Sensipar^® (cinacalcet HCl) Tablets

Sensipar^® (cinacalcet hydrochloride) is a calcimimetic agent that increases the sensitivity of the calcium-sensing receptor to activation by extracellular calcium. Its empirical formula is C₂₂H₂₂F₃N•HCl with a molecular weight of 393.9 g/mol (hydrochloride salt) and 357.4 g/mol (free base). It has one chiral center having an R-absolute configuration. The R­enantiomer is the more potent enantiomer and has been shown to be responsible for pharmacodynamic activity.

Cinacalcet HCl is a white to off-white, crystalline solid that is soluble in methanol or 95% ethanol and slightly soluble in water.

Sensipar^® tablets are formulated as light-green, film-coated, oval-shaped tablets for oral administration in strengths of 30 mg, 60 mg, and 90 mg of cinacalcet HCl as the free base equivalent (33 mg, 66 mg, and 99 mg as the hydrochloride salt, respectively).

Cinacalcet HCl is described chemically as N-[1-(R)-(-)-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-1-aminopropane hydrochloride and has the following structural formula:

Inactive Ingredients: Sensipar^® tablets are comprised of the active ingredient, and the following inactive ingredients: pre-gelatinized starch, microcrystalline cellulose, povidone, crospovidone, colloidal silicon dioxide, and magnesium stearate. Tablets are coated with color (Opadry^®II green) and clear film-coat (Opadry^® clear), carnauba wax, and Opacode^® black ink.

Secondary hyperparathyroidism (HPT) in patients with chronic kidney disease (CKD) is a progressive disease, associated with increases in parathyroid hormone (PTH) levels and derangements in calcium and phosphorus metabolism. Increased PTH stimulates osteoclastic activity resulting in cortical bone resorption and marrow fibrosis. The goals of treatment of secondary hyperparathyroidism are to lower levels of PTH, calcium, and phosphorus in the blood, in order to prevent progressive bone disease and the systemic consequences of disordered mineral metabolism. In CKD patients on dialysis with uncontrolled secondary HPT, reductions in PTH are associated with a favorable impact on bone-specific alkaline phosphatase (BALP), bone turnover and bone fibrosis.

The calcium-sensing receptor on the surface of the chief cell of the parathyroid gland is the principal regulator of PTH secretion. Sensipar^® directly lowers PTH levels by increasing the sensitivity of the calcium-sensing receptor to extracellular calcium. The reduction in PTH is associated with a concomitant decrease in serum calcium levels.

An in vitro study indicates that cinacalcet is a strong inhibitor of CYP2D6, but not of CYP1A2, CYP2C9, CYP2C19, and CYP3A4.

Ketoconazole: Cinacalcet AUC_(0-inf) and C_max increased 2.3 and 2.2 times, respectively, when a single 90 mg cinacalcet dose on Day 5 was administered to subjects treated with 200 mg ketoconazole twice daily for 7 days compared to 90 mg cinacalcet given alone (see DOSAGE AND ADMINISTRATION).

Calcium Carbonate: No significant pharmacokinetic interaction was observed when 1500 mg calcium carbonate was coadministered with 100 mg cinacalcet.

Pantoprazole: No significant pharmacokinetic interaction was observed when cinacalcet 90 mg was administered to subjects treated with 80 mg pantoprazole daily for 3 days.

Sevelamer HCl: No significant pharmacokinetic interaction was observed when 2400 mg sevelamer HCl was coadministered with 90 mg cinacalcet tablet (subjects subsequently received 2400 mg sevelamer HCl two more times on Day 1 and three more times on Day 2).

Amitriptyline: Concurrent administration of 25 mg or 100 mg cinacalcet with 50 mg amitriptyline increased amitriptyline exposure and nortriptyline (active metabolite) exposure by approximately 20% in CYP2D6 extensive metabolizers.

Warfarin: R- and S-warfarin pharmacokinetics and warfarin pharmacodynamics were not affected in subjects treated with warfarin 25 mg who received cinacalcet 30 mg twice daily. The lack of effect of cinacalcet on the pharmacokinetics of R- and S-warfarin and the absence of auto-induction upon multiple dosing in patients indicates that cinacalcet is not an inducer of CYP2C9 in humans.

