Parsabiv

Name: Parsabiv

What should I do if I forget a dose?

This medication is only given with your dialysis treatment. If you miss a scheduled dialysis treatment, skip the missed dose of medication and continue your regular dosing schedule at the next dialysis session.

Side effects

The following adverse reactions are discussed in greater detail in other sections of the labeling:

  • Hypocalcemia [see WARNINGS AND PRECAUTIONS]
  • Worsening Heart Failure [see WARNINGS AND PRECAUTIONS]
  • Upper Gastrointestinal Bleeding [see WARNINGS AND PRECAUTIONS]
  • Adynamic Bone [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The data in Table 2 are derived from two placebo-controlled clinical studies in patients with chronic kidney disease and secondary hyperparathyroidism on hemodialysis. The data reflect exposure of 503 patients to PARSABIV with a mean duration of exposure to PARSABIV of 23.6 weeks. The mean age of patients was approximately 58 years, and 60% of the patients were male. Of the total patients, 67% were Caucasian, 28% were Black or African American, 2.6% were Asian, 1.2% were Native Hawaiian or Other Pacific Islander, and 1.6% were categorized as Other.

Table 2 shows common adverse reactions associated with the use of PARSABIV in the pool of placebo-controlled studies. These adverse reactions occurred more commonly on PARSABIV than on placebo and were reported in at least 5% of patients treated with PARSABIV.

Table 2: Adverse Reactions Reported in ≥ 5% of PARSABIV-Treated Patients

Adverse Reaction* Placebo
(N = 513)
PARSABIV
(N = 503)
Blood calcium decreaseda 10% 64%
Muscle spasms 7% 12%
Diarrhea 9% 11%
Nausea 6% 11%
Vomiting 5% 9%
Headache 6% 8%
Hypocalcemiab 0.2% 7%
Paresthesiac 1% 6%
* Included adverse reactions reported with at least 1% greater incidence in the PARSABIV group compared to the placebo group.
aAsymptomatic reductions in calcium below 7.5 mg/dL or clinically significant asymptomatic reductions in corrected serum calcium between 7.5 and < 8.3 mg/dL (that required medical management)
bSymptomatic reductions in corrected serum calcium < 8.3 mg/dL
cParesthesia includes preferred terms of paresthesia and hypoesthesia

Other adverse reactions associated with the use of PARSABIV but reported in < 5% of patients in the PARSABIV group in the two placebo-controlled clinical studies were:

  • Hyperkalemia: 3% and 4% for placebo and PARSABIV, respectively.
  • Hospitalization for Heart Failure: 1% and 2% for placebo and PARSABIV, respectively.
  • Myalgia: 0.2% and 2% for placebo and PARSABIV, respectively.
  • Hypophosphatemia: 0.2% and 1% for placebo and PARSABIV, respectively.

Description Of Selected Adverse Reactions

Hypocalcemia

In the combined placebo-controlled studies, a higher proportion of patients on PARSABIV developed at least one corrected serum calcium value below 7.0 mg/dL (7.6% PARSABIV, 3.1% placebo), below 7.5 mg/dL (27% PARSABIV, 5.5% placebo), and below 8.3 mg/dL (79% PARSABIV, 19% placebo). In the combined placebo-controlled studies, 1% of patients in the PARSABIV group and 0% of patients in the placebo group discontinued treatment due to an adverse reaction attributed to a low corrected serum calcium.

Hypophosphatemia

In the combined placebo-controlled studies, 18% of patients treated with PARSABIV and 8.2% of patients treated with placebo had at least one measured phosphorus level below the lower normal limit (i.e., 2.2 mg/dl).

QTc Interval Prolongation Secondary to Hypocalcemia

In the combined placebo-controlled studies, more patients treated with PARSABIV experienced a maximum increase from baseline of greater than 60 msec in the QTcF interval (0% placebo versus 1.2% PARSABIV). The patient incidence of maximum post-baseline predialysis QTcF > 500 msec in the placebo and PARSABIV groups was 1.9% and 4.8%, respectively.

