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Cinacalcet

Class: Antiparathyroid Agents
- Calcium-sensing Receptor Agonists
- Calcimetic Agents
VA Class: HS900
Chemical Name: N-[1-(R)-(-)-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-1-aminopropane hydrochloride
Molecular Formula: C22H22F3N HCl
CAS Number: 364782-34-3
Brands: Sensipar

Medically reviewed by Drugs.com on Aug 18, 2021. Written by ASHP.

Introduction

Calcimimetic agent; binds to and increases sensitivity of calcium-sensing receptors on parathyroid glands to extracellular calcium, resulting in decreased serum parathyroid hormone (PTH) and calcium concentrations.

Uses for Cinacalcet

Secondary Hyperparathyroidism Associated with Chronic Renal Disease

Treatment of secondary hyperparathyroidism associated with chronic renal disease in patients who are undergoing hemodialysis or peritoneal dialysis.

Safety and efficacy in patients who are not undergoing dialysis have not been established.

May be used alone or in conjunction with vitamin D analogs and/or phosphate binders.

Effects on clinical outcomes remain to be fully determined. The primary finding of the EVOLVE trial (a lack of effect on mortality or major cardiovascular events ) is controversial because of study limitations.

Hypercalcemia Associated with Parathyroid Carcinoma

Management of hypercalcemia associated with parathyroid carcinoma; designated an orphan drug by FDA for this use.

Hypercalcemia Associated with Primary Hyperparathyroidism

Treatment of hypercalcemia associated with primary hyperparathyroidism in patients who would be candidates for parathyroidectomy based on serum calcium concentrations but who are unable to undergo the surgery; designated an orphan drug by FDA for this use.

Cinacalcet Dosage and Administration

Administration

Oral Administration

Administer orally with food or shortly after a meal. (See Food under Pharmacokinetics.)

Swallow tablets whole; do not divide.

Dosage

Available as cinacalcet hydrochloride; dosage expressed in terms of cinacalcet.

Individualize dosage.

Severe or prolonged nausea and vomiting can result in dehydration and worsening hypercalcemia; carefully monitor electrolytes in patients with these adverse effects.

Adults

Secondary Hyperparathyroidism Associated with Chronic Renal Disease
Oral

Usual initial dosage: 30 mg once daily.

Manufacturer recommends increasing dosage no more frequently than every 2–4 weeks through sequential adjustments to 60, 90, 120, and 180 mg once daily to achieve a target intact parathyroid hormone (iPTH) concentration of 150–300 pg/mL.

Median dosage was 90 mg daily in 6-month clinical studies; patients with milder disease generally required lower dosages.

Do not initiate cinacalcet if baseline serum calcium concentration is <8.4 mg/dL.

Measure serum calcium and phosphorus concentrations within 1 week and iPTH concentrations 1–4 weeks after initiation or subsequent dosage adjustment; do not assess serum iPTH concentrations earlier than 12 hours following an oral dose.

If serum calcium concentrations fall to <8.4 mg/dL but remain >7.5 mg/dL, or if manifestations of hypocalcemia occur, may use calcium-containing phosphate binders and/or vitamin D analogs to increase serum calcium concentrations.

If serum calcium concentrations fall to <7.5 mg/dL, or hypocalcemia manifestations persist and vitamin D dosage cannot be increased, withhold cinacalcet. When serum calcium concentrations reach 8 mg/dL and/or manifestations of hypocalcemia have resolved, may reinitiate cinacalcet using the next lowest dosage.

Once maintenance dosage is established, measure serum calcium and phosphorus concentrations monthly.

Hypercalcemia Associated with Parathyroid Carcinoma
Oral

Usual initial dosage: 30 mg twice daily.

Increase dosage every 2–4 weeks through sequential adjustments to 60 mg twice daily, 90 mg twice daily, and 90 mg 3 or 4 times daily as needed to normalize serum calcium concentrations.

Measure serum calcium concentration within 1 week of cinacalcet initiation or dosage adjustment; measure every 2 months once an appropriate maintenance dosage has been established.

Hypercalcemia Associated with Primary Hyperparathyroidism
Oral

Usual initial dosage: 30 mg twice daily.

Increase dosage every 2–4 weeks through sequential adjustments to 60 mg twice daily, 90 mg twice daily, and 90 mg 3 or 4 times daily as needed to normalize serum calcium concentrations.

Measure serum calcium concentration within 1 week of cinacalcet initiation or dosage adjustment; measure every 2 months once an appropriate maintenance dosage has been established.

Special Populations

No special population dosage recommendations at this time. (See Hepatic Impairment under Cautions.)

Cautions for Cinacalcet

Contraindications

  • Serum calcium concentrations below lower limit of normal.

Warnings/Precautions

Hypocalcemia

Fatal or life-threatening hypocalcemia reported, including in pediatric patients (see Pediatric Use under Cautions). Substantial lowering of serum calcium can cause paresthesias, myalgia, muscle spasm, tetany, seizures, QT-interval prolongation, and ventricular arrhythmias.

