Cinacalcet

1 INDICATIONS AND USAGE 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 )] .

2 DOSAGE AND ADMINISTRATION Cinacalcet tablets should be taken with food or shortly after a meal ( 2.1 ). Tablets should always be taken whole and not divided ( 2.1 ) Secondary HPT in patients with CKD on dialysis ( 2.2 ): Starting dose is 30 mg once daily. Titrate dose no more frequently than every 2 to 4 weeks through sequential doses of 30, 60, 90, 120, and 180 mg once daily as necessary to achieve targeted intact parathyroid hormone (iPTH) levels. iPTH levels should be measured no earlier than 12 hours after most recent dose. Hypercalcemia in patients with PC or hypercalcemia in patients with primary HPT ( 2.3 ): Starting dose is 30 mg twice daily. Titrate dose every 2 to 4 weeks through sequential doses of 30 mg twice daily, 60 mg twice daily, 90 mg twice daily, and 90 mg three or four times daily as necessary to normalize serum calcium levels. Once the maintenance dose has been established, monitor serum calcium approximately monthly for patients with secondary HPT and every 2 months for patients with PC or primary HPT ( 2.4 ) 2.1 Administration Cinacalcet tablets should be taken with food or shortly after a meal. Cinacalcet tablets are administered orally and should always be taken whole and not chewed, crushed, or divided. 2.2 Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease on Dialysis The recommended starting oral dose of cinacalcet tablets is 30 mg once daily. Serum calcium and serum phosphorus should be measured within 1 week and intact parathyroid hormone (iPTH) should be measured 1 to 4 weeks after initiation or dose adjustment of cinacalcet tablets [see Dosage and Administration ( 2.3 )] . Cinacalcet tablets should be titrated no more frequently than every 2 to 4 weeks through sequential doses of 30, 60, 90, 120, and 180 mg once daily to target iPTH levels of 150 to 300 pg/mL. Serum iPTH levels should be assessed no earlier than 12 hours after dosing with cinacalcet tablets. Cinacalcet tablets can be used alone or in combination with vitamin D sterols and/or phosphate binders. During dose titration, serum calcium levels should be monitored frequently and if levels decrease below the normal range, appropriate steps should be taken to increase serum calcium levels, such as by providing supplemental calcium, initiating or increasing the dose of calcium-based phosphate binder, initiating or increasing the dose of vitamin D sterols, or temporarily withholding treatment with cinacalcet tablets [see Dosage and Administration ( 2.4 ) and Warnings and Precautions ( 5.1 )] . 2.3 Patients with Parathyroid Carcinoma and Primary Hyperparathyroidism The recommended starting oral dose of cinacalcet tablet is 30 mg twice daily. The dose of cinacalcet tablets should be titrated every 2 to 4 weeks through sequential doses of 30 mg twice daily, 60 mg twice daily, and 90 mg twice daily, and 90 mg 3 or 4 times daily as necessary to normalize serum calcium levels. Serum calcium should be measured within 1 week after initiation or dose adjustment of cinacalcet tablets [see Dosage and Administration ( 2.4 ) and Warnings and Precautions ( 5.1 )]. 2.4 Switching from Parsabiv (etelcalcetide) to Cinacalcet Discontinue etelcalcetide for at least 4 weeks prior to starting Cinacalcet. Ensure corrected serum calcium is at or above the lower limit of normal prior to Cinacalcet initiation [see Warnings and Precautions (5.1)] . Initiate Cinacalcet treatment at a starting dose of 30 mg once daily. 2.5 Monitoring for Hypocalcemia Once the maintenance dose has been established, serum calcium should be measured approximately monthly for patients with secondary hyperparathyroidism with CKD on dialysis, and every 2 months for patients with parathyroid carcinoma or primary hyperparathyroidism [see Dosage and Administration ( 2.2 , 2.3 )] . For secondary hyperparathyroidism patients with CKD on dialysis, 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 cinacalcet tablets 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 cinacalcet tablets [see Dosage and Administration ( 2.2 )] .

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 cinacalcet were nausea and vomiting. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Cipla Ltd., at 1-866-604-3268 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 Placebo (n = 470) Cinacalcet (n = 656) Event Included are events that were reported at a greater incidence in the cinacalcet group than in the placebo group (%) (%) 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 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 Study1 Adverse reactions that occurred in ≥ 5% frequency in the cinacalcet group and a difference ≥1% compared to the placebo group (Safety Analysis Set) 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 5.0 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 cinacalcet tablets 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 tablets in these patient populations is generally consistent with that seen in patients with CKD on dialysis. Forty six patients were treated with cinacalcet tablets 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 tablets 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 Cinacalcet Tablets Parathyroid Carcinoma (n=29) n (%) Intractable pHPT (n=17) n (%) Total (n=46) n (%) Number of Subjects Reporting Adverse Reactions 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) 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 cinacalcet tablets 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 tablets 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 tablets 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 tablets 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. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of cinacalcet tablets. 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)