Hypersensitivity

In the combined placebo-controlled studies, the subject incidence of adverse reactions potentially related to hypersensitivity was 4.4% in the PARSABIV group and 3.7% in the placebo group. Hypersensitivity reactions in the PARSABIV group were pruritic rash, urticaria, and face edema.

Immunogenicity

As with all peptide therapeutics, there is potential for immunogenicity. The detection of anti-drug binding antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to etelcalcetide with the incidence of antibodies to other products may be misleading.

In clinical studies, 7.1% (71 out of 995) of patients with secondary hyperparathyroidism treated with PARSABIV for up to 6 months tested positive for binding anti-etelcalcetide antibodies. Fifty-seven out of 71 had pre-existing anti-etelcalcetide antibodies. No evidence of altered pharmacokinetic profile, clinical response, or safety profile was associated with pre-existing or developing anti-etelcalcetide antibodies. If formation of anti-etelcalcetide binding antibodies with a clinically significant effect is suspected, contact Amgen at 1-800-77-AMGEN (1-800-772-6436) to discuss antibody testing.

Parsabiv Usage

Parsabiv is given at the end of your hemodialysis session, three times a week, through the tube (bloodline) that connects you to the machine. Your healthcare provider will administer it for you.

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

Uses For Parsabiv

Etelcalcetide injection is used to used to treat secondary hyperparathyroidism in patients with chronic kidney disease who are on dialysis. Hyperparathyroidism is a condition that is caused when the parathyroid glands located in the neck make too much parathyroid hormone (PTH). This hormone controls the concentrations of calcium and phosphorus in your blood. Paricalcitol helps lower the amount of PTH which lowers the calcium and phosphorus concentrations.

This medicine is to be given only by or under the direct supervision of your doctor.

Indications and usage

Parsabiv is indicated for the treatment of secondary hyperparathyroidism (HPT) in adult patients with chronic kidney disease (CKD) on hemodialysis.

Limitations of Use:

Parsabiv has not been studied in adult patients with parathyroid carcinoma, primary hyperparathyroidism, or with chronic kidney disease who are not on hemodialysis and is not recommended for use in these populations.

Warnings and precautions

      Hypocalcemia

Parsabiv lowers serum calcium [see Adverse Reactions (6.1)] and can lead to hypocalcemia, sometimes severe. Significant lowering of serum calcium can cause paresthesias, myalgias, muscle spasms, seizures, QT interval prolongation, and ventricular arrhythmia.

QT Interval Prolongation and Ventricular Arrhythmia

In the combined placebo-controlled studies, more patients treated with Parsabiv experienced a maximum increase from baseline of greater than 60 msec in the QTcF interval (0% placebo versus 1.2% Parsabiv). In these studies, the incidence of a maximum post-baseline predialysis QTcF > 500 msec in the placebo and Parsabiv groups was 1.9% and 4.8%, respectively [see Adverse Reactions (6.1)]. 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 Parsabiv. Closely monitor corrected serum calcium and QT interval in patients at risk receiving Parsabiv.

Seizures

Significant reductions in corrected serum calcium may lower the threshold for seizures. Patients with a history of seizure disorder may be at increased risk for seizures if they develop hypocalcemia due to Parsabiv. Monitor corrected serum calcium in patients with seizure disorders receiving Parsabiv.

Concurrent administration of Parsabiv with another oral calcium-sensing receptor agonist could result in severe, life-threatening hypocalcemia. Patients switching from cinacalcet to Parsabiv should discontinue cinacalcet for at least 7 days prior to initiating Parsabiv [see Dosage and Administration (2.4)]. Closely monitor corrected serum calcium in patients receiving Parsabiv and concomitant therapies known to lower serum calcium.

