Cinacalcet is an oral calcimimetic agent, and represents the first approved agent within this drug class. It is indicated for the treatment of patients with secondary hyperparathyroidism due to chronic kidney disease, in patients with hypercalcemia associated with parathyroid carcinoma, and in patients with severe hypercalcemia due to primary hyperparathyroidism who are unable to undergo parathyroidectomy. Cinacalcet directly reduces parathyroid hormone (PTH) while lowering the calcium-phosphorus product. This action is consistent with the National Kidney Foundation Disease Outcomes Quality Initiative (K/DOQI) clinical practice guidelines for bone metabolism and disease in chronic kidney disease. In a clinical trial, cinacalcet was shown to reduce high serum calcium levels in patients with parathyroid carcinoma (manufacturer data). With nearly 500 patients developing this rare condition annually, cinacalcet was granted orphan designation by the FDA. Cinacalcet was originally approved by the FDA in March 2004.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-Administer with food or shortly after a meal.
Oral Solid Formulations
-Administer whole. Do not chew, crush, or divide tablets.
Gastrointestinal symptoms are the most common adverse reactions associated with cinacalcet therapy. Nausea (31%) and vomiting (27%) were reported by cinacalcet treated patients in 3 double-blind, placebo-controlled trials. Diarrhea was reported by 21% of the patients. In a 46 subject open-label study involving 29 patients with parathyroid carcinoma and 17 with intractable primary hyperparathyroidism, nausea occurred in 63% and vomiting in 46% of patients. Severe or prolonged cases of nausea and vomiting may lead to dehydration and worsening of hypercalcemia; therefore, monitor electrolytes in patients with these symptoms. Other adverse reactions among patients with parathyroid carcinoma and primary hyperparathyroidism include constipation (13%) and dehydration (15%). Anorexia was noted in 6% to 15% of patients across all clinical trials.
During clinical trials, seizures were observed in 1.4% (43/3,049) of patients receiving cinacalcet vs. 0.7% (5/687) of patients receiving placebo. While the basis for the difference in seizure rate is unclear, the seizure threshold is lowered by significant reductions in serum calcium concentrations. Concurrent administration of cinacalcet with calcium-lowering drugs could result in severe hypocalcemia. Monitor serum calcium concentrations in patients with seizure disorder receiving cinacalcet. Educate patients on the symptoms of hypocalcemia and instruct them to contact a healthcare provider if they occur. If corrected serum calcium falls below the lower limit of normal or symptoms of hypocalcemia develop, start or increase calcium supplementation. Cinacalcet dosage reduction or discontinuation may be necessary.
Adynamic bone disease (renal osteodystrophy) may develop if intact parathyroid hormone (iPTH) concentrations fall below 100 pg/mL. Three patients with mild hyperparathyroid disease at the beginning of the study developed adynamic bone disease during cinacalcet treatment. Two of these patients had iPTH concentrations below 100 pg/mL at multiple times during the study. In three 6-month phase 3 trials in patients with chronic kidney disease on dialysis, 11% of cinacalcet-treated patients had mean iPTH values below 100 pg/mL. If iPTH concentrations fall below 150 to 300 pg/mL, reduce dosages of or discontinue cinacalcet and/or vitamin D sterol.
In clinical trials, hypotension (7% cinacalcet vs. 12% placebo) and worsening heart failure (2% in both groups) were reported. During postmarketing surveillance, isolated cases of hypotension, worsening heart failure, and/or arrhythmia exacerbation were reported in patients with impaired cardiac function taking cinacalcet. A causal relationship to cinacalcet could not be excluded, and may be due to a reduction in serum calcium concentrations. QT prolongation and ventricular arrhythmias also have been reported secondary to hypocalcemia in patients receiving cinacalcet. Hypertension and non-cardiac chest pain (unspecified) were reported in 7% and 6%, respectively, of cinacalcet recipients with secondary hyperparathyroidism and chronic kidney disease on dialysis.
Rash (unspecified) (2.2%) and hypersensitivity reactions (9.4%) were reported from the long-term, randomized, double-blind, placebo-controlled study for cinacalcet vs. placebo (1.9% and 8.3%, respectively). Hypersensitivity reactions including angioedema and urticaria have been reported with cinacalcet during postmarketing surveillance.
Adverse CNS effects reported during clinical trials of cinacalcet include dizziness (10%), paresthesias (20%), headache (13%), and depression (13%). Paresthesias and depression may occur as symptoms of hypocalcemia from cinacalcet.
Arthralgia occurred in 13% of patients during cinacalcet clinical trials. Myalgia was observed in 15% of patients on dialysis with chronic kidney disease and primary hyperparathyroidism; myalgia may occur as a symptom of hypocalcemia due to cinacalcet. Limb pain was reported in 11% of patients. Chondrocalcinosis pyrophosphate (acute pseudogout) was reported in postmarketing surveillance.
General adverse events reported during cinacalcet therapy in clinical trials include bone fractures (17%), fatigue (17%), asthenia (7% to 15%), and infection (5% to 11%). Upper respiratory infections and access infections were reported in 11% and 5% of patients, respectively.
