous LD 50 is 2600 mg/kg, 800 mg/kg, and 4600 mg/kg, respectively. The Lowest published toxic dose (TDLo) in a female is 6250 μg/kg. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Furoscix, Lasix •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Frusemide Furosemid Furosemida Furosemide Furosemidu Furosemidum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Furosemide is a loop diuretic used to treat hypertension and edema in congestive heart failure, liver cirrhosis, renal disease, and hypertension. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Guanfacine interact?

•Drug A: Abaloparatide •Drug B: Guanfacine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Guanfacine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Guanfacine is indicated alone or as an adjunct with stimulants to treat ADHD. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Guanfacine is a selective alpha-2A adrenergic receptor agonist but it is unclear how this translates to the treatment of ADHD. It has a long duration of action as it is given once daily and a wide therapeutic window as fatal overdoses have not been described in literature. Patients should be counselled regarding the risk of hypotension, bradycardia, and syncope. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Guanfacine is a selective alpha-2A adrenergic receptor agonist, which reduces the effects of the sympathetic nervous system on the heart and circulatory system. The link between guanfacine’s molecular mechanism and it’s effect on the treatment of ADHD has not been determined. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Guanfacine is 80% orally bioavailable. 1mg immediate release oral guanfacine reaches a C max of 2.5±0.6ng/mL with a T max of 3.0h and an AUC of 56±15ng*h/mL. 1mg extended release oral guanfacine reaches a C max of 1.0±0.3ng/mL with a T max of 6.0h and an AUC of 32±9ng*h/mL. In adults, a 4mg oral extended release dose reaches a C max of 3.58±1.39ng/mL with a T max of 5.5h; in children, a 2mg oral extended relsease dose reaches a C max of 2.6±1.03ng/mL with a T max of 4.98h; in adolescents, a 2mg oral extended release dose reaches a C max of 1.7±0.43ng/mL with a T max of 4.96h. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Guanfacine has a volume of distribution of 6.3L/kg. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Guanfacine is approximately 70% protein bound in serum. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Guanfacine is oxidized by CYP3A4 to it's main metabolite, 3-hydroxyguanfacine. 3-hydroxyguanfacine is then either glucuronidated or sulphated. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Guanfacine is 57.0±32.0% eliminated in the urine in patients with normal renal function. Patients with a glomerular filtration rate (GFR) of 10-30mL/min eliminate 14.0±9.0% of a dose in the urine, while patients with a GFR of <1mL/min eliminate 7.5±2.4% of a dose in the urine. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Guanfacine has a half life of 17 hours, but this may range from 10-30 hours. The half life is largely independant of renal function. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Guanfacine has a total body cleraance of 360±262mL/min and a renal clearance of 233±245mL/min in patients with normal renal function. Patients with a glomerular filtration rate (GFR) of 10-30mL/min had a total body clearance of 308±274mL/min and a renal clearance of 34±22mL/min. Patients with a GFR of <1mL/min had a total body clearance of 257±187mL/min and a renal clearance of 18±15mL/min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The oral LD 50 in rats is 142mg/kg and 15.3mg/kg in mice. The subcutaneous LD 50 in rats is 114mg/kg and 46mg/kg in mice. Patients experiencing and overdose may present with hypotension, drowsiness, lethargy, and bradycardia. Overdose should be managed by first calling local poison control. Patients may require intravenous saline to maintain blood pressure. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Intuniv, Tenex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Guanfacine is an alpha-2A adrenergic receptor agonist used to treat ADHD.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Guanfacine interact? Information: •Drug A: Abaloparatide •Drug B: Guanfacine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Guanfacine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Guanfacine is indicated alone or as an adjunct with stimulants to treat ADHD. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Guanfacine is a selective alpha-2A adrenergic receptor agonist but it is unclear how this translates to the treatment of ADHD. It has a long duration of action as it is given once daily and a wide therapeutic window as fatal overdoses have not been described in literature. Patients should be counselled regarding the risk of hypotension, bradycardia, and syncope. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Guanfacine is a selective alpha-2A adrenergic receptor agonist, which reduces the effects of the sympathetic nervous system on the heart and circulatory system. The link between guanfacine’s molecular mechanism and it’s effect on the treatment of ADHD has not been determined. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Guanfacine is 80% orally bioavailable. 1mg immediate release oral guanfacine reaches a C max of 2.5±0.6ng/mL with a T max of 3.0h and an AUC of 56±15ng*h/mL. 1mg extended release oral guanfacine reaches a C max of 1.0±0.3ng/mL with a T max of 6.0h and an AUC of 32±9ng*h/mL. In adults, a 4mg oral extended release dose reaches a C max of 3.58±1.39ng/mL with a T max of 5.5h; in children, a 2mg oral extended relsease dose reaches a C max of 2.6±1.03ng/mL with a T max of 4.98h; in adolescents, a 2mg oral extended release dose reaches a C max of 1.7±0.43ng/mL with a T max of 4.96h. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Guanfacine has a volume of distribution of 6.3L/kg. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Guanfacine is approximately 70% protein bound in serum. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Guanfacine is oxidized by CYP3A4 to it's main metabolite, 3-hydroxyguanfacine. 3-hydroxyguanfacine is then either glucuronidated or sulphated. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Guanfacine is 57.0±32.0% eliminated in the urine in patients with normal renal function. Patients with a glomerular filtration rate (GFR) of 10-30mL/min eliminate 14.0±9.0% of a dose in the urine, while patients with a GFR of <1mL/min eliminate 7.5±2.4% of a dose in the urine. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Guanfacine has a half life of 17 hours, but this may range from 10-30 hours. The half life is largely independant of renal function. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Guanfacine has a total body cleraance of 360±262mL/min and a renal clearance of 233±245mL/min in patients with normal renal function. Patients with a glomerular filtration rate (GFR) of 10-30mL/min had a total body clearance of 308±274mL/min and a renal clearance of 34±22mL/min. Patients with a GFR of <1mL/min had a total body clearance of 257±187mL/min and a renal clearance of 18±15mL/min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The oral LD 50 in rats is 142mg/kg and 15.3mg/kg in mice. The subcutaneous LD 50 in rats is 114mg/kg and 46mg/kg in mice. Patients experiencing and overdose may present with hypotension, drowsiness, lethargy, and bradycardia. Overdose should be managed by first calling local poison control. Patients may require intravenous saline to maintain blood pressure. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Intuniv, Tenex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Guanfacine is an alpha-2A adrenergic receptor agonist used to treat ADHD. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Halothane interact?

•Drug A: Abaloparatide •Drug B: Halothane •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Halothane is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the induction and maintenance of general anesthesia •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Halothane is a general inhalation anesthetic used for induction and maintenance of general anesthesia. It reduces the blood pressure and frequently decreases the pulse rate and depresses respiration. It induces muscle relaxation and reduces pains sensitivity by altering tissue excitability. It does so by decreasing the extent of gap junction mediated cell-cell coupling and altering the activity of the channels that underlie the action potential. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Halothane causes general anaethesia due to its actions on multiple ion channels, which ultimately depresses nerve conduction, breathing, cardiac contractility. Its immobilizing effects have been attributed to its binding to potassium channels in cholinergic neurons. Halothane's effect are also likely due to binding to NMDA and calcium channels, causing hyperpolarization. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Halothane is metabolized in the liver, primarily by CYP2E1, and to a lesser extent by CYP3A4 and CYP2A6. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): No half-life available •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Toxic effects of halothane include malignant hyperthermia and hepatitis. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Alotano Bromochlorotrifluoroethane Halotano Halothane Halothanum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Halothane is a general inhalation anesthetic used for the induction and maintenance of general anesthesia.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Halothane interact? Information: •Drug A: Abaloparatide •Drug B: Halothane •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Halothane is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the induction and maintenance of general anesthesia •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Halothane is a general inhalation anesthetic used for induction and maintenance of general anesthesia. It reduces the blood pressure and frequently decreases the pulse rate and depresses respiration. It induces muscle relaxation and reduces pains sensitivity by altering tissue excitability. It does so by decreasing the extent of gap junction mediated cell-cell coupling and altering the activity of the channels that underlie the action potential. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Halothane causes general anaethesia due to its actions on multiple ion channels, which ultimately depresses nerve conduction, breathing, cardiac contractility. Its immobilizing effects have been attributed to its binding to potassium channels in cholinergic neurons. Halothane's effect are also likely due to binding to NMDA and calcium channels, causing hyperpolarization. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Halothane is metabolized in the liver, primarily by CYP2E1, and to a lesser extent by CYP3A4 and CYP2A6. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): No half-life available •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Toxic effects of halothane include malignant hyperthermia and hepatitis. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Alotano Bromochlorotrifluoroethane Halotano Halothane Halothanum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Halothane is a general inhalation anesthetic used for the induction and maintenance of general anesthesia. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Hydralazine interact?

•Drug A: Abaloparatide •Drug B: Hydralazine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Hydralazine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Hydralazine is indicated alone or adjunct to standard therapy to treat essential hypertension. A combination product with isosorbide dinitrate is indicated as an adjunct therapy in the treatment of heart failure. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Hydralazine interferes with calcium transport to relax arteriolar smooth muscle and lower blood pressure. Hydralazine has a short duration of action of 2-6h. This drug has a wide therapeutic window, as patients can tolerate doses of up to 300mg. Patients should be cautioned regarding the risk of developing systemic lupus erythematosus syndrome. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Hydralazine may interfere with calcium transport in vascular smooth muscle by an unknown mechanism to relax arteriolar smooth muscle and lower blood pressure. The interference with calcium transport may be by preventing influx of calcium into cells, preventing calcium release from intracellular compartments, directly acting on actin and myosin, or a combination of these actions. This decrease in vascular resistance leads to increased heart rate, stroke volume, and cardiac output. Hydralazine also competes with protocollagen prolyl hydroxylase (CPH) for free iron. This competition inhibits CPH mediated hydroxylation of HIF-1α, preventing the degradation of HIF-1α. Induction of HIF-1α and VEGF promote proliferation of endothelial cells and angiogenesis. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Taking oral hydralazine with food improves the bioavailability of the drug. An intravenous dose of 0.3mg/kg leads to an AUC of 17.5-29.4µM*min and a 1mg/kg oral dose leads to an AUC of 4.0-30.4µM*min. The C max of oral hydralazine is 0.12-1.31µM depending on the acetylator status of patients. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The volume of distribution is 1.34±0.79L/kg in congestive heart failure patients and 1.98±0.22L/kg in hypertensive patients. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Hydralazine is 87% protein bound in serum likely to human serum albumin. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Acetylation is a minor metabolic pathway for hydralazine; the major pathway is hydroxylation followed by glucuronidation. There are 5 identified metabolic pathways for hydralazine. Hydralazine can be metabolized to phthalazine or α-ketoglutarate hydrazone. These metabolites can be further converted to phthalazinone or hydralazine can be metabolized directly to phthalazinone. Hydralazine can undergo a reversible converstion to the active hydralazine acetone hydrazone. Hydralazine is spontaneously converted to the active pyruvic acid hydrazone or the pyruvic acid hydrazone tricyclic dehydration product, and these metabolites can convert back and forth between these 2 forms. Hydralazine can be converted to hydrazinophthalazinone, which is further converted to the active acetylhydrazinophthalazinone. The final metabolic process hydralazine can undergo is the conversion to an unnamed hydralazine metabolite, which is further metabolized to 3-methyl-s-triazolophthalazine (MTP). MTP can be metabolized to 9-hydroxy-methyltriazolophthalazine or 3-hydroxy-methyltriazolophthalazine; the latter is converted to triazolophthalazine. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): <10% of hydralazine is recovered in the feces; 65-90% is recovered in the urine. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Hydralazine has a half life of 2.2-7.8h in rapid acetylators and 2.0-5.8h in slow acetylators. The half life in heart failure patients is 57-241 minutes with an average of 105 minutes and in hypertensive patients is 200 minutes for rapid acetylators and 297 minutes for slow acetylators. Hydralazine is subject to polymorphic acetylation; slow acetylators generally have higher plasma levels of hydralazine and require lower doses to maintain control of pressure. However, other factors, such as acetylation being a minor metabolic pathway for hydralazine, will contribute to differences in elimination rates. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The majority of hydralazine clearance is extrahepatic- 55% for rapid acetylators and 70% for slow acetylators. The average clearance in congestive heart failure patients is 1.77±0.48L/kg/h, while hypertensive patients have an average clearance of 42.7±8.9mL/min/kg. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The oral LD 50 in rats is 173-187mg/kg and the highest known dose an adult human has survived is 10g orally. Patients experiencing an overdose may present with hypotension, tachycardia, headache, flushing, myocardial ischemia, myocardial infarction, cardiac arrhythmia, and shock. Overdose can be treated through emptying the gastric contents and administering activated charcoal, though these treatments may cause further arrhythmias and shock. Supportive and symptomatic treatment should be administered. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Apresoline, Bidil •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 1-Hydrazinophthalazine 1-Phthalazinylhydrazine 6-Hydralazine Hidralazina Hydralazin Hydralazine Hydralazinum Hydrallazine Hydrazinophthalazine Hypophthalin Idralazina •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Hydralazine is an antihypertensive agent used for the management of essential hypertension or severe hypertension associated with conditions requiring immediate action, heart failure, and pre-eclampsia or eclampsia .

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Hydralazine interact? Information: •Drug A: Abaloparatide •Drug B: Hydralazine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Hydralazine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Hydralazine is indicated alone or adjunct to standard therapy to treat essential hypertension. A combination product with isosorbide dinitrate is indicated as an adjunct therapy in the treatment of heart failure. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Hydralazine interferes with calcium transport to relax arteriolar smooth muscle and lower blood pressure. Hydralazine has a short duration of action of 2-6h. This drug has a wide therapeutic window, as patients can tolerate doses of up to 300mg. Patients should be cautioned regarding the risk of developing systemic lupus erythematosus syndrome. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Hydralazine may interfere with calcium transport in vascular smooth muscle by an unknown mechanism to relax arteriolar smooth muscle and lower blood pressure. The interference with calcium transport may be by preventing influx of calcium into cells, preventing calcium release from intracellular compartments, directly acting on actin and myosin, or a combination of these actions. This decrease in vascular resistance leads to increased heart rate, stroke volume, and cardiac output. Hydralazine also competes with protocollagen prolyl hydroxylase (CPH) for free iron. This competition inhibits CPH mediated hydroxylation of HIF-1α, preventing the degradation of HIF-1α. Induction of HIF-1α and VEGF promote proliferation of endothelial cells and angiogenesis. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Taking oral hydralazine with food improves the bioavailability of the drug. An intravenous dose of 0.3mg/kg leads to an AUC of 17.5-29.4µM*min and a 1mg/kg oral dose leads to an AUC of 4.0-30.4µM*min. The C max of oral hydralazine is 0.12-1.31µM depending on the acetylator status of patients. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The volume of distribution is 1.34±0.79L/kg in congestive heart failure patients and 1.98±0.22L/kg in hypertensive patients. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Hydralazine is 87% protein bound in serum likely to human serum albumin. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Acetylation is a minor metabolic pathway for hydralazine; the major pathway is hydroxylation followed by glucuronidation. There are 5 identified metabolic pathways for hydralazine. Hydralazine can be metabolized to phthalazine or α-ketoglutarate hydrazone. These metabolites can be further converted to phthalazinone or hydralazine can be metabolized directly to phthalazinone. Hydralazine can undergo a reversible converstion to the active hydralazine acetone hydrazone. Hydralazine is spontaneously converted to the active pyruvic acid hydrazone or the pyruvic acid hydrazone tricyclic dehydration product, and these metabolites can convert back and forth between these 2 forms. Hydralazine can be converted to hydrazinophthalazinone, which is further converted to the active acetylhydrazinophthalazinone. The final metabolic process hydralazine can undergo is the conversion to an unnamed hydralazine metabolite, which is further metabolized to 3-methyl-s-triazolophthalazine (MTP). MTP can be metabolized to 9-hydroxy-methyltriazolophthalazine or 3-hydroxy-methyltriazolophthalazine; the latter is converted to triazolophthalazine. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): <10% of hydralazine is recovered in the feces; 65-90% is recovered in the urine. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Hydralazine has a half life of 2.2-7.8h in rapid acetylators and 2.0-5.8h in slow acetylators. The half life in heart failure patients is 57-241 minutes with an average of 105 minutes and in hypertensive patients is 200 minutes for rapid acetylators and 297 minutes for slow acetylators. Hydralazine is subject to polymorphic acetylation; slow acetylators generally have higher plasma levels of hydralazine and require lower doses to maintain control of pressure. However, other factors, such as acetylation being a minor metabolic pathway for hydralazine, will contribute to differences in elimination rates. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The majority of hydralazine clearance is extrahepatic- 55% for rapid acetylators and 70% for slow acetylators. The average clearance in congestive heart failure patients is 1.77±0.48L/kg/h, while hypertensive patients have an average clearance of 42.7±8.9mL/min/kg. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The oral LD 50 in rats is 173-187mg/kg and the highest known dose an adult human has survived is 10g orally. Patients experiencing an overdose may present with hypotension, tachycardia, headache, flushing, myocardial ischemia, myocardial infarction, cardiac arrhythmia, and shock. Overdose can be treated through emptying the gastric contents and administering activated charcoal, though these treatments may cause further arrhythmias and shock. Supportive and symptomatic treatment should be administered. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Apresoline, Bidil •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 1-Hydrazinophthalazine 1-Phthalazinylhydrazine 6-Hydralazine Hidralazina Hydralazin Hydralazine Hydralazinum Hydrallazine Hydrazinophthalazine Hypophthalin Idralazina •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Hydralazine is an antihypertensive agent used for the management of essential hypertension or severe hypertension associated with conditions requiring immediate action, heart failure, and pre-eclampsia or eclampsia . Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Hydrochlorothiazide interact?

•Drug A: Abaloparatide •Drug B: Hydrochlorothiazide •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Hydrochlorothiazide is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Hydrochlorothiazide is indicated alone or in combination for the management of edema associated with congestive heart failure, hepatic cirrhosis, nephrotic syndrome, acute glomerulonephritis, chronic renal failure, and corticosteroid and estrogen therapy. Hydrochlorothiazide is also indicated alone or in combination for the management of hypertension. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Hydrochlorothiazide prevents the reabsorption of sodium and water from the distal convoluted tubule, allowing for the increased elimination of water in the urine. Hydrochlorothiazide has a wide therapeutic window as dosing is individualized and can range from 25-100mg. Hydrochlorothiazide should be used with caution in patients with reduced kidney or liver function. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Hydrochlorothiazide is transported from the circulation into epithelial cells of the distal convoluted tubule by the organic anion transporters OAT1, OAT3, and OAT4. From these cells, hydrochlorothiazide is transported to the lumen of the tubule by multidrug resistance associated protein 4 (MRP4). Normally, sodium is reabsorbed into epithelial cells of the distal convoluted tubule and pumped into the basolateral interstitium by a sodium-potassium ATPase, creating a concentration gradient between the epithelial cell and the distal convoluted tubule that promotes the reabsorption of water. Hydrochlorothiazide acts on the proximal region of the distal convoluted tubule, inhibiting reabsorption by the sodium-chloride symporter, also known as Solute Carrier Family 12 Member 3 (SLC12A3). Inhibition of SLC12A3 reduces the magnitude of the concentration gradient between the epithelial cell and distal convoluted tubule, reducing the reabsorption of water. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): An oral dose of hydrochlorothiazide is 65-75% bioavailable, with a T max of 1-5 hours, and a C max of 70-490ng/mL following doses of 12.5-100mg. When taken with a meal, bioavailability is 10% lower, C max is 20% lower, and T max increases from 1.6 to 2.9 hours. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The volume of distribution varies widely from one study to another with values of 0.83-4.19L/kg. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Hydrochlorothiazide is 40-68% protein bound in plasma. Hydrochlorothiazide has been shown to bind to human serum albumin. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Hydrochlorothiazide is not metabolized. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Hydrochlorothiazide is eliminated in the urine as unchanged hydrochlorothiazide. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The plasma half life of hydrochlorothiazide is 5.6-14.8h. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The renal clearance of hydrochlorothiazide in patients with normal renal function is 285mL/min. Patients with a creatinine clearance of 31-80mL/min have an average hydroxychlorothiazide renal clearance of 75mL/min, and patients with a creatinine clearance of ≤30mL/min have an average hydroxychlorothiazide renal clearance of 17mL/min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The oral LD 50 of hydrochlorothiazide is >10g/kg in mice and rats. Patients experiencing an overdose may present with hypokalemia, hypochloremia, and hyponatremia. Treat patients with symptomatic and supportive treatment including fluids and electrolytes. Vasopressors may be administered to treat hypotension and oxygen may be given for respiratory impairment. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Accuretic, Actelsar Hct, Aldactazide, Altace HCT, Atacand, Atacand Hct, Avalide, Benicar Hct, Diovan Hct, Exforge Hct, Hyzaar, Ifirmacombi, Karvezide, Lopressor Hct, Lotensin Hct, Maxzide, Micardis-hct, Olmetec Plus, Tekturna Hct, Teveten HCT, Tribenzor, Urozide, Vaseretic, Viskazide, Zestoretic, Ziac •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Hydrochlorothiazide is a thiazide diuretic used to treat edema associated with a number of conditions, and hypertension.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Hydrochlorothiazide interact? Information: •Drug A: Abaloparatide •Drug B: Hydrochlorothiazide •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Hydrochlorothiazide is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Hydrochlorothiazide is indicated alone or in combination for the management of edema associated with congestive heart failure, hepatic cirrhosis, nephrotic syndrome, acute glomerulonephritis, chronic renal failure, and corticosteroid and estrogen therapy. Hydrochlorothiazide is also indicated alone or in combination for the management of hypertension. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Hydrochlorothiazide prevents the reabsorption of sodium and water from the distal convoluted tubule, allowing for the increased elimination of water in the urine. Hydrochlorothiazide has a wide therapeutic window as dosing is individualized and can range from 25-100mg. Hydrochlorothiazide should be used with caution in patients with reduced kidney or liver function. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Hydrochlorothiazide is transported from the circulation into epithelial cells of the distal convoluted tubule by the organic anion transporters OAT1, OAT3, and OAT4. From these cells, hydrochlorothiazide is transported to the lumen of the tubule by multidrug resistance associated protein 4 (MRP4). Normally, sodium is reabsorbed into epithelial cells of the distal convoluted tubule and pumped into the basolateral interstitium by a sodium-potassium ATPase, creating a concentration gradient between the epithelial cell and the distal convoluted tubule that promotes the reabsorption of water. Hydrochlorothiazide acts on the proximal region of the distal convoluted tubule, inhibiting reabsorption by the sodium-chloride symporter, also known as Solute Carrier Family 12 Member 3 (SLC12A3). Inhibition of SLC12A3 reduces the magnitude of the concentration gradient between the epithelial cell and distal convoluted tubule, reducing the reabsorption of water. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): An oral dose of hydrochlorothiazide is 65-75% bioavailable, with a T max of 1-5 hours, and a C max of 70-490ng/mL following doses of 12.5-100mg. When taken with a meal, bioavailability is 10% lower, C max is 20% lower, and T max increases from 1.6 to 2.9 hours. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The volume of distribution varies widely from one study to another with values of 0.83-4.19L/kg. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Hydrochlorothiazide is 40-68% protein bound in plasma. Hydrochlorothiazide has been shown to bind to human serum albumin. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Hydrochlorothiazide is not metabolized. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Hydrochlorothiazide is eliminated in the urine as unchanged hydrochlorothiazide. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The plasma half life of hydrochlorothiazide is 5.6-14.8h. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The renal clearance of hydrochlorothiazide in patients with normal renal function is 285mL/min. Patients with a creatinine clearance of 31-80mL/min have an average hydroxychlorothiazide renal clearance of 75mL/min, and patients with a creatinine clearance of ≤30mL/min have an average hydroxychlorothiazide renal clearance of 17mL/min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The oral LD 50 of hydrochlorothiazide is >10g/kg in mice and rats. Patients experiencing an overdose may present with hypokalemia, hypochloremia, and hyponatremia. Treat patients with symptomatic and supportive treatment including fluids and electrolytes. Vasopressors may be administered to treat hypotension and oxygen may be given for respiratory impairment. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Accuretic, Actelsar Hct, Aldactazide, Altace HCT, Atacand, Atacand Hct, Avalide, Benicar Hct, Diovan Hct, Exforge Hct, Hyzaar, Ifirmacombi, Karvezide, Lopressor Hct, Lotensin Hct, Maxzide, Micardis-hct, Olmetec Plus, Tekturna Hct, Teveten HCT, Tribenzor, Urozide, Vaseretic, Viskazide, Zestoretic, Ziac •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Hydrochlorothiazide is a thiazide diuretic used to treat edema associated with a number of conditions, and hypertension. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Hydroflumethiazide interact?