Measure corrected serum calcium prior to initiation of Parsabiv. Do not initiate in patients if the corrected serum calcium is less than the lower limit of normal. Monitor corrected serum calcium within 1 week after initiation or dose adjustment and every 4 weeks during treatment with Parsabiv [see Dosage and Administration (2.2)]. 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 increases in dialysate calcium concentration). Parsabiv dose reduction or discontinuation of Parsabiv may be necessary [see Dosage and Administration (2.2)].

      Worsening Heart Failure

In clinical studies with Parsabiv, cases of hypotension, congestive heart failure, and decreased myocardial performance have been reported. In clinical studies, heart failure requiring hospitalization occurred in 2% of Parsabiv-treated patients and 1% of placebo-treated patients. Reductions in corrected serum calcium may be associated with congestive heart failure, however, a causal relationship to Parsabiv could not be completely excluded. Closely monitor patients treated with Parsabiv for worsening signs and symptoms of heart failure.

      Upper Gastrointestinal Bleeding

In clinical studies, two patients treated with Parsabiv in 1253 patient-years of exposure had upper gastrointestinal (GI) bleeding noted at the time of death while no patient in the control groups in 384 patient-years of exposure had upper GI bleeding noted at the time of death. The exact cause of GI bleeding in these patients is unknown, and there were too few cases to determine whether these cases were related to Parsabiv.

Patients with risk factors for upper GI bleeding (such as known gastritis, esophagitis, ulcers, or severe vomiting) may be at increased risk for GI bleeding while receiving Parsabiv treatment. Monitor patients for worsening of common GI adverse reactions of nausea and vomiting associated with Parsabiv [see Adverse Reactions (6.1)] and for signs and symptoms of GI bleeding and ulcerations during Parsabiv therapy. Promptly evaluate and treat any suspected GI bleeding.

      Adynamic Bone

Adynamic bone may develop if PTH levels are chronically suppressed. If PTH levels decrease below the recommended target range, the dose of vitamin D sterols and/or Parsabiv should be reduced or therapy discontinued. After discontinuation, resume therapy at a lower dose to maintain PTH levels in the target range [see Dosage and Administration (2.1)].

Adverse reactions

The following adverse reactions are discussed in greater detail in other sections of the labeling:

  • Hypocalcemia [see Warnings and Precautions (5.1)]
  • Worsening Heart Failure [see Warnings and Precautions (5.2)]
  • Upper Gastrointestinal Bleeding [see Warnings and Precautions (5.3)]
  • Adynamic Bone [see Warnings and Precautions (5.4)]

      Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The data in Table 2 are derived from two placebo-controlled clinical studies in patients with chronic kidney disease and secondary hyperparathyroidism on hemodialysis. The data reflect exposure of 503 patients to Parsabiv with a mean duration of exposure to Parsabiv of 23.6 weeks. The mean age of patients was approximately 58 years, and 60% of the patients were male. Of the total patients, 67% were Caucasian, 28% were Black or African American, 2.6% were Asian, 1.2% were Native Hawaiian or Other Pacific Islander, and 1.6% were categorized as Other. 

Table 2 shows common adverse reactions associated with the use of Parsabiv in the pool of placebo-controlled studies. These adverse reactions occurred more commonly on Parsabiv than on placebo and were reported in at least 5% of patients treated with Parsabiv.

Table 2: Adverse Reactions Reported in ≥ 5% of Parsabiv-Treated Patients
Adverse Reaction* Placebo
(N = 513)
Parsabiv
(N = 503)
Blood calcium decreaseda 10% 64%
Muscle spasms 7% 12%
Diarrhea 9% 11%
Nausea 6% 11%
Vomiting 5% 9%
Headache 6% 8%
Hypocalcemiab 0.2% 7%
Paresthesiac 1% 6%
* Included adverse reactions reported with at least 1% greater incidence in the Parsabiv group compared to the placebo group
a Asymptomatic reductions in calcium below 7.5 mg/dL or clinically significant asymptomatic reductions in corrected serum calcium between 7.5 and < 8.3 mg/dL (that required medical management)
b Symptomatic reductions in corrected serum calcium < 8.3 mg/dL
c Paresthesia includes preferred terms of paresthesia and hypoesthesia

