CINACALCET- cinacalcet_tablet, film coated

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. Reduction in iPTH levels correlated with the plasma cinacalcet concentrations in patients with CKD. The nadir in iPTH level occurs approximately 2 to 6 hours post dose, corresponding with the maximum plasma concentration (C max Absorption and Distribution max max (0-infinite) max (0-infinite) max [see Use in Specific Populations (8. 5) Hepatic Impairment (0-infinite) (0-infinite) [see Use in Specific Populations (8. 7) [see Use in Specific Populations (8. 6) In vitro in vivo Table 5. Effect of co-administered drugs on cinacalcet *Single dose. Co-administered drug and dosing regimen Cinacalcet 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 up arrow127% up arrow116% 1500 mg calcium carbonate, single dose 100 mg down arrow6% down arrow5% 80 mg pantoprazole daily for 3 days 90 mg on day 3 up arrow1% down arrow3% 2400 mg sevelamer hydrochloride three times a day for 2 days 90 mg on day 1 with first dose of sevelamer down arrow4% down arrow7% Table 6. Effect of cinacalcet co-administration on other drugs *No significant change in prothrombin time. dagger double dagger 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 * dagger up arrow1 % for R-warfarin down arrow10 % for R-warfarin 90 mg daily for 7 days to CYP2D6 extensive metabolizers 50 mg desipramine dagger up arrow264% up arrow75% 90 mg daily for 5 days 2 mg midazolam dagger up arrow5% down arrow5% 25 or 100 mg single dose to CYP2D6 extensive metabolizers 50 mg amitriptyline single dose up arrow21 to 22% for amitriptyline double dagger up arrow13 to 21% for amitriptyline double dagger.

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 Limitations of Use: Hypercalcemia in adult patients with Parathyroid Carcinoma (PC). 2 Severe hypercalcemia in adult patients with primary HPT who are unable to undergo parathyroidectomy. 3 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) 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) Cinacalcet tablets are indicated for the treatment of hypercalcemia in adult patients with Parathyroid Carcinoma [see Clinical Studies (14. 2) Cinacalcet tablets are indicated for the treatment of severe hypercalcemia in adult patients with primary HPT who are unable to undergo parathyroidectomy [see Clinical Studies (14.

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 severe 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) Cinacalcet tablets should be taken with food or shortly after a meal. 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) [see Dosage and Administration (2. 4) Warnings and Precautions (5. 1) The recommended starting oral dose of cinacalcet tablets 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. 1) Discontinue etelcalcetide for at least 4 weeks prior to starting cinacalcet tablets. Ensure corrected serum calcium is at or above the lower limit of normal prior to cinacalcet tablets initiation [see Warnings and Precautions (5. 1) 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. 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 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.

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. , >= 25%) associated with cinacalcet were nausea and vomiting. (6) To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361-3993; or FDA at 1-800-FDA-1088 or www. gov/medwatch 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. Adverse Reactions with Frequency >=5% in Patients on Dialysis in Short-Term Studies for up to 6 Months * Event*: Placebo (n = 470) (%) Cinacalcet (n = 656) (%) Nausea 19 31 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 >= Table 2. Frequency of Adverse Reactions in Dialysis Patients Treated for up to 64 Months in a Long-Term Study 1 1 Placebo (n=1923) Cinacalcet (n=1938) 3699 subject-years 4044 subject-years Percent of subjects reporting Adverse Reactions (%) 90. 2 Nausea 15. 1 Vomiting 13. 6 Diarrhea 18. 5 Dyspnea 11. 7 Hypotension 10. 6 Headache 9. 5 Hypocalcemia 1. 2 Muscle spasms 9. 1 Abdominal pain 9. 9 Abdominal pain upper 6. 2 Hyperkalemia 6. 1 Upper respiratory tract infection 6. 6 Dyspepsia 4. 4 Dizziness 4. 3 Decreased appetite 3. 9 Asthenia 3. 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. 6%), rash (2. 9%), hypersensitivity reactions (9. Seizures were observed in 0. 7% (1/140) of cinacalcet-treated patients and 0% (0/46) of placebo-treated patients in all clinical studies. 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. Cinacalcet Parathyroid Carcinoma (n=29) Intractable pHPT (n=17) Total (n=46) n (%) n (%) n (%) Number of Subjects Reporting Adverse Reactions 28 (97) 17 (100) 45 (98) 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. 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. 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. The following adverse reactions have been identified during post approval use of cinacalcet. 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) To report SUSPECTED ADVERSE REACTIONS contact AvKARE at 1-855-361-3993; email drugsafety@avkare. com; or FDA at 1-800-FDA-1088 or www. gov/medwatch.

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.

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. 4 Risk Summary [see Data] Data Risk Summary 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) 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) Clinical Pharmacology (12. 3) No dosage adjustment is necessary for renal impairment [see Clinical Pharmacology (12. 3) 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 [see Clinical Pharmacology (12.

