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Etelcalcetide Hydrochloride

Class: Antiparathyroid Agents
Chemical Name: Disulfide with l-cysteine,N-acetyl-d-cysteinyl-d-alanyl-d-arginyl-d-arginyl-d-arginyl-d-alanyl-d-argininamide hydrochloride
Molecular Formula: C38H73N21O10S2xHCl
CAS Number: 1334237-71-6
Brands: Parsabiv

Introduction

Calcimimetic agent; binds to and increases sensitivity of calcium-sensing receptors on parathyroid glands to extracellular calcium, resulting in reduced serum parathyroid hormone (PTH) and calcium concentrations.1 2 3 4 6

Uses for Etelcalcetide Hydrochloride

Secondary Hyperparathyroidism Associated with Chronic Renal Disease

Treatment of secondary hyperparathyroidism associated with chronic renal disease in patients undergoing hemodialysis.1 5 7 8

Additional studies needed to determine effects on clinical outcomes, including cardiovascular morbidity and mortality.5

Safety and efficacy not established in patients with chronic renal disease who are not undergoing hemodialysis; use not recommended in these patients.1

Other Uses

Safety and efficacy not established in patients with parathyroid carcinoma or primary hyperparathyroidism; use not recommended in these patients.1

Etelcalcetide Hydrochloride Dosage and Administration

Administration

IV Administration

Administer by direct (“bolus”) IV injection into the venous line of the dialysis circuit during the rinse-back procedure at the end of hemodialysis or IV after completion of the rinse-back procedure.1

Administer only at the end of hemodialysis sessions.1 If a regularly scheduled hemodialysis session is missed, do not administer the missed dose.1 (See Dosage under Dosage and Administration.)

Do not admix with any other solutions or dilute prior to administration.1

Dosage

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

Adults

Secondary Hyperparathyroidism Associated with Chronic Renal Disease
IV

Initially, 5 mg 3 times weekly.1

In patients being switched from cinacalcet to etelcalcetide, allow ≥7 days to elapse between discontinuance of cinacalcet and initiation of etelcalcetide; use initial etelcalcetide dose of 5 mg.1

Do not initiate etelcalcetide, increase dosage, or reinitiate following an interruption in therapy if albumin-corrected serum calcium concentration is below the lower limit of normal (LLN).1

Titrate dosage to achieve a maintenance dosage within the range of 2.5–15 mg 3 times weekly that maintains PTH concentration within the recommended target range and albumin-corrected serum calcium concentration within the normal range.1

Mean dosage in clinical trials was 7.2 mg 3 times weekly; patients with lower baseline PTH concentrations received lower average dosages.1

Measure albumin-corrected serum calcium concentration 1 week following initiation or subsequent dosage adjustment and every 4 weeks during maintenance therapy.1 Measure PTH concentration 4 weeks following initiation or subsequent dosage adjustment and according to standard practice during maintenance therapy.1

If albumin-corrected serum calcium concentration is within the normal range and PTH concentration is above the recommended target range, increase dosage in 2.5- or 5-mg increments no more frequently than every 4 weeks based on PTH concentration.1

If PTH concentration is below target range, reduce dosage or withhold drug.1 If albumin-corrected serum calcium concentration is less than LLN but ≥7.5 mg/dL and there are no manifestations of hypocalcemia, consider reducing or withholding etelcalcetide or using concomitant therapies to increase albumin-corrected serum calcium.1 If withheld, reinitiate etelcalcetide at a lower dosage when PTH returns to target range and hypocalcemia is corrected.1

If albumin-corrected serum calcium concentration is <7.5 mg/dL or if manifestations of hypocalcemia occur, withhold drug and treat hypocalcemia.1 Reinitiate at a dose 5 mg lower than the last administered dose (or 2.5 mg if the last administered dose was 2.5 or 5 mg) once albumin-corrected serum calcium concentration has returned to normal, manifestations of hypocalcemia have resolved, and predisposing factors for hypocalcemia have been addressed.1

If a regularly scheduled hemodialysis session is missed, do not administer the missed dose.1 Resume therapy at the prescribed dosage with the next scheduled hemodialysis session.1 If doses are missed for >2 weeks, reinitiate at the recommended initial dose of 5 mg (or 2.5 mg if that was the patient's last dose).1

Prescribing Limits

Adults

Secondary Hyperparathyroidism Associated with Chronic Renal Disease
IV

Maximum 15 mg 3 times weekly.1

Special Populations

No special population dosage recommendations at this time.1

Cautions for Etelcalcetide Hydrochloride

Contraindications

  • Known hypersensitivity to etelcalcetide or any ingredient in the formulation. 1

