TH 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 mat
