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Sensipar

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Sensipar

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Hypocalcemia

Sensipar (cinacalcet) lowers serum calcium and, therefore, patients should be carefully monitored for the occurrence of hypocalcemia. Potential manifestations of hypocalcemia include paresthesias, myalgias, muscle cramping, tetany, and convulsions.

Serum calcium should be measured within 1 week after initiation or dose adjustment of Sensipar (cinacalcet) . Once the maintenance dose has been established, serum calcium should be measured approximately monthly [see DOSAGE AND ADMINISTRATION].

If serum calcium falls below 8.4 mg/dL but remains above 7.5 mg/dL, or if symptoms of hypocalcemia occur, calcium-containing phosphate binders and/or vitamin D sterols can be used to raise serum calcium. If serum calcium falls below 7.5 mg/dL, or if symptoms of hypocalcemia persist and the dose of vitamin D cannot be increased, withhold administration of Sensipar (cinacalcet) until serum calcium levels reach 8.0 mg/dL and/or symptoms of hypocalcemia have resolved. Treatment should be reinitiated using the next lowest dose of Sensipar [see DOSAGE AND ADMINISTRATION].

In 26-week studies of patients with CKD on dialysis, 66% of patients receiving Sensipar (cinacalcet) compared with 25% of patients receiving placebo developed at least one serum calcium value < 8.4 mg/dL. Less than 1% of patients in each group permanently discontinued study drug due to hypocalcemia.

Sensipar (cinacalcet) is not indicated for patients with CKD not on dialysis. In patients with secondary HPT and CKD not on dialysis, the long-term safety and efficacy of Sensipar (cinacalcet) have not been established. Clinical studies indicate that Sensipar (cinacalcet) -treated patients with CKD not on dialysis have an increased risk for hypocalcemia compared with Sensipar (cinacalcet) -treated patients with CKD on dialysis, which may be due to lower baseline calcium levels. In a phase 3 study of 32 weeks duration and including 404 patients with CKD not on dialysis (302 cinacalcet, 102 placebo), in which the median dose for cinacalcet was 60 mg per day at the completion of the study, 80% of Sensipar (cinacalcet) treated patients experienced at least one serum calcium value < 8.4 mg/dL compared with 5% of patients receiving placebo.

Seizures

In three clinical studies of patients with CKD on dialysis, 5% of the patients in both the Sensipar (cinacalcet) and placebo groups reported a history of seizure disorder at baseline. During the studies, seizures (primarily generalized or tonic-clonic) were observed in 1.4% (9/656) of Sensipar (cinacalcet) treated patients and 0.4% (2/470) of placebo-treated patients. Five of the nine Sensipar (cinacalcet) -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 antiseizure 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 (cinacalcet) , particularly in patients with a history of a seizure disorder.

Hypotension and/or Worsening Heart Failure

In postmarketing safety surveillance, isolated, idiosyncratic cases of hypotension, worsening heart failure, and/or arrhythmia have been reported in patients with impaired cardiac function, in which a causal relationship to Sensipar (cinacalcet) could not be completely excluded and which may be mediated by reductions in serum calcium levels [see ADVERSE REACTIONS].

Adynamic Bone Disease

Adynamic bone disease may develop if iPTH levels are suppressed below 100 pg/mL. One clinical study evaluated bone histomorphometry in patients treated with Sensipar (cinacalcet) for 1 year. Three patients with mild hyperparathyroid bone disease at the beginning of the study developed adynamic bone disease during treatment with Sensipar (cinacalcet) . Two of these patients had iPTH levels below 100 pg/mL at multiple time points during the study. In three 6-month, phase 3 studies conducted in patients with CKD on dialysis, 11% of patients treated with Sensipar (cinacalcet) had mean iPTH values below 100 pg/mL during the efficacy-assessment phase. If iPTH levels decrease below 150 pg/mL in patients treated with Sensipar (cinacalcet) , the dose of Sensipar (cinacalcet) and/or vitamin D sterols should be reduced or therapy discontinued.

Hepatic Impairment

Cinacalcet exposure, as defined by the Area Under the Curve (AUC0-inf), is increased by 2.4 and 4.2 fold in patients with moderate and severe hepatic impairment, respectively. These patients should be monitored throughout treatment with Sensipar (cinacalcet) [see Use In Specific Populations and CLINICAL PHARMACOLOGY].

Laboratory Tests

Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease on Dialysis

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 (cinacalcet) . Once the maintenance dose has been established, serum calcium and serum phosphorus should be measured approximately monthly, and iPTH every 1 to 3 months [see DOSAGE AND ADMINISTRATION]. Measurements of PTH during the Sensipar (cinacalcet) studies were obtained using the Nichols iPTH immunoradiometric assay (IRMA).