Reduction in intact PTH (iPTH) levels correlated with cinacalcet concentrations in CKD patients. The nadir in iPTH level occurs approximately 2 to 6 hours post dose, corresponding with the C_max of cinacalcet. After steady state is reached, serum calcium concentrations remain constant over the dosing interval in CKD patients.

Three 6-month, multicenter, randomized, double-blind, placebo-controlled clinical studies of similar design were conducted in CKD patients on dialysis. A total of 665 patients were randomized to Sensipar^® and 471 patients to placebo. The mean age of the patients was 54 years, 62% were male, and 52% Caucasian. The average baseline iPTH level by the Nichols intact immunoradiometric assay (IRMA) was 712 pg/mL, with 26% of the patients having a baseline iPTH level > 800 pg/mL. The mean baseline Ca x P ion product was 61 mg²/dL². The average duration of dialysis prior to study enrollment was 67 months. Ninety-six percent of patients were on hemodialysis and 4% peritoneal dialysis. At study entry, 66% of the patients were receiving vitamin D sterols and 93% were receiving phosphate binders. Sensipar^® (or placebo) was initiated at a dose of 30 mg once daily and titrated every 3 or 4 weeks to a maximum dose of 180 mg once daily to achieve an iPTH of ≤ 250 pg/mL. The dose was not increased if a patient had any of the following: iPTH < 200 pg/mL, serum calcium < 7.8 mg/dL, or any symptoms of hypocalcemia. If a patient experienced symptoms of hypocalcemia or had a serum calcium < 8.4 mg/dL, calcium supplements and/or calcium-based phosphate binders could be increased. If these measures were insufficient, the vitamin D dose could be increased. Approximately 70% of the Sensipar^® patients and 80% of the placebo patients completed the 6-month studies. In the primary efficacy analysis, 40% of Sensipar^® patients and 5% of placebo patients achieved an iPTH ≤ 250 pg/mL (p<0.001) (Table 1, Figure 1). Secondary efficacy parameters also improved in patients treated with Sensipar^®. These studies showed that Sensipar^® reduced PTH while lowering Ca x P, calcium and phosphorus levels (Table 1, Figure 2). The median dose of Sensipar^® at the completion of the studies was 90 mg. Patients with milder disease typically required lower doses.

Reductions in iPTH and Ca x P were maintained for up to 12 months of treatment.

Sensipar^® decreased iPTH and Ca x P levels regardless of disease severity (i.e., baseline iPTH value), duration of dialysis, and whether or not vitamin D sterols were administered. Approximately 60% of patients with mild (iPTH ≥ 300 to ≤ 500 pg/mL), 41% with moderate (iPTH > 500 to 800 pg/mL), and 11% with severe (iPTH > 800 pg/mL) secondary HPT achieved a mean iPTH value of 250 pg/mL. Plasma iPTH levels were measured using the Nichols IRMA.

Ten patients with parathyroid carcinoma were enrolled in an open-label study. The study consisted of 2 phases, a dose-titration phase and a maintenance phase.

The range of exposure was 2 to 16 weeks in the titration phase (n = 10) and 16 to 48 weeks (n = 3) for the maintenance phase. Baseline mean (SD) serum calcium was 14.7 (1.8) mg/dL. The range of change from baseline to last measurement was –7.5 to 2.7 mg/dL during the titration phase and –7.4 to 0.9 mg/dL during the maintenance phase (Figure 3). No patients maintained a serum calcium level within the normal range. The doses ranged from 70 mg twice daily to 90 mg four times daily for patients in the maintenance phase.

Sensipar^® is indicated for the treatment of secondary hyperparathyroidism in patients with Chronic Kidney Disease on dialysis.

Sensipar^® is indicated for the treatment of hypercalcemia in patients with parathyroid carcinoma.

Sensipar^® is contraindicated in patients with hypersensitivity to any component(s) of this product.

