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Uses

Cinacalcet hydrochloride is used for the treatment of secondary hyperparathyroidism associated with chronic renal disease in patients who are undergoing hemodialysis or peritoneal dialysis, the treatment of hypercalcemia associated with parathyroid carcinoma, and the treatment of hypercalcemia associated with primary hyperparathyroidism in patients who would be candidates for parathyroidectomy based on serum calcium concentrations but who are unable to undergo the surgery.

Secondary Hyperparathyroidism Associated with Chronic Renal Disease

Cinacalcet hydrochloride is used for the treatment of secondary hyperparathyroidism associated with chronic renal disease in patients who are undergoing hemodialysis or peritoneal dialysis. Safety and efficacy in patients who are not undergoing dialysis have not been established; use of cinacalcet in these patients is not recommended because of an increased risk of hypocalcemia.(See Hypocalcemia under Cautions: Warnings/Precautions.) Cinacalcet may be used alone or in conjunction with vitamin D analogs and/or phosphate binders.

Secondary hyperparathyroidism in patients with chronic renal disease is a progressive condition associated with increases in parathyroid hormone (PTH, parathormone) concentrations and derangements in calcium and phosphorus metabolism. Increased PTH stimulates osteoclastic activity, resulting in cortical bone resorption and marrow fibrosis. The principal goals of therapy for this condition are to lower concentrations of PTH, calcium, and phosphorus in the blood in order to prevent progressive bone disease and systemic consequences of disordered mineral metabolism. Vitamin D analogs are used to decrease PTH secretion, and calcium salts or non-calcium-containing phosphate binders (e.g., sevelamer hydrochloride) are used to reduce intestinal absorption of phosphates. However, neither treatment immediately decreases PTH synthesis and secretion, and both calcium salts and vitamin D analogs may contribute to vascular and soft-tissue calcification. Vitamin D analogs increase absorption and plasma concentrations of calcium and phosphate, and hypercalcemia is common in patients receiving calcium salts. Episodes of hypercalcemia and hyperphosphatemia often are aggravated by the use of large doses of calcium salts to sequester phosphate in the intestine, particularly when used in conjunction with vitamin D analogs. Sevelamer hydrochloride may provide similar reductions in phosphorus concentrations as calcium salts but with less risk of causing hypercalcemia; however, sevelamer hydrochloride usually is administered with calcium salts or with calcitriol or another vitamin D analog to decrease elevated serum PTH concentrations. The calcimimetic agents cinacalcet and etelcalcetide decrease serum PTH concentrations while also decreasing serum calcium and phosphorus concentrations in dialysis patients with secondary hyperparathyroidism.

In three 6-month, randomized, controlled clinical studies in adults with chronic renal disease who were undergoing hemodialysis (96%) or peritoneal dialysis (4%), 665 patients received cinacalcet and 471 patients received placebo. Cinacalcet was initiated at a dosage of 30 mg once daily, and dosage was titrated every 3-4 weeks, up to a maximum dosage of 180 mg once daily, to achieve an intact PTH (iPTH) concentration (as measured by Nichols PTH immunometric assay) of 250 pg/mL or less. The mean baseline plasma iPTH concentration was 712 pg/mL, and 26% of patients had a baseline iPTH concentration exceeding 800 pg/mL. The mean duration of dialysis prior to study enrollment was 67 months, and 66% of patients were receiving vitamin D analogs and 93% were receiving phosphate binders at study entry.

In these 3 studies, a decrease in iPTH from baseline to the target value of 250 pg/mL or less was achieved in 40 or 5% of patients receiving cinacalcet or placebo, respectively. In addition, serum calcium and phosphorus concentrations and serum calcium times serum phosphorus product (Ca x P) were decreased by a median of 5.5-7.4, 8.6-12.4, and 14-19.7% from baseline in patients receiving cinacalcet; these parameters were not substantially changed in patients receiving placebo. Cinacalcet decreased iPTH concentration and serum Ca x P product regardless of disease severity (as determined by baseline iPTH concentration), duration of dialysis, and whether or not vitamin D analogs were administered. Approximately 60% of patients with mild (iPTH 300- 500 pg/mL), 41% of those with moderate (iPTH 500-800 pg/mL), and 11% of those with severe (iPTH exceeding 800 pg/mL) secondary hyperparathyroidism achieved a mean iPTH value of 250 pg/mL. Decreases in iPTH concentrations and serum Ca x P product have been maintained for up to 2 years with continued cinacalcet therapy.

