Etelcalcetide is an intravenous, calcimimetic and calcium-sensing receptor (CaSR) agonist indicated for secondary hyperparathyroidism in adults with chronic kidney disease on hemodialysis. Etelcalcetide is administered 3 times weekly at the end of hemodialysis sessions. Etelcalcetide lowers serum calcium which may lead to serious, life-threatening hypocalcemia associated with seizures, QT prolongation, and ventricular arrhythmias. Ensure corrected serum calcium is at or above the lower limit of normal before starting etelcalcetide therapy, and monitor corrected serum calcium throughout treatment. Etelcalcetide has not been studied in patients with parathyroid carcinoma, primary hyperparathyroidism, or chronic kidney disease not on hemodialysis and is not recommended for use in these patients. Etelcalcetide was FDA-approved in February 2017.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-The solution is clear and colorless.
Intravenous Administration
-Ensure corrected serum calcium is at or above the lower limit of normal prior to initiation, dose increase, or reinitiation of therapy after dose interruption.
-Do not dilute prior to administration.
-Etelcalcetide is removed by the dialyzer membrane and must be administered after blood is no longer circulating through the dialyzer.
-Administer by IV bolus into the venous line of the dialysis circuit at the end of the hemodialysis session during rinse back or IV after rinse back. Administer a sufficient volume of saline (e.g., 150 mL of rinse back) after etelcalcetide injection into the dialysis tubing. If etelcalcetide is administered after rinse back, administer etelcalcetide IV followed by at least 10 mL of saline flush.
-If a regularly scheduled hemodialysis session is missed, do not administer the missed dose. Resume etelcalcetide therapy at the end of the next hemodialysis session at the prescribed dose. If doses are missed for more than 2 weeks, reinitiate etelcalcetide at the recommended starting dose of 5 mg (or 2.5 mg if that was the patient's last dose).
Etelcalcetide lowers serum calcium concentrations and can lead to hypocalcemia, sometimes severe. Seizures, secondary to hypocalcemia, have been reported in postmarketing surveillance. Measure corrected serum calcium prior to initiating etelcalcetide therapy, and monitor corrected serum calcium within 1 week after initiation or dose adjustment and every 4 weeks during treatment. Educate patients on the symptoms of hypocalcemia, and advise them to contact a healthcare provider if they occur. If corrected serum calcium falls below the lower limit of normal or symptoms of hypocalcemia develop, start or increase calcium supplementation (including calcium, calcium-containing phosphate binders, and/or vitamin D sterols, or increase calcium in the dialysate). Etelcalcetide dose reduction or discontinuation may be necessary. In clinical trials, asymptomatic decreases in serum calcium of less than 7.5 mg/dL or clinically asymptomatic reductions in corrected serum calcium between 7.5 mg/dL and less than 8.3 mg/dL that required medical management were reported in 64% of etelcalcetide-treated patients compared to 10% of those receiving placebo. Hypocalcemia (symptomatic reductions in corrected serum calcium of less than 8.3 mg/dL) was reported in 7% of patients receiving etelcalcetide compared to 0.2% of those receiving placebo.
During clinical trials of etelcalcetide, upper GI bleeding was reported in 2 patients. The exact cause of GI bleeding is unknown and too few cases occurred to determine whether these cases were related to etelcalcetide. Monitor patients for worsening of common GI adverse reactions (i.e., nausea and vomiting) and for signs and symptoms of GI bleeding and ulcerations. Promptly evaluate and treat any suspected GI bleeding. Nausea, vomiting, and diarrhea were reported in 11%, 9%, and 11%, respectively, of etelcalcetide-treated patients vs. 6%, 5%, 9%, respectively, with placebo.
During etelcalcetide clinical trials, muscle spasms (muscle cramps) were reported in 12% of etelcalcetide-treated patients compared to 7% of those receiving placebo. Myalgia was reported in 2% of patients receiving etelcalcetide vs. 0.2% with placebo. Paresthesias, including hypoesthesia, were reported in 6% of the etelcalcetide group compared to 1% of the placebo group.
Headache was reported in 8% of patients receiving etelcalcetide during clinical trials compared to 6% of those receiving placebo.
