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Sensipar

Generic Name: Cinacalcet Hydrochloride
Class: Antiparathyroid 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

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.1 2 12 13 16 17 31

Uses for Sensipar

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.1 18

Safety and efficacy in patients who are not undergoing dialysis have not been established.1

May be used alone or in conjunction with vitamin D analogs and/or phosphate binders.1

Effects on clinical outcomes remain to be fully determined.35 The primary finding of the EVOLVE trial (a lack of effect on mortality or major cardiovascular events32 ) is controversial because of study limitations.33 34 35

Hypercalcemia Associated with Parathyroid Carcinoma

Management of hypercalcemia associated with parathyroid carcinoma; designated an orphan drug by FDA for this use.1 18 20 23 26

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.1 24 25 26

Sensipar Dosage and Administration

Administration

Oral Administration

Administer orally with food or shortly after a meal.1 (See Food under Pharmacokinetics.)

Swallow tablets whole; do not divide.1

Dosage

Available as cinacalcet hydrochloride; dosage expressed in terms of cinacalcet.1

Individualize dosage.1

Severe or prolonged nausea and vomiting can result in dehydration and worsening hypercalcemia; carefully monitor electrolytes in patients with these adverse effects.1

Adults

Secondary Hyperparathyroidism Associated with Chronic Renal Disease
Oral

Usual initial dosage: 30 mg once daily.1

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.1

Median dosage was 90 mg daily in 6-month clinical studies; patients with milder disease generally required lower dosages.1

Do not initiate cinacalcet if baseline serum calcium concentration is <8.4 mg/dL.1

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.1

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.1

If serum calcium concentrations fall to <7.5 mg/dL, or hypocalcemia manifestations persist and vitamin D dosage cannot be increased, withhold cinacalcet.1 When serum calcium concentrations reach 8 mg/dL and/or manifestations of hypocalcemia have resolved, may reinitiate cinacalcet using the next lowest dosage.1

Once maintenance dosage is established, measure serum calcium and phosphorus concentrations monthly.1

Hypercalcemia Associated with Parathyroid Carcinoma
Oral

Usual initial dosage: 30 mg twice daily.1

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.1

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.1

Hypercalcemia Associated with Primary Hyperparathyroidism
Oral

Usual initial dosage: 30 mg twice daily.1

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.1

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.1

Special Populations

No special population dosage recommendations at this time.1 (See Hepatic Impairment under Cautions.)

Cautions for Sensipar

Contraindications

  • Serum calcium concentrations below lower limit of normal.1

Warnings/Precautions

Hypocalcemia

Fatal or life-threatening hypocalcemia reported, including in pediatric patients (see Pediatric Use under Cautions).1 Substantial lowering of serum calcium can cause paresthesias, myalgia, muscle spasm, tetany, seizures, QT-interval prolongation, and ventricular arrhythmias.1

Seizures (mainly generalized or tonic-clonic) reported in 1.4 or 0.7% of patients receiving cinacalcet or placebo, respectively.1 Reason for reported difference is unclear, but substantial reductions in serum calcium concentrations may lower seizure threshold.1

Cases of QT-interval prolongation and ventricular arrhythmia secondary to hypocalcemia reported.1

Isolated idiosyncratic cases of hypotension, worsening heart failure, and/or arrhythmia reported in patients with impaired cardiac function.1 Causal relationship to cinacalcet not excluded; effects possibly mediated by reductions in serum calcium.1

Nondialysis patients with chronic renal disease and secondary hyperparathyroidism are at increased risk for developing hypocalcemia;1 29 safety and efficacy in such patients not established.1

Carefully monitor patients for the occurrence of hypocalcemia; particularly close monitoring required in patients with history of seizure disorder.1

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.1 (See Secondary Hyperparathyroidism Associated with Chronic Renal Disease under Dosage and Administration.)

Upper GI Bleeding

Upper GI bleeding reported, but exact cause not established.1 Patients with risk factors for upper GI bleeding (e.g., gastritis, esophagitis, ulcers, severe vomiting) may be at increased risk.1

Monitor patients for worsening of nausea and vomiting and for signs and symptoms of GI bleeding or ulceration.1 Immediately evaluate and treat if GI bleeding is suspected.1

Adynamic Bone Disease

Adynamic bone disease may develop if iPTH concentrations are suppressed below 100 pg/mL.1

Decrease dosage or discontinue cinacalcet and/or vitamin D analogs if iPTH concentrations fall below 150 pg/mL.1

Specific Populations

Pregnancy

Category C.1 Pregnancy surveillance program (800-772-6436).1

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Discontinue nursing or the drug.1 Encourage women who opt to continue cinacalcet treatment while nursing to enroll in manufacturer's lactation surveillance program (800-772-6436).1

Pediatric Use

Safety and efficacy not established in patients <18 years of age; not indicated for use in pediatric patients.1 19

FDA announced suspension of pediatric clinical trials of cinacalcet after death of a 14-year-old adolescent with severe hypocalcemia occurred during a trial.1 22

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.1

Hepatic Impairment

Closely monitor serum phosphorus, iPTH, and serum calcium concentrations in patients with moderate or severe hepatic impairment.1 (See Absorption: Special Populations and also Elimination: Special Populations, under Pharmacokinetics.)

