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warnings and cautions
5 WARNINGS AND PRECAUTIONS Hypocalcemia : Life threatening events and fatal outcomes were reported. Hypocalcemia can prolong QT interval, lower the threshold for seizures, and cause hypotension, worsening heart failure, and/or arrhythmia. Monitor serum calcium carefully for the occurrence of hypocalcemia during treatment. ( 2.4 , 5.1 ) Upper Gastrointestinal (GI) Bleeding: Patients with risk factors for upper GI bleeding may be at increased risk. Monitor patients and promptly evaluate and treat any suspected GI bleeding. ( 5.2 ) Hypotension, Worsening Heart Failure and/or Arrhythmias : In postmarketing safety surveillance, isolated, idiosyncratic cases of hypotension, worsening heart failure, and/or arrhythmia have been reported in patients with impaired cardiac function. ( 5.3 ) Adynamic B one D isease : May develop if iPTH levels are suppressed below 100 pg/mL. ( 5.4 ) 5.1 Hypocalcemia Sensipar lowers serum calcium and can lead to hypocalcemia [see Adverse Reactions ( 6.1 )]. Significant lowering of serum calcium can cause paresthesias, myalgias, muscle spasms, tetany, seizures, QT interval prolongation and ventricular arrhythmia. Life threatening events and fatal outcomes associated with hypocalcemia have been reported in patients treated with Sensipar, including in pediatric patients. The safety and effectiveness of Sensipar have not been established in pediatric patients [see Pediatric Use ( 8.4 )]. Sensipar is not indicated for patients with CKD not on dialysis [see I ndications and Usage ( 1 )] . 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. QT Interval Prolongation and V entricular A rr h ythmia Decreases in serum calcium can also prolong the QT interval, potentially resulting in ventricular arrhythmia. Cases of QT prolongation and ventricular arrhythmia have been reported in patients treated with Sensipar. Patients with congenital long QT syndrome, history of QT interval prolongation, family history of long QT syndrome or sudden cardiac death, and other conditions that predispose to QT interval prolongation and ventricular arrhythmia may be at increased risk for QT interval prolongation and ventricular arrhythmias if they develop hypocalcemia due to Sensipar. Closely monitor corrected serum calcium and QT interval in patients at risk receiving Sensipar. 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. Monitor serum calcium levels in patients with seizure disorders receiving Sensipar . Concurrent Administration with Other Calcium-Lowering Drug Products Concurrent administration of Sensipar with calcium-lowering drugs including other calcium-sensing receptor agonists could result in severe hypocalcemia. Closely monitor serum calcium in patients receiving Sensipar and concomitant therapies known to lower serum calcium levels. Patient Education and Hypocalcemia Treatment Educate patients on the symptoms of hypocalcemia and advise them to contact a healthcare provider if they occur. If corrected serum calcium falls below the lower limit of normal or symptoms of hypocalcemia develop, start or increase calcium supplementation (including calcium, calcium-containing phosphate binders, and/or vitamin D sterols or increases in dialysate calcium concentration). Sensipar dose reduction or discontinuation of Sensipar may be necessary [see Dosage and Administration ( 2.2 )]. 5.2 Upper Gastrointestinal Bleeding Cases of gastrointestinal bleeding, mostly upper gastrointestinal bleeding, have occurred in patients using calcimimetics, including Sensipar, from postmarketing and clinical trial sources. The exact cause of GI bleeding in these patients is unknown. Patients with risk factors for upper GI bleeding (such as known gastritis, esophagitis, ulcers or severe vomiting) may be at increased risk for GI bleeding when receiving Sensipar treatment. Monitor patients for worsening of common GI adverse reactions of nausea and vomiting associated with Sensipar [see Adverse Reactions ( 6.1 )] and for signs and symptoms of GI bleeding and ulcerations during Sensipar therapy. Promptly evaluate and treat any suspected GI bleeding. 5.3 Hypotension, Worsening Heart Failure and/or Arrhythmias 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.
