Parsabiv (etelcalcetide hydrochloride)

Dosage of etelcalcetide hydrochloride is expressed in terms of etelcalcetide.

For the management of secondary hyperparathyroidism associated with chronic renal disease in patients who are undergoing hemodialysis, the recommended initial adult dosage of etelcalcetide is 5 mg 3 times weekly. For patients who are being switched from cinacalcet to etelcalcetide therapy, an interval of at least 7 days should elapse between discontinuance of cinacalcet and initiation of etelcalcetide; patients being switched from cinacalcet should receive an initial etelcalcetide dose of 5 mg. If the albumin-corrected serum calcium concentration is below the lower limit of normal, etelcalcetide therapy should not be initiated or reinitiated (following an interruption in therapy) and the dosage should not be increased.

The maintenance dosage of etelcalcetide must be individualized within the range of 2.5-15 mg 3 times weekly to achieve a dosage that maintains parathyroid hormone (PTH) concentration within the recommended target range and albumin-corrected serum calcium concentration within the normal range. Albumin-corrected serum calcium concentration should be measured 1 week following initiation of therapy or subsequent dosage adjustment and every 4 weeks during maintenance therapy with the drug. In addition, PTH concentration should be measured 4 weeks following initiation of therapy or subsequent dosage adjustment and according to standard practice during maintenance therapy.

In patients with albumin-corrected serum calcium concentration within the normal range and PTH concentration above the recommended target range, the dosage of etelcalcetide should be increased based on the patient's PTH concentration in increments of 2.5 or 5 mg no more frequently than every 4 weeks.

The etelcalcetide dosage should be decreased or therapy with etelcalcetide should be withheld in patients with PTH concentration below the target range. In patients with albumin-corrected serum calcium concentration less than the lower limit of normal but at least 7.5 mg/dL and in whom manifestations of hypocalcemia are not present, consideration should be given to reducing or withholding etelcalcetide or to using concomitant therapies to increase albumin-corrected serum calcium. If etelcalcetide is withheld, the drug should be reinitiated at a lower dosage when PTH returns to the target range and hypocalcemia has been corrected.

Etelcalcetide should be withheld and hypocalcemia should be treated if the albumin-corrected serum calcium concentration falls below 7.5 mg/dL or if manifestations of hypocalcemia are present. Once albumin-corrected serum calcium concentration has returned to normal, manifestations of hypocalcemia have resolved, and predisposing factors for hypocalcemia have been addressed, etelcalcetide should be reinitiated 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).

If a regularly scheduled hemodialysis session is missed, the missed dose of etelcalcetide should not be administered. Instead, therapy should be resumed at the prescribed dosage with the next scheduled hemodialysis session. If doses of etelcalcetide are missed for more than 2 weeks, etelcalcetide should be reinitiated at the recommended initial dose of 5 mg (or 2.5 mg if that was the patient's last dose).

Etelcalcetide hydrochloride is administered 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 the rinse-back procedure has been completed. Etelcalcetide should be administered only at the end of hemodialysis sessions. If a regularly scheduled hemodialysis session is missed, the missed dose of etelcalcetide should not be administered. (See Dosage and Administration: Dosage.)

Etelcalcetide hydrochloride solution is clear and colorless; the vial should be visually inspected for particulate matter and discoloration prior to administration and should be discarded if either is present. Etelcalcetide hydrochloride should not be admixed with any other solutions or diluted prior to administration.

No dosing information is available for this tab.

Etelcalcetide is neither a substrate nor an inhibitor or inducer of cytochrome P-450 (CYP) isoenzymes.

Etelcalcetide is neither a substrate nor an inhibitor of the efflux and uptake transporter proteins 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. In addition, etelcalcetide is not a substrate of peptide transporters (PEPT) 1 and 2 and does not inhibit the bile salt export pump (BSEP).

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Etelcalcetide/Cinacalcet; Evocalcet

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Etelcalcetide is a calcimimetic agent that binds to the extracellular domain of the calcium-sensing receptor (CaSR) and enhances activation of the receptor by extracellular calcium.(1) Cinacalcet and evocalcet also increase the sensitivity of the CaSR to extracellular calcium but bind to the CaSR but at the transmembrane region of the receptor.(2-4) Activation of the CaSR decreases parathyroid hormone (PTH) secretion and subsequently decreases calcium levels. Additive decreases in PTH with subsequent additive decreases in calcium levels may occur with concurrent use.