Other adverse reactions associated with the use of Parsabiv but reported in < 5% of patients in the Parsabiv group in the two placebo-controlled clinical studies were:

  • Hyperkalemia: 3% and 4% for placebo and Parsabiv, respectively.
  • Hospitalization for Heart Failure: 1% and 2% for placebo and Parsabiv, respectively.
  • Myalgia: 0.2% and 2% for placebo and Parsabiv, respectively.
  • Hypophosphatemia: 0.2% and 1% for placebo and Parsabiv, respectively.

Description of Selected Adverse Reactions

Hypocalcemia

In the combined placebo-controlled studies, a higher proportion of patients on Parsabiv developed at least one corrected serum calcium value below 7.0 mg/dL (7.6% Parsabiv, 3.1% placebo), below 7.5 mg/dL (27% Parsabiv, 5.5% placebo), and below 8.3 mg/dL (79% Parsabiv, 19% placebo). In the combined placebo-controlled studies, 1% of patients in the Parsabiv group and 0% of patients in the placebo group discontinued treatment due to an adverse reaction attributed to a low corrected serum calcium.

Hypophosphatemia

In the combined placebo-controlled studies, 18% of patients treated with Parsabiv and 8.2% of patients treated with placebo had at least one measured phosphorus level below the lower normal limit (i.e., 2.2 mg/dL).

QTc Interval Prolongation Secondary to Hypocalcemia 

In the combined placebo-controlled studies, more patients treated with Parsabiv experienced a maximum increase from baseline of greater than 60 msec in the QTcF interval (0% placebo versus 1.2% Parsabiv). The patient incidence of maximum post-baseline predialysis QTcF > 500 msec in the placebo and Parsabiv groups was 1.9% and 4.8%, respectively.

Hypersensitivity

In the combined placebo-controlled studies, the subject incidence of adverse reactions potentially related to hypersensitivity was 4.4% in the Parsabiv group and 3.7% in the placebo group. Hypersensitivity reactions in the Parsabiv group were pruritic rash, urticaria, and face edema.

      Immunogenicity

As with all peptide therapeutics, there is potential for immunogenicity. The detection of anti-drug binding antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to etelcalcetide with the incidence of antibodies to other products may be misleading.

In clinical studies, 7.1% (71 out of 995) of patients with secondary hyperparathyroidism treated with Parsabiv for up to 6 months tested positive for binding anti-etelcalcetide antibodies. Fifty-seven out of 71 had pre-existing anti-etelcalcetide antibodies.

No evidence of altered pharmacokinetic profile, clinical response, or safety profile was associated with pre-existing or developing anti-etelcalcetide antibodies. If formation of anti-etelcalcetide binding antibodies with a clinically significant effect is suspected, contact Amgen at 1-800-77-AMGEN (1-800-772-6436) to discuss antibody testing.

Clinical pharmacology

      Mechanism of Action

Etelcalcetide is a calcimimetic agent that allosterically modulates the calcium-sensing receptor (CaSR). Etelcalcetide binds to the CaSR and enhances activation of the receptor by extracellular calcium. Activation of the CaSR on parathyroid chief cells decreases PTH secretion.

      Pharmacodynamics

Following a single intravenous bolus administration of etelcalcetide, PTH levels decreased within 30 minutes post-dose. In the single-dose study, the extent and duration of the reduction in PTH increased with increasing dose. Reduction in PTH levels correlated with plasma etelcalcetide concentrations in hemodialysis patients. The reduction in PTH resulted in reductions in calcium and attenuation of post-dialytic phosphate elevation. The effect of reducing PTH levels was maintained throughout the 6-month dosing period when etelcalcetide was administered by intravenous bolus three times a week.