•Drug A: Abaloparatide •Drug B: Hydroflumethiazide •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Hydroflumethiazide is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Used as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. Also used in the management of hypertension either as the sole therapeutic agent or to enhance the effect of other antihypertensive drugs in the more severe forms of hypertension. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Hydroflumethiazide is an oral thiazide used to treat hypertension and edema. High blood pressure adds to the workload of the heart and arteries. If it continues for a long time, the heart and arteries may not function properly. This can damage the blood vessels of the brain, heart, and kidneys, resulting in a stroke, heart failure, or kidney failure. High blood pressure may also increase the risk of heart attacks. Like other thiazides, Hydroflumethiazide promotes water loss from the body (diuretics). Thiazides inhibit Na+/Cl- reabsorption from the distal convoluted tubules in the kidneys. Thiazides also cause loss of potassium and an increase in serum uric acid. Thiazides are often used to treat hypertension, but their hypotensive effects are not necessarily due to their diuretic activity. Thiazides have been shown to prevent hypertension-related morbidity and mortality although the mechanism is not fully understood. Thiazides cause vasodilation by activating calcium-activated potassium channels (large conductance) in vascular smooth muscles and inhibiting various carbonic anhydrases in vascular tissue. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Hydroflumethiazide is a thiazide diuretic that inhibits water reabsorption in the nephron by inhibiting the sodium-chloride symporter (SLC12A3) in the distal convoluted tubule, which is responsible for 5% of total sodium reabsorption. Normally, the sodium-chloride symporter transports sodium and chloride from the lumen into the epithelial cell lining the distal convoluted tubule. The energy for this is provided by a sodium gradient established by sodium-potassium ATPases on the basolateral membrane. Once sodium has entered the cell, it is transported out into the basolateral interstitium via the sodium-potassium ATPase, causing an increase in the osmolarity of the interstitium, thereby establishing an osmotic gradient for water reabsorption. By blocking the sodium-chloride symporter, Hydroflumethiazide effectively reduces the osmotic gradient and water reabsorption throughout the nephron. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Hydroflumethiazide is incompletely but fairly rapidly absorbed from the gastrointestinal tract •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 74% •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Essentially unchanged •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): It appears to have a biphasic biological half-life with an estimated alpha-phase of about 2 hours and an estimated beta-phase of about 17 hours •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Overdoses lead to diuresis, lethargy progressing to coma, with minimal cardiorespiratory depression and with or without significant serum electrolyte changes or dehydration. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Saluron •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Hydroflumethiazide is a thiazide diuretic used to treat hypertension as well as edema due to congestive heart failure and liver cirrhosis.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Hydroflumethiazide interact? Information: •Drug A: Abaloparatide •Drug B: Hydroflumethiazide •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Hydroflumethiazide is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Used as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. Also used in the management of hypertension either as the sole therapeutic agent or to enhance the effect of other antihypertensive drugs in the more severe forms of hypertension. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Hydroflumethiazide is an oral thiazide used to treat hypertension and edema. High blood pressure adds to the workload of the heart and arteries. If it continues for a long time, the heart and arteries may not function properly. This can damage the blood vessels of the brain, heart, and kidneys, resulting in a stroke, heart failure, or kidney failure. High blood pressure may also increase the risk of heart attacks. Like other thiazides, Hydroflumethiazide promotes water loss from the body (diuretics). Thiazides inhibit Na+/Cl- reabsorption from the distal convoluted tubules in the kidneys. Thiazides also cause loss of potassium and an increase in serum uric acid. Thiazides are often used to treat hypertension, but their hypotensive effects are not necessarily due to their diuretic activity. Thiazides have been shown to prevent hypertension-related morbidity and mortality although the mechanism is not fully understood. Thiazides cause vasodilation by activating calcium-activated potassium channels (large conductance) in vascular smooth muscles and inhibiting various carbonic anhydrases in vascular tissue. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Hydroflumethiazide is a thiazide diuretic that inhibits water reabsorption in the nephron by inhibiting the sodium-chloride symporter (SLC12A3) in the distal convoluted tubule, which is responsible for 5% of total sodium reabsorption. Normally, the sodium-chloride symporter transports sodium and chloride from the lumen into the epithelial cell lining the distal convoluted tubule. The energy for this is provided by a sodium gradient established by sodium-potassium ATPases on the basolateral membrane. Once sodium has entered the cell, it is transported out into the basolateral interstitium via the sodium-potassium ATPase, causing an increase in the osmolarity of the interstitium, thereby establishing an osmotic gradient for water reabsorption. By blocking the sodium-chloride symporter, Hydroflumethiazide effectively reduces the osmotic gradient and water reabsorption throughout the nephron. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Hydroflumethiazide is incompletely but fairly rapidly absorbed from the gastrointestinal tract •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 74% •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Essentially unchanged •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): It appears to have a biphasic biological half-life with an estimated alpha-phase of about 2 hours and an estimated beta-phase of about 17 hours •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Overdoses lead to diuresis, lethargy progressing to coma, with minimal cardiorespiratory depression and with or without significant serum electrolyte changes or dehydration. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Saluron •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Hydroflumethiazide is a thiazide diuretic used to treat hypertension as well as edema due to congestive heart failure and liver cirrhosis. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Iloprost interact?

•Drug A: Abaloparatide •Drug B: Iloprost •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Iloprost is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Inhaled iloprost solution is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve a composite endpoint consisting of exercise tolerance, symptoms (NYHA Class), and lack of deterioration. Studies establishing effectiveness included predominately patients with NYHA Functional Class III–IV symptoms and etiologies of idiopathic or heritable PAH (65%) or PAH associated with connective tissue diseases (23%). Intravenous iloprost is indicated for the treatment of severe frostbite in adults to reduce the risk of digit amputations. Effectiveness was established in young, healthy adults who suffered frostbite at high altitudes. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Iloprost is a synthetic analogue of prostacyclin PGI2 that dilates systemic and pulmonary arterial vascular beds. There are two diastereoisomers of iloprost and the 4S isomer is reported to exhibit a higher potency in dilating blood vessels compared to the 4R isomer. In patients with primary pulmonary hypertension, iloprost decreased pulmonary vascular resistance and pulmonary artery pressure. Iloprost was shown to inhibit platelet aggregation, but whether this effect contributes to its vasodilatory action has not been elucidated. Iloprost is reported to attenuate ischemia-induced tissue injury. When administered intravenously in patients with peripheral vascular conditions such as critical leg ischemia and delayed amputation, iloprost was shown to promote cytoprotection. In isolated animal heart preparations and in intact animals with ischemia-reperfusion injury, preserved myocardial function was observed following iloprost administraion. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): In pulmonary arterial hypertension, endothelial vasoactive mediators such as nitric oxide and prostacyclin are released to induce vasoconstriction. Iloprost mimics the biological actions of prostacyclin, a short-lived prostanoid and potent vasodilator mainly produced in the vascular endothelium. The exact mechanism of iloprost in cytoprotection has not been fully elucidated; however, it is proposed that iloprost decreases catecholamine outflow from sympathetic nerve terminals, preserves mitochondrial function, and reduces oxidative stress. Decreased neutrophil accumulation and membrane stabilization have also been suggested. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Following inhalation of iloprost (5 mcg) patients with pulmonary hypertension have iloprost peak plasma levels of approximately 150 pg/mL. Iloprost was generally not detectable in plasma 30 minutes to one hour after inhalation. The absolute bioavailability of inhaled iloprost has not been determined. When iloprost was administered via intravenous infusion at a rate of 2 ng/kg/min, steady-state plasma concentrations were 85 ng/L. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Following intravenous infusion, the apparent steady-state volume of distribution was 0.7 to 0.8 L/kg in healthy subjects. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Iloprost is approximately 60% protein-bound, mainly to albumin, and this ratio is concentration-independent in the range of 30 to 3000 pg/mL. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): In vitro studies reveal that cytochrome P450-dependent metabolism plays only a minor role in the biotransformation of iloprost. Iloprost is metabolized principally via β-oxidation of the carboxyl side chain. The main metabolite is tetranor-iloprost, which was shown to be pharmacologically inactive in animal experiments. In rabbits, dinor-iloprost has also been identified as a drug metabolite. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Unchanged iloprost and its metabolites are mainly excreted in urine. About 70% of the drug and metabolites undergo renal excretion. Following the administration of intravenous infusion at the rate of 2 ng/kg/min and oral dose at 0.1 ug/kg, fecal excretion was 12% and 17%, respectively. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The half-life of iloprost is 20 to 30 minutes. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Clearance in normal subjects was approximately 20 mL/min/kg. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The oral LD 50 in rats is >100 mg/kg. Cases of overdose have been reported. Frequently observed symptoms following overdose are dizziness, headache, flushing, nausea, jaw pain or back pain. Hypotension, vomiting, and diarrhea are possible. A specific antidote is not known. Interruption of the inhalation session, monitoring, and symptomatic measures are recommended. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Ventavis •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Iloprost is a synthetic prostacyclin analog used to treat pulmonary arterial hypertension (PAH) and frostbites.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Iloprost interact? Information: •Drug A: Abaloparatide •Drug B: Iloprost •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Iloprost is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Inhaled iloprost solution is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve a composite endpoint consisting of exercise tolerance, symptoms (NYHA Class), and lack of deterioration. Studies establishing effectiveness included predominately patients with NYHA Functional Class III–IV symptoms and etiologies of idiopathic or heritable PAH (65%) or PAH associated with connective tissue diseases (23%). Intravenous iloprost is indicated for the treatment of severe frostbite in adults to reduce the risk of digit amputations. Effectiveness was established in young, healthy adults who suffered frostbite at high altitudes. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Iloprost is a synthetic analogue of prostacyclin PGI2 that dilates systemic and pulmonary arterial vascular beds. There are two diastereoisomers of iloprost and the 4S isomer is reported to exhibit a higher potency in dilating blood vessels compared to the 4R isomer. In patients with primary pulmonary hypertension, iloprost decreased pulmonary vascular resistance and pulmonary artery pressure. Iloprost was shown to inhibit platelet aggregation, but whether this effect contributes to its vasodilatory action has not been elucidated. Iloprost is reported to attenuate ischemia-induced tissue injury. When administered intravenously in patients with peripheral vascular conditions such as critical leg ischemia and delayed amputation, iloprost was shown to promote cytoprotection. In isolated animal heart preparations and in intact animals with ischemia-reperfusion injury, preserved myocardial function was observed following iloprost administraion. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): In pulmonary arterial hypertension, endothelial vasoactive mediators such as nitric oxide and prostacyclin are released to induce vasoconstriction. Iloprost mimics the biological actions of prostacyclin, a short-lived prostanoid and potent vasodilator mainly produced in the vascular endothelium. The exact mechanism of iloprost in cytoprotection has not been fully elucidated; however, it is proposed that iloprost decreases catecholamine outflow from sympathetic nerve terminals, preserves mitochondrial function, and reduces oxidative stress. Decreased neutrophil accumulation and membrane stabilization have also been suggested. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Following inhalation of iloprost (5 mcg) patients with pulmonary hypertension have iloprost peak plasma levels of approximately 150 pg/mL. Iloprost was generally not detectable in plasma 30 minutes to one hour after inhalation. The absolute bioavailability of inhaled iloprost has not been determined. When iloprost was administered via intravenous infusion at a rate of 2 ng/kg/min, steady-state plasma concentrations were 85 ng/L. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Following intravenous infusion, the apparent steady-state volume of distribution was 0.7 to 0.8 L/kg in healthy subjects. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Iloprost is approximately 60% protein-bound, mainly to albumin, and this ratio is concentration-independent in the range of 30 to 3000 pg/mL. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): In vitro studies reveal that cytochrome P450-dependent metabolism plays only a minor role in the biotransformation of iloprost. Iloprost is metabolized principally via β-oxidation of the carboxyl side chain. The main metabolite is tetranor-iloprost, which was shown to be pharmacologically inactive in animal experiments. In rabbits, dinor-iloprost has also been identified as a drug metabolite. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Unchanged iloprost and its metabolites are mainly excreted in urine. About 70% of the drug and metabolites undergo renal excretion. Following the administration of intravenous infusion at the rate of 2 ng/kg/min and oral dose at 0.1 ug/kg, fecal excretion was 12% and 17%, respectively. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The half-life of iloprost is 20 to 30 minutes. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Clearance in normal subjects was approximately 20 mL/min/kg. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The oral LD 50 in rats is >100 mg/kg. Cases of overdose have been reported. Frequently observed symptoms following overdose are dizziness, headache, flushing, nausea, jaw pain or back pain. Hypotension, vomiting, and diarrhea are possible. A specific antidote is not known. Interruption of the inhalation session, monitoring, and symptomatic measures are recommended. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Ventavis •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Iloprost is a synthetic prostacyclin analog used to treat pulmonary arterial hypertension (PAH) and frostbites. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Imipramine interact?

•Drug A: Abaloparatide •Drug B: Imipramine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Imipramine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the relief of symptoms of depression and as temporary adjunctive therapy in reducing enuresis in children aged 6 years and older. May also be used off-label to manage panic disorders with or without agoraphobia, as a second line agent for ADHD in children and adolescents, to manage bulimia nervosa, for short-term management of acute depressive episodes in bipolar disorder and schizophrenia, for the treatment of acute stress disorder and posttraumatic stress disorder, and for symptomatic treatment of postherpetic neuralgia and painful diabetic neuropathy. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Imipramine is a tricyclic antidepressant with general pharmacological properties similar to those of structurally related tricyclic antidepressant drugs such as amitriptyline and doxepin. While it acts to block both, imipramine displays a much higher affinity for the serotonin reuptake transporter than for the norepinephrine reuptake transporter. Imipramine produces effects similar to other monoamine targeting antidepressants, increasing serotonin- and norepinephrine-based neurotransmission. This modulation of neurotransmission produces a complex range of changes in brain structure and function along with an improvement in depressive symptoms. The changes include increases in hippocampal neurogenesis and reduced downregulation of this neurogenesis in response to stress. These implicate brain derived neurotrophic factor signalling as a necessary contributor to antidepressant effect although the link to the direct increase in monoamine neurotransmission is unclear. Serotonin reuptake targeting agents may also produce a down-regulation in β-adrenergic receptors in the brain. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Imipramine works by inhibiting the neuronal reuptake of the neurotransmitters norepinephrine and serotonin. It binds the sodium-dependent serotonin transporter and sodium-dependent norepinephrine transporter reducing the reuptake of norepinephrine and serotonin by neurons. Depression has been linked to a lack of stimulation of the post-synaptic neuron by norepinephrine and serotonin. Slowing the reuptake of these neurotransmitters increases their concentration in the synaptic cleft, producing knock-on effects in protein kinase signalling which is thought to contribute to changes in neurotransmission and brain physiology which relieves symptoms of depression. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Rapidly and well absorbed (>95%) after oral administration. The primary site of absorption is the small intestine as the basic amine groups are ionized in the acidic environment of the stomach, preventing movement across tissues. Bioavailability ranges from 29-77% due to high inter-individual variability. Peak plasma concentration is usually attained 2-6 hours following oral administration. Absorption is unaffected by food. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Imipramine has a high apparent volume of distribution of 10-20 L/kg. The drug is known to accumulate in the brain at concentrations 30-40 times that in systemic circulation. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Imipramine is 60-96% bound to plasma proteins in circulation. It is known to bind albumin, α1-acid glycoprotein, and lipoproteins. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Imipramine is nearly exclusively metabolized by the liver. Imipramine is converted to desipramine by CYP1A2, CYP3A4, CYP2C19. Both imipramine and desipramine are hydroxylated by CYP2D6. Desipramine is an active metabolite. Minor metabolic pathways include dealkylation to form an imidodibenzyl product as well as demethylation of desipramine to didemethylimipramine and subsequent hydroxylation. Less than 5% of orally administered imipramine is excreted unchanged. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Imipramine is primarily excreted in the urine with less than 5% present as the parent compound •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Imipramine has a mean half life of 12 h. Its active metabolite, desipramine has a mean half life of 22.5 h. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Imipramine has a mean clearance of 1 L/h/kg. Its active metabolite, desipramine has a mean clearance of 1.8 L/h/kg. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The anticholinergic actvity of imipramine can produce dry mucous membranes, blurred vision, increased intraocular pressure, hyperthermia, constipation, adynamic ileus, urinary retention, delayed micturition, and dilation of the urinary tract. Central nervous system and neuromuscular effects include drowsiness, lethargy, fatigue, agitation, excitement, nightmares, restlessness, insomnia, confusion, disturbed concentration, disorientation, delusions, and hallucinations. Effects on the GI tract include anorexia, nausea and vomiting, diarrhea, abdominal cramps, increases in pancreatic enzymes, epigastric distress, stomatitis, peculiar taste, and black tongue. Rarely agranulocytosis, thrombocytopenia, eosinophilia, leukopenia, and purpura have occured. Infants whose mothers were receiving tricyclic antidepressants prior to delivery have experienced cardiac problems, irritability, respiratory distress, muscle spasms, seizures, and urinary retention. Serotonin syndrome can occur when used in conjunction with other pro-serotonergic drugs. LD 50 Values Rat - Oral 250 mg/kg - Intraperitoneal 79mg/kg - Subcutaneous 250 mg/kg - Intravenous 15.9 mg/kg Mouse - Oral 188 mg/kg - Intraperitoneal 51.6 mg/kg - Subcutaneous 195 μg/kg - Intravenous 21 mg/kg Human range of toxicity is considered to include single dosages greater than 5 mg/kg. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Tofranil •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Imipramin Imipramina Imipramine Imipraminum Imizine •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Imipramine is a tricyclic antidepressant indicated for the treatment of depression and to reduce childhood enuresis.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Imipramine interact? Information: •Drug A: Abaloparatide •Drug B: Imipramine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Imipramine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the relief of symptoms of depression and as temporary adjunctive therapy in reducing enuresis in children aged 6 years and older. May also be used off-label to manage panic disorders with or without agoraphobia, as a second line agent for ADHD in children and adolescents, to manage bulimia nervosa, for short-term management of acute depressive episodes in bipolar disorder and schizophrenia, for the treatment of acute stress disorder and posttraumatic stress disorder, and for symptomatic treatment of postherpetic neuralgia and painful diabetic neuropathy. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Imipramine is a tricyclic antidepressant with general pharmacological properties similar to those of structurally related tricyclic antidepressant drugs such as amitriptyline and doxepin. While it acts to block both, imipramine displays a much higher affinity for the serotonin reuptake transporter than for the norepinephrine reuptake transporter. Imipramine produces effects similar to other monoamine targeting antidepressants, increasing serotonin- and norepinephrine-based neurotransmission. This modulation of neurotransmission produces a complex range of changes in brain structure and function along with an improvement in depressive symptoms. The changes include increases in hippocampal neurogenesis and reduced downregulation of this neurogenesis in response to stress. These implicate brain derived neurotrophic factor signalling as a necessary contributor to antidepressant effect although the link to the direct increase in monoamine neurotransmission is unclear. Serotonin reuptake targeting agents may also produce a down-regulation in β-adrenergic receptors in the brain. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Imipramine works by inhibiting the neuronal reuptake of the neurotransmitters norepinephrine and serotonin. It binds the sodium-dependent serotonin transporter and sodium-dependent norepinephrine transporter reducing the reuptake of norepinephrine and serotonin by neurons. Depression has been linked to a lack of stimulation of the post-synaptic neuron by norepinephrine and serotonin. Slowing the reuptake of these neurotransmitters increases their concentration in the synaptic cleft, producing knock-on effects in protein kinase signalling which is thought to contribute to changes in neurotransmission and brain physiology which relieves symptoms of depression. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Rapidly and well absorbed (>95%) after oral administration. The primary site of absorption is the small intestine as the basic amine groups are ionized in the acidic environment of the stomach, preventing movement across tissues. Bioavailability ranges from 29-77% due to high inter-individual variability. Peak plasma concentration is usually attained 2-6 hours following oral administration. Absorption is unaffected by food. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Imipramine has a high apparent volume of distribution of 10-20 L/kg. The drug is known to accumulate in the brain at concentrations 30-40 times that in systemic circulation. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Imipramine is 60-96% bound to plasma proteins in circulation. It is known to bind albumin, α1-acid glycoprotein, and lipoproteins. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Imipramine is nearly exclusively metabolized by the liver. Imipramine is converted to desipramine by CYP1A2, CYP3A4, CYP2C19. Both imipramine and desipramine are hydroxylated by CYP2D6. Desipramine is an active metabolite. Minor metabolic pathways include dealkylation to form an imidodibenzyl product as well as demethylation of desipramine to didemethylimipramine and subsequent hydroxylation. Less than 5% of orally administered imipramine is excreted unchanged. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Imipramine is primarily excreted in the urine with less than 5% present as the parent compound •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Imipramine has a mean half life of 12 h. Its active metabolite, desipramine has a mean half life of 22.5 h. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Imipramine has a mean clearance of 1 L/h/kg. Its active metabolite, desipramine has a mean clearance of 1.8 L/h/kg. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The anticholinergic actvity of imipramine can produce dry mucous membranes, blurred vision, increased intraocular pressure, hyperthermia, constipation, adynamic ileus, urinary retention, delayed micturition, and dilation of the urinary tract. Central nervous system and neuromuscular effects include drowsiness, lethargy, fatigue, agitation, excitement, nightmares, restlessness, insomnia, confusion, disturbed concentration, disorientation, delusions, and hallucinations. Effects on the GI tract include anorexia, nausea and vomiting, diarrhea, abdominal cramps, increases in pancreatic enzymes, epigastric distress, stomatitis, peculiar taste, and black tongue. Rarely agranulocytosis, thrombocytopenia, eosinophilia, leukopenia, and purpura have occured. Infants whose mothers were receiving tricyclic antidepressants prior to delivery have experienced cardiac problems, irritability, respiratory distress, muscle spasms, seizures, and urinary retention. Serotonin syndrome can occur when used in conjunction with other pro-serotonergic drugs. LD 50 Values Rat - Oral 250 mg/kg - Intraperitoneal 79mg/kg - Subcutaneous 250 mg/kg - Intravenous 15.9 mg/kg Mouse - Oral 188 mg/kg - Intraperitoneal 51.6 mg/kg - Subcutaneous 195 μg/kg - Intravenous 21 mg/kg Human range of toxicity is considered to include single dosages greater than 5 mg/kg. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Tofranil •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Imipramin Imipramina Imipramine Imipraminum Imizine •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Imipramine is a tricyclic antidepressant indicated for the treatment of depression and to reduce childhood enuresis. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Indapamide interact?