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity

Pruritic rash, urticaria, and facial edema reported.1

Hypocalcemia

Can cause hypocalcemia, including severe hypocalcemia.1 Substantial lowering of serum calcium can cause paresthesias, myalgia, muscle spasms, seizures, QT-interval prolongation, and ventricular arrhythmias.1

A maximum increase from baseline in QT interval (corrected for heart rate using Fridericia's method; QTcF) of >60 msec occurred in 1.2 or 0% of patients receiving etelcalcetide or placebo, respectively; maximum postbaseline predialysis QTcF interval of >500 msec occurred in 4.8 or 1.9% of patients receiving etelcalcetide or placebo, respectively.1

Patients with congenital long QT syndrome, history of QT-interval prolongation, family history of long QT syndrome or sudden cardiac death, or other conditions that predispose to QT-interval prolongation and ventricular arrhythmias may be at increased risk for QT-interval prolongation and ventricular arrhythmias if hypocalcemia occurs.1

Substantial reductions in albumin-corrected serum calcium concentration may lower seizure threshold.1 Patients with a history of seizure disorder may be at increased risk for seizures if hypocalcemia occurs.1

Concomitant use of etelcalcetide with another calcium-sensing receptor agonist (e.g., cinacalcet) could result in severe, life-threatening hypocalcemia.1

Monitor patients regularly for hypocalcemia, including severe hypocalcemia.1 (See Dosage under Dosage and Administration.) Particularly close monitoring of albumin-corrected serum calcium concentrations required in patients predisposed to QT-interval prolongation, ventricular arrhythmias, or seizures and in those receiving concomitant therapies that can lower serum calcium concentrations.1 In addition, closely monitor QT interval in patients at risk for QT-interval prolongation or ventricular arrhythmias.1

If albumin-corrected serum calcium falls below the LLN or if manifestations of hypocalcemia develop, take appropriate steps (e.g., supplement calcium, initiate or increase dosage of calcium-containing phosphate binders and/or vitamin D analogs, increase dialysate calcium concentration, reduce dosage or discontinue etelcalcetide) to increase serum calcium concentrations.1 (See Dosage under Dosage and Administration.)

Heart Failure

Hypotension, congestive heart failure, and decreased myocardial performance reported.1 Reductions in albumin-corrected serum calcium may be associated with congestive heart failure, but causal relationship to etelcalcetide not completely excluded.1 Closely monitor patients receiving etelcalcetide for worsening symptoms of heart failure.1

Upper GI Bleeding

Upper GI bleeding reported, but causal relationship to etelcalcetide 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 PTH concentration is chronically suppressed.1 If PTH concentration falls below the recommended target range, reduce dosage or discontinue vitamin D analogs and/or etelcalcetide.1 (See Dosage under Dosage and Administration.)

Immunogenicity

Potential for immunogenicity.1 Anti-etelcalcetide antibodies detected in 7.1% of patients who received etelcalcetide for up to 6 months.1

No alterations in pharmacokinetics, clinical response, or safety associated with preexisting or developing anti-etelcalcetide antibodies.1

If antibody formation resulting in clinically important effects is suspected, contact Amgen at 800-772-6436 to discuss antibody testing.1

Specific Populations

Pregnancy

Data lacking on use in pregnant women.1 Effects in animal studies (reduced fetal growth, slight increase in perinatal pup mortality, delay in parturition, and transient effects on pup growth) observed at dosages that produced maternal toxicity, including hypocalcemia.1

Lactation

Present in milk in lactating rats at concentrations similar to plasma concentrations.1 Not known whether etelcalcetide distributes into human milk, affects milk production, or affects the breast-fed infant.1 Use not recommended because of potential for adverse effects, including hypocalcemia, in nursing infants.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

No clinically important differences in plasma concentrations and no overall differences in safety or efficacy observed between geriatric patients and younger adults.1

Hepatic Impairment

Pharmacokinetics not formally studied in patients with hepatic impairment.1

Renal Impairment

Principally eliminated via hemodialysis in patients with chronic renal disease undergoing hemodialysis.1 Not indicated in patients with chronic renal disease who are not undergoing hemodialysis.1

Common Adverse Effects

Asymptomatic reductions in blood calcium concentration,1 5 muscle spasms,1 5 diarrhea,1 5 nausea,1 5 vomiting,1 5 headache,1 5 symptomatic hypocalcemia,1 5 paresthesia.1 5

Interactions for Etelcalcetide Hydrochloride

Not a substrate nor an inhibitor or inducer of CYP isoenzymes.1

Not a substrate nor an inhibitor of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporters (OAT) 1 and 3, organic anion transport proteins (OATP) 1B1 and 1B3, and organic cation transporter (OCT) 2; not a substrate of peptide transporters (PEPT) 1 and 2; and not an inhibitor of bile salt export pump (BSEP).1