During placebo-controlled clinical trials, 18% of patients treated with etelcalcetide and 8.2% of those receiving placebo had at least 1 measured serum phosphorus concentration below the lower normal limit of 2.2 mg/dL. Hypophosphatemia was reported in 1% and 0.2% of etelcalcetide and placebo groups, respectively.
Worsening heart failure has been reported with the use of etelcalcetide. In clinical trials, heart failure requiring hospitalization occurred in 2% of patients treated with etelcalcetide compared to 1% of placebo-treated patients. Closely monitor heart failure patients treated with etelcalcetide for worsening signs and symptoms of heart failure.
QT prolongation has occurred with etelcalcetide treatment. In the placebo-controlled trials, more patients treated with etelcalcetide experienced a maximum increase from baseline of more than 60 msec in the QTcF interval (1.2% vs. 0% placebo). Maximum post-baseline predialysis QTcF more than 500 msec was reported in 4.8% of patients in the etelcalcetide group compared to 1.9% in the placebo group. Patients with congenital long QT syndrome, history of QT interval prolongation, family history of long QT syndrome or sudden cardiac death, and other conditions that predispose to QT interval prolongation and ventricular arrhythmia may be at increased risk for QT interval prolongation and ventricular arrhythmias if they develop hypocalcemia due to etelcalcetide. Closely monitor corrected serum calcium and QT interval in at-risk patients receiving etelcalcetide.
Hypersensitivity reactions, including rash, pruritus, urticaria, and facial edema, were reported in 4.4% of patients receiving etelcalcetide compared to 3.7% of those receiving placebo in clinical trials. Anaphylactic reactions have been reported in postmarketing surveillance.
Adynamic bone (renal osteodystrophy) may develop if parathyroid hormone (PTH) concentrations are chronically suppressed. If PTH concentrations decrease below the recommended target range, reduce the dose of vitamin D sterols and/or etelcalcetide or discontinue therapy. If therapy is discontinued, resume therapy at a lower dose to maintain PTH concentrations within the target range.
Antibody formation is possible during etelcalcetide therapy. During clinical trials, 7.1% of patients with secondary hypoparathyroidism treated with etelcalcetide for up to 6 months tested positive for anti-etelcalcetide antibodies. Approximately 80% had preexisting anti-etelcalcetide antibodies. No evidence of altered pharmacokinetics, clinical response, or safety profile was associated with preexisting or developing anti-etelcalcetide antibodies. Clinicians should contact the manufacturer to discuss antibody testing if formation of anti-etelcalcetide binding antibodies with a clinically significant effect is suspected in a patient.
Etelcalcetide is contraindicated in patients with known hypersensitivity to etelcalcetide or any of its excipients. Hypersensitivity reactions, including facial edema and anaphylactic reaction, have occurred with the use of etelcalcetide.
Do not use etelcalcetide in patients with hypocalcemia. Etelcalcetide lowers serum calcium and can cause hypocalcemia, sometimes severe. Significant hypocalcemia can cause paresthesias, myalgias, muscle spasms, seizures, QT interval prolongation, and ventricular arrhythmias. Measure corrected serum calcium prior to initiating etelcalcetide therapy, and monitor corrected serum calcium within 1 week after initiation or dose adjustment and every 4 weeks during treatment. Educate patients on the symptoms of hypocalcemia, and advise them to contact a healthcare provider if they occur.
Use etelcalcetide cautiously in patients with a seizure disorder. Etelcalcetide lowers serum calcium and significant reductions in corrected serum calcium may lower the seizure threshold. Patients with a history of seizure disorder may be at increased risk for seizures if they develop hypocalcemia during treatment with etelcalcetide. Monitor corrected serum calcium in patients with seizure disorders who are receiving etelcalcetide.
Use etelcalcetide with caution in patients with congenital long QT syndrome, history of QT prolongation, family history of long QT syndrome or sudden cardiac death, and other conditions that predispose to QT interval prolongation and ventricular arrhythmias. These patients may be at increased risk of QT prolongation and ventricular arrhythmias if they develop hypocalcemia during etelcalcetide therapy. Closely monitor corrected serum calcium and QT interval in at-risk patients receiving etelcalcetide.
Use etelcalcetide with caution in patients with heart failure; cases of worsening heart failure requiring hospitalization have been reported in patients with heart failure being treated with etelcalcetide. Hypocalcemia may be associated with heart failure; however, a causal relationship to etelcalcetide could not be excluded. Monitor patients with heart failure treated with etelcalcetide for worsening signs and symptoms of heart failure.