•Drug A: Abaloparatide •Drug B: Indapamide •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Indapamide is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Indapamide is a diuretic indicated for use as monotherapy or in combination with other blood pressure-lowering agents to treat hypertension. It may also be used to treat fluid and salt retention associated with congestive heart failure. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Classified as a sulfonamide diuretic, indapamide is an effective antihypertensive agent and by extension, has shown efficacy in the prevention of target organ damage. Administration of indapamide produces water and electrolyte loss, with higher doses associated with increased diuresis. Severe and clinically significant electrolyte disturbances may occur with indapamide use - for example, hypokalemia resulting from renal potassium loss may lead to QTc prolongation. Further electrolyte imbalances may occur due to renal excretion of sodium, chloride, and magnesium. Other indapamide induced changes include increases in plasma renin and aldosterone, and reduced calcium excretion in the urine. In many studies investigating the effects of indapamide in both non-diabetic and diabetic hypertensive patients, glucose tolerance was not significantly altered. However, additional studies are necessary to assess the long term metabolic impacts of indapamide, since thiazide related impaired glucose tolerance can take several years to develop in non-diabetic patients. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Indapamide acts on the nephron, specifically at the proximal segment of the distal convoluted tubule where it inhibits the Na+/Cl- cotransporter, leading to reduced sodium reabsorption. As a result, sodium and water are retained in the lumen of the nephron for urinary excretion. The effects that follow include reduced plasma volume, reduced venous return, lower cardiac output, and ultimately decreased blood pressure. Interestingly, it is likely that thiazide-like diuretics such as indapamide have additional blood pressure lowering mechanisms that are unrelated to diuresis. This is exemplified by the observation that the antihypertensive effects of thiazides are sustained 4-6 weeks after initiation of therapy, despite recovering plasma and extracellular fluid volumes. Some studies have suggested that indapamide may decrease responsiveness to pressor agents while others have suggested it can decrease peripheral resistance. Although it is clear that diuresis contributes to the antihypertensive effects of indapamide, further studies are needed to investigate the medication’s ability to decrease peripheral vascular resistance and relax vascular smooth muscle. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): The bioavailability of indapamide is virtually complete after an oral dose and is unaffected by food or antacids. Indapamide is highly lipid-soluble due to its indoline moiety - a characteristic that likely explains why indapamide’s renal clearance makes up less than 10% of its total systemic clearance. The Tmax occurs approximately 2.3 hours after oral administration. The Cmax and AUC 0-24 values are 263 ng/mL and 2.95 ug/hr/mL, respectively. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Some sources report an apparent volume of distribution of 25 L for indapamide, while others report a value of approximately 60 L. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Approximately 76-79% of indapamide is protein bound. Indapamide binds primarily to alpha 1-acid glycoprotein and less significantly to serum albumin and lipoproteins. In the blood, indapamide is extensively and preferentially bound to erythrocytes. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): As a result of extensive metabolism in the liver, the majority of indapamide excreted is metabolized, with only 7% remaining unchanged. In humans, as many as 19 distinct indapamide metabolites may be produced, although not all have been identified. There are several metabolic routes through which indapamide may be metabolized, and CYP3A4 is the main enzyme involved in the corresponding hydroxylation, carboxylation, and dehydrogenation reactions. Indapamide can undergo dehydrogenation to form M5, then oxidation to form M4, then further hydroxylation at the indole moiety to form M2. These reactions are facilitated by CYP3A4. Another route of metabolism occurs when indapamide is first hydroxylated to M1 by CYP3A4. M1 then undergoes dehydrogenation to form M3 and is further oxidized to form M2. Hydroxylation of indapamide’s indole moiety is thought to form the major metabolite (M1), which is less pharmacologically active compared to its parent compound according to animal studies. Indapamide may also undergo epoxidation via CYP3A4 to form a reactive epoxide intermediate. The unstable epoxide intermediate may then undergo dihydroxylation via microsomal epoxide hydrolase to form M6, or glutathione conjugation to form M7. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): An estimated 60-70% of indapamide is eliminated in the urine, while 16-23% is eliminated in the feces. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Indapamide is characterized by biphasic elimination. In healthy subjects, indapamide's elimination half-life can range from 13.9 to 18 hours. The long half-life is conducive to once-daily dosing. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Indapamide's renal and hepatic clearance values are reported to be 1.71 mL/min and 20-23.4 mL/min, respectively. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Indapamide overdose symptoms may include but are not limited to nausea, vomiting, gastrointestinal disorders, electrolyte disturbances and weakness. Other signs of overdose include respiratory depression and severe hypotension. In cases of overdose, supportive care interventions may be necessary to manage symptoms. Emesis and gastric lavage may be recommended to empty the stomach; however, patients should be monitored closely for any electrolyte or fluid imbalances. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Coversyl •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Indapamide is a thiazide diuretic used to treat hypertension as well as edema due to congestive heart failure.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Indapamide interact? Information: •Drug A: Abaloparatide •Drug B: Indapamide •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Indapamide is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Indapamide is a diuretic indicated for use as monotherapy or in combination with other blood pressure-lowering agents to treat hypertension. It may also be used to treat fluid and salt retention associated with congestive heart failure. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Classified as a sulfonamide diuretic, indapamide is an effective antihypertensive agent and by extension, has shown efficacy in the prevention of target organ damage. Administration of indapamide produces water and electrolyte loss, with higher doses associated with increased diuresis. Severe and clinically significant electrolyte disturbances may occur with indapamide use - for example, hypokalemia resulting from renal potassium loss may lead to QTc prolongation. Further electrolyte imbalances may occur due to renal excretion of sodium, chloride, and magnesium. Other indapamide induced changes include increases in plasma renin and aldosterone, and reduced calcium excretion in the urine. In many studies investigating the effects of indapamide in both non-diabetic and diabetic hypertensive patients, glucose tolerance was not significantly altered. However, additional studies are necessary to assess the long term metabolic impacts of indapamide, since thiazide related impaired glucose tolerance can take several years to develop in non-diabetic patients. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Indapamide acts on the nephron, specifically at the proximal segment of the distal convoluted tubule where it inhibits the Na+/Cl- cotransporter, leading to reduced sodium reabsorption. As a result, sodium and water are retained in the lumen of the nephron for urinary excretion. The effects that follow include reduced plasma volume, reduced venous return, lower cardiac output, and ultimately decreased blood pressure. Interestingly, it is likely that thiazide-like diuretics such as indapamide have additional blood pressure lowering mechanisms that are unrelated to diuresis. This is exemplified by the observation that the antihypertensive effects of thiazides are sustained 4-6 weeks after initiation of therapy, despite recovering plasma and extracellular fluid volumes. Some studies have suggested that indapamide may decrease responsiveness to pressor agents while others have suggested it can decrease peripheral resistance. Although it is clear that diuresis contributes to the antihypertensive effects of indapamide, further studies are needed to investigate the medication’s ability to decrease peripheral vascular resistance and relax vascular smooth muscle. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): The bioavailability of indapamide is virtually complete after an oral dose and is unaffected by food or antacids. Indapamide is highly lipid-soluble due to its indoline moiety - a characteristic that likely explains why indapamide’s renal clearance makes up less than 10% of its total systemic clearance. The Tmax occurs approximately 2.3 hours after oral administration. The Cmax and AUC 0-24 values are 263 ng/mL and 2.95 ug/hr/mL, respectively. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Some sources report an apparent volume of distribution of 25 L for indapamide, while others report a value of approximately 60 L. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Approximately 76-79% of indapamide is protein bound. Indapamide binds primarily to alpha 1-acid glycoprotein and less significantly to serum albumin and lipoproteins. In the blood, indapamide is extensively and preferentially bound to erythrocytes. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): As a result of extensive metabolism in the liver, the majority of indapamide excreted is metabolized, with only 7% remaining unchanged. In humans, as many as 19 distinct indapamide metabolites may be produced, although not all have been identified. There are several metabolic routes through which indapamide may be metabolized, and CYP3A4 is the main enzyme involved in the corresponding hydroxylation, carboxylation, and dehydrogenation reactions. Indapamide can undergo dehydrogenation to form M5, then oxidation to form M4, then further hydroxylation at the indole moiety to form M2. These reactions are facilitated by CYP3A4. Another route of metabolism occurs when indapamide is first hydroxylated to M1 by CYP3A4. M1 then undergoes dehydrogenation to form M3 and is further oxidized to form M2. Hydroxylation of indapamide’s indole moiety is thought to form the major metabolite (M1), which is less pharmacologically active compared to its parent compound according to animal studies. Indapamide may also undergo epoxidation via CYP3A4 to form a reactive epoxide intermediate. The unstable epoxide intermediate may then undergo dihydroxylation via microsomal epoxide hydrolase to form M6, or glutathione conjugation to form M7. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): An estimated 60-70% of indapamide is eliminated in the urine, while 16-23% is eliminated in the feces. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Indapamide is characterized by biphasic elimination. In healthy subjects, indapamide's elimination half-life can range from 13.9 to 18 hours. The long half-life is conducive to once-daily dosing. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Indapamide's renal and hepatic clearance values are reported to be 1.71 mL/min and 20-23.4 mL/min, respectively. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Indapamide overdose symptoms may include but are not limited to nausea, vomiting, gastrointestinal disorders, electrolyte disturbances and weakness. Other signs of overdose include respiratory depression and severe hypotension. In cases of overdose, supportive care interventions may be necessary to manage symptoms. Emesis and gastric lavage may be recommended to empty the stomach; however, patients should be monitored closely for any electrolyte or fluid imbalances. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Coversyl •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Indapamide is a thiazide diuretic used to treat hypertension as well as edema due to congestive heart failure. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Irbesartan interact?

•Drug A: Abaloparatide •Drug B: Irbesartan •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Irbesartan is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Irbesartan is indicated to treat hypertension and diabetic nephropathy in hypertensive patients with type 2 diabetes, elevated serum creatinine, and proteinuria. A combination product with hydrochlorothiazide is indicated for hypertension in patients with uncontrolled hypertension with monotherapy or first line in patients not expected to be well controlled with monotherapy. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Irbesartan is an angiotensin receptor blocker used to treat hypertension and diabetic nephropathy. It has a long duration of action as it is usually taken once daily and a wide therapeutic index as doses may be as low as 150mg daily but doses of 900mg/day were well tolerated in healthy human subjects. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Irbesartan prevents angiotensin II binding to the AT 1 receptor in tissues like vascular smooth muscle and the adrenal gland. Irbesartan and its active metabolite bind the AT 1 receptor with 8500 times more affinity than they bind to the AT 2 receptor. Irbesartan's prevention of angiotensin II binding causes vascular smooth muscle relaxation and prevents the secretion of aldosterone, lowering blood pressure. Angiotensin II would otherwise bind to the AT 1 receptor, inducing vasoconstriction and aldosterone secretion, raising blood pressure. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Irbesartan is 60-80% bioavailable with a T max of 1.5-2hours. Taking irbesartan with food does not affect the bioavailability. In one study, healthy subjects were given single or multiple oral doses of 150mg, 300mg, 600mg, and 900mg of irbesartan. A single 150mg dose resulted in an AUC of 9.7±3.0µg\•hr/mL, a T max of 1.5 hours, a half life of 16±7 hours, and a C max of 1.9±0.4µg/mL. A single 300mg dose resulted in an AUC of 20.0±5.2µg\•hr/mL, a T max of 1.5 hours, a half life of 14±7 hours, and a C max of 2.9±0.9µg/mL. A single 600mg dose resulted in an AUC of 32.6±11.9µg\•hr/mL, a T max of 1.5 hours, a half life of 14±8 hours, and a C max of 4.9±1.2µg/mL. A single 900mg dose resulted in an AUC of 44.8±20.0µg\•hr/mL, a T max of 1.5 hours, a half life of 17±7 hours, and a C max of 5.3±1.9µg/mL. Multiple 150mg doses resulted in an AUC of 9.3±3.0µg\•hr/mL, a T max of 1.5 hours, a half life of 11±4 hours, and a C max of 2.04±0.4µg/mL. Multiple 300mg doses resulted in an AUC of 19.8±5.8µg\•hr/mL, a T max of 2.0 hours, a half life of 11±5 hours, and a C max of 3.3±0.8µg/mL. Multiple 600mg doses resulted in an AUC of 31.9±9.7µg\•hr/mL, a T max of 1.5 hours, a half life of 15±7 hours, and a C max of 4.4±0.7µg/mL. Multiple 900mg doses resulted in an AUC of 34.2±9.3µg\•hr/mL, a T max of 1.8 hours, a half life of 14±6 hours, and a C max of 5.6±2.1µg/mL. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The volume of distribution of irbesartan is 53-93L. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Irbesartan is 90% protein bound in plasma, mainly to albumin and α 1 -acid glycoprotein. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Irbesaran is largely metabolized by glucuronidation and oxidation in the liver. The majority of metabolism occurs through the action of CYP2C9 with a negligible contribution from CYP3A4. Some hydroxylation also occurs in irbesartan metabolism. Irbesartan can be glucuronidated by UGT1A3 to the M8 metabolite, oxidized to the M3 metabolite, or hydroxylated by CYP2C9 to one of the M4, M5, or M7 metabolites. The M4, M5, and M7 metabolites are all hydroxylated to become the M1 metabolite, which is then oxidized to the M2 metabolite. The M4 metabolite can also be oxidized to the M6 metabolite before hydroxylation to the M2 metabolite. Finally, the minor metabolite SR 49498 is generated from irbesartan by an unknown mechanism. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): 20% of a radiolabelled oral dose of irbesartan is recovered in urine, and the rest is recovered in the feces. <2% of the dose is recovered in urine as the unchanged drug. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The terminal elimination half life of irbesartan is 11-15 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Total plasma clearance of irbesartan is 157-176mL/min while renal clearance is 3.0-3.5mL/min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The oral TDLO in humans is 30mg/kg/6W. Symptoms of overdose include hypotension and tachycardia or bradycardia. Terlipressin may be given to treat hypotension and tachycardia if conventional vasopressors fail to control blood pressure. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Avalide, Avapro, Ifirmacombi, Karvea, Karvezide •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Irbesartan •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Irbesartan is an angiotensin receptor blocker used to treat hypertension, delay progression of diabetic nephropathy, and treat congestive heart failure.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Irbesartan interact? Information: •Drug A: Abaloparatide •Drug B: Irbesartan •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Irbesartan is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Irbesartan is indicated to treat hypertension and diabetic nephropathy in hypertensive patients with type 2 diabetes, elevated serum creatinine, and proteinuria. A combination product with hydrochlorothiazide is indicated for hypertension in patients with uncontrolled hypertension with monotherapy or first line in patients not expected to be well controlled with monotherapy. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Irbesartan is an angiotensin receptor blocker used to treat hypertension and diabetic nephropathy. It has a long duration of action as it is usually taken once daily and a wide therapeutic index as doses may be as low as 150mg daily but doses of 900mg/day were well tolerated in healthy human subjects. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Irbesartan prevents angiotensin II binding to the AT 1 receptor in tissues like vascular smooth muscle and the adrenal gland. Irbesartan and its active metabolite bind the AT 1 receptor with 8500 times more affinity than they bind to the AT 2 receptor. Irbesartan's prevention of angiotensin II binding causes vascular smooth muscle relaxation and prevents the secretion of aldosterone, lowering blood pressure. Angiotensin II would otherwise bind to the AT 1 receptor, inducing vasoconstriction and aldosterone secretion, raising blood pressure. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Irbesartan is 60-80% bioavailable with a T max of 1.5-2hours. Taking irbesartan with food does not affect the bioavailability. In one study, healthy subjects were given single or multiple oral doses of 150mg, 300mg, 600mg, and 900mg of irbesartan. A single 150mg dose resulted in an AUC of 9.7±3.0µg\•hr/mL, a T max of 1.5 hours, a half life of 16±7 hours, and a C max of 1.9±0.4µg/mL. A single 300mg dose resulted in an AUC of 20.0±5.2µg\•hr/mL, a T max of 1.5 hours, a half life of 14±7 hours, and a C max of 2.9±0.9µg/mL. A single 600mg dose resulted in an AUC of 32.6±11.9µg\•hr/mL, a T max of 1.5 hours, a half life of 14±8 hours, and a C max of 4.9±1.2µg/mL. A single 900mg dose resulted in an AUC of 44.8±20.0µg\•hr/mL, a T max of 1.5 hours, a half life of 17±7 hours, and a C max of 5.3±1.9µg/mL. Multiple 150mg doses resulted in an AUC of 9.3±3.0µg\•hr/mL, a T max of 1.5 hours, a half life of 11±4 hours, and a C max of 2.04±0.4µg/mL. Multiple 300mg doses resulted in an AUC of 19.8±5.8µg\•hr/mL, a T max of 2.0 hours, a half life of 11±5 hours, and a C max of 3.3±0.8µg/mL. Multiple 600mg doses resulted in an AUC of 31.9±9.7µg\•hr/mL, a T max of 1.5 hours, a half life of 15±7 hours, and a C max of 4.4±0.7µg/mL. Multiple 900mg doses resulted in an AUC of 34.2±9.3µg\•hr/mL, a T max of 1.8 hours, a half life of 14±6 hours, and a C max of 5.6±2.1µg/mL. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The volume of distribution of irbesartan is 53-93L. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Irbesartan is 90% protein bound in plasma, mainly to albumin and α 1 -acid glycoprotein. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Irbesaran is largely metabolized by glucuronidation and oxidation in the liver. The majority of metabolism occurs through the action of CYP2C9 with a negligible contribution from CYP3A4. Some hydroxylation also occurs in irbesartan metabolism. Irbesartan can be glucuronidated by UGT1A3 to the M8 metabolite, oxidized to the M3 metabolite, or hydroxylated by CYP2C9 to one of the M4, M5, or M7 metabolites. The M4, M5, and M7 metabolites are all hydroxylated to become the M1 metabolite, which is then oxidized to the M2 metabolite. The M4 metabolite can also be oxidized to the M6 metabolite before hydroxylation to the M2 metabolite. Finally, the minor metabolite SR 49498 is generated from irbesartan by an unknown mechanism. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): 20% of a radiolabelled oral dose of irbesartan is recovered in urine, and the rest is recovered in the feces. <2% of the dose is recovered in urine as the unchanged drug. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The terminal elimination half life of irbesartan is 11-15 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Total plasma clearance of irbesartan is 157-176mL/min while renal clearance is 3.0-3.5mL/min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The oral TDLO in humans is 30mg/kg/6W. Symptoms of overdose include hypotension and tachycardia or bradycardia. Terlipressin may be given to treat hypotension and tachycardia if conventional vasopressors fail to control blood pressure. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Avalide, Avapro, Ifirmacombi, Karvea, Karvezide •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Irbesartan •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Irbesartan is an angiotensin receptor blocker used to treat hypertension, delay progression of diabetic nephropathy, and treat congestive heart failure. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Isocarboxazid interact?

•Drug A: Abaloparatide •Drug B: Isocarboxazid •Severity: MODERATE •Description: Isocarboxazid may increase the orthostatic hypotensive activities of Abaloparatide. •Extended Description: Incidences of orthostatic hypotension have occurred with monoamine oxidase inhibitors (MAOIs) therapy 1. Co-administration of hypotensive drugs in presence of a MAOI may result in increased risk for developing orthostatic hypotension due to an additive effect. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Isocarboxazid is indicated for the treatment of the enduring and debilitating symptoms of depression that have not responded to other antidepressant drugs. Depression is a common but serious mood disorder. The patient will present changes in its feelings, thoughts, and ability to handle everyday activities. For a mood disorder to be considered as depression, the symptoms should be present for at least two weeks. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): In vivo and in vitro studies demonstrated isocarboxazid-driven inhibition of MAO in the brain, heart, and liver. The reduced MAO activity, caused by isocarboxazid, results in an increased concentration of serotonin, epinephrine, norepinephrine, and dopamine in storage sites throughout the central nervous system (CNS) and sympathetic nervous system. The increase of one or more monoamines is the basis for the antidepressant activity of MAO inhibitors like isocarboxazid. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Isocarboxazid works by irreversibly blocking the action of monoamine oxidases (MAO) in the nervous system. MAO subtypes A and B are involved in the metabolism of serotonin and catecholamine neurotransmitters such as epinephrine, norepinephrine, and dopamine. Isocarboxazid, as a nonselective MAO inhibitor, binds irreversibly to monoamine oxidase-A (MAO-A) and monoamine oxidase-B (MAO-B). Isocarboxacid, like other monoamine oxidase inhibitors, are unique psychopharmacological agents whose clinical effect is related to the direct action of the monoamine oxidases to transform them into reactive metabolites. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): The pharmacokinetic profile of isocarboxazid have not been fully studied but it is suggested that its properties should be fairly similar to the ones of some analogs like phenelzine and tranylcypromine. These drugs are readily absorbed by the GI tract, present a low bioavailability and reach peak concentrations in 1-2 hours. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): The pharmacokinetic profile of isocarboxazid have not been fully studied but it is suggested that its properties should be fairly similar to the ones of some analogs like phenelzine and tranylcypromine. These drugs present a very high protein binding percentage. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): The pharmacokinetic profile of isocarboxazid have not been fully studied but it is suggested that its properties should be fairly similar to the ones of some analogs like phenelzine and tranylcypromine. These drugs are rapidly metabolized by acetylation in the liver. As part of the metabolism, hippuric acid is a major metabolite. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Most of the eliminated dose is found in the urine, accounting for the 42.5% of the administered dose after 24 hours. From this amount, 75% of the renally eliminated drug is in the form of hippuric acid. Another section of the eliminated dose is observed through the intestinal tract and it accounts for 22% of the administered dose after 24 hours. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The pharmacokinetic profile of isocarboxazid have not been fully studied but it is suggested that its properties should be fairly similar to the ones of some analogs like phenelzine and tranylcypromine. The isocarboxazid half-life is of little interest as it is an irreversible monoamine oxidase inhibitor. These drugs present a very short half-life of 1.5-4 hours due to rapid hepatic metabolism. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Long-term toxicity studies to evaluate the carcinogenic, mutagenic and fertility impairment potential have not been conducted. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Marplan •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Isocarboxazid is a monoamine oxidase inhibitor used to treat enduring and debilitating symptoms of depression following inadequate clinical response to other antidepressant drugs.

Incidences of orthostatic hypotension have occurred with monoamine oxidase inhibitors (MAOIs) therapy 1. Co-administration of hypotensive drugs in presence of a MAOI may result in increased risk for developing orthostatic hypotension due to an additive effect. The severity of the interaction is moderate.

Question: Does Abaloparatide and Isocarboxazid interact? Information: •Drug A: Abaloparatide •Drug B: Isocarboxazid •Severity: MODERATE •Description: Isocarboxazid may increase the orthostatic hypotensive activities of Abaloparatide. •Extended Description: Incidences of orthostatic hypotension have occurred with monoamine oxidase inhibitors (MAOIs) therapy 1. Co-administration of hypotensive drugs in presence of a MAOI may result in increased risk for developing orthostatic hypotension due to an additive effect. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Isocarboxazid is indicated for the treatment of the enduring and debilitating symptoms of depression that have not responded to other antidepressant drugs. Depression is a common but serious mood disorder. The patient will present changes in its feelings, thoughts, and ability to handle everyday activities. For a mood disorder to be considered as depression, the symptoms should be present for at least two weeks. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): In vivo and in vitro studies demonstrated isocarboxazid-driven inhibition of MAO in the brain, heart, and liver. The reduced MAO activity, caused by isocarboxazid, results in an increased concentration of serotonin, epinephrine, norepinephrine, and dopamine in storage sites throughout the central nervous system (CNS) and sympathetic nervous system. The increase of one or more monoamines is the basis for the antidepressant activity of MAO inhibitors like isocarboxazid. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Isocarboxazid works by irreversibly blocking the action of monoamine oxidases (MAO) in the nervous system. MAO subtypes A and B are involved in the metabolism of serotonin and catecholamine neurotransmitters such as epinephrine, norepinephrine, and dopamine. Isocarboxazid, as a nonselective MAO inhibitor, binds irreversibly to monoamine oxidase-A (MAO-A) and monoamine oxidase-B (MAO-B). Isocarboxacid, like other monoamine oxidase inhibitors, are unique psychopharmacological agents whose clinical effect is related to the direct action of the monoamine oxidases to transform them into reactive metabolites. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): The pharmacokinetic profile of isocarboxazid have not been fully studied but it is suggested that its properties should be fairly similar to the ones of some analogs like phenelzine and tranylcypromine. These drugs are readily absorbed by the GI tract, present a low bioavailability and reach peak concentrations in 1-2 hours. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): The pharmacokinetic profile of isocarboxazid have not been fully studied but it is suggested that its properties should be fairly similar to the ones of some analogs like phenelzine and tranylcypromine. These drugs present a very high protein binding percentage. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): The pharmacokinetic profile of isocarboxazid have not been fully studied but it is suggested that its properties should be fairly similar to the ones of some analogs like phenelzine and tranylcypromine. These drugs are rapidly metabolized by acetylation in the liver. As part of the metabolism, hippuric acid is a major metabolite. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Most of the eliminated dose is found in the urine, accounting for the 42.5% of the administered dose after 24 hours. From this amount, 75% of the renally eliminated drug is in the form of hippuric acid. Another section of the eliminated dose is observed through the intestinal tract and it accounts for 22% of the administered dose after 24 hours. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The pharmacokinetic profile of isocarboxazid have not been fully studied but it is suggested that its properties should be fairly similar to the ones of some analogs like phenelzine and tranylcypromine. The isocarboxazid half-life is of little interest as it is an irreversible monoamine oxidase inhibitor. These drugs present a very short half-life of 1.5-4 hours due to rapid hepatic metabolism. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Long-term toxicity studies to evaluate the carcinogenic, mutagenic and fertility impairment potential have not been conducted. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Marplan •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Isocarboxazid is a monoamine oxidase inhibitor used to treat enduring and debilitating symptoms of depression following inadequate clinical response to other antidepressant drugs. Output: Incidences of orthostatic hypotension have occurred with monoamine oxidase inhibitors (MAOIs) therapy 1. Co-administration of hypotensive drugs in presence of a MAOI may result in increased risk for developing orthostatic hypotension due to an additive effect. The severity of the interaction is moderate.

Does Abaloparatide and Isoflurane interact?

•Drug A: Abaloparatide •Drug B: Isoflurane •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Isoflurane is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For induction and maintenance of general anesthesia. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Isoflurane is a general inhalation anesthetic used for induction and maintenance of general anesthesia. It induces muscle relaxation and reduces pains sensitivity by altering tissue excitability. It does so by decreasing the extent of gap junction mediated cell-cell coupling and altering the activity of the channels that underlie the action potential. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Isoflurane induces a reduction in junctional conductance by decreasing gap junction channel opening times and increasing gap junction channel closing times. Isoflurane also activates calcium dependent ATPase in the sarcoplasmic reticulum by increasing the fluidity of the lipid membrane. Also appears to bind the D subunit of ATP synthase and NADH dehydogenase. Isoflurane also binds to the GABA receptor, the large conductance Ca activated potassium channel, the glutamate receptor and the glycine receptor. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Minimal •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): No half-life available •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): LC50=15300 ppm/3 hrs (inhalation by rat) •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Forane, Terrell •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Isoflurane Isoflurano Isofluranum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Isoflurane is an inhaled general anesthetic used in surgery.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Isoflurane interact? Information: •Drug A: Abaloparatide •Drug B: Isoflurane •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Isoflurane is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For induction and maintenance of general anesthesia. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Isoflurane is a general inhalation anesthetic used for induction and maintenance of general anesthesia. It induces muscle relaxation and reduces pains sensitivity by altering tissue excitability. It does so by decreasing the extent of gap junction mediated cell-cell coupling and altering the activity of the channels that underlie the action potential. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Isoflurane induces a reduction in junctional conductance by decreasing gap junction channel opening times and increasing gap junction channel closing times. Isoflurane also activates calcium dependent ATPase in the sarcoplasmic reticulum by increasing the fluidity of the lipid membrane. Also appears to bind the D subunit of ATP synthase and NADH dehydogenase. Isoflurane also binds to the GABA receptor, the large conductance Ca activated potassium channel, the glutamate receptor and the glycine receptor. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Minimal •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): No half-life available •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): LC50=15300 ppm/3 hrs (inhalation by rat) •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Forane, Terrell •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Isoflurane Isoflurano Isofluranum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Isoflurane is an inhaled general anesthetic used in surgery. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Isosorbide dinitrate interact?