Effects of cinacalcet therapy on clinical outcomes, including cardiovascular morbidity and mortality, remain to be fully determined. Because disorders of bone and mineral metabolism, including secondary hyperparathyroidism, are thought to contribute to the risk of cardiovascular disease in patients with chronic renal disease, the efficacy of cinacalcet for reducing the risk of death or major cardiovascular events was evaluated in the EVOLVE trial, a randomized, double-blind study in 3883 patients with moderate-to-severe secondary hyperparathyroidism who were undergoing hemodialysis. However, in the unadjusted intention-to-treat analysis, the study failed to demonstrate a reduction in risk of all-cause mortality or nonfatal cardiovascular events (myocardial infarction, hospitalization for unstable angina, heart failure, or peripheral vascular event). Although EVOLVE was a large trial, its interpretation has been debated because of study limitations, including some that diminished statistical power. Patients in this study received either cinacalcet (median dosage of 55 mg daily, median treatment duration of 21.2 months) or placebo (median treatment duration of 17.5 months); all patients could receive standard therapy (e.g., calcium supplements, phosphate binders, vitamin D analogs). Only 38.3% of cinacalcet-treated patients achieved the maximum allowed dosage of 180 mg daily. Approximately 20% of placebo recipients began receiving commercially available cinacalcet prior to experiencing a primary event and 62% of cinacalcet-treated patients discontinued the study drug. In the unadjusted intention-to-treat analysis, death or nonfatal cardiovascular event occurred in 48.2% of patients in the cinacalcet group and 49.2% of patients in the placebo group (hazard ratio: 0.93 [95% confidence interval: 0.85-1.02]). In a secondary analysis after adjustment for baseline characteristics, the hazard ratio was 0.88 (95% confidence interval: 0.79-0.97).

Hypercalcemia Associated with Parathyroid Carcinoma

Cinacalcet hydrochloride is used for the management of hypercalcemia associated with parathyroid carcinoma and has been designated an orphan drug by FDA for use in this condition.

In an uncontrolled open-label study, 29 patients with advanced parathyroid carcinoma and a mean baseline serum calcium concentration of 14.1 mg/dL received cinacalcet for 2-16 weeks (dosage-titration phase); 19 of these patients completed the dosage-titration phase and subsequently received maintenance therapy with the drug. The total median duration of treatment was 229 days. Cinacalcet was initiated at a dosage of 30 mg twice daily and dosage was adjusted every 2 weeks until the serum calcium concentration was 10 mg/dL or less, a maximum dosage of 90 mg 4 times daily was reached, or adverse effects precluded further increases in dosage. Cinacalcet dosages in the study ranged from 30 mg twice daily to 90 mg 4 times daily. By the end of the dosage-titration phase, serum calcium concentrations had decreased by at least 1 mg/dL in 62% of patients, and the mean serum calcium concentration was 12.4 mg/dL (a mean reduction of 1.7 mg/dL).

Hypercalcemia Associated with Primary Hyperparathyroidism

Cinacalcet hydrochloride is used for the treatment of hypercalcemia associated with primary hyperparathyroidism in patients who would be candidates for parathyroidectomy based on serum calcium concentrations but who are unable to undergo the surgery. Cinacalcet has been designated an orphan drug by FDA for use in this condition.

