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warnings and cautions
5 WARNINGS AND PRECAUTIONS Hypocalcemia and/or seizures: May occur due to significant reductions in serum calcium. ( 5.1 , 5.2 ) Isolated, idiosyncratic occurrences of hypotension, worsening heart failure, and/or arrhythmia: Have been reported in patients with impaired cardiac function during Sensipar treatment, which may be mediated by reductions in serum calcium. ( 5.3 ) Adynamic bone disease: May develop if iPTH levels are suppressed below 100 pg/mL. ( 5.4 ) Laboratory tests: Serum calcium, serum phosphorus, and iPTH levels should be monitored during the dose initiation, dose titration, and maintenance therapy. ( 5.6 ) Hepatic Impairment: Cinacalcet exposure is increased in patients with moderate and severe hepatic impairment. Patients should be closely monitored throughout treatment. ( 5.5 , 8.7 ) 5.1 Hypocalcemia Sensipar 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. Once the maintenance dose has been established, serum calcium should be measured approximately monthly [see Dosage and Administration ( 2.1 )] . 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 reinitiated using the next lowest dose of Sensipar [see Dosage and Administration ( 2.1 )] . In 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. Sensipar 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 have not been established. Clinical studies indicate that Sensipar-treated patients with CKD not on dialysis have an increased risk for hypocalcemia compared with Sensipar-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-treated patients experienced at least one serum calcium value < 8.4 mg/dL compared with 5% of patients receiving placebo. 5.2 Seizures In clinical studies, seizures (primarily generalized or tonic-clonic) were observed in 1.4% (43/3049) of Sensipar-treated patients and 0.7% (5/687) of placebo-treated patients. 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 Warnings and Precautions ( 5.1 )] . 5.3 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 could not be completely excluded and which may be mediated by reductions in serum calcium levels [see Adverse Reactions ( 6.2 )]. 5.4 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 for 1 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 three 6-month, phase 3 studies conducted in patients with CKD 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 150 pg/mL in patients treated with Sensipar, the dose of Sensipar and/or vitamin D sterols should be reduced or therapy discontinued. 5.5 Hepatic Impairment Cinacalcet exposure, as defined by the Area Under the Curve (AUC 0-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 [see Use in Specific Populations ( 8.7 ) and Clinical Pharmacology ( 12.3 )] . 5.6 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. 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 ( 2.1 )] . Measurements of PTH during the Sensipar 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. 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 or Primary Hyperparathyroidism 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 ( 2.2 )] .
6 ADVERSE REACTIONS The most frequently reported adverse reactions (incidence in patients ≥ 5% in the Sensipar group) were nausea, vomiting, and diarrhea. ( 6.1 , 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Amgen Medical Information at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease on Dialysis In three double-blind, placebo-controlled clinical trials, 1126 patients with CKD on dialysis received study drug (656 Sensipar, 470 placebo) for up to 6 months. The most frequently reported adverse reactions (incidence of at least 5% in the Sensipar group and greater than placebo) are provided in Table 1 . The most frequently reported adverse reactions in the Sensipar group were nausea, vomiting, and diarrhea. Seizures were observed in 1.4% (13/910) of cinacalcet-treated patients and 0.7% (5/641) of placebo-treated patients across all completed placebo controlled trials. Table 1. Adverse Reaction Incidence (≥ 5%) in Patients on Dialysis Placebo Sensipar (n = 470) (n = 656) Event: (%) (%) Nausea 19 31 Vomiting 15 27 Diarrhea 20 21 Myalgia 14 15 Dizziness 8 10 Hypertension 5 7 Asthenia 4 7 Anorexia 4 6 Pain Chest, Non-Cardiac 4 6 Access Infection 4 5 The incidence of serious adverse reactions was similar in the Sensipar and placebo groups (29% vs. 31%, respectively). 12-Month Experience with Sensipar in Secondary Hyperparathyroidism Two hundred sixty-six patients from two of the phase 3 studies in patients with CKD on dialysis 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 reactions in this long term extension study were comparable to those observed in the original phase 3 studies. Parathyroid Carcinoma and Primary Hyperparathyroidism The safety profile of Sensipar in these patient populations is generally consistent with that seen in patients with CKD on dialysis. Forty six patients were treated with cinacalcet in a single arm study, 29 with Parathyroid Carcinoma and 17 with intractable pHPT. Nine (20%) of the patients withdrew from the study due to adverse events. The most frequent adverse reactions and the most frequent cause of withdrawal in these patient populations were nausea and vomiting. Severe or prolonged cases of nausea and vomiting can lead to dehydration and worsening hypercalcemia so careful monitoring of electrolytes is recommended in patients with these symptoms. Eight patients died while on study, 7 with Parathyroid Carcinoma (24%) and 1 (6%) with intractable pHPT. Causes of death were cardiovascular (5 patients), multi-organ failure (1 patient), gastrointestinal hemorrhage (1 patient) and metastatic carcinoma (1 patient). Adverse events of hypocalcemia were reported in three patients (7%). Seizures were observed in 0.7% (1/140) of cinacalcet-treated patients and 0.0% (0/46) of placebo-treated patients in all clinical studies. Table 2. Adverse Reactions Occurring in ≥ 10% of Total Subjects N=Number of subjects receiving at least one dose of study drug. Preferred Term Cinacalcet Parathyroid Carcinoma (N=29) Intractable pHPT (N=17) Total (N=46) n (%) n (%) n (%) Number of Subjects Reporting Adverse Events 28 (97) 17 (100) 45 (98) Nausea 19 (66) 10 (59) 29 (63) Vomiting 15 (52) 6 (35) 21 (46) Paresthesia 4 (14) 5 (29) 9 (20) Fatigue 6 (21) 2 (12) 8 (17) Fracture 6 (21) 2 (12) 8 (17) Hypercalcemia 6 (21) 2 (12) 8 (17) Anorexia 6 (21) 1 (6) 7 (15) Asthenia 5 (17) 2 (12) 7 (15) Dehydration 7 (24) 0 (0) 7 (15) Anemia 5 (17) 1 (6) 6 (13) Arthralgia 5 (17) 1 (6) 6 (13) Constipation 3 (10) 3 (18) 6 (13) Depression 3 (10) 3 (18) 6 (13) Headache 6 (21) 0 (0) 6 (13) Infection Upper Respiratory 3 (10) 2 (12) 5 (11) Pain Limb 3 (10) 2 (12) 5 (11) 6.2 Postmarketing Experience with Sensipar The following adverse reactions have been identified during postapproval 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. Rash, hypersensitivity reactions (including angioedema and urticaria), diarrhea, and myalgia have been identified as adverse reactions during postapproval use of Sensipar. Isolated, idiosyncratic cases of hypotension, worsening heart failure, and/or arrhythmia have been reported in Sensipar-treated patients with impaired cardiac function in postmarketing safety surveillance.