Cinacalcet

Cinacalcet is a positive modulator of the calcium sensing receptor indicated for: Secondary Hyperparathyroidism (HPT) in adult patients with chronic kidney disease (CKD) on dialysis. ( 1.1) Limitations of Use: Cinacalcet tablets are not indicated for use in patients with CKD who are not on dialysis Hypercalcemia in adult patients with Parathyroid Carcinoma (PC). ( 1.2 ) Hypercalcemia in adult patients with primary HPT for whom parathyroidectomy would be indicated on the basis of serum calcium levels, but who are unable to undergo parathyroidectomy. ( 1.3 )

1.1 Secondary Hyperparathyroidism Cinacalcet tablets are indicated for the treatment of secondary hyperparathyroidism (HPT) in adult patients with chronic kidney disease (CKD) on dialysis [see Clinical Studies (14.1) ]. Limitations of Use: Cinacalcet tablets are not indicated for use in patients with CKD who are not on dialysis because of an increased risk of hypocalcemia [see Warnings and Precautions (5.1) ] .

1.2 Parathyroid Carcinoma Cinacalcet tablets are indicated for the treatment of hypercalcemia in adult patients with Parathyroid Carcinoma [see Clinical Studies (14.2) ] .

1.3 Primary Hyperparathyroidism Cinacalcet tablets are indicated for the treatment of hypercalcemia in adult patients with primary HPT for whom parathyroidectomy would be indicated on the basis of serum calcium levels, but who are unable to undergo parathyroidectomy [see Clinical Studies (14.3) ].

Cinacalcet tablets, 30 mg are light green, film-coated, oval shaped, biconvex tablets debossed with “80” on one side and “Y” on the other side. Cinacalcet tablets, 60 mg are light green, film-coated, oval shaped, biconvex tablets debossed with “81” on one side and “Y” on the other side. Cinacalcet tablets, 90 mg are light green, film-coated, oval shaped, biconvex tablets debossed with “82” on one side and “Y” on the other side. Tablets: 30 mg, 60 mg, and 90 mg tablets ( 3 )

Cinacalcet tablets treatment initiation is contraindicated if serum calcium is less than the lower limit of the normal range [see Warnings and Precautions (5.1) ] . Cinacalcet tablets treatment initiation is contraindicated if serum calcium is less than the lower limit of the normal range. ( 4 , 5.1 )

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 Bone Disease : May develop if iPTH levels are suppressed below 100 pg/mL. (5.4)

5.1 Hypocalcemia Cinacalcet 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 cinacalcet, including in pediatric patients. The safety and effectiveness of cinacalcet have not been established in pediatric patients [see Pediatric Use (8.4) ]. Cinacalcet is not indicated for patients with CKD not on dialysis [see Indications and Usage (1) ]. In patients with secondary HPT and CKD not on dialysis, the long-term safety and efficacy of cinacalcet have not been established. Clinical studies indicate that cinacalcet-treated patients with CKD not on dialysis have an increased risk for hypocalcemia compared with 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 cinacalcet-treated patients experienced at least one serum calcium value < 8.4 mg/dL compared with 5% of patients receiving placebo. QT Interval Prolongation and Ventricular Arrhythmia 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 cinacalcet. 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 cinacalcet. Closely monitor corrected serum calcium and QT interval in patients at risk receiving cinacalcet. Seizures In clinical studies, seizures (primarily generalized or tonic-clonic) were observed in 1.4% (43/3049) of cinacalcet-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 cinacalcet. Concurrent Administration with Other Calcium-Lowering Drug Products Concurrent administration of cinacalcet with calcium-lowering drugs including other calcium- sensing receptor agonists could result in severe hypocalcemia. Closely monitor serum calcium in patients receiving cinacalcet 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). Cinacalcet dose reduction or discontinuation of cinacalcet 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 cinacalcet, 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 cinacalcet treatment. Monitor patients for worsening of common GI adverse reactions of nausea and vomiting associated with cinacalcet [see Adverse Reactions (6.1) ] and for signs and symptoms of GI bleeding and ulcerations during cinacalcet 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 cinacalcet 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 cinacalcet for 1 year. Three patients with mild hyperparathyroid bone disease at the beginning of the study developed adynamic bone disease during treatment with 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 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 cinacalcet, the dose of cinacalcet and/or vitamin D sterols should be reduced or therapy discontinued.

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 cinacalcet were nausea and vomiting. (6) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 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 cinacalcet, 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 cinacalcet-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 * Included are events that were reported at a greater incidence in the cinacalcet group than in the placebo group. Event*: Placebo (n=470) (%) Cinacalcet (n=656) (%) Nausea Vomiting Diarrhea Myalgia Dizziness Hypertension Asthenia Anorexia Pain Chest, Non-Cardiac Dialysis Access Site Infection 19 15 20 14 8 5 4 4 4 4 31 27 21 15 10 7 7 6 6 5 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 cinacalcet group), the most frequently reported adverse reactions (incidence of ≥ 5% in the cinacalcet 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 1 Adverse reactions that occurred in ≥ 5% frequency in the cinacalcet 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. Placebo (n=1923) Cinacalcet (n=1938) 3699 subject-years 4044 subject-years Percent of subjects reporting Adverse Reactions (%) 90.9