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. 1 Cinacalcet is a strong inhibitor of CYP2D6. Dose adjustments may be required for concomitant medications that are predominantly metabolized by CYP2D6. 2 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. , ketoconazole, itraconazole). The iPTH and serum calcium concentrations should be closely monitored in these patients [see Clinical Pharmacology (12. 3) Cinacalcet is a strong inhibitor of CYP2D6. Dose adjustments may be required for concomitant medications that are predominantly metabolized by CYP2D6 (e. , desipramine, metoprolol, and carvedilol) and particularly those with a narrow therapeutic index (e. , flecainide and most tricyclic antidepressants) [see Clinical Pharmacology (12.

OVERDOSAGE
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 [see Warnings and Precautions (5.1)
NONCLINICAL TOXICOLOGY
Carcinogenicity in vivo
CLINICAL STUDIES
Three 6-month, multicenter, randomized, double-blind, placebo-controlled clinical studies of similar design were conducted in patients with CKD on dialysis. A total of 665 patients were randomized to cinacalcet and 471 patients to placebo. The mean age of the patients was 54 years, 62% were male, and 52% were Caucasian. The average baseline iPTH level by the Nichols IRMA was 712 pg/mL, with 26% of the patients having a baseline iPTH level > 800 pg/mL. The mean baseline Ca x P product was 61 mg 2 2 Table 7. Effects of Cinacalcet on iPTH, Ca x P, Serum Calcium, and Serum Phosphorus in 6-month Phase 3 Studies (Patients on Dialysis) ** p < 0. 001 compared with placebo; p-values presented for primary endpoint only. a Study 1 Study 2 Study 3 Placebo (n = 205) Cinacalcet (n = 205) Placebo (n = 165) Cinacalcet (n = 166) Placebo (n = 101) Cinacalcet (n = 294) iPTH a a 2 2 535 537 556 547 ** 670 703 ** Ca x P 2 2 2 2 Calcium Phosphorus Data are presented for patients who completed the studies; Placebo (n = 342), Cinacalcet (n = 439). Data are presented for patients who completed the studies; Placebo (n = 342), Cinacalcet (n = 439). Reductions in iPTH and Ca x P were maintained for up to 12 months of treatment. Cinacalcet decreased iPTH and Ca x P levels regardless of disease severity (i. , baseline iPTH value), duration of dialysis, and whether or not vitamin D sterols were administered. Approximately 60% of patients with mild (iPTH >= 300 to <= 500 pg/mL), 41% with moderate (iPTH > 500 to 800 pg/mL), and 11% with severe (iPTH > 800 pg/mL) secondary HPT achieved a mean iPTH value of <= 250 pg/mL. Plasma iPTH levels were measured using the Nichols IRMA. Mean (SE) iPTH Values (Pooled Phase 3 Studies) Figure 2. Mean (SE) Ca x P Values (Pooled Phase 3 Studies) Twenty-nine patients with Parathyroid Carcinoma were enrolled in a single-arm, open-label study. The study consisted of two phases, a dose-titration phase and a maintenance phase. Patients initially received 30 mg cinacalcet twice daily and then were titrated every 2 weeks to a maximum dose of 90 mg four times daily. Dosage escalation during the variable-length (2 to 16 weeks) titration phase continued until the serum calcium concentration was <= 10 mg/dL (2. 5 mmol/L), the patient reached the highest possible dosage, or adverse events precluded further dosage increases. End of Titration (EOT) phase could occur at any visit from week 2 to 16. Patients at EOT are those who completed titration. Figure 3 Seventeen patients with severe hypercalcemia due to primary HPT, who had failed or had contraindications to parathyroidectomy, participated in an open-label, single-arm study. In this trial, severe hypercalcemia was defined as a screening serum calcium level of > 12. Patients initially received 30 mg cinacalcet twice daily and then were titrated every 2 weeks to a maximum dose of 90 mg 4 times daily. Seventeen patients entered the study. The median exposure to cinacalcet was 270 days (range: 32 to 1,105). At baseline the mean (SE) serum calcium was 12. At the end of the titration phase the mean (SE) serum calcium was 10. 3) mg/dL, which is a mean reduction of 2. 3) mg/dL from baseline. Figure 4 illustrates mean serum calcium (mg/dL) over time for all patients still on study at each time point from the beginning of titration to study visit week 80. Daily dose during the study ranged from 30 mg twice a day to 90 mg four times a day. Mean Serum Calcium (SE) at Baseline, End of Titration, and Scheduled Maintenance Visits (Patients with Severe intractable primary HPT) n = Number of patients with non-missing values at the timepoint. Mean Serum Calcium (SE) at Baseline, End of Titration, and Scheduled Maintenance Visits (Patients with Severe intractable primary HPT).

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CINACALCET- cinacalcet_tablet, film coated Product manual source documgent