•Drug A: Abaloparatide •Drug B: Isosorbide dinitrate •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Isosorbide dinitrate is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the prevention of angina pectoris due to coronary artery disease. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Isosorbide Dinitrate is a moderate to long acting oral organic nitrate used for the relief and prophylactic management of angina pectoris. It relaxes the vascular smooth muscle and consequent dilatation of peripheral arteries and veins, especially the latter. Dilatation of the veins promotes peripheral pooling of blood and decreases venous return to the heart, thereby reducing left ventricular end- diastolic pressure and pulmonary capillary wedge pressure (preload). Arteriolar relaxation reduces systemic vascular resistance, systolic arterial pressure, and mean arterial pressure. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Isosorbide dinitrate is converted to the active nitric oxide to activate guanylate cyclase. This activation increases levels of cyclic guanosine 3',5'-monophosphate (cGMP). cGMP activates protein kinases and causes a series of phosphorylation reactions which leads to dephosphorylation of myosin light chains of smooth muscle fibres. Finally there is a release of calcium ions which causes smooth muscle relaxation and vasodilation. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Absorption of isosorbide dinitrate after oral dosing is nearly complete, but bioavailability is highly variable (10% to 90%), with extensive first-pass metabolism in the liver. The average bioavailability of isosorbide dinitrate is about 25%. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 2 to 4 L/kg •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Very low •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Hepatic •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 1 hour •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Symptoms of overdose include reduced cardiac output and hypotension. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Bidil, Dilatrate, Isordil •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Dinitrate d'isosorbide Dinitrato de isosorbida Dinitroisosorbide Dinitrosorbide ISDN Isosorbide dinitrate Isosorbidi dinitras Sorbide nitrate Sorbidnitrate •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Isosorbide dinitrate is a vasodilator used to treat angina in coronary artery disease.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Isosorbide dinitrate interact? Information: •Drug A: Abaloparatide •Drug B: Isosorbide dinitrate •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Isosorbide dinitrate is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the prevention of angina pectoris due to coronary artery disease. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Isosorbide Dinitrate is a moderate to long acting oral organic nitrate used for the relief and prophylactic management of angina pectoris. It relaxes the vascular smooth muscle and consequent dilatation of peripheral arteries and veins, especially the latter. Dilatation of the veins promotes peripheral pooling of blood and decreases venous return to the heart, thereby reducing left ventricular end- diastolic pressure and pulmonary capillary wedge pressure (preload). Arteriolar relaxation reduces systemic vascular resistance, systolic arterial pressure, and mean arterial pressure. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Isosorbide dinitrate is converted to the active nitric oxide to activate guanylate cyclase. This activation increases levels of cyclic guanosine 3',5'-monophosphate (cGMP). cGMP activates protein kinases and causes a series of phosphorylation reactions which leads to dephosphorylation of myosin light chains of smooth muscle fibres. Finally there is a release of calcium ions which causes smooth muscle relaxation and vasodilation. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Absorption of isosorbide dinitrate after oral dosing is nearly complete, but bioavailability is highly variable (10% to 90%), with extensive first-pass metabolism in the liver. The average bioavailability of isosorbide dinitrate is about 25%. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 2 to 4 L/kg •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Very low •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Hepatic •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 1 hour •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Symptoms of overdose include reduced cardiac output and hypotension. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Bidil, Dilatrate, Isordil •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Dinitrate d'isosorbide Dinitrato de isosorbida Dinitroisosorbide Dinitrosorbide ISDN Isosorbide dinitrate Isosorbidi dinitras Sorbide nitrate Sorbidnitrate •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Isosorbide dinitrate is a vasodilator used to treat angina in coronary artery disease. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Isosorbide mononitrate interact?

•Drug A: Abaloparatide •Drug B: Isosorbide mononitrate •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Isosorbide mononitrate is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Isosorbide mononitrate is indicated for the prevention and management of angina pectoris due to coronary artery disease. The onset of action of oral isosorbide mononitrate is not sufficiently rapid to be useful in aborting an acute anginal episode. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Isosorbide mononitrate is an anti-anginal agent and vasodilator that relaxes vascular smooth muscle to prevent and manage angina pectoris. The pharmacological action is mediated by the active metabolite, nitric oxide, which is released when isosorbide mononitrate is metabolized. Nitric oxide works on both arteries and veins, but predominantly veins: by relaxing veins and reducing the central venous pressure, nitric oxide causes venous pooling and a decrease in the venous return to the heart, thus decreasing cardiac preload. In healthy subjects, the stroke volume is decreased and venous pooling can occur in the standing posture, leading to postural hypotension and dizziness. At therapeutic doses of isosorbide mononitrate, nitric oxide has a bigger effect on larger muscular arteries over small resistance arteries. Arterial relaxation leads to reduced systemic vascular resistance and systolic blood (aortic) pressure, decreasing to decreased cardiac afterload. The direct dilator effect on coronary arteries opposes the coronary artery spasm in variant angina or angina pectoris. At larger doses, nitric oxide causes the resistance arteries and arterioles to dilate, reducing arterial pressure via coronary vasodilatation. This leads to increased coronary blood flow. Reduced cardiac preload and afterload caused by nitric oxide causes a reduction in myocardial oxygen consumption; decreased myocardial oxygen demand, along with increased coronary blood flow, leads to an increased in the oxygen content of coronary sinus blood and the relief from ischemia. The end effect of isosorbide mononitrate include decreased cardiac oxygen consumption, redistribution coronary flow toward ischemic areas via collaterals, and the relief of coronary spasms. Nitric oxide can also increase the rate of relaxation of cardiac muscles, which is an effect outside of vascular smooth muscles. Organic nitrates can also relax other types of smooth muscles, including esophageal and biliary smooth muscle. The anti-anginal activity of isosorbide mononitrate was observed about 1 hour after dosing, and the peak effect was achieved from 1-4 hours after dosing. The duration of anti-anginal action of at least 12 hours was observed with an asymmetrical dosing regimen. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Isosorbide mononitrate acts as a prodrug for nitric oxide (NO), which is a potent vasodilator gas that is released when the drug is metabolized. NO activates soluble guanylyl cyclase in vascular endothelial cells, which increases the intracellular concentrations of cyclic GMP (cGMP). cGMP activates cGMP-dependent protein kinases, such as protein kinase G and I, which activates the downstream intracellular cascades. The downstream cascade results in reduced intracellular concentrations of calcium, caused by processes including inhibition of IP 3 -mediated pathway, phosphorylation of big calcium-activated potassium channel leading to cell hyperpolarization and reduced calcium influx, and increased calcium efflux via the Ca2+-ATPase-pump. Reduced intracellular calcium concentrations lead to the dephosphorylation of myosin light chains and the relaxation of smooth muscle cells. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Upon oral administration, isosorbide mononitrate is rapidly and completely absorbed from the gastrointestinal tract. Isosorbide mononitrate has a dose-linear kinetics and the absolute bioavailability is nearly 100%. The Cmax is reached within 30 to 60 minutes following administration. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The volume of distribution is approximately 0.6 L/kg, which is approximately the volume of total body water. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Isosorbide mononitrate is about 5% bound to plasma proteins. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Isosorbide mononitrate is not subject to first pass metabolism in human liver. Detectable metabolites include isosorbide, sorbitol, and 2-glucuronide of mononitrate, which are pharmacologically inactive. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): In a human radio-labelled drug study, about 93% of the total dose was excreted in the urine within 48 hours. Following oral administration of 20 mg, only 2% of isosorbide mononitrate was excreted unchanged in the urine within 24 hours. Among the excreted dose, nearly half of the dose was found de-nitrated in urine as isosorbide and sorbitol: approximately 30% is excreted as isosorbide and about 17% is the 2-glucuronide of mononitrate. These metabolites were not vasoactive or pharmacologically active. Renal excretion was complete after 5 days, and fecal excretion accounted for only 1% of drug elimination. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The elimination half-life of isosorbide mononitrate is about 5 hours. The elimination half-life of its metabolites, isosorbide and 2-glucuronide of mononitrate, are 8 hours and 6 hours, respectively. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The total body clearance is 115-120 mL/min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The oral LD 50 is 2010 mg/kg in rats and 1771 mg/kg in mice. The symptoms of overdose from isosorbide mononitrate is associated with vasodilatation, venous pooling, reduced cardiac output, and hypotension. These symptoms can be accompanied by several manifestations, including increased intracranial pressure (possibly along with persistent throbbing headache, confusion, and moderate fever), vertigo, palpitations, visual disturbances, nausea and vomiting (possibly along with colic and bloody diarrhea), syncope (especially in the upright posture), air hunger and dyspnea (later followed by reduced ventilatory effort), diaphoresis (with flushed or cold and clammy skin), heart blocks and bradycardia, paralysis, coma, seizures, and death. There is limited clinical information on the management of isosorbide mononitrate overdose; it is advised that venodilatation and arterial hypovolemia from overdose are responded with therapy aimed to increase in central fluid volume. However, this method may be potentially hazardous in patients with renal disease or congestive heart failure: invasive monitoring may be required in these patients. The patient's legs should be passively elevated, and intravenous infusion of normal saline or similar fluid is recommended. Isosorbide mononitrate was shown to be significantly removed from the systemic circulation via hemodialysis. The use of epinephrine or other arterial vasoconstrictors is not recommended. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Imdur, Ismo, Monoket •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): ISMN Isosorbide 5-mononitrate Isosorbide 5-nitrate Isosorbide mononitrate Isosorbidi mononitras Mononitrate d'isosorbide Mononitrato de isosorbida Monosorbitrate •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Isosorbide mononitrate is a nitrate used to prevent and treat angina and to treat angina caused by coronary artery disease.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Isosorbide mononitrate interact? Information: •Drug A: Abaloparatide •Drug B: Isosorbide mononitrate •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Isosorbide mononitrate is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Isosorbide mononitrate is indicated for the prevention and management of angina pectoris due to coronary artery disease. The onset of action of oral isosorbide mononitrate is not sufficiently rapid to be useful in aborting an acute anginal episode. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Isosorbide mononitrate is an anti-anginal agent and vasodilator that relaxes vascular smooth muscle to prevent and manage angina pectoris. The pharmacological action is mediated by the active metabolite, nitric oxide, which is released when isosorbide mononitrate is metabolized. Nitric oxide works on both arteries and veins, but predominantly veins: by relaxing veins and reducing the central venous pressure, nitric oxide causes venous pooling and a decrease in the venous return to the heart, thus decreasing cardiac preload. In healthy subjects, the stroke volume is decreased and venous pooling can occur in the standing posture, leading to postural hypotension and dizziness. At therapeutic doses of isosorbide mononitrate, nitric oxide has a bigger effect on larger muscular arteries over small resistance arteries. Arterial relaxation leads to reduced systemic vascular resistance and systolic blood (aortic) pressure, decreasing to decreased cardiac afterload. The direct dilator effect on coronary arteries opposes the coronary artery spasm in variant angina or angina pectoris. At larger doses, nitric oxide causes the resistance arteries and arterioles to dilate, reducing arterial pressure via coronary vasodilatation. This leads to increased coronary blood flow. Reduced cardiac preload and afterload caused by nitric oxide causes a reduction in myocardial oxygen consumption; decreased myocardial oxygen demand, along with increased coronary blood flow, leads to an increased in the oxygen content of coronary sinus blood and the relief from ischemia. The end effect of isosorbide mononitrate include decreased cardiac oxygen consumption, redistribution coronary flow toward ischemic areas via collaterals, and the relief of coronary spasms. Nitric oxide can also increase the rate of relaxation of cardiac muscles, which is an effect outside of vascular smooth muscles. Organic nitrates can also relax other types of smooth muscles, including esophageal and biliary smooth muscle. The anti-anginal activity of isosorbide mononitrate was observed about 1 hour after dosing, and the peak effect was achieved from 1-4 hours after dosing. The duration of anti-anginal action of at least 12 hours was observed with an asymmetrical dosing regimen. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Isosorbide mononitrate acts as a prodrug for nitric oxide (NO), which is a potent vasodilator gas that is released when the drug is metabolized. NO activates soluble guanylyl cyclase in vascular endothelial cells, which increases the intracellular concentrations of cyclic GMP (cGMP). cGMP activates cGMP-dependent protein kinases, such as protein kinase G and I, which activates the downstream intracellular cascades. The downstream cascade results in reduced intracellular concentrations of calcium, caused by processes including inhibition of IP 3 -mediated pathway, phosphorylation of big calcium-activated potassium channel leading to cell hyperpolarization and reduced calcium influx, and increased calcium efflux via the Ca2+-ATPase-pump. Reduced intracellular calcium concentrations lead to the dephosphorylation of myosin light chains and the relaxation of smooth muscle cells. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Upon oral administration, isosorbide mononitrate is rapidly and completely absorbed from the gastrointestinal tract. Isosorbide mononitrate has a dose-linear kinetics and the absolute bioavailability is nearly 100%. The Cmax is reached within 30 to 60 minutes following administration. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The volume of distribution is approximately 0.6 L/kg, which is approximately the volume of total body water. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Isosorbide mononitrate is about 5% bound to plasma proteins. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Isosorbide mononitrate is not subject to first pass metabolism in human liver. Detectable metabolites include isosorbide, sorbitol, and 2-glucuronide of mononitrate, which are pharmacologically inactive. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): In a human radio-labelled drug study, about 93% of the total dose was excreted in the urine within 48 hours. Following oral administration of 20 mg, only 2% of isosorbide mononitrate was excreted unchanged in the urine within 24 hours. Among the excreted dose, nearly half of the dose was found de-nitrated in urine as isosorbide and sorbitol: approximately 30% is excreted as isosorbide and about 17% is the 2-glucuronide of mononitrate. These metabolites were not vasoactive or pharmacologically active. Renal excretion was complete after 5 days, and fecal excretion accounted for only 1% of drug elimination. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The elimination half-life of isosorbide mononitrate is about 5 hours. The elimination half-life of its metabolites, isosorbide and 2-glucuronide of mononitrate, are 8 hours and 6 hours, respectively. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The total body clearance is 115-120 mL/min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The oral LD 50 is 2010 mg/kg in rats and 1771 mg/kg in mice. The symptoms of overdose from isosorbide mononitrate is associated with vasodilatation, venous pooling, reduced cardiac output, and hypotension. These symptoms can be accompanied by several manifestations, including increased intracranial pressure (possibly along with persistent throbbing headache, confusion, and moderate fever), vertigo, palpitations, visual disturbances, nausea and vomiting (possibly along with colic and bloody diarrhea), syncope (especially in the upright posture), air hunger and dyspnea (later followed by reduced ventilatory effort), diaphoresis (with flushed or cold and clammy skin), heart blocks and bradycardia, paralysis, coma, seizures, and death. There is limited clinical information on the management of isosorbide mononitrate overdose; it is advised that venodilatation and arterial hypovolemia from overdose are responded with therapy aimed to increase in central fluid volume. However, this method may be potentially hazardous in patients with renal disease or congestive heart failure: invasive monitoring may be required in these patients. The patient's legs should be passively elevated, and intravenous infusion of normal saline or similar fluid is recommended. Isosorbide mononitrate was shown to be significantly removed from the systemic circulation via hemodialysis. The use of epinephrine or other arterial vasoconstrictors is not recommended. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Imdur, Ismo, Monoket •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): ISMN Isosorbide 5-mononitrate Isosorbide 5-nitrate Isosorbide mononitrate Isosorbidi mononitras Mononitrate d'isosorbide Mononitrato de isosorbida Monosorbitrate •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Isosorbide mononitrate is a nitrate used to prevent and treat angina and to treat angina caused by coronary artery disease. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Isoxsuprine interact?

•Drug A: Abaloparatide •Drug B: Isoxsuprine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abaloparatide is combined with Isoxsuprine. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): No indication available •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): No mechanism of action available •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): No half-life available •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Isoxsuprine is a beta-adrenergic agonist used in the symptomatic treatment of cerebrovascular insufficiency, peripheral vascular disease of arteriosclerosis obliterans, thromboangiitis obliterans (Buerger's disease) and Raynaud's disease.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Isoxsuprine interact? Information: •Drug A: Abaloparatide •Drug B: Isoxsuprine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Abaloparatide is combined with Isoxsuprine. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): No indication available •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): No mechanism of action available •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): No half-life available •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Isoxsuprine is a beta-adrenergic agonist used in the symptomatic treatment of cerebrovascular insufficiency, peripheral vascular disease of arteriosclerosis obliterans, thromboangiitis obliterans (Buerger's disease) and Raynaud's disease. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Isradipine interact?

•Drug A: Abaloparatide •Drug B: Isradipine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Isradipine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the management of mild to moderate essential hypertension. It may be used alone or concurrently with thiazide-type diuretics. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Isradipine decreases arterial smooth muscle contractility and subsequent vasoconstriction by inhibiting the influx of calcium ions through L-type calcium channels. Calcium ions entering the cell through these channels bind to calmodulin. Calcium-bound calmodulin then binds to and activates myosin light chain kinase (MLCK). Activated MLCK catalyzes the phosphorylation of the regulatory light chain subunit of myosin, a key step in muscle contraction. Signal amplification is achieved by calcium-induced calcium release from the sarcoplasmic reticulum through ryanodine receptors. Inhibition of the initial influx of calcium decreases the contractile activity of arterial smooth muscle cells and results in vasodilation. The vasodilatory effects of isradipine result in an overall decrease in blood pressure. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Isradipine belongs to the dihydropyridine (DHP) class of calcium channel blockers (CCBs), the most widely used class of CCBs. There are at least five different types of calcium channels in Homo sapiens: L-, N-, P/Q-, R- and T-type. CCBs target L-type calcium channels, the major channel in muscle cells that mediates contraction. Similar to other DHP CCBs, isradipine binds directly to inactive calcium channels stabilizing their inactive conformation. Since arterial smooth muscle depolarizations are longer in duration than cardiac muscle depolarizations, inactive channels are more prevalent in smooth muscle cells. Alternative splicing of the alpha-1 subunit of the channel gives isradipine additional arterial selectivity. At therapeutic sub-toxic concentrations, isradipine has little effect on cardiac myocytes and conduction cells. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Isradipine is 90%-95% absorbed and is subject to extensive first-pass metabolism, resulting in a bioavailability of about 15%-24%. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 95% •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Hepatic. Completely metabolized prior to excretion and no unchanged drug is detected in the urine. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Approximately 60% to 65% of an administered dose is excreted in the urine and 25% to 30% in the feces. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 8 hours •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Symptoms of overdose include lethargy, sinus tachycardia, and transient hypotension. Significant lethality was observed in mice given oral doses of over 200 mg/kg and rabbits given about 50 mg/kg of isradipine. Rats tolerated doses of over 2000 mg/kg without effects on survival. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Isradipine is a dihydropyridine calcium channel blocker used for the treatment of hypertension.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Isradipine interact? Information: •Drug A: Abaloparatide •Drug B: Isradipine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Isradipine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the management of mild to moderate essential hypertension. It may be used alone or concurrently with thiazide-type diuretics. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Isradipine decreases arterial smooth muscle contractility and subsequent vasoconstriction by inhibiting the influx of calcium ions through L-type calcium channels. Calcium ions entering the cell through these channels bind to calmodulin. Calcium-bound calmodulin then binds to and activates myosin light chain kinase (MLCK). Activated MLCK catalyzes the phosphorylation of the regulatory light chain subunit of myosin, a key step in muscle contraction. Signal amplification is achieved by calcium-induced calcium release from the sarcoplasmic reticulum through ryanodine receptors. Inhibition of the initial influx of calcium decreases the contractile activity of arterial smooth muscle cells and results in vasodilation. The vasodilatory effects of isradipine result in an overall decrease in blood pressure. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Isradipine belongs to the dihydropyridine (DHP) class of calcium channel blockers (CCBs), the most widely used class of CCBs. There are at least five different types of calcium channels in Homo sapiens: L-, N-, P/Q-, R- and T-type. CCBs target L-type calcium channels, the major channel in muscle cells that mediates contraction. Similar to other DHP CCBs, isradipine binds directly to inactive calcium channels stabilizing their inactive conformation. Since arterial smooth muscle depolarizations are longer in duration than cardiac muscle depolarizations, inactive channels are more prevalent in smooth muscle cells. Alternative splicing of the alpha-1 subunit of the channel gives isradipine additional arterial selectivity. At therapeutic sub-toxic concentrations, isradipine has little effect on cardiac myocytes and conduction cells. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Isradipine is 90%-95% absorbed and is subject to extensive first-pass metabolism, resulting in a bioavailability of about 15%-24%. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 95% •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Hepatic. Completely metabolized prior to excretion and no unchanged drug is detected in the urine. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Approximately 60% to 65% of an administered dose is excreted in the urine and 25% to 30% in the feces. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 8 hours •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Symptoms of overdose include lethargy, sinus tachycardia, and transient hypotension. Significant lethality was observed in mice given oral doses of over 200 mg/kg and rabbits given about 50 mg/kg of isradipine. Rats tolerated doses of over 2000 mg/kg without effects on survival. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Isradipine is a dihydropyridine calcium channel blocker used for the treatment of hypertension. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Labetalol interact?

•Drug A: Abaloparatide •Drug B: Labetalol •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Labetalol is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Labetalol injections are indicated to control blood pressure in severe hypertension. Labetalol tablets are indicated alone or in combination with antihypertensives like thiazides and loop diuretics to manage hypertension. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Labetalol antagonizes various adrenergic receptors to decrease blood pressure. The duration of action is long as it is generally given twice daily, and the therapeutic window is wide as patients usually take 200-400mg twice daily. Patients susceptible to bronchospasms should not use labetalol unless they are unresponsive to or intolerant of other antihypertensives. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Labetalol non-selectively antagonizes beta-adrenergic receptors, and selectively antagonizes alpha-1-adrenergic receptors. Following oral administration, labetalol has 3 times the beta-blocking ability than alpha-blocking ability. This increases to 6.9 times following intravenous administration. Antagonism of alpha-1-adrenergic receptors leads to vasodilation and decreased vascular resistance. This leads to a decrease in blood pressure that is most pronounced while standing. Antagonism of beta-1-adrenergic receptors leads to a slight decrease in heart rate. Antagonism of beta-2-adrenergic receptors leads to some of the side effects of labetalol such as bronchospasms, however this may be slightly attenuated by alpha-1-adrenergic antagonism. Labetalol leads to sustained vasodilation over the long term without a significant decrease in cardiac output or stroke volume, and a minimal decrease in heart rate. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): 100mg and 200mg oral doses of labetalol have a T max of 20 minutes to 2 hours. Bioavailability may be as low as 11% or as high as 86% and may increase in older patients or when taken with food. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): In normotensive patients, the volume of distribution is 805L. In hypertensive patients, the volume of distribution is between 188-747L with an average of 392L. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Labetalol is approximately 50% protein bound in serum. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): The metabolism of labetalol has not been fully described in the literature but studies in sheep show an N-dealkylation to 3-amino-1-phenyl butane. This metabolite may be further metabolized to benzylacetone and 3-amino-(4-hydroxyphenyl)butane. Labetalol in humans is mainly metabolized to glucuronide metabolites such as the O-phenyl-glucuronide and the N-glucuronide. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Radiolabelled doses of labetalol are 55-60% recovered in the urine and 12-27% recovered in the feces. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Labetalol has a half life of 1.7-6.1 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Labetalol has a plasma clearance of approximately 1500mL/min and a whole blood clearance of 1100mL/min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The oral LD 50 in mice is 600mg/kg and in rats is >2g/kg. The intravenous LD 50 in mice and rats is 50-60mg/kg. Patients experiencing an overdose may present with excessive hypotension and bradycardia. Patients should be placed on their back with their legs raised to maintain perfusion of the brain. Oral overdoses may be treated with gastric lavage or emesis, bradycardia may be treated with atropine or epinephrine, cardiac failure may be treated with digitalis and a diuretic, hypotension may be treated with vasopressors, bronchospasms may be treated with epinephrine or a beta 2 agonist, and seizures may be treated with diazepam. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Trandate •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Labetalol Labétalol Labetalolum Labetolol •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Labetalol is an alpha and beta adrenergic antagonist used to treat hypertension, angina, and sympathetic overactivity syndrome.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Labetalol interact? Information: •Drug A: Abaloparatide •Drug B: Labetalol •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Labetalol is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Labetalol injections are indicated to control blood pressure in severe hypertension. Labetalol tablets are indicated alone or in combination with antihypertensives like thiazides and loop diuretics to manage hypertension. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Labetalol antagonizes various adrenergic receptors to decrease blood pressure. The duration of action is long as it is generally given twice daily, and the therapeutic window is wide as patients usually take 200-400mg twice daily. Patients susceptible to bronchospasms should not use labetalol unless they are unresponsive to or intolerant of other antihypertensives. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Labetalol non-selectively antagonizes beta-adrenergic receptors, and selectively antagonizes alpha-1-adrenergic receptors. Following oral administration, labetalol has 3 times the beta-blocking ability than alpha-blocking ability. This increases to 6.9 times following intravenous administration. Antagonism of alpha-1-adrenergic receptors leads to vasodilation and decreased vascular resistance. This leads to a decrease in blood pressure that is most pronounced while standing. Antagonism of beta-1-adrenergic receptors leads to a slight decrease in heart rate. Antagonism of beta-2-adrenergic receptors leads to some of the side effects of labetalol such as bronchospasms, however this may be slightly attenuated by alpha-1-adrenergic antagonism. Labetalol leads to sustained vasodilation over the long term without a significant decrease in cardiac output or stroke volume, and a minimal decrease in heart rate. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): 100mg and 200mg oral doses of labetalol have a T max of 20 minutes to 2 hours. Bioavailability may be as low as 11% or as high as 86% and may increase in older patients or when taken with food. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): In normotensive patients, the volume of distribution is 805L. In hypertensive patients, the volume of distribution is between 188-747L with an average of 392L. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Labetalol is approximately 50% protein bound in serum. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): The metabolism of labetalol has not been fully described in the literature but studies in sheep show an N-dealkylation to 3-amino-1-phenyl butane. This metabolite may be further metabolized to benzylacetone and 3-amino-(4-hydroxyphenyl)butane. Labetalol in humans is mainly metabolized to glucuronide metabolites such as the O-phenyl-glucuronide and the N-glucuronide. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Radiolabelled doses of labetalol are 55-60% recovered in the urine and 12-27% recovered in the feces. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Labetalol has a half life of 1.7-6.1 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Labetalol has a plasma clearance of approximately 1500mL/min and a whole blood clearance of 1100mL/min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The oral LD 50 in mice is 600mg/kg and in rats is >2g/kg. The intravenous LD 50 in mice and rats is 50-60mg/kg. Patients experiencing an overdose may present with excessive hypotension and bradycardia. Patients should be placed on their back with their legs raised to maintain perfusion of the brain. Oral overdoses may be treated with gastric lavage or emesis, bradycardia may be treated with atropine or epinephrine, cardiac failure may be treated with digitalis and a diuretic, hypotension may be treated with vasopressors, bronchospasms may be treated with epinephrine or a beta 2 agonist, and seizures may be treated with diazepam. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Trandate •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Labetalol Labétalol Labetalolum Labetolol •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Labetalol is an alpha and beta adrenergic antagonist used to treat hypertension, angina, and sympathetic overactivity syndrome. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Lacidipine interact?

