Hypocalcemia).
PRECAUTIONS
GENERAL
HYPOCALCEMIA
Sensipar™ lowers serum calcium, and therefore patients should be carefully monitored for the occurrence of hypocalcemia. Potential manifestations of hypocalcemia include paresthesias, myalgias, cramping, tetany, and convulsions.
Sensipar™ treatment should not be initiated if serum calcium is less than the lower limit of the normal range (8.4 mg/dL). Serum calcium should be measured within 1 week after initiation or dose adjustment of Sensipar™. 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™ until serum calcium levels reach 8.0 mg/dL, and/or symptoms of hypocalcemia have resolved. Treatment should be re-initiated using the next lowest dose of Sensipar™ (see DOSAGE AND ADMINISTRATION).
In the 26-week studies of patients with CKD on dialysis, 66% of patients receiving Sensipar™ 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.
In CKD patients with secondary HPT not on dialysis, the long-term safety and efficacy of Sensipar™ have not been established. Exploratory investigation indicates that CKD patients not on dialysis have an increased risk for hypocalcemia compared to CKD patients on dialysis, which may be due to lower baseline calcium levels. In a small, short-term study, in which the median dose of cinacalcet was 30 mg at the completion of the study, 74% of cinacalcet-treated patients experienced at least one serum calcium value < 8.4 mg/dL.
ADYNAMIC BONE DISEASE
Adynamic bone disease may develop if iPTH levels are suppressed below 100 pg/mL when assessed using the standard Nichols IRMA. One clinical study evaluated bone histomorphometry in patients treated with Sensipar™ for one year. Three patients with mild hyperparathyroid bone disease at the beginning of the study developed adynamic bone disease during treatment with Sensipar™. Two of these patients had iPTH levels below 100 pg/mL at multiple time points during the study. In the three 6-month, phase 3 studies conducted in CKD patients on dialysis, 11% of patients treated with Sensipar™ had mean iPTH values below 100 pg/mL during the efficacy-assessment phase. If iPTH levels decrease below the NKF-K/DOQI recommended target range (150-300 pg/mL) 1 in patients treated with Sensipar™, the dose of Sensipar™ and/or vitamin D sterols should be reduced or therapy discontinued.
HEPATIC INSUFFICIENCY
Cinacalcet exposure as assessed by AUC(0-inf) in patients with moderate and severe hepatic impairment (as indicated by the Child-Pugh method) were 2.4 and 4.2 times higher, respectively, than that in normals. Patients with moderate and severe hepatic impairment should be monitored throughout treatment with Sensipar™ (see CLINICAL PHARMACOLOGY, Pharmacokinetics and DOSAGE AND ADMINISTRATION).
INFORMATION FOR PATIENTS
It is recommended that Sensipar™ be taken with food or shortly after a meal. Tablets should be taken whole and should not be divided.
LABORATORY TESTS
PATIENTS WITH CKD ON DIALYSIS WITH SECONDARY HYPERPARATHYROIDISM
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™. Once the maintenance dose has been established, serum calcium and serum phosphorus should be measured approximately monthly, and PTH every 1 to 3 months (see DOSAGE AND ADMINISTRATION). All iPTH measurements during the Sensipar™ trials were obtained using the Nichols IRMA.
In patients with end-stage renal disease, testosterone levels are often below the normal range. In a placebo-controlled trial in patients with CKD on dialysis, there were reductions in total and free testosterone in male patients following six months of treatment with Sensipar™. Levels of total testosterone decreased by a median of 15.8% in the Sensipar™-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™-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
Serum calcium should be measured within 1 week after initiation or dose adjustment of Sensipar™. Once maintenance dose levels have been established, serum calcium should be measured every 2 months (see DOSAGE AND ADMINISTRATION).
DRUG INTERACTIONS AND/OR DRUG/LABORATORY TEST INTERACTIONS
See CLINICAL PHARMACOLOGY, Pharmacokinetics and Drug Interactions.
Effect of Sensipar™ on other drugs:
Drugs metabolized by cytochrome P450 2D6 (CYP2D6): Sensipar™ is a strong in vitro inhibitor of CYP2D6. Therefore, dose adjustments of concomitant medications that are predominantly metabolized by CYP2D6 and have a narrow therapeutic index (e.g., flecainide, vinblastine, thioridazine and most tricyclic antidepressants) may be required.
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.
Effect of other drugs on Sensipar™:
Sensipar™ is metabolized by multiple cytochrome P450 enzymes, primarily CYP3A4, CYP2D6, and CYP1A2.
Ketoconazole: Sensipar™ is metabolized in part by CYP3A4. Co-administration of ketoconazole, a strong inhibitor of CYP3A4, increased cinacalcet exposure following a single 90 mg dose of Sensipar™ by 2.3 fold. 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 DOSAGE AND ADMINISTRATION).
CARCINOGENESIS, MUTAGENESIS, AND IMPAIRMENT OF FERTILITY
Carcinogenicity: Standard lifetime dietary carcinogenicity bioassays were conducted in mice and rats. Mice were given dietary doses of 15, 50, 125 mg/kg/day in males and 30, 70, 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, 35 mg/kg/day in males and 5, 20, 35 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 or in the Chinese Hamster Ovary (CHO) cell HGPRT forward mutation assay and CHO cell chromosomal aberration assay, with and without metabolic activation or in the in vivo mouse micronucleus assay.
Impairment of fertility: Female rats were given oral gavage doses of 5, 25, 75 mg/kg/day 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 post-mating. 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.
PREGNANCY CATEGORY C
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.
LACTATING WOMEN
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.
PEDIATRIC USE
The safety and efficacy of Sensipar™ in pediatric patients have not been established.
GERIATRIC USE
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).