12.3 Pharmacokinetics Absorption and Distribution After oral administration of cinacalcet, C max is achieved in approximately 2 to 6 hours. Cinacalcet C max and AUC (0-infinite) were increased by 82% and 68%, respectively, following administration with a high-fat meal compared with fasting in healthy volunteers. The C max and AUC (0-infinite) of cinacalcet were increased by 65% and 50%, respectively, when cinacalcet was administered with a low-fat meal compared with fasting. After absorption, cinacalcet concentrations decline in a biphasic fashion with an initial half-life of approximately 6 hours and terminal half-life of 30 to 40 hours. Steady-state drug levels are achieved within 7 days, and the mean accumulation ratio is approximately 2 with once daily oral administration. The median accumulation ratio is approximately 2 to 5 with twice daily oral administration. The AUC and C max of cinacalcet increase proportionally over the dose range of 30 to 180 mg once daily. The pharmacokinetic profile of cinacalcet does not change over time with once daily dosing of 30 to 180 mg. The volume of distribution is approximately 1000 L, indicating extensive distribution. Cinacalcet is approximately 93% to 97% bound to plasma protein(s). The ratio of blood cinacalcet concentration to plasma cinacalcet concentration is 0.80 at a blood cinacalcet concentration of 10 ng/mL. Metabolism and Excretion Cinacalcet is metabolized by multiple enzymes, primarily CYP3A4, CYP2D6, and CYP1A2. After administration of a 75 mg radiolabeled dose to healthy volunteers, cinacalcet was metabolized via: 1) oxidative N-dealkylation to hydrocinnamic acid and hydroxy-hydrocinnamic acid, which are further metabolized via β-oxidation and glycine conjugation; the oxidative N-dealkylation process also generates metabolites that contain the naphthalene ring; and 2) oxidation of the naphthalene ring on the parent drug forming dihydrodiols, which are further conjugated with glucuronic acid. The plasma concentrations of the major circulating metabolites, including the cinnamic acid derivatives and glucuronidated dihydrodiols, markedly exceed the parent drug concentrations. The hydrocinnamic acid metabolite and glucuronide conjugates have minimal or no calcimimetic activity. Renal excretion of metabolites was the primary route of elimination of radioactivity. Approximately 80% of the dose was recovered in the urine and 15% in the feces. Specific Populations Age: Geriatric Population The pharmacokinetic profile of cinacalcet in geriatric patients (age ≥ 65 years, n = 12) is similar to that for patients who are < 65 years of age (n = 268) [see Use in Specific Populations ( 8.5 )] . Hepatic Impairment The disposition of a 50 mg cinacalcet tablets single dose was compared between patients with hepatic impairment and patients with normal hepatic function. Cinacalcet exposure (AUC (0-infinite) ) was comparable between healthy volunteers and patients with mild hepatic impairment. However, in patients with moderate and severe hepatic impairment (as indicated by the Child-Pugh method), cinacalcet exposures (AUC (0-infinite) ) were 2.4 and 4.2 fold higher, respectively, than that in healthy volunteers. The mean half-life of cinacalcet increased from 49 hours in healthy volunteers to 65 hours and 84 hours in patients with moderate and severe hepatic impairment, respectively. Protein binding of cinacalcet is not affected by impaired hepatic function [see Use in Specific Populations ( 8.7 )]. Renal Impairment The pharmacokinetic profile of a 75 mg cinacalcet tablets single dose in patients with mild, moderate, and severe renal impairment, and those on hemodialysis or peritoneal dialysis is comparable with that in healthy volunteers [see Use in Specific Populations ( 8.6 )] . Drug Interactions In vitro studies indicate that cinacalcet is a strong inhibitor of CYP2D6, but not an inhibitor of CYP1A2, CYP2C9, CYP2C19, and CYP3A4. In vitro induction studies indicate that cinacalcet is not an inducer of CYP450 enzymes. Tables 5 and 6 list the findings from in vivo drug-drug interaction studies. Table 5. Effect of co-administered drugs on cinacalcet Co-administered drug and dosing regimen Cinacalcet Dose Single dose. Mean change in AUC (0-inf) Mean change in C max 200 mg ketoconazole twice daily for 7 days 90 mg on day 5 ↑127% ↑116% 1500 mg calcium carbonate, single dose 100 mg ↓6% ↓5% 80 mg pantoprazole daily for 3 days 90 mg on day 3 ↑1% ↓3% 2400 mg sevelamer HCl three times a day for 2 days 90 mg on day 1 with first dose of sevelamer ↓4% ↓7% Table 6. Effect of cinacalcet co-administration on other drugs Cinacalcet dosing regimen Co-administered drug Name and Dose Mean change in AUC (0-inf) Mean change in C max 30 mg twice daily for 8 days 25 mg warfarin No significant change in prothrombin time. tablet Single dose on day 5. ↑1 % for R-warfarin ↓1% for S-warfarin ↓10 % for R-warfarin ↓12 % for S-warfarin 90 mg daily for 7 days to CYP2D6 extensive metabolizers 50 mg desipramine ↑264% ↑75% 90 mg daily for 5 days 2 mg midazolam † ↑5% ↓5% 25 or 100 mg single dose to CYP2D6 extensive metabolizers 50 mg amitriptyline single dose ↑21-22% for amitriptyline ↑17-23% for nortriptyline Nortriptyline is an active metabolite of amitriptyline. ↑13-21% for amitriptyline ↑11-15% for nortriptyline