6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of labeling: Hypocalcemia [see Warnings and Precautions ( 5.1 )] Upper Gastrointestinal Bleeding [see Warnings and Precautions ( 5.2 )] Hypotension, Worsening Heart Failure and/or Arrhythmias [ see Warnings and Precautions ( 5.3 )] Adynamic Bone Disease [see Warnings and Precautions ( 5.4 )] The most common adverse reactions (i.e., ≥ 25%) associated with Sensipar were nausea and vomiting. ( 6 ) 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 are listed in Table 1. Seizures were observed in 1.4% (13/910) of Sensipar-treated patients and 0.7% (5/641) of placebo-treated patients across all completed placebo-controlled trials. Table 1. Adverse Reactions with Frequency ≥ 5% in Patients on Dialysis in Short-Term Studies for up to 6 Months 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 Dialysis Access Site Infection 4 5 *Included are events that were reported at a greater incidence in the Sensipar group than in the placebo group. In a randomized, double-blind placebo-controlled study of 3883 patients with secondary HPT and CKD receiving dialysis in which patients were treated for up to 64 months (mean duration of treatment was 21 months in the Sensipar group), the most frequently reported adverse reactions (incidence of ≥ 5% in the Sensipar group and a difference ≥ 1% compared to placebo) are listed in Table 2. Table 2. Frequency of Adverse Reactions in Dialysis Patients Treated for up to 64 Months in a Long-Term Study 1 Placebo (n = 1923) Sensipar (n = 1938) 3699 subject-years 4044 subject-years Percent of subjects reporting 90.9 93.2 Adverse Reactions (%) Nausea 15.5 29.1 Vomiting 13.7 25.6 Diarrhea 18.7 20.5 Dyspnea 11.5 13.4 Cough 9.8 11.7 Hypotension 10.5 11.6 Headache 9.6 11.5 Hypocalcemia 1.4 11.2 Muscle spasms 9.2 11.1 Abdominal pain 9.6 10.9 Abdominal pain upper 6.3 8.2 Hyperkalemia 6.1 8.1 Upper respiratory tract infection 6.3 7.6 Dyspepsia 4.6 7.4 Dizziness 4.7 7.3 Decreased appetite 3.5 5.9 Asthenia 3.8 5.4 Constipation 3.8 5.0 1 Adverse reactions that occurred in ≥ 5% frequency in the Sensipar group and a difference ≥ 1% compared to the placebo group (Safety Analysis Set). Crude incidence rate = 100 * Total number of subjects with event/ n n = Number of subjects receiving at least one dose of study drug. Additional adverse reaction rates from the long-term, randomized, double-blind placebo-controlled study for Sensipar versus placebo are as follows: seizure (2.5%, 1.6%), rash (2.2%, 1.9%), hypersensitivity reactions (9.4%, 8.3%). Patients with 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 Sensipar 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 during treatment with Sensipar in this 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 3. Adverse Reactions with Frequency ≥ 10% in a Single-Arm, Open-Label Study in Patients with Primary Hyperparathyroidism or Parathyroid Carcinoma Sensipar Parathyroid Carcinoma (n = 29) Intractable pHPT (n = 17) Total (n = 46) n (%) n (%) n (%) Number of Subjects Reporting Adverse 28 (97) 17 (100) 45 (98) Reactions 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) n = Number of subjects receiving at least one dose of study drug. pHPT = primary hyperparathyroidism. In a randomized double-blind, placebo-controlled study of 67 patients with primary hyperparathyroidism for whom parathyroidectomy would be indicated on the basis of serum calcium levels, but who are unable to undergo surgery, the most common adverse reactions are listed in Table 4. Table 4 . Adverse Reactions Occurring in ≥ 10% of Subjects in a Double - Blind, Placebo - Controlled Study in Patients with Primary Hyperparathyroidism Adverse Reaction Placebo (n = 34) n (%) Cinacalcet (n = 33) n (%) Nausea 6 (18) 10 (30) Muscle spasms 0 (0) 6 (18) Headache 2 (6) 4 (12) Back pain 2 (6) 4 (12) n = Number of subjects receiving at least one dose of study drug Coded using MedDRA version 16.0. Hypocalcemia In 26-week studies of patients with secondary HPT and CKD on dialysis 66% of patients receiving Sensipar compared with 25% of patients receiving placebo developed at least one serum calcium value less than 8.4 