CLINICAL EFFECTS: Concurrent administration of etelcalcetide with another oral calcium-sensing receptor agonist may result in severe, life-threatening, hypocalcemia. Hypocalcemia can cause paresthesias, myalgias, muscle spasms, seizures, QT prolongation, and ventricular arrhythmias.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of etelcalcetide recommends discontinuation of cinacalcet at least 7 days prior to starting etelcalcetide. When transitioning from cinacalcet to etelcalcetide, initiate etelcalcetide at a starting dose of 5 mg.(1) The US manufacturer of cinacalcet recommends discontinuation of etelcalcetide for at least 4 weeks prior to initiating cinacalcet. Initiate cinacalcet at a starting dose of 30 mg daily.(2) The UK manufacturer of cinacalcet states that an appropriate washout period of etelcalcetide has not been studied and recommends completion of at least three subsequent hemodialysis sessions and ensuring normal serum calcium before initiating cinacalcet.(3) The manufacturer of evocalcet does not provide recommendations for concurrent use with etelcalcetide but similar additive effects are expected based on a similar mechanism as cinacalcet.(4) Consider similar washout periods when transitioning from etelcalcetide to evocalcet. Before initiating these calcimimetics, ensure corrected serum calcium is at or above the lower limit of normal. Closely monitor corrected serum calcium and concurrent therapies known to lower serum calcium. Serum calcium monitoring is recommended within 1 week after initiation of etelcalcetide and every 4 weeks during treatment.(1)

DISCUSSION: Concurrent administration of etelcalcetide with other oral calcium-sensing receptor agonists may result in severe, life-threatening, hypocalcemia. Pooled data from two placebo-controlled clinical studies in patients with chronic kidney disease and secondary hyperparathyroidism on hemodialysis were reviewed with a mean duration of 23.6 weeks. More patients on etelcalcetide versus placebo developed at least one corrected serum calcium level less than 7 mg/dL (7.6% v. 3.1%, respectively), less than 7.5 mg/dL (27% v. 5.5%, respectively), and less than 8.3 mg/dL (79% v. 19%, respectively). Symptomatic reductions in serum calcium less than 8.3 mg/dL occurred in 7% of patients receiving etelcalcetide versus 0.2% of patients receiving placebo.(1)

There are no severe interactions for this drug.

There are no moderate interactions for this drug.

Etelcalcetide is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation.

There are no contraindication contraindications for this drug.

• Congenital long QT syndrome
• Gastrointestinal hemorrhage
• Hypocalcemia

• Chronic heart failure
• Lower seizure threshold
• Seizure disorder

Adverse effects reported in clinical trials in 5% or more of patients receiving etelcalcetide and more frequently than in those receiving placebo include asymptomatic reductions in blood calcium concentration, muscle spasms, diarrhea, nausea, vomiting, headache, symptomatic hypocalcemia, and paresthesia.

More Frequent

• Hypocalcemia

Less Frequent

• Hypophosphatemia
• Hypotension

Rare or Very Rare

• Adynamic bone disease
• Chronic heart failure
• Hyperkalemia
• Prolonged QT interval
• Upper GI bleed
• Urticaria
• Ventricular arrhythmias

More Frequent

• Diarrhea
• Headache disorder
• Muscle spasm
• Nausea
• Paresthesia
• Vomiting

Rare or Very Rare

• Facial edema
• Myalgia
• Pruritus of skin
• Skin rash

No enhanced messaging available.

Safety and efficacy of etelcalcetide have not been established in pediatric patients.

Data on use of etelcalcetide in pregnant women are lacking. IV administration of etelcalcetide in rats during the period of organogenesis through delivery and weaning resulted in a slight increase in perinatal pup mortality, delay in parturition, and transient effects on pup growth at an exposure level of 1.8 times that associated with the recommended human dosage (15 mg 3 times weekly); no effects on sexual maturation, neurobehavioral function, or reproductive function in the offspring were observed. In embryofetal development studies in rats and rabbits, reduced fetal growth was observed at etelcalcetide exposures of 2.7 and 7 times, respectively, that associated with the recommended human dosage. The effects in animal studies were observed at dosages that produced maternal toxicity, including hypocalcemia.

It is not known whether etelcalcetide is distributed into human milk, affects milk production, or affects the breast-fed infant; however, in lactating rats given radiolabeled etelcalcetide, concentrations of radioactivity in milk were comparable to those in plasma. Because of the potential for adverse effects, including hypocalcemia, in nursing infants, use of etelcalcetide in nursing women is not recommended.

Of the 503 patients in placebo-controlled studies who received etelcalcetide, 35% were 65 years of age or older, while 14% were 75 years of age or older. No clinically important differences in plasma concentrations of etelcalcetide and no overall differences in safety or efficacy were observed between geriatric patients and younger adults.