In three clinical studies of CKD patients on dialysis, 5% of the patients in both the Sensipar^® and placebo groups reported a history of seizure disorder at baseline. During the trials, seizures (primarily generalized or tonic-clonic) were observed in 1.4% (9/656) of Sensipar^®-treated patients and 0.4% (2/470) of placebo-treated patients. Five of the nine Sensipar^®-treated patients had a history of a seizure disorder and two were receiving anti-seizure medication at the time of their seizure. Both placebo-treated patients had a history of seizure disorder and were receiving anti-seizure medication at the time of their seizure. While the basis for the reported difference in seizure rate is not clear, the threshold for seizures is lowered by significant reductions in serum calcium levels. Therefore, serum calcium levels should be closely monitored in patients receiving Sensipar^®, particularly in patients with a history of a seizure disorder (see PRECAUTIONS, Hypocalcemia).

In postmarketing safety surveillance, isolated, idiosyncratic cases of hypotension and/or worsening heart failure have been reported in patients with impaired cardiac function, in which a causal relationship to Sensipar^® could not be completely excluded and may be mediated by reductions in serum calcium levels. Clinical trial data showed hypotension occurred in 7% of Sensipar^®-treated patients, 12% of placebo-treated patients, and heart failure occurred in 2% of patients receiving Sensipar^® or placebo.

It is recommended that Sensipar^® be taken with food or shortly after a meal. Tablets should be taken whole and should not be divided.

See CLINICAL PHARMACOLOGY, Pharmacokinetics and Drug Interactions.

In pregnant female rats given oral gavage doses of 2, 25, 50 mg/kg/day during gestation no teratogenicity was observed at doses up to 50 mg/kg/day (exposure 4 times those resulting with a human oral dose of 180 mg/day based on AUC comparison). Decreased fetal body weights were observed at all doses (less than 1 to 4 times a human oral dose of 180 mg/day based on AUC comparison) in conjunction with maternal toxicity (decreased food consumption and body weight gain).

In pregnant female rabbits given oral gavage doses of 2, 12, 25 mg/kg/day during gestation no adverse fetal effects were observed (exposures less than with a human oral dose of 180 mg/day based on AUC comparisons). Reductions in maternal food consumption and body weight gain were seen at doses of 12 and 25 mg/kg/day.

In pregnant rats given oral gavage doses of 5, 15, 25 mg/kg/day during gestation through lactation no adverse fetal or pup (post-weaning) effects were observed at 5 mg/kg/day (exposures less than with a human therapeutic dose of 180 mg/day based on AUC comparisons). Higher doses of 15 and 25 mg/kg/day (exposures 2-3 times a human oral dose of 180 mg/day based on AUC comparisons) were accompanied by maternal signs of hypocalcemia (periparturient mortality and early postnatal pup loss), and reductions in postnatal maternal and pup body-weight gain. Sensipar^® has been shown to cross the placental barrier in rabbits.

There are no adequate and well-controlled studies in pregnant women. Sensipar^® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Studies in rats have shown that Sensipar^® is excreted in the milk with a high milk-to-plasma ratio. It is not known whether this drug is excreted in human milk. Considering these data in rats and because many drugs are excreted in human milk and because of the potential for clinically significant adverse reactions in infants from Sensipar^®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the lactating woman.

The safety and efficacy of Sensipar^® in pediatric patients have not been established.

Of the 1136 patients enrolled in the Sensipar^® phase 3 clinical program, 26% were ≥ 65 years old, and 9% were ≥ 75 years old. No differences in the safety and efficacy of Sensipar^® were observed in patients greater or less than 65 years of age (see DOSAGE AND ADMINISTRATION, Geriatric Patients).

In 3 double-blind placebo-controlled clinical trials, 1126 CKD patients on dialysis received study drug (656 Sensipar^®, 470 placebo) for up to 6 months. The most frequently reported adverse events (incidence of at least 5% in the Sensipar^® group and greater than placebo) are provided in Table 2. The most frequently reported events in the Sensipar^® group were nausea, vomiting, and diarrhea.

The incidence of serious adverse events (29% vs. 31%) was similar in the Sensipar^® and placebo groups, respectively.

12-Month Experience with Sensipar^®: Two hundred and sixty-six patients from 2 phase 3 studies continued to receive Sensipar^® or placebo treatment in a 6-month double-blind extension study (12-month total treatment duration). The incidence and nature of adverse events in this study were similar in the two treatment groups, and comparable to those observed in the phase 3 studies.

