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  • CLASSES

    Parathyroid Hormone Analogs and Modifiers

    DEA CLASS

    Rx

    DESCRIPTION

    Intravenous, calcium-sensing receptor agonist
    Used for secondary hyperparathyroidism in adults with chronic kidney disease on hemodialysis
    Can cause severe hypocalcemia; monitor corrected serum calcium regularly

    COMMON BRAND NAMES

    PARSABIV

    HOW SUPPLIED

    Etelcalcetide/PARSABIV Intravenous Inj Sol: 1mL, 5mg

    DOSAGE & INDICATIONS

    For the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on hemodialysis.
    For patients switching from cinacalcet to etelcalcetide.
    Intravenous dosage
    Adults

    5 mg IV 3 times weekly at the end of hemodialysis treatment after discontinuing etelcacetide for at least 7 days. 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.

    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.

    MAXIMUM DOSAGE

    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.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    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

    Do not dilute prior to 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.
    Administer by intravenous bolus into the venous line of the dialysis circuit at the end of the hemodialysis session during rinse back or intravenously after rinse back.
    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).

    STORAGE

    PARSABIV:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not expose product to temperatures above 77 degrees F
    - Prior to dispensing, store in refrigerator (36 to 46 degrees F)
    - Protect from direct sunlight
    - Store in original container
    - Unrefrigerated product can be stored at temperatures not exceeding 77 degrees F for no more than 7 days prior to administration
    - Use unrefrigerated product within 4 hours of removal from original carton

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Etelcalcetide is contraindicated in patients with known hypersensitivity to etelcalcetide or any of its excipients. Hypersensitivity reactions have occurred with the use of etelcalcetide.

    Hypocalcemia

    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.

    Seizure disorder

    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.

    Long QT syndrome, QT prolongation

    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.

    Heart failure

    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.

    Esophagitis, gastritis, GI bleeding, peptic ulcer disease, vomiting

    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.

    Pregnancy

    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.

    Breast-feeding

    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.

    ADVERSE REACTIONS

    Severe

    GI bleeding / Delayed / Incidence not known
    heart failure / Delayed / Incidence not known

    Moderate

    antibody formation / Delayed / 7.1-7.1
    hypocalcemia / Delayed / 7.0-7.0
    QT prolongation / Rapid / 4.8-4.8
    edema / Delayed / 4.4-4.4
    hypophosphatemia / Delayed / 1.0-1.0
    osteodystrophy / Delayed / Incidence not known

    Mild

    muscle cramps / Delayed / 12.0-12.0
    diarrhea / Early / 11.0-11.0
    nausea / Early / 11.0-11.0
    vomiting / Early / 9.0-9.0
    headache / Early / 8.0-8.0
    paresthesias / Delayed / 6.0-6.0
    hypoesthesia / Delayed / 6.0-6.0
    urticaria / Rapid / 4.4-4.4
    pruritus / Rapid / 4.4-4.4
    rash (unspecified) / Early / 4.4-4.4
    myalgia / Early / 2.0-2.0

    DRUG INTERACTIONS

    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.

    PREGNANCY AND LACTATION

    Pregnancy

    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.

    MECHANISM OF ACTION

    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.

    PHARMACOKINETICS

    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

    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.