In patients with end-stage renal disease, testosterone levels are often below the normal range. In a placebo-controlled study in patients with CKD on dialysis, there were reductions in total and free testosterone in male patients following 6 months of treatment with Sensipar (cinacalcet) . Levels of total testosterone decreased by a median of 15.8% in the Sensipar (cinacalcet) -treated patients and by 0.6% in the placebo-treated patients. Levels of free testosterone decreased by a median of 31.3% in the Sensipar (cinacalcet) -treated patients and by 16.3% in the placebo-treated patients. The clinical significance of these reductions in serum testosterone is unknown.

Patients with Parathyroid Carcinoma or Primary Hyperparathyroidism

Serum calcium should be measured within 1 week after initiation or dose adjustment of Sensipar (cinacalcet) . Once maintenance dose levels have been established, serum calcium should be measured every 2 months [see DOSAGE AND ADMINISTRATION].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Carcinogenicity

Standard lifetime dietary carcinogenicity bioassays were conducted in mice and rats. Mice were given cinacalcet at dietary doses of 15, 50, and 125 mg/kg/day in males and 30, 70, and 200 mg/kg/day in females (exposures up to 2 times those resulting with a human oral dose of 180 mg/day based on AUC comparison). Rats were given dietary doses of 5, 15, and 35 mg/kg/day in males and 5, 20, 3, and 5 mg/kg/day in females (exposures up to 2 times those resulting with a human oral dose of 180 mg/day based on AUC comparison). No increased incidence of tumors was observed following treatment with cinacalcet.

Mutagenicity

Cinacalcet was not genotoxic in the Ames bacterial mutagenicity assay, nor in the Chinese Hamster Ovary (CHO) cell HGPRT forward mutation assay and CHO cell chromosomal aberration assay, with and without metabolic activation, nor in the in vivo mouse micronucleus assay.

Impairment of Fertility

Female rats were given oral gavage doses of 5, 25, and 75 mg/kg/day cinacalcet beginning 2 weeks before mating and continuing through gestation day 7. Male rats were given oral doses 4 weeks prior to mating, during mating (3 weeks) and 2 weeks postmating. No effects were observed in male or female fertility at 5 and 25 mg/kg/day (exposures up to 3 times those resulting with a human oral dose of 180 mg/day based on AUC comparison). At 75 mg/kg/day, there were slight adverse effects (slight decreases in body weight and food consumption) in males and females.

Use In Specific Populations

Pregnancy: Category C

In pregnant female rats given oral gavage doses of 2, 25, 50 mg/kg/day cinacalcet 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 area under the curve [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 cinacalcet 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. Sensipar (cinacalcet) has been shown to cross the placental barrier in rabbits.

In pregnant rats given oral gavage doses of 5, 15, 25 mg/kg/day cinacalcet 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 cinacalcet (exposures 2 to 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.

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

Women who become pregnant during Sensipar (cinacalcet) treatment are encouraged to enroll in Amgen's Pregnancy Surveillance Program. Patients or their physicians should call 1-800-772-6436 (1-800-77-AMGEN) to enroll.

Nursing Mothers

Studies in rats have shown that Sensipar (cinacalcet) 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 there is a potential for clinically significant adverse reactions in infants who ingest Sensipar (cinacalcet) , 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.

Pediatric Use

The safety and efficacy of Sensipar (cinacalcet) in pediatric patients have not been established.

Geriatric Use

Of the 1136 patients enrolled in the Sensipar (cinacalcet) phase 3 clinical program in patients with CKD on dialysis, 26% were ≥ 65 years old, and 9% were ≥ 75 years old. No differences in the safety and efficacy of Sensipar (cinacalcet) were observed in patients greater or less than 65 years of age. No dosage adjustment is required for geriatric patients [see CLINICAL PHARMACOLOGY].

Renal Impairment

No dosage adjustment is necessary for renal impairment [see CLINICAL PHARMACOLOGY].

Hepatic Impairment

Patients with moderate and severe hepatic impairment should have serum calcium, serum phosphorus, and iPTH levels monitored closely throughout treatment with Sensipar because cinacalcet exposure (AUC0-inf) is increased by 2.4 and 4.2 fold, respectively, in these patients [see CLINICAL PHARMACOLOGY].

Last reviewed on RxList: 4/19/2011
This monograph has been modified to include the generic and brand name in many instances.

Warnings
Precautions
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