      Pharmacokinetics

The pharmacokinetics of etelcalcetide is linear and does not change over time following single (5 to 60 mg) and multiple intravenous doses (2.5 to 20 mg) in chronic kidney disease patients with secondary hyperparathyroidism requiring hemodialysis. Etelcalcetide exhibited tri-exponential decay following intravenous administration. Based on population pharmacokinetic analysis, following three times a week intravenous dosing at the end of each 3- to 6-hour hemodialysis session in chronic kidney disease patients, etelcalcetide plasma levels reached steady state in 7-8 weeks after dosing with a predicted accumulation ratio of 3- to 4-fold, and the effective half-life was 3 to 4 days. 

Distribution

In the population pharmacokinetics model, volume of distribution at steady state (Vss) was approximately 796 L. Etelcalcetide is predominately bound to plasma albumin by reversible covalent binding. Non-covalent binding of etelcalcetide to plasma proteins is low with a fraction unbound ratio of 0.53. The ratio of blood-to-plasma [14C]-etelcalcetide concentrations is approximately 0.6.

Elimination

Metabolism

Etelcalcetide is not metabolized by CYP450 enzymes. Etelcalcetide is biotransformed in blood by reversible disulfide exchange with endogenous thiols to predominantly form conjugates with serum albumin.

Following a single radiolabeled dose of etelcalcetide in chronic kidney disease patients with secondary hyperparathyroidism requiring hemodialysis, the plasma exposure of biotransformation products is approximately 5-fold higher than that of etelcalcetide and their concentration-time course parallels that of etelcalcetide.

Excretion

Etelcalcetide is cleared by renal excretion in patients with normal renal function, while hemodialysis is the predominant elimination pathway in chronic kidney disease patients requiring hemodialysis. In chronic kidney disease patients on hemodialysis, etelcalcetide was removed with a hemodialysis clearance value of 7.66 L/hr. Following a single radiolabeled dose of etelcalcetide in chronic kidney disease patients with secondary hyperparathyroidism requiring hemodialysis, approximately 60% of [14C]-etelcalcetide was recovered in dialysate, and approximately 7% recovered in urine and feces combined over 175 days of collection period.

Specific Populations

Effects of Body Weight, Gender, Race, and Age

Results of population pharmacokinetic analyses indicate that body weight (29 to 163 kg), gender, race, and age (20 to 93 years of age) do not influence the pharmacokinetics of etelcalcetide. The pharmacokinetics of etelcalcetide in patients ≥ 65 years of age and in patients < 65 years of age is similar.

Drug Interactions

In Vitro Assessment of Drug Interactions

Etelcalcetide did not inhibit or induce CYP450 enzymes, and is not a substrate of CYP450 enzymes. Etelcalcetide was not a substrate of efflux and uptake transporter proteins (P-glycoprotein [Pgp], breast cancer resistance protein [BCRP], organic anion transporter [OAT] 1 and 3, organic anion polypeptide transporter [OATP] 1B1 and 1B3, organic cation transporter [OCT] 2, and peptide transporter [PEPT] 1 and 2). Etelcalcetide was also not an inhibitor of common transporter proteins (Pgp, BCRP, OAT1, OAT3, OATP1B1, OATP1B3, OCT2, or bile salt export pump [BSEP]).

What are some things I need to know or do while I take Parsabiv?

  • Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
  • Have blood work checked as you have been told by the doctor. Talk with the doctor.
  • Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using Parsabiv while you are pregnant.

Consumer Information Use and Disclaimer

  • If your symptoms or health problems do not get better or if they become worse, call your doctor.
  • Do not share your drugs with others and do not take anyone else's drugs.
  • Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
  • Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Check with your pharmacist about how to throw out unused drugs.
  • Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about Parsabiv, please talk with your doctor, nurse, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about Parsabiv. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using Parsabiv (etelcalcetide).

Review Date: November 1, 2017

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