In an uncontrolled open-label study, 17 patients with severe hypercalcemia associated with primary hyperparathyroidism and a mean baseline serum calcium concentration of 12.7 mg/dL received cinacalcet for 2-16 weeks (dosage-titration phase); 14 of these patients completed the dosage-titration phase and subsequently received maintenance therapy with the drug. The total median duration of treatment was 270 days. Patients enrolled in the study had persistent hyperparathyroidism despite parathyroidectomy or had contraindications to the surgery. Cinacalcet was initiated at a dosage of 30 mg twice daily and dosage was adjusted every 2 weeks until the serum calcium concentration was 10 mg/dL or less, a maximum dosage of 90 mg 4 times daily was reached, or adverse effects precluded further increases in dosage. Cinacalcet dosages in the study ranged from 30 mg twice daily to 90 mg 4 times daily. By the end of the dosage-titration phase, serum calcium concentrations had decreased by at least 1 mg/dL in 88% of patients, and the mean serum calcium concentration was 10.4 mg/dL (a mean reduction of 2.3 mg/dL).

Efficacy of cinacalcet for the treatment of hypercalcemia associated with primary hyperparathyroidism also was evaluated in a double-blind, placebo-controlled study in 67 patients (mean age: 72 years) with albumin-corrected serum calcium concentrations exceeding 11.3 mg/dL but not exceeding 12.5 mg/dL who were unable to undergo parathyroidectomy. The study consisted of a 12-week dosage-titration phase followed by a 16-week efficacy-assessment phase. Cinacalcet was initiated at a dosage of 30 mg twice daily and dosage was adjusted every 3 or 4 weeks (during the dosage-titration or efficacy-assessment phase, respectively) to maintain a normal albumin-corrected serum calcium concentration (10.3 mg/dL or less). The median cinacalcet dosage at the end of the study was 60 mg daily. During the efficacy-assessment phase, serum calcium concentrations were decreased from baseline by at least 1 mg/dL in 85% of patients receiving cinacalcet compared with 6% of those receiving placebo, and the mean albumin-corrected serum calcium concentration was 10.3 mg/dL or less in 76% of cinacalcet-treated patients compared with no placebo recipients.

Dosage and Administration

Administration

Cinacalcet hydrochloride is administered orally with food or shortly after a meal.(See Description.) The tablets should be swallowed whole and should not be divided.

Dosage

Dosage of cinacalcet hydrochloride is expressed in terms of cinacalcet. Dosage of the drug must be individualized.

Because severe or prolonged nausea and vomiting can result in dehydration and worsening hypercalcemia, careful monitoring of electrolytes is recommended in patients with these adverse effects.

Secondary Hyperparathyroidism Associated with Chronic Renal Disease

For the management of secondary hyperparathyroidism associated with chronic renal disease in patients who are undergoing hemodialysis or peritoneal dialysis, the usual initial adult dosage of cinacalcet is 30 mg once daily. The manufacturer states that dosage should be increased no more frequently than every 2-4 weeks through sequential adjustments to 60, 90, 120, and 180 mg once daily to achieve a target intact parathyroid hormone (iPTH) concentration of 150-300 pg/mL. In 6-month clinical studies in this patient population, the median dosage of cinacalcet at the end of the studies was 90 mg daily; patients with milder disease generally required lower dosages. Cinacalcet therapy should not be initiated if the baseline serum calcium concentration is below the lower limit of normal (8.4 mg/dL).

Serum calcium and phosphorus concentrations should be measured within 1 week and iPTH concentrations measured 1-4 weeks after initiation or subsequent dosage adjustment of cinacalcet; serum iPTH concentrations should be assessed no earlier than 12 hours following an oral dose of the drug. If serum calcium concentrations fall below 8.4 mg/dL but remain above 7.5 mg/dL, or if manifestations of hypocalcemia occur, calcium-containing phosphate binders and/or vitamin D analogs can be used to increase serum calcium concentrations. If serum calcium concentrations fall below 7.5 mg/dL, or if manifestations of hypocalcemia persist and the dosage of vitamin D cannot be increased, administration of cinacalcet should be withheld until serum calcium concentrations reach 8 mg/dL and/or manifestations of hypocalcemia have resolved. Treatment may then be reinitiated using the next lowest dosage of cinacalcet. Once an appropriate maintenance dosage has been established, serum calcium and phosphorus concentrations should be measured approximately monthly.