Common Adverse Effects

Dialysis patients with secondary hyperparathyroidism: Nausea,1 2 12 13 16 32 vomiting,1 2 12 16 17 32 diarrhea,1 32 myalgia,1 dyspnea,1 cough,1 hypotension,1 headache,1 hypocalcemia,1 32 muscle spasms,1 abdominal pain (including upper abdominal pain),1 dizziness,1 hyperkalemia,1 upper respiratory tract infection,1 dyspepsia,1 hypertension,1 asthenia,1 anorexia/decreased appetite,1 12 noncardiac chest pain,1 access infection,1 constipation.1

Patients with hypercalcemia associated with parathyroid carcinoma or primary hyperparathyroidism: Adverse effects generally similar to those observed in dialysis patients.1

Interactions for Sensipar

Metabolized mainly by CYP1A2, 2D6, and 3A4; potent inhibitor of CYP2D6 in vitro.1 Does not inhibit CYP1A2, 2C9, 2C19, or 3A4 in vitro.1 Does not induce CYP isoenzymes in vitro.1

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A4 inhibitors: Potential increased plasma cinacalcet concentrations.1 Closely monitor iPTH and serum calcium concentrations upon initiation or discontinuance of potent CYP3A4 inhibitor; cinacalcet dosage adjustment may be required.1

Potent CYP3A4 inducers: Potential decreased plasma cinacalcet concentrations.30 Cinacalcet dosage adjustment may be required if a potent CYP3A4 inducer is initiated or discontinued.30

Potent CYP1A2 inhibitors: Potential increased plasma cinacalcet concentrations.30 Cinacalcet dosage adjustment may be required if a potent CYP1A2 inhibitor is initiated or discontinued.30

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP2D6 substrates: Potential increased plasma concentrations of drugs metabolized principally by CYP2D6.1 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.1

Specific Drugs

Drug

Interaction

Comments

Antidepressants, tricyclic

Possible increased plasma tricyclic antidepressant concentrations1

Amitriptyline: Increased AUC (by about 17–23%) and peak plasma concentration (by about 11–21%) of amitriptyline and nortriptyline (active metabolite) in CYP2D6 extensive metabolizers1

Desipramine: Desipramine AUC and peak plasma concentrations increased by 264 and 75%, respectively, in CYP2D6 extensive metabolizers1

Adjust dosage of tricyclic antidepressant if needed1

Calcium salts

Calcium carbonate: Clinically important pharmacokinetic interaction unlikely1 30

Carvedilol

Possible increased plasma carvedilol concentrations1

Adjust carvedilol dosage if needed1

Cigarette smoking

Cinacalcet clearance increased by 36–38%30

Adjust cinacalcet dosage as needed if patient starts or stops smoking30

Dextromethorphan

Dextromethorphan AUC increased 11-fold in CYP2D6 extensive metabolizers30

Flecainide

Possible increased plasma flecainide concentrations1

Adjust flecainide dosage if needed1

Itraconazole

Possible increased plasma cinacalcet concentrations1

Closely monitor iPTH and serum calcium concentrations upon initiation or discontinuance of itraconazole; adjust cinacalcet dosage if needed1

Ketoconazole

Cinacalcet AUC and peak plasma concentration increased by 127 and 116%, respectively1

Closely monitor iPTH and serum calcium concentrations upon initiation or discontinuance of ketoconazole; adjust cinacalcet dosage if needed1

Metoprolol

Possible increased plasma metoprolol concentrations1

Adjust metoprolol dosage if needed1

Midazolam

Clinically important pharmacokinetic interaction unlikely1 30

Pantoprazole

Clinically important pharmacokinetic interaction unlikely1 30

Rifampin

Possible decreased plasma cinacalcet concentrations30

Adjust cinacalcet dosage as needed if rifampin is initiated or discontinued30

Sevelamer

Clinically important pharmacokinetic interaction unlikely1 30

Warfarin

Clinically important pharmacokinetic or pharmacodynamic interaction unlikely1 30

Sensipar Pharmacokinetics

Absorption

Bioavailability

Following oral administration, peak plasma concentration usually is attained within 2–6 hours.1

Onset

Nadir in iPTH concentration occurs 2–6 hours after a dose.1

Food

Food increases extent of absorption.1

A high-fat meal increases peak plasma concentration by about 82% and AUC by about 68%.1