•Drug A: Abaloparatide •Drug B: Lacidipine •Severity: MODERATE •Description: Abaloparatide may increase the hypotensive activities of Lacidipine. •Extended Description: Lacidipine by itself is capable of demonstrating prolonged peripheral vasodilation associated with hypotension and tachycardia. There is also a theoretical possibility of bradycardia or prolonged AV conduction. However, the use of lacidipine in combination with other hypotensive agents, including antihypertensive drugs (e.g. diuretics, beta-blockers or ACE-inhibitors), may lead to additive hypotensive effect. Although no specific interaction problems have been identified in studies with common antihypertensive agents like beta-blockers and diuretics, there is a general expectation that the combination usage of lacidipine with other antihypertensives would result in a potentially over-additive and/or uncontrolled hypotensive effect [L1206]. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Indicated for the treatment of hypertension either alone or in combination with other antihypertensive agents, including β-adrenoceptor antagonists, diuretics, and ACE-inhibitors. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): acidipine is a specific and potent calcium antagonist with a predominant selectivity for calcium channels in the vascular smooth muscle. Its main action is to dilate predominantly peripheral and coronary arteries, reducing peripheral vascular resistance and lowering blood pressure. Following the oral administration of 4 mg lacidipine to volunteer subjects, a minimal prolongation of QTc interval has been observed (mean QTcF increase between 3.44 and 9.60 ms in young and elderly volunteers). •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): By blocking the voltage-dependent L-type calcium channels, it prevents the transmembrane calcium influx. Normally, calcium ions serve as intracellular messengers or activators in exictable cells including vascular smooth muscles. The influx of calcium ultimately causes the excitation and depolarization of the tissues. Lacidipine inhibits the contractile function in the vascular smooth muscle and reduce blood pressure. Due to its high membrane partition coefficient, some studies suggest that lacidipine may reach the receptor via a two-step process; it first binds and accumulates in the membrane lipid bilayer and then diffuses within the membrane to the calcium channel receptor. It is proposed that lacidipine preferentially blocks the inactivated state of the calcium channel. Through its antioxidant properties shared amongst other dihydropyridine calcium channel blockers, lacidipine demonstrates an additional clinical benefit. Its antiatherosclerotic effects are mediated by suppressing the formation of reactive oxygen species (ROS) and subsequent inflammatory actions by chemokines, cytokines and adhesion molecules, thus reducing atherosclerotic lesion formation. Lacidipine may also suppress cell proliferation and migration in smooth muscle cells and suppress the expression of matrix metalloproteinases, which affects the stability of atheromatous plaques. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Since it is a highly lipophilic compound, lacidpine is rapidly absorbed from the gastrointestinal tract following oral administration with the peak plasma concentrations reached between 30 and 150 minutes of dosing. The peak plasma concentrations display large interindividual variability, with the values ranging from 1.6 to 5.7 μg/L following single-dose oral administration of lacidipine 4mg in healthy young volunteers. Absolute bioavailability is less than 10% due to extensive first-pass metabolism in the liver. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Lacidipine is highly protein-bound (more than 95%) to predominantly albumin and to a lesser extent, alpha-1-glycoprotein. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Lacidipine undergoes complete CYP3A4-mediated hepatic metabolism, with no parent drug detected in the urine or faeces. The 2 main metabolites have no pharmacological activity. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Approximately 70% of the administered dose is eliminated as metabolites in the faeces and the remainder as metabolites in the urine. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The average terminal half-life of lacidipine ranges from between 13 and 19 hours at steady state. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): There have been no recorded cases of lacidipine tablets overdosage. Some of the symptoms of overdose include prolonged peripheral vasodilation associated with hypotension and tachycardia. Bradycardia or prolonged AV conduction could theoretically occur. As there is no known antidote for lacidipine, the use of standard general measures for monitoring cardiac function and appropriate supportive and therapeutic measures is recommended. Oral LD50 in mouse, rabbit and rat are 300mg/kg, 3200mg/kg and 980mg/kg, respectively. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Lacidipine is a lipophilic dihydropyridine calcium channel blocker with a slow onset of action used to treat hypertension.

Lacidipine by itself is capable of demonstrating prolonged peripheral vasodilation associated with hypotension and tachycardia. There is also a theoretical possibility of bradycardia or prolonged AV conduction. However, the use of lacidipine in combination with other hypotensive agents, including antihypertensive drugs (e.g. diuretics, beta-blockers or ACE-inhibitors), may lead to additive hypotensive effect. Although no specific interaction problems have been identified in studies with common antihypertensive agents like beta-blockers and diuretics, there is a general expectation that the combination usage of lacidipine with other antihypertensives would result in a potentially over-additive and/or uncontrolled hypotensive effect [L1206]. The severity of the interaction is moderate.

Question: Does Abaloparatide and Lacidipine interact? Information: •Drug A: Abaloparatide •Drug B: Lacidipine •Severity: MODERATE •Description: Abaloparatide may increase the hypotensive activities of Lacidipine. •Extended Description: Lacidipine by itself is capable of demonstrating prolonged peripheral vasodilation associated with hypotension and tachycardia. There is also a theoretical possibility of bradycardia or prolonged AV conduction. However, the use of lacidipine in combination with other hypotensive agents, including antihypertensive drugs (e.g. diuretics, beta-blockers or ACE-inhibitors), may lead to additive hypotensive effect. Although no specific interaction problems have been identified in studies with common antihypertensive agents like beta-blockers and diuretics, there is a general expectation that the combination usage of lacidipine with other antihypertensives would result in a potentially over-additive and/or uncontrolled hypotensive effect [L1206]. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Indicated for the treatment of hypertension either alone or in combination with other antihypertensive agents, including β-adrenoceptor antagonists, diuretics, and ACE-inhibitors. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): acidipine is a specific and potent calcium antagonist with a predominant selectivity for calcium channels in the vascular smooth muscle. Its main action is to dilate predominantly peripheral and coronary arteries, reducing peripheral vascular resistance and lowering blood pressure. Following the oral administration of 4 mg lacidipine to volunteer subjects, a minimal prolongation of QTc interval has been observed (mean QTcF increase between 3.44 and 9.60 ms in young and elderly volunteers). •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): By blocking the voltage-dependent L-type calcium channels, it prevents the transmembrane calcium influx. Normally, calcium ions serve as intracellular messengers or activators in exictable cells including vascular smooth muscles. The influx of calcium ultimately causes the excitation and depolarization of the tissues. Lacidipine inhibits the contractile function in the vascular smooth muscle and reduce blood pressure. Due to its high membrane partition coefficient, some studies suggest that lacidipine may reach the receptor via a two-step process; it first binds and accumulates in the membrane lipid bilayer and then diffuses within the membrane to the calcium channel receptor. It is proposed that lacidipine preferentially blocks the inactivated state of the calcium channel. Through its antioxidant properties shared amongst other dihydropyridine calcium channel blockers, lacidipine demonstrates an additional clinical benefit. Its antiatherosclerotic effects are mediated by suppressing the formation of reactive oxygen species (ROS) and subsequent inflammatory actions by chemokines, cytokines and adhesion molecules, thus reducing atherosclerotic lesion formation. Lacidipine may also suppress cell proliferation and migration in smooth muscle cells and suppress the expression of matrix metalloproteinases, which affects the stability of atheromatous plaques. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Since it is a highly lipophilic compound, lacidpine is rapidly absorbed from the gastrointestinal tract following oral administration with the peak plasma concentrations reached between 30 and 150 minutes of dosing. The peak plasma concentrations display large interindividual variability, with the values ranging from 1.6 to 5.7 μg/L following single-dose oral administration of lacidipine 4mg in healthy young volunteers. Absolute bioavailability is less than 10% due to extensive first-pass metabolism in the liver. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Lacidipine is highly protein-bound (more than 95%) to predominantly albumin and to a lesser extent, alpha-1-glycoprotein. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Lacidipine undergoes complete CYP3A4-mediated hepatic metabolism, with no parent drug detected in the urine or faeces. The 2 main metabolites have no pharmacological activity. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Approximately 70% of the administered dose is eliminated as metabolites in the faeces and the remainder as metabolites in the urine. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The average terminal half-life of lacidipine ranges from between 13 and 19 hours at steady state. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): There have been no recorded cases of lacidipine tablets overdosage. Some of the symptoms of overdose include prolonged peripheral vasodilation associated with hypotension and tachycardia. Bradycardia or prolonged AV conduction could theoretically occur. As there is no known antidote for lacidipine, the use of standard general measures for monitoring cardiac function and appropriate supportive and therapeutic measures is recommended. Oral LD50 in mouse, rabbit and rat are 300mg/kg, 3200mg/kg and 980mg/kg, respectively. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Lacidipine is a lipophilic dihydropyridine calcium channel blocker with a slow onset of action used to treat hypertension. Output: Lacidipine by itself is capable of demonstrating prolonged peripheral vasodilation associated with hypotension and tachycardia. There is also a theoretical possibility of bradycardia or prolonged AV conduction. However, the use of lacidipine in combination with other hypotensive agents, including antihypertensive drugs (e.g. diuretics, beta-blockers or ACE-inhibitors), may lead to additive hypotensive effect. Although no specific interaction problems have been identified in studies with common antihypertensive agents like beta-blockers and diuretics, there is a general expectation that the combination usage of lacidipine with other antihypertensives would result in a potentially over-additive and/or uncontrolled hypotensive effect [L1206]. The severity of the interaction is moderate.

Does Abaloparatide and Lercanidipine interact?

•Drug A: Abaloparatide •Drug B: Lercanidipine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Lercanidipine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the treatment of Hypertension, management of angina pectoris and Raynaud's syndrome •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Lercanidipine, a dihydropyridine calcium-channel blocker, is used alone or with an angiotensin-converting enzyme inhibitor, to treat hypertension, chronic stable angina pectoris, and Prinzmetal's variant angina. Lercanidipine is similar to other peripheral vasodilators. Lercanidipine inhibits the influx of extra cellular calcium across the myocardial and vascular smooth muscle cell membranes possibly by deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum. The decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): By deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum, Lercanidipine inhibits the influx of extracellular calcium across the myocardial and vascular smooth muscle cell membranes The decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): No half-life available •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Lercanidipine is a calcium channel blocker for the management of hypertension.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Lercanidipine interact? Information: •Drug A: Abaloparatide •Drug B: Lercanidipine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Lercanidipine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the treatment of Hypertension, management of angina pectoris and Raynaud's syndrome •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Lercanidipine, a dihydropyridine calcium-channel blocker, is used alone or with an angiotensin-converting enzyme inhibitor, to treat hypertension, chronic stable angina pectoris, and Prinzmetal's variant angina. Lercanidipine is similar to other peripheral vasodilators. Lercanidipine inhibits the influx of extra cellular calcium across the myocardial and vascular smooth muscle cell membranes possibly by deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum. The decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): By deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum, Lercanidipine inhibits the influx of extracellular calcium across the myocardial and vascular smooth muscle cell membranes The decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): No half-life available •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Lercanidipine is a calcium channel blocker for the management of hypertension. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Levamlodipine interact?

•Drug A: Abaloparatide •Drug B: Levamlodipine •Severity: MINOR •Description: Abaloparatide may increase the hypotensive activities of Levamlodipine. •Extended Description: The use of two drugs that both lower blood pressure may result in a more pronounced hypotensive effect. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Levamlodipine is indicated alone or in combination to treat hypertension in adults and children. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Levamlodipine inhibits L-type calcium channels in vascular smooth muscle, reducing peripheral vascular resistance and blood pressure. It is given once daily in doses of 1.25-2.5mg in children and 2.5-5mg in adults. Patients should be counselled regarding the risk of symptomatic hypotension, worsening angina, and myocardial infarction. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Levamlodipine blocks the transmembrane influx of calcium through L-type calcium channels into the vascular and cardiac smooth muscles resulting in vasodilation and a subsequent decrease in blood pressure. Levamlodipine inhibits calcium influx in vascular smooth muscle to a greater degree than in cardiac muscle, leading to decreased peripheral vascular resistance and lowered blood pressure. In vitro studies have shown a negative inotropic effect but this is unlikely to be clinically relevant. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Oral levamlodipine has a T max of 6-12h and a bioavailability of 64-90%. Absorption of levamlodipine is not significantly affected by food. 20mg or oral s-amlodipine besylate reaches a C max of 6.13±1.29ng/mL with a T max of 8.4±3.6h and an AUC of 351±72h*ng/mL. 20mg or oral s-amlodipine maleate reaches a C max of 5.07±1.09ng/mL with a T max of 10.7±3.4h and an AUC of 330±88h*ng/mL. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The volume of distribution of levamlodipine is similar to amlodipine. The volume of distribution of amlodipine is 21L/kg. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Levamlodipine is 93% protein bound in plasma, largely to human serum albumin. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Levamlodipine is 90% metabolized to inactive metabolites. Incubation with liver microsomes has shown that this metabolism is primarily mediated by CYP3A4. Levamlodipine's dehydrogenation to a pyridine metabolite (M9) is the most important metabolic pathway in human liver microsomes. This derivative can be further oxidatively deaminated or O-dealkylated, but does not appear to undergo O-demethylation like racemic amlodipine. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Levamlodipine is 60% eliminated in urine with 10% eliminated as the unmetabolized drug. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Levamlodipine has a half life of 30-50h. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The oral clearance of S-amlodipine besylate is 6.9±1.6mL/min/kg and the oral clearance of S-amlodipine maleate is 7.3±2.1mL/min/kg. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Patients experiencing an overdose may present with hypotension and reflex tachycardia. Treat overdose with cardiac and respiratory monitoring, frequent blood pressure measurement, elevation of extremities to treat hypotension, and possible administration of vasopressors. Hemodialysis is not expected to be useful as levamlodipine is highly protein bound. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Conjupri •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Levamlodipine is a calcium channel blocker used to treat hypertension.

The use of two drugs that both lower blood pressure may result in a more pronounced hypotensive effect. The severity of the interaction is minor.

Question: Does Abaloparatide and Levamlodipine interact? Information: •Drug A: Abaloparatide •Drug B: Levamlodipine •Severity: MINOR •Description: Abaloparatide may increase the hypotensive activities of Levamlodipine. •Extended Description: The use of two drugs that both lower blood pressure may result in a more pronounced hypotensive effect. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Levamlodipine is indicated alone or in combination to treat hypertension in adults and children. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Levamlodipine inhibits L-type calcium channels in vascular smooth muscle, reducing peripheral vascular resistance and blood pressure. It is given once daily in doses of 1.25-2.5mg in children and 2.5-5mg in adults. Patients should be counselled regarding the risk of symptomatic hypotension, worsening angina, and myocardial infarction. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Levamlodipine blocks the transmembrane influx of calcium through L-type calcium channels into the vascular and cardiac smooth muscles resulting in vasodilation and a subsequent decrease in blood pressure. Levamlodipine inhibits calcium influx in vascular smooth muscle to a greater degree than in cardiac muscle, leading to decreased peripheral vascular resistance and lowered blood pressure. In vitro studies have shown a negative inotropic effect but this is unlikely to be clinically relevant. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Oral levamlodipine has a T max of 6-12h and a bioavailability of 64-90%. Absorption of levamlodipine is not significantly affected by food. 20mg or oral s-amlodipine besylate reaches a C max of 6.13±1.29ng/mL with a T max of 8.4±3.6h and an AUC of 351±72h*ng/mL. 20mg or oral s-amlodipine maleate reaches a C max of 5.07±1.09ng/mL with a T max of 10.7±3.4h and an AUC of 330±88h*ng/mL. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The volume of distribution of levamlodipine is similar to amlodipine. The volume of distribution of amlodipine is 21L/kg. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Levamlodipine is 93% protein bound in plasma, largely to human serum albumin. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Levamlodipine is 90% metabolized to inactive metabolites. Incubation with liver microsomes has shown that this metabolism is primarily mediated by CYP3A4. Levamlodipine's dehydrogenation to a pyridine metabolite (M9) is the most important metabolic pathway in human liver microsomes. This derivative can be further oxidatively deaminated or O-dealkylated, but does not appear to undergo O-demethylation like racemic amlodipine. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Levamlodipine is 60% eliminated in urine with 10% eliminated as the unmetabolized drug. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Levamlodipine has a half life of 30-50h. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The oral clearance of S-amlodipine besylate is 6.9±1.6mL/min/kg and the oral clearance of S-amlodipine maleate is 7.3±2.1mL/min/kg. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Patients experiencing an overdose may present with hypotension and reflex tachycardia. Treat overdose with cardiac and respiratory monitoring, frequent blood pressure measurement, elevation of extremities to treat hypotension, and possible administration of vasopressors. Hemodialysis is not expected to be useful as levamlodipine is highly protein bound. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Conjupri •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Levamlodipine is a calcium channel blocker used to treat hypertension. Output: The use of two drugs that both lower blood pressure may result in a more pronounced hypotensive effect. The severity of the interaction is minor.

Does Abaloparatide and Levobupivacaine interact?

•Drug A: Abaloparatide •Drug B: Levobupivacaine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Levobupivacaine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the production of local or regional anesthesia for surgery and obstetrics, and for post-operative pain management •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Levobupivacaine, a local anesthetic agent, is indicated for the production of local or regional anesthesia or analgesia for surgery, for oral surgery procedures, for diagnostic and therapeutic procedures, and for obstetrical procedures. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Local anesthetics such as Levobupivacaine block the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination and conduction velocity of affected nerve fibers. Specifically, the drug binds to the intracellular portion of sodium channels and blocks sodium influx into nerve cells, which prevents depolarization. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): The plasma concentration of levobupivacaine following therapeutic administration depends on dose and also on route of administration, because absorption from the site of administration is affected by the vascularity of the tissue. Peak levels in blood were reached approximately 30 minutes after epidural administration, and doses up to 150 mg resulted in mean C max levels of up to 1.2 µg/mL. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 66.91 ±18.23 L [after intravenous administration of 40 mg in healthy volunteers] •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): >97% •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Levobupivacaine is extensively metabolized with no unchanged levobupivacaine detected in urine or feces. In vitro studies using [14 C] levobupivacaine showed that CYP3A4 isoform and CYP1A2 isoform mediate the metabolism of levobupivacaine to desbutyl levobupivacaine and 3-hydroxy levobupivacaine, respectively. In vivo, the 3-hydroxy levobupivacaine appears to undergo further transformation to glucuronide and sulfate conjugates. Metabolic inversion of levobupivacaine to R(+)-bupivacaine was not evident both in vitro and in vivo. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Following intravenous administration, recovery of the radiolabelled dose of levobupivacaine was essentially quantitative with a mean total of about 95% being recovered in urine and feces in 48 hours. Of this 95%, about 71% was in urine while 24% was in feces. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 3.3 hours •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): 39.06 ±13.29 L/h [after intravenous administration of 40 mg in healthy volunteers] •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): LD50: 5.1mg/kg in rabbit, intravenous; 18mg/kg in rabbit, oral; 207mg/kg in rabbit, parenteral; 63mg/kg in rat, subcutaneous (Archives Internationales de Pharmacodynamie et de Therapie. Vol. 200, Pg. 359, 1972.) Levobupivacaine appears to cause less myocardial depression than both bupivacaine and ropivacaine, despite being in higher concentrations. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-bupivacaine Levobupivacaína Levobupivacaine •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Levobupivacaine is a drug used for nerve block and anesthesia.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Levobupivacaine interact? Information: •Drug A: Abaloparatide •Drug B: Levobupivacaine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Levobupivacaine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the production of local or regional anesthesia for surgery and obstetrics, and for post-operative pain management •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Levobupivacaine, a local anesthetic agent, is indicated for the production of local or regional anesthesia or analgesia for surgery, for oral surgery procedures, for diagnostic and therapeutic procedures, and for obstetrical procedures. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Local anesthetics such as Levobupivacaine block the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination and conduction velocity of affected nerve fibers. Specifically, the drug binds to the intracellular portion of sodium channels and blocks sodium influx into nerve cells, which prevents depolarization. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): The plasma concentration of levobupivacaine following therapeutic administration depends on dose and also on route of administration, because absorption from the site of administration is affected by the vascularity of the tissue. Peak levels in blood were reached approximately 30 minutes after epidural administration, and doses up to 150 mg resulted in mean C max levels of up to 1.2 µg/mL. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 66.91 ±18.23 L [after intravenous administration of 40 mg in healthy volunteers] •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): >97% •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Levobupivacaine is extensively metabolized with no unchanged levobupivacaine detected in urine or feces. In vitro studies using [14 C] levobupivacaine showed that CYP3A4 isoform and CYP1A2 isoform mediate the metabolism of levobupivacaine to desbutyl levobupivacaine and 3-hydroxy levobupivacaine, respectively. In vivo, the 3-hydroxy levobupivacaine appears to undergo further transformation to glucuronide and sulfate conjugates. Metabolic inversion of levobupivacaine to R(+)-bupivacaine was not evident both in vitro and in vivo. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Following intravenous administration, recovery of the radiolabelled dose of levobupivacaine was essentially quantitative with a mean total of about 95% being recovered in urine and feces in 48 hours. Of this 95%, about 71% was in urine while 24% was in feces. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 3.3 hours •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): 39.06 ±13.29 L/h [after intravenous administration of 40 mg in healthy volunteers] •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): LD50: 5.1mg/kg in rabbit, intravenous; 18mg/kg in rabbit, oral; 207mg/kg in rabbit, parenteral; 63mg/kg in rat, subcutaneous (Archives Internationales de Pharmacodynamie et de Therapie. Vol. 200, Pg. 359, 1972.) Levobupivacaine appears to cause less myocardial depression than both bupivacaine and ropivacaine, despite being in higher concentrations. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-bupivacaine Levobupivacaína Levobupivacaine •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Levobupivacaine is a drug used for nerve block and anesthesia. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Levodopa interact?