Hypercalcemia Associated with Parathyroid Carcinoma

For the treatment of hypercalcemia associated with parathyroid carcinoma in adults, the usual initial dosage of cinacalcet is 30 mg twice daily. Dosage should be increased every 2-4 weeks through sequential adjustments to 60 mg twice daily, 90 mg twice daily, and 90 mg 3 or 4 times daily as needed to normalize serum calcium concentrations. Serum calcium concentrations should be measured within 1 week of cinacalcet initiation or dosage adjustment; once an appropriate maintenance dosage has been established, serum calcium concentrations should be measured every 2 months.

Hypercalcemia Associated with Primary Hyperparathyroidism

For the treatment of hypercalcemia associated with primary hyperparathyroidism in adults, the usual initial dosage of cinacalcet is 30 mg twice daily. Dosage should be increased every 2-4 weeks through sequential adjustments to 60 mg twice daily, 90 mg twice daily, and 90 mg 3 or 4 times daily as needed to normalize serum calcium concentrations. Serum calcium concentrations should be measured within 1 week of cinacalcet initiation or dosage adjustment; once an appropriate maintenance dosage has been established, serum calcium concentrations should be measured every 2 months.

Special Populations

The manufacturer makes no special population dosage recommendations at this time; however, close monitoring is required in patients with moderate or severe hepatic impairment.(See Hepatic Impairment under Cautions: Specific Populations.)

Cautions

Contraindications

Cinacalcet is contraindicated in patients with serum calcium concentrations below the lower limit of normal.

Warnings/Precautions

Hypocalcemia

Fatal or life-threatening hypocalcemia has been reported in patients, including pediatric patients, receiving cinacalcet (see Pediatric Use under Warnings/Precautions: Specific Populations, in Cautions). Substantial decreases in serum calcium concentrations can cause paresthesias, myalgia, muscle spasm, tetany, seizures, QT-interval prolongation, and ventricular arrhythmias.

Cases of QT-interval prolongation and ventricular arrhythmia secondary to hypocalcemia have been reported in patients receiving cinacalcet.

In clinical studies, seizures (mainly generalized or tonic-clonic) have been reported in 1.4% of patients receiving cinacalcet compared with 0.7% of those receiving placebo. Although the reason for this reported difference is not clear, substantial reductions in serum calcium concentrations may lower the seizure threshold.

Isolated idiosyncratic cases of hypotension, worsening heart failure, and/or arrhythmia have been reported during postmarketing experience in patients with impaired cardiac function who were receiving cinacalcet. A causal relationship to the drug could not be excluded; such effects might have been mediated by reductions in serum calcium concentrations.

Clinical studies indicate that nondialysis patients with secondary hyperparathyroidism associated with chronic renal disease are at greater risk for developing hypocalcemia (possibly because of lower baseline serum calcium concentrations) than are dialysis patients. In a 32-week, phase 3, placebo-controlled study in nondialysis patients, 80% of cinacalcet-treated patients had at least one serum calcium value of less than 8.4 mg/dL and 62% had 2 such consecutive values (median end-of-study dosage: 60 mg daily) compared with 5 and 1%, respectively, of placebo recipients. Safety and efficacy of cinacalcet for the treatment of secondary hyperparathyroidism associated with chronic renal disease in patients who are not undergoing dialysis have not been established.

In 6-month studies in dialysis patients with secondary hyperparathyroidism, 66% of patients receiving cinacalcet had at least one serum calcium value of less than 8.4 mg/dL, compared with 25% of those receiving placebo; 29 or 11% of patients in these respective groups had at least one calcium value of less than 7.5 mg/dL. Less than 1% of patients in each group permanently discontinued the study drug because of hypocalcemia. In the EVOLVE study, 75% of patients receiving cinacalcet for up to 64 months (median duration: 21 months) compared with 29% of patients receiving placebo had at least one serum calcium value of less than 8.4 mg/dL; 33 or 12% of patients in these respective groups had at least one serum calcium value of less than 7.5 mg/dL, generally during the first 6 months of therapy. In this study, 1.1% of patients receiving cinacalcet and 0.1% of patients receiving placebo permanently discontinued the study drug because of hypocalcemia.

In one study in patients with primary hyperparathyroidism, serum calcium value of less than 8.4 mg/dL was reported in 6 or 0% of patients receiving cinacalcet or placebo, respectively.