Hypocalcemia and hypercalcemia can occur with the administration of cinacalcet. Hypercalcemia was reported in 17% of patients with parathyroid carcinoma or intractable primary hyperparathyroidism who received cinacalcet during clinical studies. In a study of chronic kidney disease patients on dialysis, 66% of patients receiving cinacalcet developed 1 or more serum calcium concentrations less than 8.4 mg/dL; less than 1% of these patients discontinued cinacalcet permanently. Although not indicated in chronic kidney disease patients not requiring dialysis, 80% of non-dialysis patients experienced 1 or more serum calcium concentrations less than 8.4 mg/dL after 32 weeks of cinacalcet treatment (median dose 60 mg) compared to 5% of patients receiving placebo; patients that are not on dialysis may be at increased risk for hypocalcemia. Monitor patients carefully for symptoms of hypocalcemia, which include, but are not limited to, burning, numbness, pricking, tickling, or tingling of the face, lips, tongue, hands, or feet, muscle pain, muscle cramps of the back and legs, tetany, laryngospasm, irritability, confusion, depression, hallucinations, and convulsions or seizures. If the serum calcium concentration falls below 8.4 mg/dL but remains more than 7.5 mg/dL, or if symptoms of hypocalcemia occur, calcium-containing phosphate binders and/or vitamin D sterols may be used to increase serum calcium concentrations. If the serum calcium concentration remains below 7.5 mg/dL or if symptoms persist or the dose of vitamin D cannot be increased, hold cinacalcet administration until serum calcium concentrations reach 8 mg/dL, and/or symptoms of hypocalcemia have resolved. Treatment may then be restarted at the next lowest dose.
Anemia was observed in 13% of patients who received cinacalcet during clinical trials. A total of 17% of patients with parathyroid carcinoma (n = 29) experienced anemia, while 5% of patients with intractable primary hyperparathyroidism (n = 17) reported anemia.
Cases of GI bleeding, mostly upper GI bleeding, have occurred in patients receiving cinacalcet. The exact cause of GI bleeding in these patients is unknown. Monitor patients with risk factors for upper GI bleeding (e.g., gastritis, esophagitis, peptic ulcer disease, severe vomiting) for worsening of common GI adverse reactions of nausea and vomiting and for signs and symptoms of GI bleeding and ulcerations associated with cinacalcet. Promptly evaluate and treat any suspected GI bleeding.
Cinacalcet is contraindicated in patients with hypocalcemia (i.e., serum calcium concentrations less than the lower limit of the normal range). Cinacalcet lowers serum calcium concentrations. Life threatening events and fatal outcomes associated with hypocalcemia have been reported in patients treated with cinacalcet. Significant hypocalcemia can cause paresthesias, myalgias, muscle spasms, tetany, seizures, QT interval prolongation, and ventricular arrhythmias. Measure serum calcium concentrations within 1 week after dosage initiation or adjustment and then approximately once every month after establishing a maintenance dose. If serum calcium concentrations decrease below the normal range, supplement with calcium, start or increase dosage of calcium-based phosphate binder or vitamin D sterol, or temporarily withhold cinacalcet therapy. The long-term safety and efficacy of cinacalcet in non-dialysis patients has not been established. Patients with chronic kidney disease that are not on dialysis who are receiving cinacalcet appear to be at increased risk for hypocalcemia possibly because these patients tend to have lower baseline serum calcium concentrations.
Monitor serum calcium concentrations in patients with seizure disorder receiving cinacalcet. During clinical trials, seizures were reported with a higher incidence in patients treated with cinacalcet compared to placebo. While the basis for the difference in seizure rate is unclear, the seizure threshold is lowered by significant reductions in serum calcium concentrations. Concurrent administration of cinacalcet with calcium-lowering drugs could result in severe hypocalcemia. Educate patients on the symptoms of hypocalcemia and instruct them to contact a healthcare provider if they occur. If corrected serum calcium falls below the lower limit of normal or symptoms of hypocalcemia develop, start or increase calcium supplementation. Cinacalcet dosage reduction or discontinuation may be necessary.
Decreases in serum calcium can prolong the QT interval, potentially resulting in ventricular arrhythmias. Patients with congenital long QT syndrome, history of QT interval prolongation, family history of long QT syndrome or sudden cardiac death, and other conditions that predispose to QT interval prolongation and ventricular arrhythmia may be at increased risk of QT prolongation and ventricular arrhythmias if they develop hypocalcemia. Closely monitor corrected serum calcium and QT interval in at-risk patients receiving cinacalcet.
Monitor serum calcium, serum phosphorus, and intact parathyroid hormone concentrations closely throughout cinacalcet treatment in patients with moderate to severe hepatic disease. Cinacalcet exposure (AUC) is increased by 2.4 and 4.2-fold in patients with moderate and severe hepatic disease, respectively.
Monitor patients with risk factors for upper GI bleeding (e.g., gastritis, esophagitis, peptic ulcer disease, severe vomiting) for worsening of common GI adverse reactions of nausea and vomiting and for signs and symptoms of GI bleeding and ulcerations associated with cinacalcet. Promptly evaluate and treat any suspected GI bleeding. Patients with risk factors for upper GI bleeding may be at increased risk for GI bleeding during treatment with cinacalcet. Cases of GI bleeding, mostly upper GI bleeding, have occurred in patients receiving cinacalcet. The exact cause of GI bleeding in these patients is unknown.