•Drug A: Abaloparatide •Drug B: Levodopa •Severity: MINOR •Description: The risk or severity of hypotension and orthostatic hypotension can be increased when Abaloparatide is combined with Levodopa. •Extended Description: It is known that levodopa-carbidopa therapy with or without the concomitant use of MAO-A or MAO-B inhibitors is associated with the risk for developing symptomatic postural hypotension. Co-administration of levodopa-containing medications with other agents known to cause orthostatic hypotension may result in an additive risk for experiencing decreased blood pressure or severe orthostatic hypotension. Levodopa is typically in a combination product with carbidopa. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Levodopa on its own is formulated as an oral inhalation powder indicated for intermittent treatment of off episodes in Parkinson's patients who are already being treated with carbidopa and levodopa. Levodopa is most commonly formulated as an oral tablet with a peripheral dopa decarboxylase inhibitor indicated for treatment of Parkinson's disease, post-encephalitic parkinsonism, and symptomatic parkinsonism following carbon monoxide intoxication or manganese intoxication. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Levodopa is able to cross the blood-brain barrier while dopamine is not. The addition of a peripheral dopa decarboxylase inhibitor prevents the conversion of levodopa to dopamine in the periphery so that more levodopa can reach the blood-brain barrier. Once past the blood-brain barrier, levodopa is converted to dopamine by aromatic-L-amino-acid decarboxylase. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Levodopa by various routes crosses the blood brain barrier, is decarboxylated to form dopamine. This supplemental dopamine performs the role that endogenous dopamine cannot due to a decrease of natural concentrations and stimulates dopaminergic receptors. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Orally inhaled levodopa reaches a peak concentration in 0.5 hours with a bioavailability than is 70% that of the immediate release levodopa tablets with a peripheral dopa decarboxylase inhibitor like carbidopa or benserazide. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 168L for orally inhaled levodopa. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Levodopa binding to plasma proteins is negligible. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Levodopa is either converted to dopamine by aromatic-L-amino-acid decarboxylase or O-methylated to 3-O-methyldopa by catechol-O-methyltransferase. 3-O-methyldopa cannot be metabolized to dopamine. Once levodopa is converted to dopamine, it is converted to sulfated or glucuronidated metabolites, epinephrine E, or homovanillic acid through various metabolic processes. The primary metabolites are 3,4-dihydroxyphenylacetic acid (13-47%) and homovanillic acid (23-39%). •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): After 48 hours, 0.17% of an orally administered dose is recovered in stool, 0.28% is exhaled, and 78.4% is recovered in urine •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 2.3 hours for orally inhaled levodopa. Oral levodopa has a half life of 50 minutes but when combined with a peripheral dopa decarboxylase inhibitor, the half life is increased to 1.5 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Intravenously administered levodopa is cleared at a rate of 14.2mL/min/kg in elderly patients and 23.4mL/min/kg in younger patients. When given carbidopa, the clearance of levodopa was 5.8mL/min/kg in elderyly patients and 9.3mL/min/kg in younger patients. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): There is no readily available data for the use of levodopa in pregnancy. Rabbits treated with levodopa and carbidopa produced smaller litters and their offspring developed visceral and skeletal deformities. Levodopa may lower prolactin and interfere with lactation but there is limited human data to demonstrate this effect. Levodopa is present in human breast milk and so the potential effects of nursing while taking levodopa should be considered before prescribing levodopa to nursing mothers. There is currently a lack of data on the safety and effectiveness of using levodopa in pediatric patients. Patients over 65 years of age are more likely to experience adverse effects associated with taking levodopa, however this generally is not sufficient to exclude this patient group from treatment. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Dhivy, Duodopa, Duopa, Inbrija, Parcopa, Prolopa, Rytary, Sinemet, Stalevo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Dihydroxy-L-phenylalanine L-DOPA Levodopa Levodopum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Levodopa is a dopamine precursor used in the management of Parkinson's disease, often in combination with carbidopa, as well as other conditions associated with parkinsonism.

It is known that levodopa-carbidopa therapy with or without the concomitant use of MAO-A or MAO-B inhibitors is associated with the risk for developing symptomatic postural hypotension. Co-administration of levodopa-containing medications with other agents known to cause orthostatic hypotension may result in an additive risk for experiencing decreased blood pressure or severe orthostatic hypotension. Levodopa is typically in a combination product with carbidopa. The severity of the interaction is minor.

Question: Does Abaloparatide and Levodopa interact? Information: •Drug A: Abaloparatide •Drug B: Levodopa •Severity: MINOR •Description: The risk or severity of hypotension and orthostatic hypotension can be increased when Abaloparatide is combined with Levodopa. •Extended Description: It is known that levodopa-carbidopa therapy with or without the concomitant use of MAO-A or MAO-B inhibitors is associated with the risk for developing symptomatic postural hypotension. Co-administration of levodopa-containing medications with other agents known to cause orthostatic hypotension may result in an additive risk for experiencing decreased blood pressure or severe orthostatic hypotension. Levodopa is typically in a combination product with carbidopa. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Levodopa on its own is formulated as an oral inhalation powder indicated for intermittent treatment of off episodes in Parkinson's patients who are already being treated with carbidopa and levodopa. Levodopa is most commonly formulated as an oral tablet with a peripheral dopa decarboxylase inhibitor indicated for treatment of Parkinson's disease, post-encephalitic parkinsonism, and symptomatic parkinsonism following carbon monoxide intoxication or manganese intoxication. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Levodopa is able to cross the blood-brain barrier while dopamine is not. The addition of a peripheral dopa decarboxylase inhibitor prevents the conversion of levodopa to dopamine in the periphery so that more levodopa can reach the blood-brain barrier. Once past the blood-brain barrier, levodopa is converted to dopamine by aromatic-L-amino-acid decarboxylase. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Levodopa by various routes crosses the blood brain barrier, is decarboxylated to form dopamine. This supplemental dopamine performs the role that endogenous dopamine cannot due to a decrease of natural concentrations and stimulates dopaminergic receptors. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Orally inhaled levodopa reaches a peak concentration in 0.5 hours with a bioavailability than is 70% that of the immediate release levodopa tablets with a peripheral dopa decarboxylase inhibitor like carbidopa or benserazide. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 168L for orally inhaled levodopa. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Levodopa binding to plasma proteins is negligible. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Levodopa is either converted to dopamine by aromatic-L-amino-acid decarboxylase or O-methylated to 3-O-methyldopa by catechol-O-methyltransferase. 3-O-methyldopa cannot be metabolized to dopamine. Once levodopa is converted to dopamine, it is converted to sulfated or glucuronidated metabolites, epinephrine E, or homovanillic acid through various metabolic processes. The primary metabolites are 3,4-dihydroxyphenylacetic acid (13-47%) and homovanillic acid (23-39%). •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): After 48 hours, 0.17% of an orally administered dose is recovered in stool, 0.28% is exhaled, and 78.4% is recovered in urine •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 2.3 hours for orally inhaled levodopa. Oral levodopa has a half life of 50 minutes but when combined with a peripheral dopa decarboxylase inhibitor, the half life is increased to 1.5 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Intravenously administered levodopa is cleared at a rate of 14.2mL/min/kg in elderly patients and 23.4mL/min/kg in younger patients. When given carbidopa, the clearance of levodopa was 5.8mL/min/kg in elderyly patients and 9.3mL/min/kg in younger patients. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): There is no readily available data for the use of levodopa in pregnancy. Rabbits treated with levodopa and carbidopa produced smaller litters and their offspring developed visceral and skeletal deformities. Levodopa may lower prolactin and interfere with lactation but there is limited human data to demonstrate this effect. Levodopa is present in human breast milk and so the potential effects of nursing while taking levodopa should be considered before prescribing levodopa to nursing mothers. There is currently a lack of data on the safety and effectiveness of using levodopa in pediatric patients. Patients over 65 years of age are more likely to experience adverse effects associated with taking levodopa, however this generally is not sufficient to exclude this patient group from treatment. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Dhivy, Duodopa, Duopa, Inbrija, Parcopa, Prolopa, Rytary, Sinemet, Stalevo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Dihydroxy-L-phenylalanine L-DOPA Levodopa Levodopum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Levodopa is a dopamine precursor used in the management of Parkinson's disease, often in combination with carbidopa, as well as other conditions associated with parkinsonism. Output: It is known that levodopa-carbidopa therapy with or without the concomitant use of MAO-A or MAO-B inhibitors is associated with the risk for developing symptomatic postural hypotension. Co-administration of levodopa-containing medications with other agents known to cause orthostatic hypotension may result in an additive risk for experiencing decreased blood pressure or severe orthostatic hypotension. Levodopa is typically in a combination product with carbidopa. The severity of the interaction is minor.

Does Abaloparatide and Levosimendan interact?

•Drug A: Abaloparatide •Drug B: Levosimendan •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Levosimendan is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For short term treatment of acutely decompensated severe chronic heart failure (CHF). Also being investigated for use/treatment in heart disease. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Levosimendan is a new Ca -sensitizing inotropic agent. Ca sensitizers represent a new class of inotropic agents, which overcome the disadvantages associated with currently available inotropic agents in as they are not associated with an increased risk of arrhythmias, cell injury and death due to Ca overload in myocardial cells; they do not increase the activation energy; and they have the potential to reverse contractile dysfunction under pathophysiologic conditions, such as acidosis or myocardial stunning. Levosimendan has not been approved for use in the U.S. or Canada. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Levosimendan appears to increase myofilament calcium sensitivity by binding to cardiac troponin C in a calcium-dependent manner. This stabilizes the calcium-induced conformational change of troponin C, thereby (1) changing actin-myosin cross-bridge kinetics apparently without increasing the cycling rate of the cross-bridges or myocardial ATP consumption, (2) increasing the effects of calcium on cardiac myofilaments during systole and (3) improving contraction at low energy cost (inotropic effect). Calcium concentration and, therefore, sensitization decline during diastole, allowing normal or improved diastolic relaxation. Levosimendan also leads to vasodilation through the opening of ATP-sensitive potassium channels. By these inotropic and vasodilatory actions, levosimendan increases cardiac output without increasing myocardial oxygen demand. Levosimendan also has a selective phosphodiesterase (PDE)-III inhibitory action that may contribute to the inotropic effect of this compound under certain experimental conditions. It has been reported that levosimendan may act preferentially as a Ca sensitizer at lower concentrations, whereas at higher concentrations its action as a PDE-III inhibitor becomes more prominent in experimental animals and humans. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): The bioavailability of oral levosimendan is 85 ± 6% in healthy volunteers and 84 ± 4% in patients. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 98% bound to plasma protein. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Complete metabolism, with some active metabolites (OR-1855 and OR-1896) possibly extending the drug's haemodynamic effects. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Eliminination half-life is approximately 1 hour. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Levosimendan is a calcium sensitizer indicated to treat acutely decompensated severe chronic heart failure.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Levosimendan interact? Information: •Drug A: Abaloparatide •Drug B: Levosimendan •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Levosimendan is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For short term treatment of acutely decompensated severe chronic heart failure (CHF). Also being investigated for use/treatment in heart disease. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Levosimendan is a new Ca -sensitizing inotropic agent. Ca sensitizers represent a new class of inotropic agents, which overcome the disadvantages associated with currently available inotropic agents in as they are not associated with an increased risk of arrhythmias, cell injury and death due to Ca overload in myocardial cells; they do not increase the activation energy; and they have the potential to reverse contractile dysfunction under pathophysiologic conditions, such as acidosis or myocardial stunning. Levosimendan has not been approved for use in the U.S. or Canada. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Levosimendan appears to increase myofilament calcium sensitivity by binding to cardiac troponin C in a calcium-dependent manner. This stabilizes the calcium-induced conformational change of troponin C, thereby (1) changing actin-myosin cross-bridge kinetics apparently without increasing the cycling rate of the cross-bridges or myocardial ATP consumption, (2) increasing the effects of calcium on cardiac myofilaments during systole and (3) improving contraction at low energy cost (inotropic effect). Calcium concentration and, therefore, sensitization decline during diastole, allowing normal or improved diastolic relaxation. Levosimendan also leads to vasodilation through the opening of ATP-sensitive potassium channels. By these inotropic and vasodilatory actions, levosimendan increases cardiac output without increasing myocardial oxygen demand. Levosimendan also has a selective phosphodiesterase (PDE)-III inhibitory action that may contribute to the inotropic effect of this compound under certain experimental conditions. It has been reported that levosimendan may act preferentially as a Ca sensitizer at lower concentrations, whereas at higher concentrations its action as a PDE-III inhibitor becomes more prominent in experimental animals and humans. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): The bioavailability of oral levosimendan is 85 ± 6% in healthy volunteers and 84 ± 4% in patients. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 98% bound to plasma protein. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Complete metabolism, with some active metabolites (OR-1855 and OR-1896) possibly extending the drug's haemodynamic effects. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Eliminination half-life is approximately 1 hour. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Levosimendan is a calcium sensitizer indicated to treat acutely decompensated severe chronic heart failure. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Linezolid interact?

•Drug A: Abaloparatide •Drug B: Linezolid •Severity: MODERATE •Description: Linezolid may increase the orthostatic hypotensive activities of Abaloparatide. •Extended Description: Incidences of orthostatic hypotension have occurred with monoamine oxidase inhibitors (MAOIs) therapy 1. Co-administration of hypotensive drugs in presence of a MAOI may result in increased risk for developing orthostatic hypotension due to an additive effect. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Linezolid is indicated in adults and children for the treatment of infections caused by susceptible Gram-positive bacteria, including nosocomial pneumonia, community-acquired pneumonia, skin and skin structure infections, and vancomycin-resistant Enterococcus faecium infections. Examples of susceptible bacteria include Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, and Streptococcus agalactiae. Linezolid is not indicated for the treatment of Gram-negative infections, nor has it been evaluated for use longer than 28 days. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Linezolid is an oxazolidinone antibacterial agent effective against most strains of aerobic Gram-positive bacteria and mycobacteria. It appears to be bacteriostatic against both staphylococci and enterococci and bactericidal against most isolates of streptococci. Linezolid has shown some in vitro activity against Gram-negative and anaerobic bacteria but is not considered efficacious against these organisms. Linezolid is a reversible and non-selective inhibitor of monoamine oxidase (MAO) enzymes and can therefore contribute to the development of serotonin syndrome when administered alongside serotonergic agents such as selective serotonin re-uptake inhibitors (SSRIs) or tricyclic antidepressants (TCAs). Linezolid should not be used for the treatment of catheter-related bloodstream infections or catheter-site infections, as the risk of therapy appears to outweigh its benefits under these circumstances. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Linezolid exerts its antibacterial effects by interfering with bacterial protein translation. It binds to a site on the bacterial 23S ribosomal RNA of the 50S subunit and prevents the formation of a functional 70S initiation complex, which is essential for bacterial reproduction, thereby preventing bacteria from dividing. Point mutations in the bacterial 23S rRNA can lead to linezolid resistance, and the development of linezolid-resistant Enterococcus faecium and Staphylococcus aureus have been documented during its clinical use. As antimicrobial susceptibility patterns are geographically distinct, local antibiograms should be consulted to ensure adequate coverage of relevant pathogens prior to use. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Linezolid is extensively absorbed following oral administration and has an absolute bioavailability of approximately 100%. Maximum plasma concentrations are reached within approximately 1 to 2 hours after dosing (T max ) and range from 8.1-12.9 mcg/mL after single doses and 11.0-21.2 mcg/mL after multiple dosing. The absorption of orally administered linezolid is not significantly affected by co-administration with food and it may therefore be given without regard to the timing of meals. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): At steady-state, the volume of distribution of linezolid in healthy adults is approximately 40-50 liters. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Plasma protein binding of linezolid is approximately 31% - primarily to serum albumin - and is concentration-dependent. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Linezolid is primarily metabolized to two inactive metabolites: an aminoethoxyacetic acid metabolite (PNU-142300) and a hydroxyethyl glycine metabolite (PNU-142586), both of which are the result of morpholine ring oxidation. The hydroxyethyl glycine metabolite - the most abundant of the two metabolites - is likely generated via non-enzymatic processes, though further detail has not been elucidated. While the specific enzymes responsible for the biotransformation of linezolid are unclear, it does not appear to be subject to metabolism via the CYP450 enzyme system, nor does it meaningfully inhibit or induce these enzymes. Linezolid is, however, a reversible and non-selective inhibitor of monoamine oxidase enzymes. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Urinary excretion is the primary means by which linezolid and its metabolic products are excreted. Following the administration of a radiolabeled dose of linezolid under steady-state conditions, approximately 84% of radioactivity was recovered in the urine, of which approximately 30% is unchanged parent drug, 40% is the hydroxyethyl glycine metabolite, and 10% is the aminoethoxyacetic acid metabolite. Fecal elimination is comparatively minor, with no parent drug observed in feces and only 6% and 3% of an administered dose found in the feces as the hydroxyethyl glycine metabolite and the aminoethoxyacetic acid metabolite, respectively. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The elimination half-life is estimated to be between 5 and 7 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Total clearance of linezolid is estimated to be 100-200 mL/min, the majority of which appears to be non-renal. Mean renal clearance is approximately 40 mL/min, which suggests net tubular reabsorption, while non-renal clearance is estimated to account for roughly 65% of total clearance, or 70-150 mL/min on average. Variability in linezolid clearance is high, particularly for non-renal clearance. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Clinical signs of overdosage observed in rats were decreased activity and ataxia (2000 mg/kg/day) and in dogs were vomiting and tremors (3000 mg/kg/day). Treatment of overdose should involve symptomatic and supportive measures and may include hemodialysis if clinically necessary. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Zyvox, Zyvoxam •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Linezolid Linezolide Linezolidum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Linezolid is an oxazolidinone antibiotic used to treat infections by susceptible strains of aerobic Gram-positive bacteria.

Incidences of orthostatic hypotension have occurred with monoamine oxidase inhibitors (MAOIs) therapy 1. Co-administration of hypotensive drugs in presence of a MAOI may result in increased risk for developing orthostatic hypotension due to an additive effect. The severity of the interaction is moderate.

Question: Does Abaloparatide and Linezolid interact? Information: •Drug A: Abaloparatide •Drug B: Linezolid •Severity: MODERATE •Description: Linezolid may increase the orthostatic hypotensive activities of Abaloparatide. •Extended Description: Incidences of orthostatic hypotension have occurred with monoamine oxidase inhibitors (MAOIs) therapy 1. Co-administration of hypotensive drugs in presence of a MAOI may result in increased risk for developing orthostatic hypotension due to an additive effect. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Linezolid is indicated in adults and children for the treatment of infections caused by susceptible Gram-positive bacteria, including nosocomial pneumonia, community-acquired pneumonia, skin and skin structure infections, and vancomycin-resistant Enterococcus faecium infections. Examples of susceptible bacteria include Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, and Streptococcus agalactiae. Linezolid is not indicated for the treatment of Gram-negative infections, nor has it been evaluated for use longer than 28 days. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Linezolid is an oxazolidinone antibacterial agent effective against most strains of aerobic Gram-positive bacteria and mycobacteria. It appears to be bacteriostatic against both staphylococci and enterococci and bactericidal against most isolates of streptococci. Linezolid has shown some in vitro activity against Gram-negative and anaerobic bacteria but is not considered efficacious against these organisms. Linezolid is a reversible and non-selective inhibitor of monoamine oxidase (MAO) enzymes and can therefore contribute to the development of serotonin syndrome when administered alongside serotonergic agents such as selective serotonin re-uptake inhibitors (SSRIs) or tricyclic antidepressants (TCAs). Linezolid should not be used for the treatment of catheter-related bloodstream infections or catheter-site infections, as the risk of therapy appears to outweigh its benefits under these circumstances. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Linezolid exerts its antibacterial effects by interfering with bacterial protein translation. It binds to a site on the bacterial 23S ribosomal RNA of the 50S subunit and prevents the formation of a functional 70S initiation complex, which is essential for bacterial reproduction, thereby preventing bacteria from dividing. Point mutations in the bacterial 23S rRNA can lead to linezolid resistance, and the development of linezolid-resistant Enterococcus faecium and Staphylococcus aureus have been documented during its clinical use. As antimicrobial susceptibility patterns are geographically distinct, local antibiograms should be consulted to ensure adequate coverage of relevant pathogens prior to use. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Linezolid is extensively absorbed following oral administration and has an absolute bioavailability of approximately 100%. Maximum plasma concentrations are reached within approximately 1 to 2 hours after dosing (T max ) and range from 8.1-12.9 mcg/mL after single doses and 11.0-21.2 mcg/mL after multiple dosing. The absorption of orally administered linezolid is not significantly affected by co-administration with food and it may therefore be given without regard to the timing of meals. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): At steady-state, the volume of distribution of linezolid in healthy adults is approximately 40-50 liters. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Plasma protein binding of linezolid is approximately 31% - primarily to serum albumin - and is concentration-dependent. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Linezolid is primarily metabolized to two inactive metabolites: an aminoethoxyacetic acid metabolite (PNU-142300) and a hydroxyethyl glycine metabolite (PNU-142586), both of which are the result of morpholine ring oxidation. The hydroxyethyl glycine metabolite - the most abundant of the two metabolites - is likely generated via non-enzymatic processes, though further detail has not been elucidated. While the specific enzymes responsible for the biotransformation of linezolid are unclear, it does not appear to be subject to metabolism via the CYP450 enzyme system, nor does it meaningfully inhibit or induce these enzymes. Linezolid is, however, a reversible and non-selective inhibitor of monoamine oxidase enzymes. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Urinary excretion is the primary means by which linezolid and its metabolic products are excreted. Following the administration of a radiolabeled dose of linezolid under steady-state conditions, approximately 84% of radioactivity was recovered in the urine, of which approximately 30% is unchanged parent drug, 40% is the hydroxyethyl glycine metabolite, and 10% is the aminoethoxyacetic acid metabolite. Fecal elimination is comparatively minor, with no parent drug observed in feces and only 6% and 3% of an administered dose found in the feces as the hydroxyethyl glycine metabolite and the aminoethoxyacetic acid metabolite, respectively. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The elimination half-life is estimated to be between 5 and 7 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Total clearance of linezolid is estimated to be 100-200 mL/min, the majority of which appears to be non-renal. Mean renal clearance is approximately 40 mL/min, which suggests net tubular reabsorption, while non-renal clearance is estimated to account for roughly 65% of total clearance, or 70-150 mL/min on average. Variability in linezolid clearance is high, particularly for non-renal clearance. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Clinical signs of overdosage observed in rats were decreased activity and ataxia (2000 mg/kg/day) and in dogs were vomiting and tremors (3000 mg/kg/day). Treatment of overdose should involve symptomatic and supportive measures and may include hemodialysis if clinically necessary. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Zyvox, Zyvoxam •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Linezolid Linezolide Linezolidum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Linezolid is an oxazolidinone antibiotic used to treat infections by susceptible strains of aerobic Gram-positive bacteria. Output: Incidences of orthostatic hypotension have occurred with monoamine oxidase inhibitors (MAOIs) therapy 1. Co-administration of hypotensive drugs in presence of a MAOI may result in increased risk for developing orthostatic hypotension due to an additive effect. The severity of the interaction is moderate.

Does Abaloparatide and Lisinopril interact?

•Drug A: Abaloparatide •Drug B: Lisinopril •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Lisinopril is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Lisinopril is indicated for the treatment of acute myocardial infarction, hypertension in patients ≥6 years, and as an adjunct therapy for heart failure. A combination product with hydrochlorothiazide is indicated for the treatment of hypertension. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Lisinopril is an angiotensin converting enzyme inhibitor used to treat hypertension, heart failure, and myocardial infarction. Lisinopril is not a prodrug, and functions by inhibition of angiotensin converting enzyme as well as the renin angiotensin aldosterone system. It has a wide therapeutic index and a long duration of action as patients are generally given 10-80mg daily. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Angiotensin II constricts coronary blood vessels and is positively inotropic, which under normal circumstances, would increase vascular resistance and oxygen consumption. This action can eventually lead to myocyte hypertrophy and vascular smooth muscle cell proliferation. Lisinopril is an angiotensin converting enzyme inhibitor (ACEI), preventing the conversion of angiotensin I to angiotensin II. This action prevents myocyte hypertrophy and vascular smooth muscle cell proliferation seen in untreated patients. Increased levels of bradykinin also exhibit vasodilating effects for patients taking ACEIs. Lisinopril also inhibits renin's conversion of angiotensin to angiotensin I. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Lisinopril is 6-60% orally bioavailable with an average of 25% bioavailability. Lisinopril reaches a C max of 58ng/mL with a T max of 6-8h. Lisinopril's absorption is not affected by food. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The apparent volume of distribution of lisinopril is 124L. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Lisinopril has not been demonstrated to bind to serum proteins. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Lisinopril is not metabolized and is excreted as the unchanged drug. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Lisinopril is entirely eliminated exclusively in the urine. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Lisinopril has an effective half life of accumulation of 12.6h and a terminal half life of 46.7h. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): A 30kg child has a typical clearance of 10L/h, which increases with renal function. The mean renal clearance of lisinopril in healthy adult males is 121mL/min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The oral and subcutaneous LD 50 in rats is >8500mg/kg and in mice is >9100mg/kg. The oral LDLO in women is 1200µg/kg/16D and in men is 43mg/kg/43W. Patients experiencing an overdose of lisinopril may present with hypotension. Patients should be treated with intravenous saline to restore blood pressure. Lisinopril can be removed from the blood by hemodialysis due to it not being protein bound. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Prinivil, Qbrelis, Zestoretic, Zestril •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Lisinopril Lisinoprilum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Lisinopril is an ACE inhibitor used to treat hypertension, heart failure, and acute myocardial infarction.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Lisinopril interact? Information: •Drug A: Abaloparatide •Drug B: Lisinopril •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Lisinopril is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Lisinopril is indicated for the treatment of acute myocardial infarction, hypertension in patients ≥6 years, and as an adjunct therapy for heart failure. A combination product with hydrochlorothiazide is indicated for the treatment of hypertension. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Lisinopril is an angiotensin converting enzyme inhibitor used to treat hypertension, heart failure, and myocardial infarction. Lisinopril is not a prodrug, and functions by inhibition of angiotensin converting enzyme as well as the renin angiotensin aldosterone system. It has a wide therapeutic index and a long duration of action as patients are generally given 10-80mg daily. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Angiotensin II constricts coronary blood vessels and is positively inotropic, which under normal circumstances, would increase vascular resistance and oxygen consumption. This action can eventually lead to myocyte hypertrophy and vascular smooth muscle cell proliferation. Lisinopril is an angiotensin converting enzyme inhibitor (ACEI), preventing the conversion of angiotensin I to angiotensin II. This action prevents myocyte hypertrophy and vascular smooth muscle cell proliferation seen in untreated patients. Increased levels of bradykinin also exhibit vasodilating effects for patients taking ACEIs. Lisinopril also inhibits renin's conversion of angiotensin to angiotensin I. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Lisinopril is 6-60% orally bioavailable with an average of 25% bioavailability. Lisinopril reaches a C max of 58ng/mL with a T max of 6-8h. Lisinopril's absorption is not affected by food. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The apparent volume of distribution of lisinopril is 124L. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Lisinopril has not been demonstrated to bind to serum proteins. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Lisinopril is not metabolized and is excreted as the unchanged drug. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Lisinopril is entirely eliminated exclusively in the urine. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Lisinopril has an effective half life of accumulation of 12.6h and a terminal half life of 46.7h. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): A 30kg child has a typical clearance of 10L/h, which increases with renal function. The mean renal clearance of lisinopril in healthy adult males is 121mL/min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The oral and subcutaneous LD 50 in rats is >8500mg/kg and in mice is >9100mg/kg. The oral LDLO in women is 1200µg/kg/16D and in men is 43mg/kg/43W. Patients experiencing an overdose of lisinopril may present with hypotension. Patients should be treated with intravenous saline to restore blood pressure. Lisinopril can be removed from the blood by hemodialysis due to it not being protein bound. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Prinivil, Qbrelis, Zestoretic, Zestril •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Lisinopril Lisinoprilum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Lisinopril is an ACE inhibitor used to treat hypertension, heart failure, and acute myocardial infarction. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Lofexidine interact?