Seizures (mainly generalized or tonic-clonic) reported in 1.4 or 0.7% of patients receiving cinacalcet or placebo, respectively. Reason for reported difference is unclear, but substantial reductions in serum calcium concentrations may lower seizure threshold.

Cases of QT-interval prolongation and ventricular arrhythmia secondary to hypocalcemia reported.

Isolated idiosyncratic cases of hypotension, worsening heart failure, and/or arrhythmia reported in patients with impaired cardiac function. Causal relationship to cinacalcet not excluded; effects possibly mediated by reductions in serum calcium.

Nondialysis patients with chronic renal disease and secondary hyperparathyroidism are at increased risk for developing hypocalcemia; safety and efficacy in such patients not established.

Carefully monitor patients for the occurrence of hypocalcemia; particularly close monitoring required in patients with history of seizure disorder.

If serum calcium concentration falls to <8.4 mg/dL or if hypocalcemia manifestations occur in patients with secondary hyperparathyroidism associated with chronic renal disease, take appropriate steps (e.g., supplement calcium, initiate or increase dosage of calcium-containing phosphate binder or vitamin D analog, temporarily discontinue cinacalcet administration) to increase serum calcium concentrations. (See Secondary Hyperparathyroidism Associated with Chronic Renal Disease under Dosage and Administration.)

Upper GI Bleeding

Upper GI bleeding reported, but exact cause not established. Patients with risk factors for upper GI bleeding (e.g., gastritis, esophagitis, ulcers, severe vomiting) may be at increased risk.

Monitor patients for worsening of nausea and vomiting and for signs and symptoms of GI bleeding or ulceration. Immediately evaluate and treat if GI bleeding is suspected.

Adynamic Bone Disease

Adynamic bone disease may develop if iPTH concentrations are suppressed below 100 pg/mL.

Decrease dosage or discontinue cinacalcet and/or vitamin D analogs if iPTH concentrations fall below 150 pg/mL.

Specific Populations

Pregnancy

Category C. Pregnancy surveillance program (800-772-6436).

Lactation

Distributed into milk in rats; not known whether distributed into human milk. Discontinue nursing or the drug. Encourage women who opt to continue cinacalcet treatment while nursing to enroll in manufacturer's lactation surveillance program (800-772-6436).

Pediatric Use

Safety and efficacy not established in patients <18 years of age; not indicated for use in pediatric patients.

FDA announced suspension of pediatric clinical trials of cinacalcet after death of a 14-year-old adolescent with severe hypocalcemia occurred during a trial.

Geriatric Use

No substantial differences in pharmacokinetics, safety, and efficacy relative to younger adults; however, greater sensitivity of some older patients cannot be ruled out.

Hepatic Impairment

Closely monitor serum phosphorus, iPTH, and serum calcium concentrations in patients with moderate or severe hepatic impairment. (See Absorption: Special Populations and also Elimination: Special Populations, under Pharmacokinetics.)

Common Adverse Effects

Dialysis patients with secondary hyperparathyroidism: Nausea, vomiting, diarrhea, myalgia, dyspnea, cough, hypotension, headache, hypocalcemia, muscle spasms, abdominal pain (including upper abdominal pain), dizziness, hyperkalemia, upper respiratory tract infection, dyspepsia, hypertension, asthenia, anorexia/decreased appetite, noncardiac chest pain, access infection, constipation.

Patients with hypercalcemia associated with parathyroid carcinoma or primary hyperparathyroidism: Adverse effects generally similar to those observed in dialysis patients.

Interactions for Cinacalcet

Metabolized mainly by CYP1A2, 2D6, and 3A4; potent inhibitor of CYP2D6 in vitro. Does not inhibit CYP1A2, 2C9, 2C19, or 3A4 in vitro. Does not induce CYP isoenzymes in vitro.

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A4 inhibitors: Potential increased plasma cinacalcet concentrations. Closely monitor iPTH and serum calcium concentrations upon initiation or discontinuance of potent CYP3A4 inhibitor; cinacalcet dosage adjustment may be required.

Potent CYP3A4 inducers: Potential decreased plasma cinacalcet concentrations. Cinacalcet dosage adjustment may be required if a potent CYP3A4 inducer is initiated or discontinued.

Potent CYP1A2 inhibitors: Potential increased plasma cinacalcet concentrations. Cinacalcet dosage adjustment may be required if a potent CYP1A2 inhibitor is initiated or discontinued.

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP2D6 substrates: Potential increased plasma concentrations of drugs metabolized principally by CYP2D6. Dosage adjustment may be required if cinacalcet is administered concomitantly with a drug that is metabolized principally by CYP2D6, particularly one with a narrow therapeutic index.