The safety and efficacy of cinacalcet in neonates, infants, children, and adolescents have not been established. Cinacalcet use for the treatment of secondary hyperparathyroidism in pediatric patients with chronic kidney disease on dialysis was evaluated in 2 randomized, controlled studies of 47 patients (6 to 17 years; Study 1 and 2) and in a single-arm study of 17 patients (28 days to 5 years; Study 3) who received at least 1 dose of cinacalcet. Study 1 was terminated because of a fatality in a cinacalcet-treated patient who was noted to be severely hypocalcemic at the time of death. The cause of death was multifactorial; however, a contribution of cinacalcet to the death could not be excluded. Changes in cinacalcet dosing were implemented in the other studies to minimize the risk of severe hypocalcemia. Data from those studies did not establish a safe and effective cinacalcet dosage in pediatric populations.
Data on the use of cinacalcet in human pregnancy are limited to case reports and insufficient to inform a drug associated risk of adverse developmental outcomes. In animal reproduction studies of rats exposed to cinacalcet at 2 to 3 times the systemic concentrations (based on AUC) at the maximum recommended human dose (MRHD) of 180 mg/day during organogenesis through weaning, peripartum and early postnatal pup loss and reduced pup body weight gain were observed in the presence of maternal hypocalcemia. When rats and rabbits were given oral doses resulting in exposures less than with a human oral dose of 180 mg/day based on AUC comparisons, no adverse fetal effects were observed. Reductions in maternal food consumption and body weight gain were noted. Cinacalcet has been shown to cross the placental barrier in rabbits.
There are no data on the presence of cinacalcet in human milk, the effects on the breast-fed infant, or the effects on milk production. Cinacalcet is excreted into the milk of rats. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for cinacalcet and any potential adverse effects on the breast-fed infant from cinacalcet or the underlying maternal condition.
Use cinacalcet with caution in patients with heart failure; isolated cases of hypotension, worsening heart failure, and/or arrhythmia exacerbation were reported in patients with impaired cardiac function taking cinacalcet. A causal relationship to cinacalcet could not be excluded and may be due to a reduction in serum calcium concentrations.
For the treatment of hypercalcemia in patients with parathyroid carcinoma:
Oral dosage:
Adults: Initially, 30 mg PO twice daily. Dosage should be titrated every 2 to 4 weeks through sequential doses of 60 mg PO twice daily, 90 mg PO twice daily, and 90 mg PO 3 to 4 times daily as necessary to normalize serum calcium concentrations. Measure serum calcium within 1 week of initiation or dose adjustment. Once maintenance dose has been established, measure serum calcium every 2 months.
For the treatment of hyperparathyroidism:
-for severe hypercalcemia in patients with primary hyperparathyroidism who are unable to undergo parathyroidectomy:
Oral dosage:
Adults: Initially, 30 mg PO twice daily. Dosage should be titrated every 2 to 4 weeks through sequential doses of 60 mg PO twice daily, 90 mg PO twice daily, and 90 mg PO 3 to 4 times daily as necessary to normalize serum calcium concentrations. Measure serum calcium within 1 week of initiation or dose adjustment. Once maintenance dose has been established, measure serum calcium every 2 months.
-for patients with secondary hyperparathyroidism and chronic kidney disease undergoing dialysis (CKD Stage 5):
Oral dosage:
Adults: Initially, 30 mg PO once daily. Serum calcium and phosphorus should be measured within 1 week. Intact parathyroid hormone (iPTH) serum concentration should be measured 1 to 4 weeks after initiation or dose adjustment. Titrate every 2 to 4 weeks through sequential doses of 60, 90, 120, and 180 mg PO once daily to a target iPTH concentration consistent with the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) recommendation for CKD patients undergoing dialysis (150 to 300 pg/mL). During dose titration, serum calcium concentrations should be monitored frequently; low concentrations of calcium should be treated with supplemental calcium, a calcium-based phosphate binder, or initiating/increasing the dose of vitamin D. Doses of cinacalcet titrated up to 300 mg PO once daily have been safely administered to patients receiving dialysis.
-for patients with secondary hyperparathyroidism and chronic kidney disease undergoing dialysis (CKD Stage 5) switching from etelcalcetide to cinacalcet:
Oral dosage:
Adults: Initially, 30 mg PO once daily after discontinuing etelcalcetide for at least 4 weeks prior to initiating cinacalcet. Ensure corrected serum calcium is at or above the lower limit of normal prior to cinacalcet initiation.
-for patients with secondary hyperparathyroidism and chronic kidney disease not undergoing dialysis (e.g., CKD stage 3 and 4)*:
Oral dosage:
Adults: Preliminary data from a study in 54 patients with stage 3 or 4 CKD indicate that cinacalcet is effective in decreasing iPTH concentrations. In this study, patients were initiated on 30 mg PO once daily and titrated every 3 weeks to a maximum dose of 180 mg PO once daily for iPTH concentrations that did not decrease by at least 30% as compared to baseline. After 18 weeks of treatment, 56% of patients receiving cinacalcet compared to 19% of patients receiving placebo experienced a decrease in iPTH concentrations of 30% or more (p = 0.006); furthermore, iPTH concentrations decreased by a mean of 32% compared to baseline in patients taking cinacalcet compared to an increase of 6% in patients taking placebo (p less than 0.001). At study end, 52% of patients were receiving 30 mg PO once daily, and 30% were receiving 60 mg PO once daily. Serum calcium concentrations decreased by an average of 7% and the mean calcium concentration remained within the normal range throughout the study. Approximately 28% of patients were receiving vitamin D analogs at study start, and approximately 43% were receiving phosphate binders. Of note, the manufacturer reports of another study in which the majority of patients (80%) not requiring dialysis experienced at least one serum concentration of calcium less than 8.4 mg/dL.