93.2 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 Additional adverse reaction rates from the long-term, randomized, double-blind placebo-controlled study for cinacalcet 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 cinacalcet 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 during treatment with cinacalcet 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% (0/46) 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 n=Number of subjects receiving at least one dose of study drug. pHPT=primary hyperparathyroidism. Cinacalcet Parathyroid Carcinoma (n=29) Intractable pHPT (n=17) Total (n=46) n (%) n (%) n (%) Number of Subjects Reporting Adverse Reactions Nausea Vomiting Paresthesia Fatigue Fracture Hypercalcemia Anorexia Asthenia Dehydration Anemia Arthralgia Constipation Depression Headache Infection Upper Respiratory Pain Limb 28 (97) 19 (66) 15 (52) 4 (14) 6 (21) 6 (21) 6 (21) 6 (21) 5 (17) 7 (24) 5 (17) 5 (17) 3 (10) 3 (10) 6 (21) 3 (10) 3 (10) 17 (100) 10 (59) 6 (35) 5 (29) 2 (12) 2 (12) 2 (12) 1 (6) 2 (12) 0 (0) 1 (6) 1 (6) 3 (18) 3 (18) 0 (0) 2 (12) 2 (12) 45 (98) 29 (63) 21 (46) 9 (20) 8 (17) 8 (17) 8 (17) 7 (15) 7 (15) 7 (15) 6 (13) 6 (13) 6 (13) 6 (13) 6 (13) 5 (11) 5 (11) 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 n = Number of subjects receiving at least one dose of study drug Coded using MedDRA version 16.0. 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) Hypocalcemia In 26-week studies of patients with secondary HPT and CKD on dialysis 66% of patients receiving cinacalcet 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 cinacalcet 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 cinacalcet 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 cinacalcet 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 cinacalcet-treated patients and 0% (0/34) of placebo-treated patients. […]

Co-administration with a strong CYP3A4 inhibitor may increase serum levels of cinacalcet. Dose adjustment and monitoring of iPTH serum phosphorus and serum calcium may be required. ( 7.1 ) Cinacalcet is a strong inhibitor of CYP2D6. Dose adjustments may be required for concomitant medications that are predominantly metabolized by CYP2D6. ( 7.2 )

7.1 Strong CYP3A4 Inhibitors Cinacalcet is partially metabolized by CYP3A4. Dose adjustment of cinacalcet may be required if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole). The iPTH and serum calcium concentrations should be closely monitored in these patients [see Clinical Pharmacology (12.3) ] . 7.2 CYP2D6 Substrates Cinacalcet is a strong inhibitor of CYP2D6. Dose adjustments may be required for concomitant medications that are predominantly metabolized by CYP2D6 (e.g., desipramine, metoprolol, and carvedilol) and particularly those with a narrow therapeutic index (e.g., flecainide and most tricyclic antidepressants) [see Clinical Pharmacology (12.3) ] .

Pediatric Use: A fatal outcome was reported in a pediatric clinical trial patient with severe hypocalcemia. Cinacalcet is not indicated for use in pediatric patients. ( 8.4 )

8.1 Pregnancy Risk Summary Limited case reports of cinacalcet use in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes. In animal reproduction studies, when female rats were exposed to cinacalcet during the period of organogenesis through to weaning at 2 to 3 times the systemic drug levels (based on AUC) at the maximum recommended human dose (MRHD) of 180 mg/day, peripartum and early postnatal pup loss and reduced pup body weight gain were observed in the presence of maternal hypocalcemia [see Data] . The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data 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 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. 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.

8.2 Lactation Risk Summary There are no data regarding the presence of cinacalcet in human milk or effects on the breastfed infant or on milk production. Studies in rats showed that cinacalcet was excreted in the milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for cinacalcet and any potential adverse effects on the breastfed infant from cinacalcet or from the underlying maternal condition.

8.4 Pediatric Use The safety and efficacy of cinacalcet have not been established in pediatric patients. The use of cinacalcet for the treatment of secondary HPT in pediatric patients with CKD on dialysis was evaluated in two randomized, controlled studies (Pediatric Study 1 and Study 2) where 47 pediatric patients aged 6 years to less than 18 years received at least one dose of cinacalcet and in one single-arm study (Pediatric Study 3) where 17 pediatric patients aged 28 days to less than 6 years received at least one dose of cinacalcet. Dosing with cinacalcet in Pediatric Study 1 was stopped because of a fatality in a cinacalcet-treated individual. The individual was noted to be severely hypocalcemic at the time of death. The cause of death was multifactorial and a contribution of cinacalcet to the death could not be excluded [see Warnings and Precautions (5.1) ]. Study 1 was terminated and changes to cinacalcet dosing after the fatality were implemented in Pediatric Study 2 and Study 3 to minimize the risk of severe hypocalcemia. The data in Pediatric Studies 2 and 3 were insufficient to establish the safety and efficacy of cinacalcet for the treatment of secondary HPT in pediatric patients with CKD on dialysis. In aggregate, the pediatric studies did not establish a safe and effective cinacalcet dosing regimen for the pediatric population.

8.5 Geriatric Use Of the total number of subjects (n = 1136) in clinical studies of cinacalcet, 26 percent were 65 and over, and 9 percent were 75 and over. No overall differences in the safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Studies (14) and Clinical Pharmacology (12.3) ] .

8.6 Renal Impairment No dosage adjustment is necessary for renal impairment [see Clinical Pharmacology (12.3) ] .

8.7 Hepatic Impairment Patients with moderate and severe hepatic impairment should have serum calcium, serum phosphorus, and iPTH levels monitored closely throughout treatment with cinacalcet because cinacalcet exposure (AUC 0-infinite ) is increased by 2.4 and 4.2 fold, respectively, in these patients [see Clinical Pharmacology (12.3) ] .

The calcium-sensing receptor on the surface of the chief cell of the parathyroid gland is the principal regulator of PTH synthesis and secretion. Cinacalcet, the active ingredient in cinacalcet tablets, is a calcimimetic agent that directly lowers PTH levels by increasing the sensitivity of the calcium-sensing receptor to activation by extracellular calcium. The reduction in PTH is associated with a concomitant decrease in serum calcium levels.