•Drug A: Abaloparatide •Drug B: Lofexidine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Lofexidine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Lofexidine is indicated for mitigation of symptoms associated with acute withdrawal from opioids and for facilitation of the completion of opioid discontinuation treatment. It is the first non-opioid medication for the symptomatic management of opioid discontinuation. Opioid withdrawal syndrome is a debilitating manifestation of opioid dependence. This condition is extremely unpleasant lasting several days with some of the main features being abdominal pain, nausea, diarrhea, mydriasis, lacrimation, and piloerection. These symptoms are often observed after abrupt reductions in the opioid dose and can be resolved by re-administration of the opioid. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): In clinical trials, lofexidine presented more severe opioid withdrawal effects than observed with methadone. On the other hand, in clinical trials of methadone withdrawal, lofexidine effectively reduced withdrawal symptoms, especially hypotension. The clinical reports have also indicated that lofexidine presents a better outcome when used briefly. In phase 3 clinical trials, lofexidine was shown to generate a significantly higher completion rate of opioid discontinuation. Some pharmacological studies were performed and there were no off-target effects reported. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Lofexidine is a potent alpha2-adrenergic receptor agonist with some moderate agonistic affinity towards Alpha-1A adrenergic receptor and 5-HT1a, 5-HT7, 5HT2c and 5HT1d receptors. The alpha2-adrenergic receptor is normally targeted by norepinephrine and its activation inhibits the synthesis of cAMP which in turn leads to potassium efflux and suppression of neural firing and inhibition of norepinephrine release. All of this activity can reduce the heart rate, blood pressure, and attenuate sympathetic stress response. Opioids inhibit cAMP in the noradrenergic neurons and their discontinuation produces a rise in the level of cAMP. This will generate an increase in norepinephrine which is associated with the symptoms of withdrawal. The magnitude of the effect is augmented by chronic opioid use due to the compensatory mechanisms of continuous negative feedback. Therefore, chronic opioid use translates into an exacerbated production of cAMP and norepinephrine release. Lofexidine replaces the opioid-driven inhibition of cAMP production by activating the alpha2-adrenergic receptor and moderating the symptoms of opioid withdrawal. This effect is performed without interacting with opioid receptors which mediate other activities of opioid dependence or addiction. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Lofexidine has a good oral bioavailability and the peak plasma concentration occurs after 2-5 hours of oral administration. The bioavailability is registered to be even higher than 72%. About 30% of the administered dose of lofexidine is lost during first-pass metabolism. The absorption is registered to be very rapidly recirculated in the gut. After oral administration of 0.8 mg of lofexidine, a maximal dose of 1.26 ng/ml is achieved after 3 hours. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Lofexidine has a volume of distribution of 300 L, indicating that it distributes readily into the tissues. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): The protein binding of lofexidine is determined to be moderate and it represents about 55% of the administered dose. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Lofexidine metabolic ratio is highly variable among people. It is metabolized mainly by the activity of CYP2D6 and in a minor degree by CYP1A2 and CYP2C19. These enzymes catalyze the hydroxylation of lofexidine and the opening of imidazoline ring to form N-(2-aminoethyl)-2-(2,6-dichlorophenoxy)propanamide. This metabolite is deamidated and forms 2-(2,6-dichlorophenoxy) propionic acid and 2,6-dichlorophenol. These three main metabolites are inactive. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): The elimination of lofexidine is primarily through the renal system and it represents 94% of the administered dose while elimination in feces corresponds to only 0.93%. From the eliminated dose in urine, about 10% is formed by unchanged drug and 5% is constituted by the first hydrolysis product N-(2-aminoethyl)-2-(2,6-dichlorophenoxy)propanamide. 2,6-dichlorophenol represents the majority of the administered dose by occupying about 80% of the administered dose. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The reported elimination half-life of lofexidine is 11 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The total elimination clearance following intravenous administration is 17.6 L/h. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Lofexidine did not exhibit genotoxic, mutagenic nor mutagenic potential. Administration at gestational period showed a reduction in the neonatal weight, survival, and increased abortion. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Lucemyra •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Lofexidina Lofexidine Lofexidinum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Lofexidine is a centrally acting alpha2-adrenergic agonist used for the symptomatic treatment of acute opioid withdrawal syndrome to facilitate abrupt opioid discontinuation in adults.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Lofexidine interact? Information: •Drug A: Abaloparatide •Drug B: Lofexidine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Lofexidine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Lofexidine is indicated for mitigation of symptoms associated with acute withdrawal from opioids and for facilitation of the completion of opioid discontinuation treatment. It is the first non-opioid medication for the symptomatic management of opioid discontinuation. Opioid withdrawal syndrome is a debilitating manifestation of opioid dependence. This condition is extremely unpleasant lasting several days with some of the main features being abdominal pain, nausea, diarrhea, mydriasis, lacrimation, and piloerection. These symptoms are often observed after abrupt reductions in the opioid dose and can be resolved by re-administration of the opioid. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): In clinical trials, lofexidine presented more severe opioid withdrawal effects than observed with methadone. On the other hand, in clinical trials of methadone withdrawal, lofexidine effectively reduced withdrawal symptoms, especially hypotension. The clinical reports have also indicated that lofexidine presents a better outcome when used briefly. In phase 3 clinical trials, lofexidine was shown to generate a significantly higher completion rate of opioid discontinuation. Some pharmacological studies were performed and there were no off-target effects reported. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Lofexidine is a potent alpha2-adrenergic receptor agonist with some moderate agonistic affinity towards Alpha-1A adrenergic receptor and 5-HT1a, 5-HT7, 5HT2c and 5HT1d receptors. The alpha2-adrenergic receptor is normally targeted by norepinephrine and its activation inhibits the synthesis of cAMP which in turn leads to potassium efflux and suppression of neural firing and inhibition of norepinephrine release. All of this activity can reduce the heart rate, blood pressure, and attenuate sympathetic stress response. Opioids inhibit cAMP in the noradrenergic neurons and their discontinuation produces a rise in the level of cAMP. This will generate an increase in norepinephrine which is associated with the symptoms of withdrawal. The magnitude of the effect is augmented by chronic opioid use due to the compensatory mechanisms of continuous negative feedback. Therefore, chronic opioid use translates into an exacerbated production of cAMP and norepinephrine release. Lofexidine replaces the opioid-driven inhibition of cAMP production by activating the alpha2-adrenergic receptor and moderating the symptoms of opioid withdrawal. This effect is performed without interacting with opioid receptors which mediate other activities of opioid dependence or addiction. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Lofexidine has a good oral bioavailability and the peak plasma concentration occurs after 2-5 hours of oral administration. The bioavailability is registered to be even higher than 72%. About 30% of the administered dose of lofexidine is lost during first-pass metabolism. The absorption is registered to be very rapidly recirculated in the gut. After oral administration of 0.8 mg of lofexidine, a maximal dose of 1.26 ng/ml is achieved after 3 hours. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Lofexidine has a volume of distribution of 300 L, indicating that it distributes readily into the tissues. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): The protein binding of lofexidine is determined to be moderate and it represents about 55% of the administered dose. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Lofexidine metabolic ratio is highly variable among people. It is metabolized mainly by the activity of CYP2D6 and in a minor degree by CYP1A2 and CYP2C19. These enzymes catalyze the hydroxylation of lofexidine and the opening of imidazoline ring to form N-(2-aminoethyl)-2-(2,6-dichlorophenoxy)propanamide. This metabolite is deamidated and forms 2-(2,6-dichlorophenoxy) propionic acid and 2,6-dichlorophenol. These three main metabolites are inactive. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): The elimination of lofexidine is primarily through the renal system and it represents 94% of the administered dose while elimination in feces corresponds to only 0.93%. From the eliminated dose in urine, about 10% is formed by unchanged drug and 5% is constituted by the first hydrolysis product N-(2-aminoethyl)-2-(2,6-dichlorophenoxy)propanamide. 2,6-dichlorophenol represents the majority of the administered dose by occupying about 80% of the administered dose. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The reported elimination half-life of lofexidine is 11 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): The total elimination clearance following intravenous administration is 17.6 L/h. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Lofexidine did not exhibit genotoxic, mutagenic nor mutagenic potential. Administration at gestational period showed a reduction in the neonatal weight, survival, and increased abortion. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Lucemyra •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Lofexidina Lofexidine Lofexidinum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Lofexidine is a centrally acting alpha2-adrenergic agonist used for the symptomatic treatment of acute opioid withdrawal syndrome to facilitate abrupt opioid discontinuation in adults. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Losartan interact?

•Drug A: Abaloparatide •Drug B: Losartan •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Losartan is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Losartan is indicated to treat hypertension in patients older than 6 years, reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy (though this benefit may not extend to patients with African heritage), and to treat diabetic nephropathy with elevated serum creatinine and proteinuria in patients with type 2 diabetes and hypertension. Losartan with hydrochlorothiazide is indicated to treat hypertension and to reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy (though this benefit may not extend to patients with African heritage). •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Losartan is an angiotensin II receptor blocker used to treat hypertension, diabetic nephropathy, and to reduce the risk of stroke. Losartan has a long duration of action as it is given once daily. Patients taking losartan should be regularly monitored for hypotension, renal function, and potassium levels. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Losartan reversibly and competitively prevents angiotensin II binding to the AT 1 receptor in tissues like vascular smooth muscle and the adrenal gland. Losartan and its active metabolite bind the AT 1 receptor with 1000 times more affinity than they bind to the AT 2 receptor. The active metabolite of losartan is 10-40 times more potent by weight than unmetabolized losartan as an inhibitor of AT 1 and is a non-competitive inhibitor. Losartan's prevention of angiotensin II binding causes vascular smooth muscle relaxation, lowering blood pressure. Angiotensin II would otherwise bind to the AT 1 receptor and induce vasoconstriction, raising blood pressure. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Losartan is approximately 33% orally bioavailable. Losartan has a T max of 1 hour and the active metabolite has a T max of 3-4 hours. Taking losartan with food decreases the C max but does only results in a 10% decrease in the AUC of losartan and its active metabolite. A 50-80mg oral dose of losartan leads to a C max of 200-250ng/mL. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The volume of distribution of losartan is 34.4±17.9L and 10.3±1.1L for the active metabolite (E-3174). •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Losartan is 98.6-98.8% protein bound and the active metabolite (E-3174) is 99.7% protein bound in serum. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Losartan is metabolized to an aldehyde intermediate, E-3179, which is further metabolized to a carboxylic acid, E-3174, by cytochrome P450s like CYP2C9. Losartan can also be hydroxylated to an inactive metabolite, P1. Approximately 14% of losartan is metabolized to E-3174. Losartan can be metabolized by CYP3A4, CYP2C9, and CYP2C10. Losartan can also be glucuronidated by UGT1A1, UGT1A3, UGT1A10, UGT2B7, and UGT 2B17. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): A single oral dose of losartan leads to 4% recovery in the urine as unchanged losartan, 6% in the urine as the active metabolite. Oral radiolabelled losartan is 35% recovered in urine and 60% in feces. Intravenous radiolabelled losartan is 45% recovered in urine and 50% in feces. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The terminal elimination half life of losartan is 1.5-2.5 hours while the active metabolite has a half life of 6-9 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Losartan has a total plasma clearance of 600mL/min and a renal clearance of 75mL/min. E-3174, the active metabolite, has a total plasma clearance of 50mL/min and a renal clearance of 25mL/min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The oral TDLO in mice is 1000mg/kg and in rats is 2000mg/kg. In humans the TDLO for men is 10mg/kg/2W and for women is 1mg/kg/1D. Symptoms of overdose are likely to include hypotension, tachycardia, or bradycardia due to vagal stimulation. Supportive treatment should be instituted for symptomatic hypotension. Hemodialysis will not remove losartan or its active metabolite due to their high rates of protein binding. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Cozaar, Hyzaar •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Losartan •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Losartan is an angiotensin receptor blocker used to treat hypertension and diabetic nephropathy, and is used to reduce the risk of stroke.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Losartan interact? Information: •Drug A: Abaloparatide •Drug B: Losartan •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Losartan is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Losartan is indicated to treat hypertension in patients older than 6 years, reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy (though this benefit may not extend to patients with African heritage), and to treat diabetic nephropathy with elevated serum creatinine and proteinuria in patients with type 2 diabetes and hypertension. Losartan with hydrochlorothiazide is indicated to treat hypertension and to reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy (though this benefit may not extend to patients with African heritage). •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Losartan is an angiotensin II receptor blocker used to treat hypertension, diabetic nephropathy, and to reduce the risk of stroke. Losartan has a long duration of action as it is given once daily. Patients taking losartan should be regularly monitored for hypotension, renal function, and potassium levels. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Losartan reversibly and competitively prevents angiotensin II binding to the AT 1 receptor in tissues like vascular smooth muscle and the adrenal gland. Losartan and its active metabolite bind the AT 1 receptor with 1000 times more affinity than they bind to the AT 2 receptor. The active metabolite of losartan is 10-40 times more potent by weight than unmetabolized losartan as an inhibitor of AT 1 and is a non-competitive inhibitor. Losartan's prevention of angiotensin II binding causes vascular smooth muscle relaxation, lowering blood pressure. Angiotensin II would otherwise bind to the AT 1 receptor and induce vasoconstriction, raising blood pressure. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Losartan is approximately 33% orally bioavailable. Losartan has a T max of 1 hour and the active metabolite has a T max of 3-4 hours. Taking losartan with food decreases the C max but does only results in a 10% decrease in the AUC of losartan and its active metabolite. A 50-80mg oral dose of losartan leads to a C max of 200-250ng/mL. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): The volume of distribution of losartan is 34.4±17.9L and 10.3±1.1L for the active metabolite (E-3174). •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Losartan is 98.6-98.8% protein bound and the active metabolite (E-3174) is 99.7% protein bound in serum. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Losartan is metabolized to an aldehyde intermediate, E-3179, which is further metabolized to a carboxylic acid, E-3174, by cytochrome P450s like CYP2C9. Losartan can also be hydroxylated to an inactive metabolite, P1. Approximately 14% of losartan is metabolized to E-3174. Losartan can be metabolized by CYP3A4, CYP2C9, and CYP2C10. Losartan can also be glucuronidated by UGT1A1, UGT1A3, UGT1A10, UGT2B7, and UGT 2B17. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): A single oral dose of losartan leads to 4% recovery in the urine as unchanged losartan, 6% in the urine as the active metabolite. Oral radiolabelled losartan is 35% recovered in urine and 60% in feces. Intravenous radiolabelled losartan is 45% recovered in urine and 50% in feces. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The terminal elimination half life of losartan is 1.5-2.5 hours while the active metabolite has a half life of 6-9 hours. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Losartan has a total plasma clearance of 600mL/min and a renal clearance of 75mL/min. E-3174, the active metabolite, has a total plasma clearance of 50mL/min and a renal clearance of 25mL/min. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The oral TDLO in mice is 1000mg/kg and in rats is 2000mg/kg. In humans the TDLO for men is 10mg/kg/2W and for women is 1mg/kg/1D. Symptoms of overdose are likely to include hypotension, tachycardia, or bradycardia due to vagal stimulation. Supportive treatment should be instituted for symptomatic hypotension. Hemodialysis will not remove losartan or its active metabolite due to their high rates of protein binding. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Cozaar, Hyzaar •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Losartan •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Losartan is an angiotensin receptor blocker used to treat hypertension and diabetic nephropathy, and is used to reduce the risk of stroke. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Macitentan interact?

•Drug A: Abaloparatide •Drug B: Macitentan •Severity: MINOR •Description: Abaloparatide may increase the hypotensive activities of Macitentan. •Extended Description: The use of two drugs that both lower blood pressure may result in a more pronounced hypotensive effect. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Macitentan is indicated for the treatment of WHO group 1 pulmonary arterial hypertension (PAH) both alone and in combination with tadalafil. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Macitentan acts primarily by reducing vasoconstriction and cell proliferation due to endothelin overexpression. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Macitentan is an antagonist which binds to the endothelin A and B receptors (E A and E B ) and blocks signaling from endothelin-1 and -2. Pulmonary arterial hypertension has many different mechanisms which contribute to the development of endothelial dysfunction including elevated cytosolic calcium, genetic factors, epigenetic changes, and mitochondrial dysfunction. The focus of macitentan's mechanism relates to the role of overexpressed endothelin from the vascular endothelium. Endothelins are released in both a constitutive fashion from secretory vesicles and in response to stimuli via Weibel-Palade storage granules. Endothelins bind to the E A and E B receptors, with endothelins -1 and -2 having more affinity than endothelin-3. Binding to the Gq coupled E A receptor triggers Ca2+ release from the sarcoplasmic reticulum of smooth muscle cells via the phospholipase C (PLC) pathway. Downstream protein kinase C activation may also contribute to increased Ca2+ sensitivity of the contractile apparatus. E A receptor activation is also known to contribute to pulmonary artery smooth muscle cell proliferation. The binding of endothelins to the E B receptors acts in opposition to E A signaling by activating the same PLC cascade in endothelial cells to activate endothelial nitric oxide synthase. The subsequent release of nitric oxide produces vasodilation through the cyclic guanosine monophosphate cascade. Despite the greater presence of E B receptors on endothelial cells, they are still present on smooth muscle cells and may contribute to cell proliferation through the same mechanisms as E A receptors. Macitentan is thought to provide its therapeutic effect primarily via blocking signaling through E A which produces both decreased vasoconstriction via reduced smooth muscle cell contractility and attenuation of the hyperproliferation of smooth muscle cells found in PAH. Blockade of E B is less likely to contribute to a therapeutic effect as this signaling is responsible for the counter-regulatory vasodilatory signal. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Macitentan has a median Tmax of 8h although some studies have found up to 30h at higher doses. Although the bioavailability has not been experimentally determined, pharmacokinetic modeling has estimated it at 74%. Food has not been found to have a significant effect on absorption. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Macitentan has an apparent volume of distribution of 40-50L. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Macitentan is >99% bound to plasma proteins, primarily to albumin and to a lesser extent α1-acid glycoprotein. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Macitentan undergoes oxidative depropylation of the sulfonamide moiety via CYP3A4, 2C8, 2C9, and 2C19 to form the active metabolite M6. The ethylene glycol moiety undergoes oxidative cleavage via CYP2C9 to the alcohol metabolite M4. M4 is oxidized to its corresponding acid, M5, then hydrolyzed to the metabolite termed m/z 324. Oxidative depropylation of a distal carbon atom via CYP2C8, 2C9, and 2C19 forms M7. Hydrolysis of both macitentan and M5 produces M3. Finally M5 may be further metabolized via hydrolysis and hydroxylation to M2 or via glucuronidation to a glucuronide metabolite, M1. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Eliminated 50% through urine and 24% through feces. Of the 50% excreted through the urine, none of the recovered dose was in the form of the parent drug nor the active metabolite. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The half-life of elimination of macitentan is 16 hours. The half-life of elimination of the active metabolite is 40-66h •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Clearance data was not found. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): At high doses, macitentan may produce headache, nausea, and vomiting. In case of overdose standard supportive measures are recommended. Hemodialysis is not expected to contribute significantly to macitentan clearance due to its high degree of plasma protein binding. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Opsumit •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Macitentan is an endothelin receptor antagonist used to manage pulmonary arterial hypertension to delay disease progression.

The use of two drugs that both lower blood pressure may result in a more pronounced hypotensive effect. The severity of the interaction is minor.

Question: Does Abaloparatide and Macitentan interact? Information: •Drug A: Abaloparatide •Drug B: Macitentan •Severity: MINOR •Description: Abaloparatide may increase the hypotensive activities of Macitentan. •Extended Description: The use of two drugs that both lower blood pressure may result in a more pronounced hypotensive effect. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Macitentan is indicated for the treatment of WHO group 1 pulmonary arterial hypertension (PAH) both alone and in combination with tadalafil. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Macitentan acts primarily by reducing vasoconstriction and cell proliferation due to endothelin overexpression. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Macitentan is an antagonist which binds to the endothelin A and B receptors (E A and E B ) and blocks signaling from endothelin-1 and -2. Pulmonary arterial hypertension has many different mechanisms which contribute to the development of endothelial dysfunction including elevated cytosolic calcium, genetic factors, epigenetic changes, and mitochondrial dysfunction. The focus of macitentan's mechanism relates to the role of overexpressed endothelin from the vascular endothelium. Endothelins are released in both a constitutive fashion from secretory vesicles and in response to stimuli via Weibel-Palade storage granules. Endothelins bind to the E A and E B receptors, with endothelins -1 and -2 having more affinity than endothelin-3. Binding to the Gq coupled E A receptor triggers Ca2+ release from the sarcoplasmic reticulum of smooth muscle cells via the phospholipase C (PLC) pathway. Downstream protein kinase C activation may also contribute to increased Ca2+ sensitivity of the contractile apparatus. E A receptor activation is also known to contribute to pulmonary artery smooth muscle cell proliferation. The binding of endothelins to the E B receptors acts in opposition to E A signaling by activating the same PLC cascade in endothelial cells to activate endothelial nitric oxide synthase. The subsequent release of nitric oxide produces vasodilation through the cyclic guanosine monophosphate cascade. Despite the greater presence of E B receptors on endothelial cells, they are still present on smooth muscle cells and may contribute to cell proliferation through the same mechanisms as E A receptors. Macitentan is thought to provide its therapeutic effect primarily via blocking signaling through E A which produces both decreased vasoconstriction via reduced smooth muscle cell contractility and attenuation of the hyperproliferation of smooth muscle cells found in PAH. Blockade of E B is less likely to contribute to a therapeutic effect as this signaling is responsible for the counter-regulatory vasodilatory signal. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Macitentan has a median Tmax of 8h although some studies have found up to 30h at higher doses. Although the bioavailability has not been experimentally determined, pharmacokinetic modeling has estimated it at 74%. Food has not been found to have a significant effect on absorption. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Macitentan has an apparent volume of distribution of 40-50L. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Macitentan is >99% bound to plasma proteins, primarily to albumin and to a lesser extent α1-acid glycoprotein. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Macitentan undergoes oxidative depropylation of the sulfonamide moiety via CYP3A4, 2C8, 2C9, and 2C19 to form the active metabolite M6. The ethylene glycol moiety undergoes oxidative cleavage via CYP2C9 to the alcohol metabolite M4. M4 is oxidized to its corresponding acid, M5, then hydrolyzed to the metabolite termed m/z 324. Oxidative depropylation of a distal carbon atom via CYP2C8, 2C9, and 2C19 forms M7. Hydrolysis of both macitentan and M5 produces M3. Finally M5 may be further metabolized via hydrolysis and hydroxylation to M2 or via glucuronidation to a glucuronide metabolite, M1. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Eliminated 50% through urine and 24% through feces. Of the 50% excreted through the urine, none of the recovered dose was in the form of the parent drug nor the active metabolite. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The half-life of elimination of macitentan is 16 hours. The half-life of elimination of the active metabolite is 40-66h •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Clearance data was not found. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): At high doses, macitentan may produce headache, nausea, and vomiting. In case of overdose standard supportive measures are recommended. Hemodialysis is not expected to contribute significantly to macitentan clearance due to its high degree of plasma protein binding. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Opsumit •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Macitentan is an endothelin receptor antagonist used to manage pulmonary arterial hypertension to delay disease progression. Output: The use of two drugs that both lower blood pressure may result in a more pronounced hypotensive effect. The severity of the interaction is minor.

