Cinacalcet Drug Information

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.

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 . 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 .

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.

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 . Initiate Cinacalcet treatment at a starting dose of 30 mg once daily.

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 . 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 .

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

Nausea 15.5 29.1 Vomiting 13.7 25.6 Diarrhea 18.7 20.5 Dyspnea 11.5 13.4

Cough 9.8

Abdominal pain 9.6 10.9 Abdominal pain upper 6.3 8.2 Hyperkalemia 6.1 8.1

Upper respiratory tract infection 6.3

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 17 45 Nausea 19 10 29 Vomiting 15 6 21 Paresthesia 4 5 9 Fatigue 6 2 8 Fracture 6 2 8 Hypercalcemia 6 2 8 Anorexia 6 1 7 Asthenia 5 2 7 Dehydration 7 0 7 Anemia 5 1 6 Arthralgia 5 1 6 Constipation 3 3 6 Depression 3 3 6 Headache 6 0 6 Infection Upper Respiratory 3 2 5 Pain Limb 3 2 5 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 10 Muscle spasms 0 6 Headache 2 4 Back pain 2 4 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 and ≤ 12.5 mg/dL ), 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.

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)

Strong

CYP3A4 Inhibitors Cinacalcet is partially metabolized by CYP3A4. Dose adjustment of cinacalcet tablets 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 .

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) .

Pediatric Use The safety and efficacy of cinacalcet tablets 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 a 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 . 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.

Cinacalcet tablets treatment initiation is contraindicated if serum calcium is less than the lower limit of the normal range. Cinacalcet tablets treatment initiation is contraindicated if serum calcium is less than the lower limit of the normal range.

Overdosage of cinacalcet may lead to hypocalcemia. In the event of overdosage, patients should be monitored for signs and symptoms of hypocalcemia and appropriate measures taken to correct serum calcium levels . Since cinacalcet is highly protein bound, hemodialysis is not an effective treatment for overdosage of cinacalcet tablets.