mg/dL, whereas, 29% of patients receiving Sensipar compared with 11% of patients receiving placebo developed at least one serum calcium value less than 7.5 mg/dL. Less than 1% of patients in each group permanently discontinued study drug due to hypocalcemia. In a randomized, double-blind, placebo-controlled study in patients with secondary HPT and CKD receiving dialysis in which patients were treated for up to 64 months (mean duration of treatment was 21 months in the cinacalcet group), 75% of patients receiving Sensipar compared with 29% of patients receiving placebo developed at least one serum calcium value less than 8.4 mg/dL and 33% of cinacalcet patients compared with 12% of patients receiving placebo had at least one serum calcium value less than 7.5 mg/dL. Most of the cases of severe hypocalcemia less than 7.5 mg/dL (21/33 = 64%) occurred during the first 6 months. In this trial, 1.1% of patients receiving Sensipar and 0.1% of patients receiving placebo permanently discontinued study drug due to hypocalcemia. During a placebo-controlled part of a 52-week study in patients with primary HPT who met criteria for parathyroidectomy on the basis of corrected total serum calcium (> 11.3 mg/dL [2.82 mmol/L] and ≤ 12.5 mg/dL [3.12 mmol/L]), serum calcium less than 8.4 mg/dL was observed in 6.1% (2/33) of Sensipar-treated patients and 0% (0/34) of placebo-treated patients. 6.2 Postmarketing Experience The following adverse reactions have been identified 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. Rash and hypersensitivity reactions (including angioedema and urticaria), and myalgia Isolated, idiosyncratic cases of hypotension, worsening heart failure, and/or arrhythmia have been reported in patients with impaired cardiac function Gastrointestinal bleeding Chondrocalcinosis pyrophosphate (acute pseudogout)
adverse reactions table
<table><caption>Table 1. Adverse Reactions with Frequency ≥ 5% in Patients on Dialysis in Short-Term Studies for up to 6 Months</caption><col width="25"/><col width="325"/><col width="113"/><col width="400"/><tbody><tr><td styleCode="Toprule Lrule "/><td styleCode="Toprule "><content styleCode="bold"> </content></td><td styleCode="Toprule " align="center"><content styleCode="bold">Placebo</content></td><td styleCode="Toprule Rrule " align="center"><content styleCode="bold">Sensipar</content></td></tr><tr><td styleCode="Lrule "> </td><td> </td><td align="center">(n = 470)</td><td styleCode="Rrule " align="center">(n = 656)</td></tr><tr><td styleCode="Lrule " colspan="2">Event*:</td><td align="center">(%)</td><td styleCode="Rrule " align="center">(%)</td></tr><tr><td styleCode="Toprule Lrule " colspan="2">Nausea</td><td styleCode="Toprule " align="center">19</td><td styleCode="Toprule Rrule " align="center">31</td></tr><tr><td styleCode="Lrule " colspan="2">Vomiting</td><td align="center">15</td><td styleCode="Rrule " align="center">27</td></tr><tr><td styleCode="Lrule " colspan="2">Diarrhea</td><td align="center">20</td><td styleCode="Rrule " align="center">21</td></tr><tr><td styleCode="Lrule " colspan="2">Myalgia</td><td align="center">14</td><td styleCode="Rrule " align="center">15</td></tr><tr><td styleCode="Lrule " colspan="2">Dizziness</td><td align="center">8</td><td styleCode="Rrule " align="center">10</td></tr><tr><td styleCode="Lrule " colspan="2">Hypertension</td><td align="center">5</td><td styleCode="Rrule " align="center">7</td></tr><tr><td styleCode="Lrule " colspan="2">Asthenia</td><td align="center">4</td><td styleCode="Rrule " align="center">7</td></tr><tr><td styleCode="Lrule " colspan="2">Anorexia</td><td align="center">4</td><td styleCode="Rrule " align="center">6</td></tr><tr><td styleCode="Lrule " colspan="2">Pain Chest, Non-Cardiac</td><td align="center">4</td><td styleCode="Rrule " align="center">6</td></tr><tr><td styleCode="Lrule " colspan="2">Dialysis Access Site Infection</td><td align="center">4</td><td styleCode="Rrule " align="center">5</td></tr><tr><td styleCode="Toprule " colspan="4">*Included are events that were reported at a greater incidence in the Sensipar group than in the placebo group.</td></tr></tbody></table>