A low-fat meal increases peak plasma concentration by about 65% and AUC by about 50%.1

Special Populations

In patients with moderate or severe hepatic impairment, AUC was 2.4 or 4.2 times higher, respectively, than in healthy individuals.1

Distribution

Extent

Extensively distributed.1

Cinacalcet crosses the placenta in animals and is distributed into milk in rats; not known whether distributed into human milk.1

Plasma Protein Binding

About 93–97%.1

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.1

Cinacalcet is metabolized by multiple enzymes, mainly CYP3A4, CYP2D6, and CYP1A2.1

Elimination Route

Excreted in urine (80%), mainly as metabolites, and in feces (15%).1

Half-life

Biphasic; terminal half-life is 30–40 hours.1

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.1

Renal impairment (including hemodialysis or peritoneal dialysis) and age (≥65 years versus <65 years) do not alter cinacalcet pharmacokinetics.1

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1

Actions

  • Phenylethylamine calcimimetic agent.1 31

  • 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.1 2 12 13 16 17 31

  • Lowers serum PTH concentrations within a few hours after oral administration.1 2 12 13 16 17

  • In dialysis patients with secondary hyperparathyroidism, serum calcium and phosphorus concentrations usually decline as PTH concentrations decrease.1 2 12 13 16 17

Advice to Patients

  • Advise patients to report nausea, vomiting, and symptoms of hypocalcemia (e.g., paresthesias, myalgia, muscle spasms, seizures).1 Ask patients if they have a history of seizures or are taking anticonvulsants.1

  • Advise patients to report any symptoms of upper GI bleeding to their clinician.1

  • Inform patients of the importance of routine blood tests to monitor safety and efficacy of cinacalcet therapy.1

  • Importance of taking cinacalcet with food or shortly after a meal.1

  • Importance of swallowing the tablets whole (and not divided).1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Encourage women who receive cinacalcet during pregnancy or while breast-feeding to enroll in manufacturer's pregnancy or lactation surveillance program.1

  • Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (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 2017, Selected Revisions August 28, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Amgen Inc. Sensipar (cinacalcet hydrochloride) tablets prescribing information. Thousand Oaks, CA; 2017 Mar.

2. Block GA, Martin KJ, de Francisco AL et al. Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis. N Engl J Med. 2004; 350:1516-25. [PubMed 15071126]

3. Bleyer AJ, Burke SK, Dillon M et al. A comparison of the calcium-free phosphate binder sevelamer hydrochloride with calcium acetate in the treatment of hyperphosphatemia in hemodialysis patients. Am J Kidney Dis. 1999; 33:694-701. [PubMed 10196011]

4. Chertow GM, Dillon M, Burke SK et al. A randomized trial of sevelamer hydrochloride (Renagel) with and without supplemental calcium: Strategies for the control of hyperphosphatemia and hyperparathyroidism in hemodialysis patients. Clin Nephrol. 1999; 51:18-26. [PubMed 9988142]

5. Chertow GM, Burke SK, Lazarus JM et al. Poly[allylamine hydrochloride] (RenaGel): a noncalcemic phosphate binder for the treatment of hyperphosphatemia in chronic renal failure. Am J Kidney Dis. 1997; 29:66-71. [PubMed 9002531]

6. Sakhaee K, Gonzalez GB. Update on renal osteodystrophy: pathogenesis and clinical management. Am J Med Sci. 1999; 317:251-60. [PubMed 10210362]

7. Tan AU Jr, Levine BS, Mazess RB et al. Effective suppression of parathyroid hormone by 1 alpha-hydroxy-vitamin D2a in hemodialysis patients with moderate to severe secondary hyperparathyroidism. Kidney Int. 1997; 51:317-23. [PubMed 8995749]

8. Bone Care International. Hectorol (doxercalciferol) capsules prescribing information. Madison, WI; 1999 Jun 9.

9. Burke S, Dillon MA, Goldberg DI. Control of P1 with Renagel, a calcium and aluminum free phosphate binder, combined with vitamin D stabilizes iPTH in ESRD independent of Ca++. Nephrology. 1997; (Suppl 1):S183.

10. Genzyme, Boston, MA: Personal communication on sevelamer.

12. Ohashi N, Uematsu T, Nagashima M et al. The calcimimetic agent KRN 1493 lowers plasma parathyroid hormone and ionized calcium concentrations in patients with chronic renal failure on haemodialysis both on the day of haemodialysis and on the day without haemodialysis. Br J Clin Pharmacol. 2004; 57:726-34. [PubMed 15151518]

13. Lindberg JS, Moe SM, Goodman WG et al. The calcimimetic AMG 073 reduces parathyroid hormone and calcium x phosphorus in secondary hyperparathyroidism. Kidney Int. 2003; 63:248-54. [PubMed 12472790]