Patients with risk factors for GI bleeding, such as gastritis, esophagitis, peptic ulcer disease, or severe vomiting, may be at increased risk for GI bleeding while receiving etelcalcetide treatment. Severe GI bleeding has been reported with the use of etelcalcetide. Monitor patients at risk for GI bleeding for worsening of common GI adverse reactions of nausea and vomiting and for signs and symptoms of GI bleeding and ulceration during etelcalcetide therapy. Promptly evaluate and treat any suspected GI bleeding.
No data are available regarding the use of etelcalcetide in human pregnancy. In animal studies, hypocalcemia was observed at doses associated with maternal toxicity. When rats were administered etelcalcetide during organogenesis through delivery and weaning, there was a slight increase in perinatal pup mortality, delay in parturition, and transient effects on pup growth at exposures 1.8 times the human exposure of 15 mg 3 times weekly. Reduced fetal growth associated with maternal toxicities of hypocalcemia, tremors, and reductions in body weight and food consumption was observed in rats and rabbits at 2.7 and 7 times clinical exposures, respectively.
There are no data regarding the presence of etelcalcetide in human milk, the effects on the breast-fed infant, or on milk production. Etelcalcetide is present in the milk of rats at concentrations similar to those found in plasma. Due to the potential for adverse effects including hypocalcemia in breast-fed infants, avoid breast-feeding during etelcalcetide therapy.
For the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on hemodialysis:
Intravenous dosage:
Adults: 5 mg IV 3 times weekly at the end of hemodialysis treatment. Ensure corrected serum calcium is at or above the lower limit of normal prior to etelcalcetide initiation, dose increase, or reinitiating after interruption of therapy. The maintenance dose is determined by titration based on parathyroid hormone (PTH) and corrected serum calcium response. The maintenance dose is the dose that maintains PTH concentrations within the recommended target range and corrected serum calcium within the normal range. The lowest maintenance dose is 2.5 mg IV 3 times weekly; the maximum dose is 15 mg IV 3 times weekly. In clinical trials, the average etelcalcetide dose was 7.2 mg IV 3 times weekly. Compared to placebo, significantly more patients treated with etelcalcetide achieved a more than 30% reduction in PTH concentrations from baseline to efficacy assessment (weeks 20 through 27). Statistically significant reductions in mean PTH, corrected serum calcium, and serum phosphate concentrations from baseline to the end of the study were seen with etelcalcetide compared to placebo.
-for patients switching from cinacalcet to etelcalcetide:
Intravenous dosage:
Adults: 5 mg IV 3 times weekly at the end of hemodialysis treatment after discontinuing cinacalcet for at least 7 days prior to initiating etelcalcetide. Ensure corrected serum calcium is at or above the lower limit of normal prior to etelcalcetide initiation, dose increase, or reinitiating after interruption of therapy. The maintenance dose is determined by titration based on parathyroid hormone (PTH) and corrected serum calcium response. The maintenance dose is the dose that maintains PTH concentrations within the recommended target range and corrected serum calcium within the normal range. The lowest maintenance dose is 2.5 mg IV 3 times weekly; the maximum dose is 15 mg IV 3 times weekly.
Therapeutic Drug Monitoring:
-Measure corrected serum calcium concentration 1 week after initiation or dose adjustment and then every 4 weeks during maintenance therapy.
-Measure parathyroid hormone (PTH) concentration 4 weeks after initiation or dose adjustment and then per clinical practice during maintenance therapy.
-Increase the dose by 2.5 mg or 5 mg increments, no more than every 4 weeks, if corrected serum calcium is within the normal range and PTH is above the recommended target range. Do not exceed the maximum recommended dose of 15 mg IV 3 times weekly.
-Decrease or temporarily discontinue etelcalcetide if PTH concentration falls below the target range. In patients with corrected serum calcium below the lower limit of normal but at or above 7.5 mg/dL without symptoms of hypocalcemia, consider decreasing or temporarily discontinuing etelcalcetide, or use concomitant therapies to increase corrected serum calcium. If treatment is stopped, reinitiate etelcalcetide at a lower dose when the PTH is within the target range and hypocalcemia has been corrected.