Maximum Dosage Limits:
-Adults
300 mg/day PO for dialysis patients with secondary hyperparathyroidism; 360 mg/day PO for hypercalcemia associated with parathyroid carcinoma or primary hyperparathyroidism.
-Geriatric
300 mg/day PO for dialysis patients with secondary hyperparathyroidism; 360 mg/day PO for hypercalcemia associated with parathyroid carcinoma or primary hyperparathyroidism.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
In patients with moderate and severe hepatic impairment, parathyroid hormone and serum calcium concentrations should be closely monitored throughout treatment with cinacalcet. Dosage reduction may be necessary, however, no quantitative guidelines are available. The AUC values for cinacalcet in patients with moderate to severe hepatic disease are 2.4 and 4.2 times greater, respectively, than the values observed for normal patients.
Patients with Renal Impairment Dosing
No adjustments are necessary.
Intermittent hemodialysis
No adjustments are necessary. Cinacalcet is highly protein bound and is not significantly removed by dialysis.
*non-FDA-approved indication
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal if coadministration with cinacalcet is necessary; consider increasing the dose of dihydrocodeine as needed. If cinacalcet is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs of respiratory depression and sedation. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A. Cinacalcet is a moderate inhibitor of CYP2D6. Concomitant use of dihydrocodeine with cinacalcet can increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with cinacalcet may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of cinacalcet could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If cinacalcet is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Cinacalcet is a moderate inhibitor of CYP2D6.
Acetaminophen; Hydrocodone: (Moderate) Concomitant use of hydrocodone with cinacalcet may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cinacalcet could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cinacalcet is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6; cinacalcet is a moderate inhibitor of CYP2D6.
Adagrasib: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of adagrasib and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Amitriptyline: (Moderate) Monitor for an increase in tricyclic antidepressant (TCA)-related adverse reactions if coadministration with cinacalcet is necessary; a dose reduction of TCA may be necessary. Concurrent use may increase the exposure of TCAs which are CYP2D6 substrates; cinacalcet is a CYP2D6 inhibitor.
Amoxapine: (Major) Lower doses of amoxapine may be required during concurrent use of cinacalcet due to the potential for increased amoxapine exposure. If cinacalcet is discontinued, an increased dose of amoxapine may be necessary. Amoxapine is a CYP2D6 substrate; cinacalcet is a CYP2D6 inhibitor.
Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of clarithromycin and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Aripiprazole: (Moderate) Monitor for aripiprazole-related adverse reactions during concomitant use of cinacalcet. Patients receiving both a CYP3A inhibitor plus cinacalcet may require an aripiprazole dosage adjustment. Dosing recommendations vary based on aripiprazole dosage form and CYP3A inhibitor strength. See prescribing information for details. Concomitant use may increase aripiprazole exposure and risk for side effects. Aripiprazole is a CYP2D6 and CYP3A substrate; cinacalcet is a moderate CYP2D6 inhibitor.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with cinacalcet may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of cinacalcet could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If cinacalcet is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Cinacalcet is a moderate inhibitor of CYP2D6.
Atazanavir: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of atazanavir and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Atazanavir; Cobicistat: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of atazanavir and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%. (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of cobicistat and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Brexpiprazole: (Moderate) Use caution if coadministration of cinacalcet with brexpiprazole is necessary, as the systemic exposure of brexpiprazole may be increased resulting in an increase in brexpiprazole-related adverse reactions. Reduce the dose of brexpiprazole to one-quarter (25%) of the usual dose if brexpiprazole and cinacalcet are coadministered with a moderate to strong inhibitor of CYP3A. If cinacalcet is discontinued, adjust the brexpiprazole dosage to its original level. Brexpiprazole is a CYP3A and CYP2D6 substrate; cinacalcet is a moderate CYP2D6 inhibitor. Concomitant use of moderate CYP2D6 inhibitors with a strong or moderate CYP3A inhibitor increased the exposure of brexpiprazole compared to use of brexpiprazole alone.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Concomitant use of codeine with cinacalcet may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of cinacalcet could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If cinacalcet is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Cinacalcet is a moderate inhibitor of CYP2D6.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Concomitant use of codeine with cinacalcet may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of cinacalcet could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If cinacalcet is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Cinacalcet is a moderate inhibitor of CYP2D6.
Celecoxib; Tramadol: (Moderate) Monitor for reduced efficacy of tramadol, signs of opioid withdrawal, seizures, or serotonin syndrome if coadministration with cinacalcet is necessary. If cinacalcet is discontinued, consider a dose reduction of tramadol and frequently monitor for signs of respiratory depression and sedation. Tramadol is a CYP2D6 substrate and cinacalcet is a moderate CYP2D6 inhibitor. Concomitant use of tramadol with CYP2D6 inhibitors can increase the plasma concentration of tramadol and decrease the plasma concentration of the active metabolite M1. Since M1 is a more potent mu-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who have developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Ceritinib: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of ceritinib and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and ceritinib is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Chloramphenicol: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of chloramphenicol and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and chloramphenicol is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Chlordiazepoxide; Amitriptyline: (Moderate) Monitor for an increase in tricyclic antidepressant (TCA)-related adverse reactions if coadministration with cinacalcet is necessary; a dose reduction of TCA may be necessary. Concurrent use may increase the exposure of TCAs which are CYP2D6 substrates; cinacalcet is a CYP2D6 inhibitor.
Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with cinacalcet may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of cinacalcet could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If cinacalcet is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Cinacalcet is a moderate inhibitor of CYP2D6.
Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with cinacalcet may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cinacalcet could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cinacalcet is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6; cinacalcet is a moderate inhibitor of CYP2D6.
Chlorpromazine: (Moderate) Monitor for an increase in chlorpromazine-related adverse reactions, including QT prolongation, anticholinergic effects, orthostasis, and somnolence, if coadministration with cinacalcet is necessary. Concomitant use may increase chlorpromazine exposure. Chlorpromazine is a CYP2D6 substrate and cinacalcet is a moderate CYP2D6 inhibitor.
Clarithromycin: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of clarithromycin and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Clomipramine: (Moderate) Monitor for an increase in tricyclic antidepressant (TCA)-related adverse reactions if coadministration with cinacalcet is necessary; a dose reduction of TCA may be necessary. Concurrent use may increase the exposure of TCAs which are CYP2D6 substrates; cinacalcet is a CYP2D6 inhibitor.
Clozapine: (Moderate) Consider a clozapine dose reduction if coadministered with cinacalcet and monitor for adverse reactions. If cinacalcet is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP2D6 and cinacalcet is a moderate CYP2D6 inhibitor.
Cobicistat: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of cobicistat and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Codeine: (Moderate) Concomitant use of codeine with cinacalcet may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of cinacalcet could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If cinacalcet is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Cinacalcet is a moderate inhibitor of CYP2D6.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with cinacalcet may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of cinacalcet could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If cinacalcet is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Cinacalcet is a moderate inhibitor of CYP2D6.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with cinacalcet may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of cinacalcet could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If cinacalcet is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Cinacalcet is a moderate inhibitor of CYP2D6.
Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with cinacalcet may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of cinacalcet could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If cinacalcet is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Cinacalcet is a moderate inhibitor of CYP2D6.
Codeine; Promethazine: (Moderate) Concomitant use of codeine with cinacalcet may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of cinacalcet could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If cinacalcet is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Cinacalcet is a moderate inhibitor of CYP2D6.
Darunavir: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of darunavir and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Darunavir; Cobicistat: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of cobicistat and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%. (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of darunavir and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of cobicistat and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%. (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of darunavir and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Delavirdine: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of delavirdine and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and delavirdine is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Denosumab: (Moderate) Monitor serum calcium, phosphorus, and magnesium concentrations within 14 days of denosumab injection during concurrent treatment with calcimimetics such as cinacalcet. The risk for hypocalcemia and other disturbances of mineral metabolism may increase during coadministration. Monitor serum calcium concentrations closely in patients with severe renal impairment (CrCl less than 30 mL/minute) or renal failure (and/or on dialysis) receiving calcimimetics. An increased risk of hypocalcemia was seen in clinical trials involving patients with renal dysfunction. Instruct patients to seek medical care if symptoms of hypocalcemia develop.
Desipramine: (Moderate) Monitor for an increase in tricyclic antidepressant (TCA)-related adverse reactions if coadministration with cinacalcet is necessary; a dose reduction of TCA may be necessary. Concurrent use may increase the exposure of TCAs which are CYP2D6 substrates; cinacalcet is a CYP2D6 inhibitor.
Doxepin: (Moderate) Monitor for an increase in tricyclic antidepressant (TCA)-related adverse reactions if coadministration with cinacalcet is necessary; a dose reduction of TCA may be necessary. Concurrent use may increase the exposure of TCAs which are CYP2D6 substrates; cinacalcet is a CYP2D6 inhibitor.
Doxorubicin Liposomal: (Major) Avoid coadministration of doxorubicin with cinacalcet due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a major substrate of CYP2D6 and cinacalcet is a moderate CYP2D6 inhibitor. Concurrent use of CYP2D6 inhibitors with doxorubicin has resulted in clinically significant interactions.
Doxorubicin: (Major) Avoid coadministration of doxorubicin with cinacalcet due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a major substrate of CYP2D6 and cinacalcet is a moderate CYP2D6 inhibitor. Concurrent use of CYP2D6 inhibitors with doxorubicin has resulted in clinically significant interactions.
Dutasteride; Tamsulosin: (Moderate) Use caution if coadministration of cinacalcet with tamsulosin is necessary, especially at a tamsulosin dose higher than 0.4 mg, as the systemic exposure of tamsulosin may be increased resulting in increased treatment-related adverse reactions including hypotension, dizziness, and vertigo. Tamsulosin is a CYP2D6 substrate and cinacalcet is a moderate CYP2D6 inhibitor.
Eliglustat: (Major) Reduce the dose of eliglustat to 84 mg once daily in patients who are extensive or intermediate CYP2D6 metabolizers (EMs or IMs) and receiving cinacalcet. Eliglustat is contraindicated in EMs and IMs who are receiving cinacalcet plus a strong or moderate CYP3A inhibitor. Eliglustat is contraindicated in poor metabolizers (PMs) who are receiving cinacalcet plus a strong CYP3A inhibitor and should be avoided, if possible, in patients who are receiving cinacalcet plus a moderate CYP3A inhibitor. Concomitant use may increase eliglustat exposure. Eliglustat is a CYP2D6 substrate and cinacalcet is a moderate CYP2D6 inhibitor. A moderate CYP2D6 inhibitor is predicted to increase eliglustat overall exposure by 4.5-fold and 1.6-fold in extensive and intermediate metabolizers, respectively. Moderate CYP2D6s inhibitors alone are not expected to affect eliglustat concentrations in CYP2D6 poor metabolizers (PMs).