14. Genzyme. Renagel (sevelamer hydrochloride) capsules and tablets prescribing information. Cambridge, MA; 2000 Jul.

15. Slatopolsky EA, Burke SK, Dillon MA and the RenaGel Study Group. RenaGel, a nonadsorbed calcium- and aluminum-free phosphate binder, lowers serum phosphorus and parathyroid hormone. Kidney Int. 1999; 55:299-307. [PubMed 9893140]

16. Goodman WG, Hladik GA, Turner SA et al. The calcimimetic agent AMG 073 lowers plasma parathyroid hormone levels in hemodialysis patients with secondary hyperparathyroidism. J Am Soc Nephrol. 2002; 13:1017-24. [PubMed 11912261]

17. Quarles LD, Sherrard DJ, Adler S et al. The calcimimetic AMG 073 a a potential treatment for secondary hyperparathyroidism of end-stage renal disease. J Am Soc Nephrol. 2003; 14:575-83. [PubMed 12595492]

18. Anon. Cinacalcet (Sensipar). Med Lett Drugs Ther. 2004; 46:80. [PubMed 15452465]

19. Amgen Inc. Thousand Oaks, CA: Personal communication.

20. Food and Drug Administration. Cumulative list of orphan products designated and approved. Rockville, MD; From FDA website (). Accessed [2004 11 17].

21. Moe SM, Sprague SM, Cunningham J et al. Long-term treatment of secondary hyperparathyroidism with the calcimimetic cinacalcet HCl. Paper presented at 36th annual American Society of Nephrology meeting and scientific exposition. San Diego, CA: 2003 Nov 15.

22. Food and Drug Administration. Sensipar (cinacalcet hydrochloride): Drug safety communication - FDA suspends pediatric clinical trials after report of death. . Silver Spring, MD; 2013 Feb 26. From FDA website.

23. Silverberg SJ, Rubin MR, Faiman C et al. Cinacalcet hydrochloride reduces the serum calcium concentration in inoperable parathyroid carcinoma. J Clin Endocrinol Metab. 2007; 92:3803-8. [PubMed 17666472]

24. Marcocci C, Chanson P, Shoback D et al. Cinacalcet reduces serum calcium concentrations in patients with intractable primary hyperparathyroidism. J Clin Endocrinol Metab. 2009; 94:2766-72. [PubMed 19470620]

25. Khan A, Bilezikian J, Bone H et al. Cinacalcet normalizes serum calcium in a double-blind randomized, placebo-controlled study in patients with primary hyperparathyroidism with contraindications to surgery. Eur J Endocrinol. 2015; 172:527-35. [PubMed 25637076]

26. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Rockville, MD. From FDA website. Accessed 2017 March 28.

27. Cunningham J, Locatelli F, Rodriguez M. Secondary hyperparathyroidism: pathogenesis, disease progression, and therapeutic options. Clin J Am Soc Nephrol. 2011; 6:913-21. [PubMed 21454719]

28. Amgen Inc. Parsabiv (etelcalcetide hydrochloride) injection prescribing information. Thousand Oaks, CA; 2017 Feb.

29. Chonchol M, Locatelli F, Abboud HE et al. A randomized, double-blind, placebo-controlled study to assess the efficacy and safety of cinacalcet HCl in participants with CKD not receiving dialysis. Am J Kidney Dis. 2009; 53:197-207. [PubMed 19110359]

30. Amgen Europe. Mimpara (cinacalcet) tablets. Annex I: Summary of product characteristics. Breda, Netherlands. (undated).

31. Marcocci C, Cetani F. Update on the use of cinacalcet in the management of primary hyperparathyroidism. J Endocrinol Invest. 2012; 35:90-5. [PubMed 22104762]

32. EVOLVE Trial Investigators, Chertow GM, Block GA et al. Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis. N Engl J Med. 2012; 367:2482-94. [PubMed 23121374]

33. Parfrey PS, Block GA, Correa-Rotter R et al. Lessons Learned from EVOLVE for Planning of Future Randomized Trials in Patients on Dialysis. Clin J Am Soc Nephrol. 2016; 11:539-46. [PubMed 26614406]

34. Goldsmith D, Covic A, Vervloet M et al. Should patients with CKD stage 5D and biochemical evidence of secondary hyperparathyroidism be prescribed calcimimetic therapy? An ERA-EDTA position statement. Nephrol Dial Transplant. 2015; 30:698-700. [PubMed 25928337]

35. Bover J, Ureña P, Ruiz-García C et al. Clinical and Practical Use of Calcimimetics in Dialysis Patients With Secondary Hyperparathyroidism. Clin J Am Soc Nephrol. 2016; 11:161-74. [PubMed 26224878]

36. Amgen Inc. Sensipar (cinacalcet hydrochloride) tablets prescribing information. Thousand Oaks, CA; 2004 Mar 8.

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