Because cinacalcet decreases serum calcium concentrations, patients should be carefully monitored for the occurrence of hypocalcemia. Particularly close monitoring is required in patients with a history of seizure disorder. If serum calcium concentrations fall below 8.4 mg/dL or if manifestations of hypocalcemia occur in patients with secondary hyperparathyroidism associated with chronic renal disease, appropriate steps (e.g., calcium supplementation, initiation or increased dosage of calcium-containing phosphate binder or vitamin D analog, temporary discontinuance of cinacalcet administration) should be taken to increase serum calcium concentrations.(See Secondary Hyperparathyroidism Associated with Chronic Renal Disease under Dosage and Administration: Dosage.) Patients should be informed of the symptoms of hypocalcemia and advised to inform their clinician if they occur.

Upper GI Bleeding

Cases of GI bleeding, generally upper GI bleeding, have been reported during clinical trials and postmarketing experience in patients receiving calcimimetic agents, including cinacalcet. The exact cause of GI bleeding in these patients is unknown. Patients with risk factors for upper GI bleeding (e.g., gastritis, esophagitis, ulcers, severe vomiting) may be at increased risk for GI bleeding while receiving cinacalcet. Patients receiving cinacalcet should be monitored for worsening of nausea and vomiting associated with the drug and for signs and symptoms of GI bleeding and ulceration. Any suspected GI bleeding should be immediately evaluated and treated.

Adynamic Bone Disease

Adynamic bone disease may develop if intact parathyroid hormone (iPTH) concentrations are suppressed below 100 pg/mL. In a clinical study evaluating bone histomorphometry in patients treated with cinacalcet for 1 year, 3 patients with mild hyperparathyroid bone disease at the beginning of the study developed adynamic bone disease during treatment; 2 of these patients had iPTH concentrations of less than 100 pg/mL at multiple time points during the study. In three 6-month, randomized, controlled clinical studies in dialysis patients with secondary hyperparathyroidism, 11% of patients treated with cinacalcet had mean iPTH concentrations of less than 100 pg/mL during the efficacy-assessment phase. If iPTH concentrations in patients receiving cinacalcet fall below 150 pg/mL, the dosage of cinacalcet and/or vitamin D analogs should be reduced or therapy discontinued.

Specific Populations

Pregnancy

Category C. Women who become pregnant while receiving cinacalcet are encouraged to enroll in the manufacturer's pregnancy surveillance program. Patients or their clinicians should call 800-772-6436 to enroll.

Lactation

Cinacalcet is distributed into milk in rats; it is not known whether cinacalcet is distributed into human milk. A decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman. Women who opt to continue cinacalcet treatment while nursing are encouraged to enroll in the manufacturer's lactation surveillance program. Patients or their clinicians should call 800-772-6436 to enroll.

Pediatric Use

Safety and efficacy of cinacalcet in pediatric patients younger than 18 years of age have not been established, and the drug is not indicated for use in pediatric patients. In 2013, FDA announced suspension of pediatric clinical trials of the drug after the death of a 14-year-old adolescent with severe hypocalcemia occurred during a trial.

Geriatric Use

No substantial differences in the pharmacokinetic profile, safety, and efficacy of cinacalcet have been observed in patients 65 years of age or older relative to younger adults. However, greater sensitivity of some older patients cannot be ruled out.

Hepatic Impairment

In patients with moderate or severe hepatic impairment (as indicated by Child-Pugh class), cinacalcet area under the plasma concentration-time curve (AUC) was 2.4 or 4.2 times higher, respectively, than in individuals with normal hepatic function. In patients with moderate or severe hepatic impairment, serum phosphorus, iPTH, and serum calcium concentrations should be monitored closely throughout cinacalcet therapy.

Renal Impairment

Renal impairment does not alter cinacalcet pharmacokinetics.

Common Adverse Effects

The most commonly reported adverse effects of cinacalcet in patients with hypercalcemia associated with parathyroid carcinoma or primary hyperparathyroidism or in dialysis patients with secondary hyperparathyroidism are nausea and vomiting.