Postmarketing Experience with Sensipar^®: Isolated, idiosyncratic cases of hypotension and/or worsening heart failure have been reported in Sensipar^®-treated patients with impaired cardiac function in postmarketing safety surveillance. Diarrhea and myalgia have been identified as adverse reactions during post-approval use of Sensipar^®. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The most frequent adverse events in this patient group were nausea and vomiting.

Laboratory values: Serum calcium levels should be closely monitored in patients receiving Sensipar^® (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Doses titrated up to 300 mg once daily have been safely administered to patients on dialysis. Overdosage of Sensipar^® may lead to hypocalcemia. In the event of overdosage, patients should be monitored for signs and symptoms of hypocalcemia and appropriate measures taken to correct serum calcium levels (see PRECAUTIONS).  

Since Sensipar^® is highly protein bound, hemodialysis is not an effective treatment for overdosage of Sensipar^®.

Sensipar^® tablets should be taken whole and should not be divided. Sensipar^® should be taken with food or shortly after a meal.

Dosage must be individualized.

The recommended starting oral dose of Sensipar^® is 30 mg once daily. Serum calcium and serum phosphorus should be measured within 1 week and iPTH should be measured 1 to 4 weeks after initiation or dose adjustment of Sensipar^®. Sensipar^® should be titrated no more frequently than every 2 to 4 weeks through sequential doses of 60, 90, 120, and 180 mg once daily to target iPTH consistent with the NKF-K/DOQI recommendation for CKD patients on dialysis of 150-300 pg/mL.

Sensipar^® can be used alone or in combination with vitamin D sterols and/or phosphate binders.

During dose titration, serum calcium levels should be monitored frequently and if levels decrease below the normal range, appropriate steps should be taken to increase serum calcium levels, such as by providing supplemental calcium, initiating or increasing the dose of calcium-based phosphate binder, initiating or increasing the dose of vitamin D sterols, or temporarily withholding treatment with Sensipar^® (see PRECAUTIONS).

The recommended starting oral dose of Sensipar^® is 30 mg twice daily.

The dosage of Sensipar^® should be titrated every 2 to 4 weeks through sequential doses of 30 mg twice daily, 60 mg twice daily, 90 mg twice daily, and 90 mg three or four times daily as necessary to normalize serum calcium levels.

Sensipar^® is metabolized in part by the enzyme CYP3A4. Co-administration of ketoconazole, a strong inhibitor of CYP3A4, caused an approximate 2-fold increase in cinacalcet exposure. Dose adjustment of Sensipar^® may be required and PTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor (e.g., ketoconazole, erythromycin, itraconazole; see CLINICAL PHARMACOLOGY, Pharmacokinetics and PRECAUTIONS).

Sensipar^® 30 mg tablets are formulated as light-green, film-coated, oval-shaped tablets printed with “AMGEN” on one side and “30” on the opposite side, packaged in bottles of 30 tablets. (NDC 55513-073-30)

Sensipar^® 60 mg tablets are formulated as light-green, film-coated, oval-shaped tablets printed with “AMGEN” on one side and “60” on the opposite side, packaged in bottles of 30 tablets. (NDC 55513-074-30)

Sensipar^® 90 mg tablets are formulated as light-green, film-coated, oval-shaped tablets printed with “AMGEN” on one side and “90” on the opposite side, packaged in bottles of 30 tablets. (NDC 55513-075-30)

Store at 25ºC (77ºF); excursions permitted to 15-30ºC (59-86ºF). [See USP controlled room temperature].

Rx Only

This product, or its use, may be covered by one or more US Patents including US Patent Nos. 6313146, 6211244, 6031003 and 6011068, in addition to others, including patents pending.

1. National Kidney Foundation: K/DOQI clinical practice guidelines: bone metabolism and disease in chronic kidney disease. American Journal of Kidney Disease 4 2:S1-S201, 2003

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Manufactured for: Amgen

Amgen Inc.

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Issue Date: 04/2007

©2007 Amgen Inc. All rights reserved.

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