-Stop etelcalcetide and treat hypocalcemia if the corrected serum calcium is less than 7.5 mg/dL or patient has symptoms of hypocalcemia. When the corrected serum calcium is within normal limits, symptoms of hypocalcemia have resolved, and predisposing factors for hypocalcemia have been addressed, reinitiate etelcalcetide at a dose 5 mg lower than the last administered dose. If the last administered dose was 2.5 mg or 5 mg, reinitiate at 2.5 mg.
Maximum Dosage Limits:
-Adults
15 mg IV 3 times weekly.
-Geriatric
15 mg IV 3 times weekly.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Cinacalcet: (Major) Avoid the concomitant use of etelcalcetide and cinacalcet. Discontinue cinacalcet at least 7 days prior to starting etelcalcetide, and initiate etelcalcetide treatment at 5 mg IV 3 times weekly. Ensure corrected serum calcium is at or above lower limit of normal prior to etelcalcetide initiation. Concurrent use of etelcalcetide with another oral calcium-sensing receptor agonist may result in severe, life-threatening, hypocalcemia.
Denosumab: (Moderate) Monitor serum calcium, phosphorus, and magnesium concentrations within 14 days of denosumab injection during concurrent treatment with calcimimetics such as etelcalcetide. The risk for hypocalcemia and other disturbances of mineral metabolism may increase during coadministration. Monitor serum calcium concentrations closely in patients with severe renal impairment (CrCl less than 30 mL/minute) or renal failure (and/or on dialysis) receiving calcimimetics. An increased risk of hypocalcemia was seen in clinical trials involving patients with renal dysfunction. Instruct patients to seek medical care if symptoms of hypocalcemia develop.
Etelcalcetide is a calcimimetic agent that binds to the calcium-sensing receptor (CaSR) and enhances activation of the receptor by extracellular calcium. Activation of the CaSR on parathyroid chief cells decreases parathyroid hormone (PTH) secretion. The reduction in PTH is associated with a concomitant decrease in serum calcium concentrations and attenuation of post-dialytic phosphate elevation.
Etelcalcetide is administered intravenously. Etelcalcetide is predominately bound to plasma albumin by reversible covalent bonding. Etelcalcetide is not metabolized by CYP450 isoenzymes. It is biotransformed in the blood by reversible disulfide exchange with endogenous thiols to predominately form conjugates with serum albumin. The plasma exposure of biotransformation products is approximately 5-fold higher than that of etelcalcetide, and their concentration-time course parallels that of etelcalcetide. In patients undergoing hemodialysis, etelcalcetide is eliminated during hemodialysis. For those with normal renal function, etelcalcetide is excreted by the kidneys. After a single radiolabeled dose of etelcalcetide in chronic kidney disease patients with secondary hyperparathyroidism requiring hemodialysis, approximately 60% of the drug was recovered in the dialysate and 7% recovered in urine and feces combined over 175 days of collection period.
Affected cytochrome P450 isoenzymes and drug transporters: none
-Route-Specific Pharmacokinetics
Intravenous Route
Etelcalcetide follows linear pharmacokinetics and does not change over time after single and multiple intravenous doses in chronic kidney disease patients with secondary hyperparathyroidism requiring hemodialysis. After a single intravenous dose of etelcalcetide, PTH concentrations decreased within 30 minutes. The extent and duration PTH reduction increased with increasing dose. Reduction in PTH concentrations correlated with plasma etelcalcetide concentrations in hemodialysis patients. Steady state plasma concentrations are reached in 7 to 8 weeks when administered intravenously 3 times a week at the end of each 3- to 6-hour hemodialysis session. The effective half-life of etelcalcetide is 3 to 4 days. The effect of reducing PTH concentrations was maintained throughout the 6-month dosing period when etelcalcetide was administered by IV bolus 3 times a week.
-Special Populations
Geriatric
The pharmacokinetics of etelcalcetide is similar between patients >= 65 years and < 65 years.
Gender Differences
Gender does not influence the pharmacokinetics of etelcalcetide.
Ethnic Differences
Race does not influence the pharmacokinetics of etelcalcetide.
Obesity
Body weight (29 to 163 kg) does not influence the pharmacokinetics of etelcalcetide.