In 3 controlled studies in dialysis patients with secondary hyperparathyroidism, adverse effects occurring in 5% of more of patients receiving cinacalcet for up to 6 months and at an incidence higher than that reported with placebo included nausea, vomiting, diarrhea, myalgia, dizziness, hypertension, asthenia, anorexia, noncardiac chest pain, and access infection. In the EVOLVE study in dialysis patients with secondary hyperparathyroidism, adverse effects reported in 5% or more of patients receiving cinacalcet for up to 64 months and at an incidence higher than that reported with placebo included nausea, vomiting, diarrhea, dyspnea, cough, hypotension, headache, hypocalcemia, muscle spasms, abdominal pain (including upper abdominal pain), hyperkalemia, upper respiratory tract infection, dyspepsia, dizziness, decreased appetite, asthenia, and constipation.

Adverse effects in patients with hypercalcemia associated with parathyroid carcinoma or primary hyperparathyroidism generally are similar to those observed in dialysis patients.

Drug Interactions

Cinacalcet is metabolized by cytochrome P-450 (CYP) isoenzymes 1A2, 2D6, and 3A4. In vitro studies indicate that cinacalcet is a potent inhibitor of CYP2D6, but cinacalcet does not inhibit CYP isoenzymes 1A2, 2C9, 2C19, or 3A4 nor does it induce CYP isoenzymes.

Drugs Metabolized by Hepatic Microsomal Enzymes

Concomitant use of cinacalcet with drugs that are metabolized principally by CYP2D6 may result in increased plasma concentrations of the CYP2D6 substrate drug. In patients receiving cinacalcet 25 or 100 mg concurrently with amitriptyline hydrochloride 50 mg, systemic exposures to amitriptyline and its active metabolite, nortriptyline, were increased by 21-22 and 17-23%, respectively, and peak plasma concentrations of amitriptyline and nortriptyline were increased by 13-21 and 11-15%, respectively, in individuals with the CYP2D6 extensive-metabolizer phenotype. When desipramine hydrochloride (single 50-mg dose) was administered concomitantly with cinacalcet (90 mg daily for 7 days) in individuals who were extensive metabolizers of CYP2D6 substrates, systemic exposure and peak plasma concentrations of desipramine were increased by 264 and 75%, respectively. When dextromethorphan (single 30-mg dose) was administered concomitantly with multiple 50-mg doses of cinacalcet in extensive metabolizers of CYP2D6 substrates, systemic exposure of dextromethorphan was increased 11-fold. Dosage adjustment may be required if cinacalcet is administered concomitantly with a drug that is metabolized principally by CYP2D6 (e.g., carvedilol, desipramine, metoprolol), especially one with a narrow therapeutic index (e.g., flecainide, most tricyclic antidepressants).

Drugs Affecting Hepatic Microsomal Enzymes

Concomitant use of cinacalcet with potent CYP3A4 inhibitors (e.g., ketoconazole, itraconazole) may result in increased plasma cinacalcet concentrations. Following concomitant administration of a single 90-mg dose of cinacalcet with ketoconazole (200 mg twice daily for 7 days), systemic exposure and peak plasma concentrations of cinacalcet were increased by 127 and 116%, respectively. Cinacalcet dosage adjustment may be required and iPTH and serum calcium concentrations should be closely monitored if a potent CYP3A4 inhibitor is initiated or discontinued. Cinacalcet dosage adjustment also may be required if a potent CYP3A4 inducer (e.g., rifampin) is initiated or discontinued.

Clearance of cinacalcet is increased by 36-38% in cigarette smokers compared with nonsmokers, possibly because cigarette smoking induces CYP1A2. Adjustment of cinacalcet dosage may be necessary if a patient starts or stops smoking or if therapy with a potent CYP1A2 inhibitor is initiated or discontinued during cinacalcet therapy.

Calcium Salts

Clinically important pharmacokinetic interaction with calcium carbonate is unlikely.

Midazolam

Clinically important pharmacokinetic interaction is unlikely.

Pantoprazole

Clinically important pharmacokinetic interaction is unlikely.

Sevelamer Hydrochloride

Clinically important pharmacokinetic interaction is unlikely.

Warfarin

Clinically important effect on warfarin pharmacokinetics or pharmacodynamics is unlikely.

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