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of cobicistat and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of cobicistat and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Etelcalcetide: (Major) Avoid the concomitant use of etelcalcetide and cinacalcet. Discontinue cinacalcet at least 7 days prior to starting etelcalcetide, and initiate etelcalcetide treatment at 5 mg IV 3 times weekly. Ensure corrected serum calcium is at or above lower limit of normal prior to etelcalcetide initiation. Concurrent use of etelcalcetide with another oral calcium-sensing receptor agonist may result in severe, life-threatening, hypocalcemia.
Flecainide: (Moderate) Monitor for an increase in flecainide-related adverse reactions, including QT prolongation, if coadministration with cinacalcet is necessary. Flecainide is a CYP2D6 substrate and cinacalcet is a moderate CYP2D6 inhibitor. Plasma concentrations of flecainide may increase, especially in extensive CYP2D6 metabolizers.
Fluoxetine: (Moderate) Monitor for increased fluoxetine-related adverse effects if coadministered with cinacalcet. Concomitant use may increase fluoxetine exposure. Fluoxetine is a CYP2D6 substrate and cinacalcet is a moderate CYP2D6 inhibitor.
Gefitinib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with cinacalcet is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and cinacalcet is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
Grapefruit juice: (Major) Advise patients to avoid grapefruit and grapefruit juice during cinacalcet treatment due to the risk of increased cinacalcet exposure and adverse reactions. Cinacalcet is a CYP3A substrate and grapefruit juice is a strong CYP3A inhibitor.
Homatropine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with cinacalcet may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cinacalcet could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cinacalcet is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6; cinacalcet is a moderate inhibitor of CYP2D6.
Hydrocodone: (Moderate) Concomitant use of hydrocodone with cinacalcet may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cinacalcet could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cinacalcet is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6; cinacalcet is a moderate inhibitor of CYP2D6.
Hydrocodone; Ibuprofen: (Moderate) Concomitant use of hydrocodone with cinacalcet may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of cinacalcet could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If cinacalcet is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6; cinacalcet is a moderate inhibitor of CYP2D6.
Idelalisib: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of idelalisib and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and idelalisib is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Imipramine: (Moderate) Monitor for an increase in tricyclic antidepressant (TCA)-related adverse reactions if coadministration with cinacalcet is necessary; a dose reduction of TCA may be necessary. Concurrent use may increase the exposure of TCAs which are CYP2D6 substrates; cinacalcet is a CYP2D6 inhibitor.
Indinavir: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of indinavir and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and indinavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Itraconazole: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of itraconazole and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and itraconazole is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Ketoconazole: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of ketoconazole and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Lansoprazole; Amoxicillin; Clarithromycin: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of clarithromycin and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Letermovir: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of letermovir and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and letermovir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Levoketoconazole: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of ketoconazole and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Lofexidine: (Moderate) Monitor for orthostatic hypotension and bradycardia during concurrent use of lofexidine and cinacalcet. Coadministration may increase lofexidine exposure. Lofexidine is a CYP2D6 substrate; cinacalcet is a CYP2D6 inhibitor. Coadministration with a strong CYP2D6 inhibitor increased the lofexidine AUC by 28%.
Lonafarnib: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of lonafarnib and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and lonafarnib is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Lopinavir; Ritonavir: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of ritonavir and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Maprotiline: (Moderate) Monitor for an increase in maprotiline-related adverse reactions if coadministration with cinacalcet is necessary; a dose reduction of maprotiline may be necessary. Concurrent use may increase exposure of maprotiline. Maprotiline is a CYP2D6 substrate and cinacalcet is a CYP2D6 inhibitor.
Meclizine: (Moderate) Monitor for meclizine-related adverse effects, such as drowsiness and anticholinergic effects, when coadministered with cinacalcet. Concomitant use may increase the exposure to meclizine. Meclizine is a CYP2D6 substrate and cinacalcet is a CYP2D6 inhibitor.
Methadone: (Moderate) Consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation if concurrent use of cinacalcet is necessary. If cinacalcet is discontinued, methadone plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to methadone. Methadone is a substrate of CYP3A, CYP2B6, CYP2C19, CYP2C9, and CYP2D6; cinacalcet is a moderate CYP2D6 inhibitor. Concomitant use with cinacalcet can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone.
Metoprolol: (Moderate) Monitor for metoprolol-related adverse reactions, including bradycardia and hypotension, during coadministration with cinacalcet. Concomitant use may increase metoprolol serum concentrations which would decrease the cardioselectivity of metoprolol. Metoprolol is a CYP2D6 substrate and cinacalcet is a CYP2D6 inhibitor.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for metoprolol-related adverse reactions, including bradycardia and hypotension, during coadministration with cinacalcet. Concomitant use may increase metoprolol serum concentrations which would decrease the cardioselectivity of metoprolol. Metoprolol is a CYP2D6 substrate and cinacalcet is a CYP2D6 inhibitor.