Specific Drugs

Drug

Interaction

Comments

Antidepressants, tricyclic

Possible increased plasma tricyclic antidepressant concentrations

Amitriptyline: Increased AUC (by about 17–23%) and peak plasma concentration (by about 11–21%) of amitriptyline and nortriptyline (active metabolite) in CYP2D6 extensive metabolizers

Desipramine: Desipramine AUC and peak plasma concentrations increased by 264 and 75%, respectively, in CYP2D6 extensive metabolizers

Adjust dosage of tricyclic antidepressant if needed

Calcium salts

Calcium carbonate: Clinically important pharmacokinetic interaction unlikely

Carvedilol

Possible increased plasma carvedilol concentrations

Adjust carvedilol dosage if needed

Cigarette smoking

Cinacalcet clearance increased by 36–38%

Adjust cinacalcet dosage as needed if patient starts or stops smoking

Dextromethorphan

Dextromethorphan AUC increased 11-fold in CYP2D6 extensive metabolizers

Flecainide

Possible increased plasma flecainide concentrations

Adjust flecainide dosage if needed

Itraconazole

Possible increased plasma cinacalcet concentrations

Closely monitor iPTH and serum calcium concentrations upon initiation or discontinuance of itraconazole; adjust cinacalcet dosage if needed

Ketoconazole

Cinacalcet AUC and peak plasma concentration increased by 127 and 116%, respectively

Closely monitor iPTH and serum calcium concentrations upon initiation or discontinuance of ketoconazole; adjust cinacalcet dosage if needed

Metoprolol

Possible increased plasma metoprolol concentrations

Adjust metoprolol dosage if needed

Midazolam

Clinically important pharmacokinetic interaction unlikely

Pantoprazole

Clinically important pharmacokinetic interaction unlikely

Rifampin

Possible decreased plasma cinacalcet concentrations

Adjust cinacalcet dosage as needed if rifampin is initiated or discontinued

Sevelamer

Clinically important pharmacokinetic interaction unlikely

Warfarin

Clinically important pharmacokinetic or pharmacodynamic interaction unlikely

Cinacalcet Pharmacokinetics

Absorption

Bioavailability

Following oral administration, peak plasma concentration usually is attained within 2–6 hours.

Onset

Nadir in iPTH concentration occurs 2–6 hours after a dose.

Food

Food increases extent of absorption.

A high-fat meal increases peak plasma concentration by about 82% and AUC by about 68%.

A low-fat meal increases peak plasma concentration by about 65% and AUC by about 50%.

Special Populations

In patients with moderate or severe hepatic impairment, AUC was 2.4 or 4.2 times higher, respectively, than in healthy individuals.

Distribution

Extent

Extensively distributed.

Cinacalcet crosses the placenta in animals and is distributed into milk in rats; not known whether distributed into human milk.

Plasma Protein Binding

About 93–97%.

Elimination

Metabolism

Metabolized to inactive hydrocinnamic acid and to hydroxy-hydrocinnamic acid, which are further metabolized by glycine conjugation and by β-oxidation, and to glucuronidated dihydrodiols with minimal activity.

Cinacalcet is metabolized by multiple enzymes, mainly CYP3A4, CYP2D6, and CYP1A2.

Elimination Route

Excreted in urine (80%), mainly as metabolites, and in feces (15%).

Half-life

Biphasic; terminal half-life is 30–40 hours.

Special Populations

In patients with moderate or severe hepatic impairment, plasma half-life was prolonged by about 33 or 70%, respectively, compared with healthy individuals.

Renal impairment (including hemodialysis or peritoneal dialysis) and age (≥65 years versus <65 years) do not alter cinacalcet pharmacokinetics.

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).

Actions

  • Phenylethylamine calcimimetic agent.

  • Binds to and allosterically modulates calcium-sensing receptors (principal regulators of PTH secretion) on parathyroid glands to increase their sensitivity to activation by extracellular calcium, thereby inhibiting PTH secretion.

  • Lowers serum PTH concentrations within a few hours after oral administration.

  • In dialysis patients with secondary hyperparathyroidism, serum calcium and phosphorus concentrations usually decline as PTH concentrations decrease.

Advice to Patients

  • Advise patients to report nausea, vomiting, and symptoms of hypocalcemia (e.g., paresthesias, myalgia, muscle spasms, seizures). Ask patients if they have a history of seizures or are taking anticonvulsants.

  • Advise patients to report any symptoms of upper GI bleeding to their clinician.

  • Inform patients of the importance of routine blood tests to monitor safety and efficacy of cinacalcet therapy.

  • Importance of taking cinacalcet with food or shortly after a meal.

  • Importance of swallowing the tablets whole (and not divided).

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Encourage women who receive cinacalcet during pregnancy or while breast-feeding to enroll in manufacturer's pregnancy or lactation surveillance program.

  • Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Cinacalcet Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

30 mg (of cinacalcet)

Sensipar

Amgen

60 mg (of cinacalcet)

Sensipar

Amgen

90 mg (of cinacalcet)

Sensipar

Amgen

AHFS DI Essentials™. © Copyright 2022, Selected Revisions August 28, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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