Cinacalcet

FDA Drug Information • Also known as: Cinacalcet, Cinacalcet Hydrochloride

Brand Names: Cinacalcet, Cinacalcet Hydrochloride
Route: ORAL
Dosage Form: TABLET, FILM COATED
Product Type: HUMAN PRESCRIPTION DRUG

Description

11 DESCRIPTION Cinacalcet tablets contain the hydrochloride salt of the active ingredient cinacalcet, a positive modulator of the calcium sensing receptor. The empirical formula for cinacalcet is C 22 H 22 F 3 N⋅HCl with a molecular weight of 393.9 g/mol (hydrochloride salt) and 357.4 g/mol (free base). It has one chiral center having an R-absolute configuration. The R-enantiomer is the more potent enantiomer and has been shown to be responsible for pharmacodynamic activity. The hydrochloride salt of cinacalcet is a white to off-white powder, that is soluble in methanol, 95% ethanol and slightly soluble in water. Cinacalcet tablets are formulated as light-green, oval-shaped, film-coated tablets for oral administration in strengths of 30 mg, 60 mg, and 90 mg of cinacalcet as the free base equivalent (33 mg, 66 mg, and 99 mg as the hydrochloride salt, respectively). The hydrochloride salt of cinacalcet is described chemically as N-[1-(R)-(-)-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-1-aminopropane hydrochloride and has the following structural formula: Inactive Ingredients The following are the inactive ingredients in cinacalcet tablets: Lactose monohydrate, microcrystalline cellulose (GR 101 and GR 102), crospovidone, hydroxypropyl cellulose, magnesium stearate. In addition polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, iron oxide yellow, FD&C blue #2/Indigo carmine AL are included in the film coating.

What Is Cinacalcet Used For?

1 INDICATIONS & 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 is not indicated for use in patients with CKD who are not on dialysis. Hypercalcemia in adult patients with Parathyroid Carcinoma (PC). (1.2) Severe hypercalcemia in adult patients with primary HPT who are unable to undergo parathyroidectomy. (1.3) 1.1 Secondary Hyperparathyroidism Cinacalcet 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 is not indicated for use in adult 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 is indicated for the treatment of hypercalcemia in adult patients with Parathyroid Carcinoma [see Clinical Studies ( 14.2) ] . 1.3 Primary Hyperparathyroidism Cinacalcet are indicated for the treatment of severe hypercalcemia in adult patients with primary HPT who are unable to undergo parathyroidectomy [ see Clinical Studies (14.3) ].

Dosage and Administration

2 DOSAGE & 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 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) 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 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 [see Dosage and Administration (2.3)] . Cinacalcet 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 . Cinacalcet 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 [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 is 30 mg twice daily. The dose of cinacalcet 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 [ see Dosage and Administration (2.4) and...

Side Effects (Adverse Reactions)

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 Ascend Laboratories, LLC at 1-877-ASC-RX01 (877-272-7901) 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 Event*: Placebo (n=470) (%) Cinacalcet (n=656) (%) 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 cinacalcet group than in the placebo group. In a randomized, double-blind placebo controlled study of 3,883 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 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 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 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...

Drug Interactions

7 DRUG INTERACTIONS Co-administration with a strong CYP3A4 inhibitor may increase serum levels of cinacalcet. Dose adjustment and monitoring of iPTH serum phosphorous 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) ] .

Contraindications

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

Pregnancy and Breastfeeding

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 2-3 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 2-4% and 15-20%, 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...

Overdosage

10 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)]. Since cinacalcet is highly protein bound, hemodialysis is not an effective treatment for overdosage of cinacalcet .

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING Cinacalcet Tablets 30 mg are formulated as light green colored, oval shaped, film coated tablets debossed with “A33” on one side and “30” on other side, packaged in- bottles of 30 tablets (NDC 67877-503-30), bottles of 100 tablets (NDC 67877-503-01) and carton of 10 tablets (1x10 Unit-dose) (NDC 67877-503-33) Cinacalcet Tablets 60 mg are formulated as light green colored, oval shaped, film coated tablets debossed with “A34” on one side and “60” on other side, packaged in- bottles of 30 tablets (NDC 67877-504-30), bottles of 100 tablets (NDC 67877-504-01) and carton of 10 tablets (1x10 Unit-dose) (NDC 67877-504-33) Cinacalcet Tablets 90 mg are formulated as light green colored, oval shaped, film coated tablets debossed with “A35” on one side and “90” on other side, packaged in- bottles of 30 tablets (NDC 67877-505-30), bottles of 100 tablets (NDC 67877-505-01) and carton of 10 tablets (1x10 Unit-dose) (NDC 67877-505-33) Storage Store at 25ºC (77ºF); excursions permitted from 15°C to 30ºC (59°F to 86ºF). [See USP Controlled Room Temperature].

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.