Does Abaloparatide and Manidipine interact?

•Drug A: Abaloparatide •Drug B: Manidipine •Severity: MINOR •Description: Abaloparatide may increase the hypotensive activities of Manidipine. •Extended Description: The use of two drugs that both lower blood pressure may result in a more pronounced hypotensive effect. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the treatment of hypertension. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Manidipine produces vasodilation resulting in lower blood pressure. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Contraction of vascular smooth muscle is stimulated by Gq coupled receptors which produce calcium release from the sarcoplasmic reticulum. This is followed by opening of voltage dependent calcium channels and an influx of calcium into the cell ultimately producing contraction. Manidipine binds to and dissociates slowly from L- and T-type voltage dependent calcium channels on smooth muscle cells, blocking the entrance of extracellular calcium into the cell and preventing this contraction. This produces vasodilation which decreases blood pressure. Manidipine produces renal vasodilation and an increase in natriuresis. This likely contributes to the antihypertensive effect by reducing blood volume. Manidipine is selective for the vasculature and does not produce significant effects on the heart or central nervous system at clinically relevant dosages. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): The median Tmax is 1.5 h. Administration with food produces an 1.3-1.6-fold increase in Cmax but no change in Tmax. Manidipine does not accumulate significantly with multiple doses. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Manidipine is 99% bound to human plasma proteins. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Manidipine is extensively metabolized by CYP enzymes to pyridine derivatives and diphenylmethane derivatives which make up 4-7% and 22-24% of the dose excreted in the urine. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Manidipine is eliminated through extensive metabolism. 63% is eliminated in the feces and 31% in the urine as metabolites. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The half life of elimination has been observed to be dose dependent. Doses of 5, 10, and 20 mg produced half lives of 3.94, 5.02, and 7.95 h respectively. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The most common adverse events reported in clinical trials were ankle oedema (6%), headache (3.8%), palpitation (2.7%), flushing (2.2%), dizziness (1.6%), rash (0.5%) and fatigue (0.5%). •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Manidipine is a dihydropyridine calcium channel blocker used to treat hypertension.

The use of two drugs that both lower blood pressure may result in a more pronounced hypotensive effect. The severity of the interaction is minor.

Question: Does Abaloparatide and Manidipine interact? Information: •Drug A: Abaloparatide •Drug B: Manidipine •Severity: MINOR •Description: Abaloparatide may increase the hypotensive activities of Manidipine. •Extended Description: The use of two drugs that both lower blood pressure may result in a more pronounced hypotensive effect. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the treatment of hypertension. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Manidipine produces vasodilation resulting in lower blood pressure. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Contraction of vascular smooth muscle is stimulated by Gq coupled receptors which produce calcium release from the sarcoplasmic reticulum. This is followed by opening of voltage dependent calcium channels and an influx of calcium into the cell ultimately producing contraction. Manidipine binds to and dissociates slowly from L- and T-type voltage dependent calcium channels on smooth muscle cells, blocking the entrance of extracellular calcium into the cell and preventing this contraction. This produces vasodilation which decreases blood pressure. Manidipine produces renal vasodilation and an increase in natriuresis. This likely contributes to the antihypertensive effect by reducing blood volume. Manidipine is selective for the vasculature and does not produce significant effects on the heart or central nervous system at clinically relevant dosages. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): The median Tmax is 1.5 h. Administration with food produces an 1.3-1.6-fold increase in Cmax but no change in Tmax. Manidipine does not accumulate significantly with multiple doses. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): Manidipine is 99% bound to human plasma proteins. •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Manidipine is extensively metabolized by CYP enzymes to pyridine derivatives and diphenylmethane derivatives which make up 4-7% and 22-24% of the dose excreted in the urine. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Manidipine is eliminated through extensive metabolism. 63% is eliminated in the feces and 31% in the urine as metabolites. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): The half life of elimination has been observed to be dose dependent. Doses of 5, 10, and 20 mg produced half lives of 3.94, 5.02, and 7.95 h respectively. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The most common adverse events reported in clinical trials were ankle oedema (6%), headache (3.8%), palpitation (2.7%), flushing (2.2%), dizziness (1.6%), rash (0.5%) and fatigue (0.5%). •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Manidipine is a dihydropyridine calcium channel blocker used to treat hypertension. Output: The use of two drugs that both lower blood pressure may result in a more pronounced hypotensive effect. The severity of the interaction is minor.

Does Abaloparatide and Mannitol interact?

•Drug A: Abaloparatide •Drug B: Mannitol •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Mannitol is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Used for the promotion of diuresis before irreversible renal failure becomes established, the reduction of intracranial pressure, the treatment of cerebral edema, and the promotion of urinary excretion of toxic substances. Mannitol is also indicated as add-on maintenance therapy for improving pulmonary function in cystic fibrosis patients aged 18 and over who have passed the BRONCHITOL tolerance test (BTT). It is recommended that patients take an orally inhaled short-acting bronchodilator 5-15 minutes prior to every inhaled mannitol dose. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Chemically, mannitol is an alcohol and a sugar, or a polyol; it is similar to xylitol or sorbitol. However, mannitol has a tendency to lose a hydrogen ion in aqueous solutions, which causes the solution to become acidic. For this reason, it is not uncommon to add a substance to adjust its pH, such as sodium bicarbonate. Mannitol is commonly used to increase urine production (diuretic). It is also used to treat or prevent medical conditions that are caused by an increase in body fluids/water (e.g., cerebral edema, glaucoma, kidney failure). Mannitol is frequently given along with other diuretics (e.g., furosemide, chlorothiazide) and/or IV fluid replacement. Inhaled mannitol has the possibility to cause bronchospasm and hemoptysis; the occurrence of either should lead to discontinuation of inhaled mannitol. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Mannitol is an osmotic diuretic that is metabolically inert in humans and occurs naturally, as a sugar or sugar alcohol, in fruits and vegetables. Mannitol elevates blood plasma osmolality, resulting in enhanced flow of water from tissues, including the brain and cerebrospinal fluid, into interstitial fluid and plasma. As a result, cerebral edema, elevated intracranial pressure, and cerebrospinal fluid volume and pressure may be reduced. As a diurectic mannitol induces diuresis because it is not reabsorbed in the renal tubule, thereby increasing the osmolality of the glomerular filtrate, facilitating excretion of water, and inhibiting the renal tubular reabsorption of sodium, chloride, and other solutes. Mannitol promotes the urinary excretion of toxic materials and protects against nephrotoxicity by preventing the concentration of toxic substances in the tubular fluid. As an Antiglaucoma agent mannitol levates blood plasma osmolarity, resulting in enhanced flow of water from the eye into plasma and a consequent reduction in intraocular pressure. As a renal function diagnostic aid mannitol is freely filtered by the glomeruli with less than 10% tubular reabsorption. Therefore, its urinary excretion rate may serve as a measurement of glomerular filtration rate (GFR). The exact mechanism of action of inhaled mannitol in the symptomatic maintenance treatment of cystic fibrosis remains unclear. It is hypothesized that mannitol produces an osmotic gradient across the airway epithelium that draws fluid into the extracellular space and alters the properties of the airway surface mucus layer, allowing easier mucociliary clearance. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Approximately 7% of ingested mannitol is absorbed during gastrointestinal perfusion in uremic patients. Inhalation of 635 mg of mannitol powder yields a plasma C max of 13.71 μg/mL in 1.5 hours (T max ) and a mean systemic AUC of 73.15 μg*h/mL. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Mannitol administered intravenously has a volume of distribution of 34.3 L. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Mannitol is metabolized only slightly, if at all, to glycogen in the liver. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Mannitol is primarily excreted unchanged in the urine. Following oral inhalation of 635 mg of mannitol in healthy volunteers, 55% of the total dose was recovered unchanged in the urine; following oral or intravenous administration of 500 mg, the corresponding values were 54 and 87%, respectively. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Mannitol has an elimination half-life of 4.7 hours following oral administration; the mean terminal elimination half-life is similar regardless of administration route (oral, inhalation, and intravenous. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Intravenous administration of mannitol yields a total clearance of 5.1 L/hr and renal clearance of 4.4 L/hr. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Mannitol overdose may result in bronchoconstriction and should be counteracted using a short-acting bronchodilator and other symptomatic and supportive care, as necessary. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Aridol, Bronchitol, Cystosol, Osmitrol, Sag-M •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): D-Mannitol Manitol Manna Sugar Mannit Mannite Mannitol Mannitolum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Mannitol is a sugar alcohol used to test for asthma, to reduce intracranial and intraocular pressure, to measure glomerular filtration rate, and to manage pulmonary symptoms associated with cystic fibrosis.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Mannitol interact? Information: •Drug A: Abaloparatide •Drug B: Mannitol •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Mannitol is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Used for the promotion of diuresis before irreversible renal failure becomes established, the reduction of intracranial pressure, the treatment of cerebral edema, and the promotion of urinary excretion of toxic substances. Mannitol is also indicated as add-on maintenance therapy for improving pulmonary function in cystic fibrosis patients aged 18 and over who have passed the BRONCHITOL tolerance test (BTT). It is recommended that patients take an orally inhaled short-acting bronchodilator 5-15 minutes prior to every inhaled mannitol dose. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Chemically, mannitol is an alcohol and a sugar, or a polyol; it is similar to xylitol or sorbitol. However, mannitol has a tendency to lose a hydrogen ion in aqueous solutions, which causes the solution to become acidic. For this reason, it is not uncommon to add a substance to adjust its pH, such as sodium bicarbonate. Mannitol is commonly used to increase urine production (diuretic). It is also used to treat or prevent medical conditions that are caused by an increase in body fluids/water (e.g., cerebral edema, glaucoma, kidney failure). Mannitol is frequently given along with other diuretics (e.g., furosemide, chlorothiazide) and/or IV fluid replacement. Inhaled mannitol has the possibility to cause bronchospasm and hemoptysis; the occurrence of either should lead to discontinuation of inhaled mannitol. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Mannitol is an osmotic diuretic that is metabolically inert in humans and occurs naturally, as a sugar or sugar alcohol, in fruits and vegetables. Mannitol elevates blood plasma osmolality, resulting in enhanced flow of water from tissues, including the brain and cerebrospinal fluid, into interstitial fluid and plasma. As a result, cerebral edema, elevated intracranial pressure, and cerebrospinal fluid volume and pressure may be reduced. As a diurectic mannitol induces diuresis because it is not reabsorbed in the renal tubule, thereby increasing the osmolality of the glomerular filtrate, facilitating excretion of water, and inhibiting the renal tubular reabsorption of sodium, chloride, and other solutes. Mannitol promotes the urinary excretion of toxic materials and protects against nephrotoxicity by preventing the concentration of toxic substances in the tubular fluid. As an Antiglaucoma agent mannitol levates blood plasma osmolarity, resulting in enhanced flow of water from the eye into plasma and a consequent reduction in intraocular pressure. As a renal function diagnostic aid mannitol is freely filtered by the glomeruli with less than 10% tubular reabsorption. Therefore, its urinary excretion rate may serve as a measurement of glomerular filtration rate (GFR). The exact mechanism of action of inhaled mannitol in the symptomatic maintenance treatment of cystic fibrosis remains unclear. It is hypothesized that mannitol produces an osmotic gradient across the airway epithelium that draws fluid into the extracellular space and alters the properties of the airway surface mucus layer, allowing easier mucociliary clearance. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Approximately 7% of ingested mannitol is absorbed during gastrointestinal perfusion in uremic patients. Inhalation of 635 mg of mannitol powder yields a plasma C max of 13.71 μg/mL in 1.5 hours (T max ) and a mean systemic AUC of 73.15 μg*h/mL. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): Mannitol administered intravenously has a volume of distribution of 34.3 L. •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Mannitol is metabolized only slightly, if at all, to glycogen in the liver. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Mannitol is primarily excreted unchanged in the urine. Following oral inhalation of 635 mg of mannitol in healthy volunteers, 55% of the total dose was recovered unchanged in the urine; following oral or intravenous administration of 500 mg, the corresponding values were 54 and 87%, respectively. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): Mannitol has an elimination half-life of 4.7 hours following oral administration; the mean terminal elimination half-life is similar regardless of administration route (oral, inhalation, and intravenous. •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): Intravenous administration of mannitol yields a total clearance of 5.1 L/hr and renal clearance of 4.4 L/hr. •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Mannitol overdose may result in bronchoconstriction and should be counteracted using a short-acting bronchodilator and other symptomatic and supportive care, as necessary. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Aridol, Bronchitol, Cystosol, Osmitrol, Sag-M •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): D-Mannitol Manitol Manna Sugar Mannit Mannite Mannitol Mannitolum •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Mannitol is a sugar alcohol used to test for asthma, to reduce intracranial and intraocular pressure, to measure glomerular filtration rate, and to manage pulmonary symptoms associated with cystic fibrosis. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Mecamylamine interact?

•Drug A: Abaloparatide •Drug B: Mecamylamine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Mecamylamine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the treatment of moderately severe to severe essential hypertension and in uncomplicated cases of malignant hypertension •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Mecamylamine is a potent, oral antihypertensive agent and ganglion blocker, and is a secondary amine. Mecamylamine is indicated for the management of moderately severe to severe essential hypertension and in uncomplicated cases of malignant hypertension. Mecamylamine reduces blood pressure in both normotensive and hypertensive individuals. A small oral dosage often produces a smooth and predictable reduction of blood pressure. Although this antihypertensive effect is predominantly orthostatic, the supine blood pressure is also significantly reduced. Mecamylamine crosses the blood-brain and placental barriers. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Mecamylamine is a ganglionic blocker which prevents stimulation of postsynaptic receptors by acetylcholine released from presynaptic nerve endings. The hypotensive effect of Mecamylamine is attributed to reduction in sympathetic tone, vasodilation, and reduced cardiac output, and is primarily postural. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Mecamylamine is almost completely absorbed from the gastrointestinal tract •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 40% •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Mecamylamine is excreted slowly in the urine in the unchanged form. The rate of its renal elimination is influenced markedly by urinary pH. Alkalinization of the urine reduces, and acidification promotes, renal excretion of mecamylamine. Mecamylamine crosses the blood-brain and placental barriers. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): No half-life available •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Inversine, Vecamyl •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Mecamylamine is a nicotine antagonist used to treat moderate to severe essential hypertension and uncomplicated malignant hypertension.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Mecamylamine interact? Information: •Drug A: Abaloparatide •Drug B: Mecamylamine •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Mecamylamine is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For the treatment of moderately severe to severe essential hypertension and in uncomplicated cases of malignant hypertension •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Mecamylamine is a potent, oral antihypertensive agent and ganglion blocker, and is a secondary amine. Mecamylamine is indicated for the management of moderately severe to severe essential hypertension and in uncomplicated cases of malignant hypertension. Mecamylamine reduces blood pressure in both normotensive and hypertensive individuals. A small oral dosage often produces a smooth and predictable reduction of blood pressure. Although this antihypertensive effect is predominantly orthostatic, the supine blood pressure is also significantly reduced. Mecamylamine crosses the blood-brain and placental barriers. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Mecamylamine is a ganglionic blocker which prevents stimulation of postsynaptic receptors by acetylcholine released from presynaptic nerve endings. The hypotensive effect of Mecamylamine is attributed to reduction in sympathetic tone, vasodilation, and reduced cardiac output, and is primarily postural. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Mecamylamine is almost completely absorbed from the gastrointestinal tract •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 40% •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Mecamylamine is excreted slowly in the urine in the unchanged form. The rate of its renal elimination is influenced markedly by urinary pH. Alkalinization of the urine reduces, and acidification promotes, renal excretion of mecamylamine. Mecamylamine crosses the blood-brain and placental barriers. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): No half-life available •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Inversine, Vecamyl •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Mecamylamine is a nicotine antagonist used to treat moderate to severe essential hypertension and uncomplicated malignant hypertension. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Methazolamide interact?

•Drug A: Abaloparatide •Drug B: Methazolamide •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Methazolamide is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For treatment of chronic open-angle glaucoma and acute angle-closure glaucoma •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Methazolamide is topical carbonic anhydrase inhibitor. Methazolamide is indicated for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension who are insufficiently responsive to beta-blockers. Methazolamide is a sulfonamide derivative; however, it does not have any clinically significant antimicrobial properties. Although methazolamide achieves a high concentration in the cerebrospinal fluid, it is not-considered an effective anticonvulsant. Methazolamide has a weak and transient diuretic effect, therefore use results in an increase in urinary volume, with excretion of sodium, potassium and chloride. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Methazolamide is a potent inhibitor of carbonic anhydrase. Inhibition of carbonic anhydrase in the ciliary processes of the eye decreases aqueous humor secretion, presumably by slowing the formation of bicarbonate ions with subsequent reduction in sodium and fluid transport. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Methazolamide is well absorbed from the gastrointestinal tract. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 17 to 23 L •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 55% •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 14 hours •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Electrolyte imbalance, development of an acidotic state, and central nervous system effects might be expected to occur in the case of an overdose. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Methazolamide is a carbonic anhydrase inhibitor used to treat open angle glaucoma and acute angle closure glaucoma.

Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Question: Does Abaloparatide and Methazolamide interact? Information: •Drug A: Abaloparatide •Drug B: Methazolamide •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Methazolamide is combined with Abaloparatide. •Extended Description: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): For treatment of chronic open-angle glaucoma and acute angle-closure glaucoma •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Methazolamide is topical carbonic anhydrase inhibitor. Methazolamide is indicated for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension who are insufficiently responsive to beta-blockers. Methazolamide is a sulfonamide derivative; however, it does not have any clinically significant antimicrobial properties. Although methazolamide achieves a high concentration in the cerebrospinal fluid, it is not-considered an effective anticonvulsant. Methazolamide has a weak and transient diuretic effect, therefore use results in an increase in urinary volume, with excretion of sodium, potassium and chloride. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Methazolamide is a potent inhibitor of carbonic anhydrase. Inhibition of carbonic anhydrase in the ciliary processes of the eye decreases aqueous humor secretion, presumably by slowing the formation of bicarbonate ions with subsequent reduction in sodium and fluid transport. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): Methazolamide is well absorbed from the gastrointestinal tract. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): 17 to 23 L •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 55% •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 14 hours •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): Electrolyte imbalance, development of an acidotic state, and central nervous system effects might be expected to occur in the case of an overdose. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Methazolamide is a carbonic anhydrase inhibitor used to treat open angle glaucoma and acute angle closure glaucoma. Output: Co-administration of agents that are both associated with a risk for developing hypotension, including cases of severe hypotension, may create an additive hypotensive effect to prolong and intensify hypotensive effects. The severity of the interaction is minor.

Does Abaloparatide and Methohexital interact?

•Drug A: Abaloparatide •Drug B: Methohexital •Severity: MODERATE •Description: Methohexital may increase the hypotensive activities of Abaloparatide. •Extended Description: The use of barbiturates may increase hypotension.1,2 Therefore, the concomitant administration of barbiturates and hypotensive agents may lead to dangerous hypotension due to additive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Methohexital is indicated for use as an intravenous anaesthetic. It has also been commonly used to induce deep sedation. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Methohexital, a barbiturate, is used for the induction of anesthesia prior to the use of other general anesthetic agents and for induction of anesthesia for short surgical, diagnostic, or therapeutic procedures associated with minimal painful stimuli. Little analgesia is conferred by barbiturates; their use in the presence of pain may result in excitation. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Methohexital binds at a distinct binding site associated with a Cl ionopore at the GABA A receptor, increasing the duration of time for which the Cl ionopore is open. The post-synaptic inhibitory effect of GABA in the thalamus is, therefore, prolonged. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): The absolute bioavailability following rectal administration of methohexital is 17%. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 73% •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Metabolism occurs in the liver through demethylation and oxidation. Side-chain oxidation is the most important biotransformation involved in termination of biologic activity. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Excretion occurs via the kidneys through glomerular filtration. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 5.6 ± 2.7 minutes •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The onset of toxicity following an overdose of intravenously administered methohexital will be within seconds of the infusion. If methohexital is administered rectally or is ingested, the onset of toxicity may be delayed. The manifestations of an ultrashort-acting barbiturate in overdose include central nervous system depression, respiratory depression, hypotension, loss of peripheral vascular resistance, and muscular hyperactivity ranging from twitching to convulsive-like movements. Other findings may include convulsions and allergic reactions. Following massive exposure to any barbiturate, pulmonary edema, circulatory collapse with loss of peripheral vascular tone, and cardiac arrest may occur. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Brevital •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Methohexital Methohexitalum Methohexitone Metohexital •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Methohexital is an anesthetic used to induce deep sedation.

The use of barbiturates may increase hypotension.1,2 Therefore, the concomitant administration of barbiturates and hypotensive agents may lead to dangerous hypotension due to additive effects. The severity of the interaction is moderate.

Question: Does Abaloparatide and Methohexital interact? Information: •Drug A: Abaloparatide •Drug B: Methohexital •Severity: MODERATE •Description: Methohexital may increase the hypotensive activities of Abaloparatide. •Extended Description: The use of barbiturates may increase hypotension.1,2 Therefore, the concomitant administration of barbiturates and hypotensive agents may lead to dangerous hypotension due to additive effects. •Indication (Drug A): Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures. Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy. •Indication (Drug B): Methohexital is indicated for use as an intravenous anaesthetic. It has also been commonly used to induce deep sedation. •Pharmacodynamics (Drug A): Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces. It increases bone mineral density and bone formation markers in a dose-dependent manner. Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density. In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites. •Pharmacodynamics (Drug B): Methohexital, a barbiturate, is used for the induction of anesthesia prior to the use of other general anesthetic agents and for induction of anesthesia for short surgical, diagnostic, or therapeutic procedures associated with minimal painful stimuli. Little analgesia is conferred by barbiturates; their use in the presence of pain may result in excitation. •Mechanism of action (Drug A): Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis. The PTH1R couples to G s and G q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade. Abaloparatide binds to the PTH1R in target cells to activate the G s -protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity. Abaloparatide also activates G q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms. The PTH1R has two conformations with distinct ligand binding profiles. The R conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R conformation are associated with a risk for increased calcium mobilization and hypercalcemia. Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response. Abaloparatide binds to the RG conformation with greater selectivity: it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to teriparatide is attributed to the preferential binding of abaloparatide to the RG conformation. •Mechanism of action (Drug B): Methohexital binds at a distinct binding site associated with a Cl ionopore at the GABA A receptor, increasing the duration of time for which the Cl ionopore is open. The post-synaptic inhibitory effect of GABA in the thalamus is, therefore, prolonged. •Absorption (Drug A): The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) C max was 812 (118) pg/mL and the AUC 0-24 was 1622 (641) pgxhr/mL. The median T max was 0.51 hours, with a range from 0.25 to 0.52 hours. •Absorption (Drug B): The absolute bioavailability following rectal administration of methohexital is 17%. •Volume of distribution (Drug A): The volume of distribution was approximately 50 L. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): In vitro, abaloparatide was approximately 70% bound to plasma proteins. •Protein binding (Drug B): 73% •Metabolism (Drug A): Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation. •Metabolism (Drug B): Metabolism occurs in the liver through demethylation and oxidation. Side-chain oxidation is the most important biotransformation involved in termination of biologic activity. •Route of elimination (Drug A): The peptide fragments of abaloparatide are primarily eliminated through renal excretion. •Route of elimination (Drug B): Excretion occurs via the kidneys through glomerular filtration. •Half-life (Drug A): The mean half-life of abaloparatide is approximately one hour. •Half-life (Drug B): 5.6 ± 2.7 minutes •Clearance (Drug A): The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects. •Clearance (Drug B): No clearance available •Toxicity (Drug A): The LD 50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg. One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. •Toxicity (Drug B): The onset of toxicity following an overdose of intravenously administered methohexital will be within seconds of the infusion. If methohexital is administered rectally or is ingested, the onset of toxicity may be delayed. The manifestations of an ultrashort-acting barbiturate in overdose include central nervous system depression, respiratory depression, hypotension, loss of peripheral vascular resistance, and muscular hyperactivity ranging from twitching to convulsive-like movements. Other findings may include convulsions and allergic reactions. Following massive exposure to any barbiturate, pulmonary edema, circulatory collapse with loss of peripheral vascular tone, and cardiac arrest may occur. •Brand Names (Drug A): Tymlos •Brand Names (Drug B): Brevital •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Methohexital Methohexitalum Methohexitone Metohexital •Summary (Drug A): Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture. •Summary (Drug B): Methohexital is an anesthetic used to induce deep sedation. Output: The use of barbiturates may increase hypotension.1,2 Therefore, the concomitant administration of barbiturates and hypotensive agents may lead to dangerous hypotension due to additive effects. The severity of the interaction is moderate.