Mexiletine: (Moderate) Monitor for increased toxicity of mexiletine if coadministered with cinacalcet. Coadministration may increase serum concentrations of mexiletine. Mexiletine is a CYP2D6 substrate and cinacalcet is a moderate CYP2D6 inhibitor.
Mifepristone: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of mifepristone and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and mifepristone is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Nebivolol: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with cinacalcet; adjust the nebivolol dose according to blood pressure response. Concomitant use may increase the exposure of nebivolol. Nebivolol is a CYP2D6 substrate and cinacalcet is a moderate CYP2D6 inhibitor.
Nebivolol; Valsartan: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with cinacalcet; adjust the nebivolol dose according to blood pressure response. Concomitant use may increase the exposure of nebivolol. Nebivolol is a CYP2D6 substrate and cinacalcet is a moderate CYP2D6 inhibitor.
Nefazodone: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of nefazodone and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and nefazodone is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Nelfinavir: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of nelfinavir and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and nelfinavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Nirmatrelvir; Ritonavir: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of ritonavir and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Nortriptyline: (Moderate) Monitor for an increase in tricyclic antidepressant (TCA)-related adverse reactions if coadministration with cinacalcet is necessary; a dose reduction of TCA may be necessary. Concurrent use may increase the exposure of TCAs which are CYP2D6 substrates; cinacalcet is a CYP2D6 inhibitor.
Olanzapine; Fluoxetine: (Moderate) Monitor for increased fluoxetine-related adverse effects if coadministered with cinacalcet. Concomitant use may increase fluoxetine exposure. Fluoxetine is a CYP2D6 substrate and cinacalcet is a moderate CYP2D6 inhibitor.
Oliceridine: (Moderate) Monitor patients closely for respiratory depression and sedation at frequent intervals and base subsequent doses on the patient's severity of pain and response to treatment if concomitant administration of oliceridine and cinacalcet is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and cinacalcet may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects. If cinacalcet is discontinued, consider increasing the oliceridine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oliceridine is a CYP2D6 substrate and cinacalcet is a moderate CYP2D6 inhibitor.
Paroxetine: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with cinacalcet is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and cinacalcet is a strong CYP2D6 inhibitor.
Perphenazine; Amitriptyline: (Moderate) Monitor for an increase in tricyclic antidepressant (TCA)-related adverse reactions if coadministration with cinacalcet is necessary; a dose reduction of TCA may be necessary. Concurrent use may increase the exposure of TCAs which are CYP2D6 substrates; cinacalcet is a CYP2D6 inhibitor.
Pimozide: (Moderate) Monitor for pimozide-related adverse reactions, including QT prolongation and ventricular arrhythmias, if coadministered with cinacalcet. Coadministration may result in elevated pimozide concentrations. Pimozide is metabolized primarily through CYP3A, and to a lesser extent CYP1A2 and CYP2D6; cinacalcet is a moderate CYP2D6 inhibitor.
Posaconazole: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of posaconazole and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and posaconazole is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Propafenone: (Moderate) Monitor for increased propafenone toxicity if coadministered with cinacalcet; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and cinacalcet with a CYP3A inhibitor. Propafenone is a CYP3A and CYP2D6 substrate; cinacalcet is a moderate CYP2D6 inhibitor.
Propranolol: (Moderate) Monitor for increased propranolol adverse reactions, including bradycardia and hypotension, during coadministration of cinacalcet as concurrent use may increase propranolol exposure. Propranolol is a CYP2D6 substrate and cinacalcet is moderate CYP2D6 inhibitor.
Protriptyline: (Moderate) Monitor for an increase in tricyclic antidepressant (TCA)-related adverse reactions if coadministration with cinacalcet is necessary; a dose reduction of TCA may be necessary. Concurrent use may increase the exposure of TCAs which are CYP2D6 substrates; cinacalcet is a CYP2D6 inhibitor.
Ribociclib: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of ribociclib and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and ribociclib is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Ribociclib; Letrozole: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of ribociclib and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and ribociclib is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Ritonavir: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of ritonavir and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Saquinavir: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of saquinavir and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and saquinavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Tamsulosin: (Moderate) Use caution if coadministration of cinacalcet with tamsulosin is necessary, especially at a tamsulosin dose higher than 0.4 mg, as the systemic exposure of tamsulosin may be increased resulting in increased treatment-related adverse reactions including hypotension, dizziness, and vertigo. Tamsulosin is a CYP2D6 substrate and cinacalcet is a moderate CYP2D6 inhibitor.
Thioridazine: (Contraindicated) Coadministration of thioridazine and cinacalcet is contraindicated due to the potential for increased thioridazine exposure. Increased plasma concentrations of thioridazine are expected to increase the prolongation of the QTc interval associated with thioridazine and may increase the risk of serious, potentially fatal, cardiac arrhythmias, such as torsade de pointes type arrhythmias. Thioridazine is a CYP2D6 substrate and cinacalcet is a moderate CYP2D6 inhibitor.