Specific Drugs

Drug

Interaction

Calcimimetic agents (e.g., cinacalcet)

Possible severe, life-threatening hypocalcemia1

Etelcalcetide Hydrochloride Pharmacokinetics

Absorption

Onset

PTH concentrations decrease within 30 minutes following an IV dose.1

Duration

Duration and extent of PTH reduction increase with increasing dose.1

Distribution

Extent

Not known if distributed into human milk.1

Plasma Protein Binding

Principally bound to albumin by reversible covalent binding.1 Noncovalent plasma protein binding is low.1

Elimination

Metabolism

Undergoes reversible disulfide exchange with endogenous thiols in blood, principally forming conjugates with serum albumin.1 Not metabolized by CYP isoenzymes.1

Elimination Route

Eliminated mainly in urine in patients with normal renal function; hemodialysis is the principal elimination pathway in patients with chronic renal disease undergoing hemodialysis.1 In hemodialysis patients, 60% of dose recovered in dialysate and approximately 7% recovered in urine and feces over 175 days.1

Half-life

3–4 days in patients receiving etelcalcetide 3 times weekly at the end of each 3- to 6-hour hemodialysis session.1

Special Populations

Body weight (29–163 kg), gender, race, and age (20–93 years of age) do not influence etelcalcetide pharmacokinetics.1

Stability

Storage

Parenteral

Injection

2–8°C.1 Store in original container to protect from light.1

Once removed from refrigerator, use within 7 days if stored in original container; if removed from original container, protect from light and use within 4 hours.1 Do not expose to temperatures >25° C.1

Actions

  • Calcimimetic agent1 2 3 4 consisting of 7 D-amino acids linked to L-cysteine by a disulfide bond.6 7

  • 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 3 4 6

  • Lowers serum PTH concentration within 30 minutes after IV administration.1

  • In hemodialysis patients, the reduction in PTH concentrations results in reductions in serum calcium concentrations and attenuation of postdialysis phosphate elevations.1

Advice to Patients

  • Advise patients to report symptoms of hypocalcemia (e.g., paresthesias, myalgia, muscle spasms, seizures) to their clinician.1

  • Advise patients with heart failure that use of etelcalcetide may worsen heart failure and that additional monitoring may be warranted.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 etelcalcetide therapy.1

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

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.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.

Etelcalcetide Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for IV use

5 mg (of etelcalcetide) per mL (2.5, 5, and 10 mg)

Parsabiv

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

2. Wu L, Melhem M, Subramanian R et al. Drug disposition model of radiolabeled etelcalcetide in patients with chronic kidney disease and secondary hyperparathyroidism on hemodialysis. J Pharmacokinet Pharmacodyn. 2017; 44:43-53. [PubMed 28063122]

3. Blair HA. Etelcalcetide: First Global Approval. Drugs. 2016; 76:1787-1792. [PubMed 27900648]

4. Hamano N, Komaba H, Fukagawa M. Etelcalcetide for the treatment of secondary hyperparathyroidism. Expert Opin Pharmacother. 2017; :1-6. [PubMed 28277829]

5. Block GA, Bushinsky DA, Cunningham J et al. Effect of Etelcalcetide vs Placebo on Serum Parathyroid Hormone in Patients Receiving Hemodialysis With Secondary Hyperparathyroidism: Two Randomized Clinical Trials. JAMA. 2017; 317:146-155. [PubMed 28097355]

6. Fielden MR, Dean C, Black K et al. Nonclinical Safety Profile of Etelcalcetide, a Novel Peptide Calcimimetic for the Treatment of Secondary Hyperparathyroidism. Int J Toxicol. 2016; 35:294-308. [PubMed 26941242]

7. Block GA, Bushinsky DA, Cheng S et al. Effect of Etelcalcetide vs Cinacalcet on Serum Parathyroid Hormone in Patients Receiving Hemodialysis With Secondary Hyperparathyroidism: A Randomized Clinical Trial. JAMA. 2017; 317:156-164. [PubMed 28097356]

8. Fukagawa M, Yokoyama K, Shigematsu T et al. A phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of etelcalcetide (ONO-5163/AMG 416), a novel intravenous calcimimetic, for secondary hyperparathyroidism in Japanese haemodialysis patients. Nephrol Dial Transplant. 2017; [PubMed 28057872]

9. 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]

10. 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]

11. 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]

12. 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]

13. 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]

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

15. 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]

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

17. 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.

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

19. 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]

20. 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]

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

22. 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]

23. 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]

24. 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]

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

26. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 208325Orig1s000: Medical review(s). From FDA website

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

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