Tipranavir: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of tipranavir and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and tipranavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Tramadol: (Moderate) Monitor for reduced efficacy of tramadol, signs of opioid withdrawal, seizures, or serotonin syndrome if coadministration with cinacalcet is necessary. If cinacalcet is discontinued, consider a dose reduction of tramadol and frequently monitor for signs of respiratory depression and sedation. Tramadol is a CYP2D6 substrate and cinacalcet is a moderate CYP2D6 inhibitor. Concomitant use of tramadol with CYP2D6 inhibitors can increase the plasma concentration of tramadol and decrease the plasma concentration of the active metabolite M1. Since M1 is a more potent mu-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who have developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Tramadol; Acetaminophen: (Moderate) Monitor for reduced efficacy of tramadol, signs of opioid withdrawal, seizures, or serotonin syndrome if coadministration with cinacalcet is necessary. If cinacalcet is discontinued, consider a dose reduction of tramadol and frequently monitor for signs of respiratory depression and sedation. Tramadol is a CYP2D6 substrate and cinacalcet is a moderate CYP2D6 inhibitor. Concomitant use of tramadol with CYP2D6 inhibitors can increase the plasma concentration of tramadol and decrease the plasma concentration of the active metabolite M1. Since M1 is a more potent mu-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who have developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Tricyclic antidepressants: (Moderate) Monitor for an increase in tricyclic antidepressant (TCA)-related adverse reactions if coadministration with cinacalcet is necessary; a dose reduction of TCA may be necessary. Concurrent use may increase the exposure of TCAs which are CYP2D6 substrates; cinacalcet is a CYP2D6 inhibitor.
Trimipramine: (Moderate) Monitor for an increase in tricyclic antidepressant (TCA)-related adverse reactions if coadministration with cinacalcet is necessary; a dose reduction of TCA may be necessary. Concurrent use may increase the exposure of TCAs which are CYP2D6 substrates; cinacalcet is a CYP2D6 inhibitor.
Tucatinib: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of tucatinib and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Vonoprazan; Amoxicillin; Clarithromycin: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of clarithromycin and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Voriconazole: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of voriconazole and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
The course of chronic kidney disease leads to the development of altered calcium (hypocalcemia) and phosphorus (hyperphosphatemia) metabolism, increased parathyroid hormone (PTH) levels and eventually to subsequent bone disease and vascular and soft tissue calcifications. Hyperphosphatemia results from decreased renal elimination of phosphorus. Increased phosphorus levels directly suppress calcitriol production. Calcium levels decrease as a result of suppressed calcitriol production from the hyperphosphatemia and reduced calcium absorption from the GI tract. Through a feedback mechanism, hypocalcemia, hyperphosphatemia and decreased calcitriol production stimulate the release of parathyroid hormone and proliferation of parathyroid cells leading to secondary hyperparathyroidism. Bone resorption and formation are influenced by many hormonal and non-hormonal factors; hormonal factors affecting bone structure include altered PTH concentrations. When parathyroid hormone levels are too high, osteoclasts are stimulated and result in high bone turnover, leading to decreased cortical bone and bone strength and increased risk of fracture.
The calcium-sensing receptor on the surface of the chief cell of the parathyroid gland is the principal regulator of PTH secretion. Cinacalcet, mimicking calcium, increases the sensitivity of this calcium-sensing receptor, and PTH secretion is reduced. The reduction in PTH is associated with a concomitant decrease in serum calcium levels. The feedback loop is hindered and eventually slows the progression of bone disease and the systemic consequences of deranged mineral metabolism.
Cinacalcet is administered orally. It is approximately 93 to 97% bound to plasma protein(s). The volume of distribution is approximately 1,000 L, indicating extensive distribution. The plasma concentrations of major circulating metabolites, including hydrocinnamic and glucuronidated dihydrodiols, markedly exceed parent drug concentrations. The hydrocinnamic metabolite was shown to be inactive while the glucuronide conjugates have minimal or no calcimimetic activity. The primary route of elimination of the metabolites was renal excretion. Approximately 80% of the oral dose was recovered in the urine and 15% in the feces.
Affected cytochrome P450 isoenzymes and drug transporters: CYP2D6, CYP3A4, CYP1A2
Cinacalcet is a strong inhibitor of CYP2D6. It is metabolized by multiple enzymes, primarily CYP3A4, CYP2D6, and CYP1A2.
-Route-Specific Pharmacokinetics
Oral Route
After oral administration of cinacalcet, Cmax is achieved in approximately 2 to 6 hours. Administration with a high-fat meal increased Cmax and AUC by 82% and 68%, respectively, and increased 65% and 50% when given with a low-fat meal compared to a fasting state. The terminal half-life is 30 to 40 hours and steady-state drug concentrations are achieved within 7 days. The Cmax and AUC increase proportionally over the dose range of 30 to 180 mg PO once daily. However, the pharmacokinetic profile does not change over time with this dose range.
-Special Populations
Hepatic Impairment
In patients with moderate and severe hepatic impairment (as assessed by the Child-Pugh method), cinacalcet exposures (AUC) after a single 50 mg cinacalcet dose were 2.4 and 4.2-fold higher, respectively, than in healthy volunteers. The mean half-life increased from 49 hours in healthy volunteers to 65 hours and 84 hours in patients with moderate and severe hepatic impairment, respectively.
Renal Impairment
The pharmacokinetic profile of a single 75 mg cinacalcet dose in patients with mild, moderate, or severe renal disease and those on hemodialysis or peritoneal dialysis is comparable with that in healthy volunteers.
Geriatric
The pharmacokinetics of cinacalcet in geriatric patients (age 65 years or more, n = 12) are similar to those for patients who are younger than 65 years (n = 268).