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Cerdelga

Generic Name: Eliglustat
Class: Other Miscellaneous Therapeutic Agents
Chemical Name: N-[(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-pyrrolidin-1-ylpropan-2-yl]octanamide
Molecular Formula: C23H36N2O4
CAS Number: 1000191-50-3

Introduction

Eliglustat is a glucosylceramide synthase inhibitor.

Uses for Cerdelga

Eliglustat has the following uses:

Eliglustat is a glucosylceramide synthase inhibitor indicated for the long-term treatment of adult patients with Gaucher disease type 1 who are CYP2D6 extensive metabolizers (EMs), intermediate metabolizers (IMs), or poor metabolizers (PMs) as detected by an FDA-cleared test.1

Eliglustat has the following limitations of use:

CYP2D6 ultra-rapid metabolizers may not achieve adequate concentrations of eliglustat to achieve a therapeutic effect.1

A specific dosage cannot be recommended for CYP2D6 indeterminate metabolizers.1

Cerdelga Dosage and Administration

General

Eliglustat is available in the following dosage form(s) and strength(s):

  • 84 mg capsules.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

  • Select patients using an FDA-cleared test for determining CYP2D6 genotype.1

  • CYP2D6 EMs or IMs: 84 mg orally twice daily.1

  • CYP2D6 PMs: 84 mg orally once daily.1

  • Swallow capsules whole, do not crush, dissolve or open capsules.1

  • Avoid eating grapefruit or drinking grapefruit juice.1

Cautions for Cerdelga

Contraindications

  • CYP2D6 EMs and IMs taking a strong or moderate CYP2D6 inhibitor with a strong or moderate CYP3A inhibitor.1

  • CYP2D6 IMs and PMs taking a strong CYP3A inhibitor.1

Warnings/Precautions

Drug-Drug Interactions

Eliglustat is a CYP2D6 and CYP3A substrate. Drugs that inhibit CYP2D6 and CYP3A metabolism pathways may significantly increase the exposure to eliglustat and result in prolongation of the PR, QTc, and/or QRS cardiac intervals that could result in cardiac arrhythmias. Some drugs that are inhibitors of CYP2D6 and CYP3A are contraindicated with eliglustat depending on the patient's CYP2D6 metabolizer status.1

ECG Changes And Potential For Cardiac Arrhythmias

Use of eliglustat in patients with pre-existing cardiac conditions has not been studied during clinical trials. Because eliglustat is predicted to cause increases in ECG intervals (PR, QTc, and QRS) at substantially elevated eliglustat plasma concentrations, use of eliglustat is not recommended in patients with pre-existing cardiac disease (congestive heart failure, recent acute myocardial infarction, bradycardia, heart block, ventricular arrhythmia), long QT syndrome, and in combination with Class IA (e.g., quinidine, procainamide) and Class III (e.g., amiodarone, sotalol) antiarrhythmic medications.1

Specific Populations

Pregnancy

Pregnancy Category C.1

Risk Summary: There are no adequate or well-controlled studies with eliglustat in pregnant women. However, animal reproduction studies have been conducted for eliglustat. In these animal studies, a spectrum of anomalies at doses 6 times the recommended human dose were observed in orally dosed rats. No fetal harm was observed with oral administration of eliglustat to pregnant rabbits at dose levels 10 times the recommended human dose. Eliglustat should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.1

Disease-associated Maternal and Embryo-fetal Risk: Women with Gaucher disease type 1 have an increased risk of spontaneous abortion, especially if disease symptoms are not treated and controlled pre-conception and during a pregnancy. Pregnancy may exacerbate existing Gaucher disease type 1 symptoms or result in new disease manifestations. Gaucher disease type 1 manifestations may lead to adverse pregnancy outcomes including hepatosplenomegaly, which can interfere with the normal growth of a pregnancy, and thrombocytopenia, which can lead to increased bleeding and possible hemorrhage.1

Animal Data: Reproduction studies have been performed in pregnant rats at oral doses up to 120 mg/kg/day (about 6 times the recommended human dose based on body surface area) and in pregnant rabbits at oral doses up to 100 mg/kg/day (about 10 times the recommended human dose based on body surface area). In rats, at 120 mg/kg/day (about 6 times the recommended human dose based on body surface area), eliglustat increased the number of late resorptions, dead fetuses and post implantation loss, reduced fetal body weight, and caused fetal cerebral variations (dilated cerebral ventricles), fetal skeletal variations (poor bone ossification) and fetal skeletal malformations (abnormal number of ribs or lumbar vertebra). Eliglustat did not cause fetal harm in rabbits at oral doses up to 100 mg/kg/day (about 10 times the recommended human dose based on body surface area). In a pre and postnatal development study in rats, eliglustat did not show any significant adverse effects on pre and postnatal development at doses up to 100 mg/kg/day (about 5 times the recommended human dose based on body surface area).1

Nursing Mothers

It is not known whether eliglustat is present in human milk. Because many drugs are present in human milk, and because of the potential for serious adverse reactions in nursing infants from eliglustat, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the lactating woman.1

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.1

Geriatric Use

Clinical studies of eliglustat did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Clinical experience has not identified differences in responses between the elderly and younger patients.1

Renal Impairment

There is no dosage adjustment required for patients with mild renal impairment. Eliglustat has not been studied in patients with moderate to severe renal impairment or end-stage renal disease (ESRD). Use of eliglustat in these patients is not recommended.1

Hepatic Impairment

Eliglustat has not been studied in patients with hepatic impairment. Use of eliglustat is not recommended in all stages of hepatic impairment or cirrhosis.1

Poor Metabolizers

Dosing of eliglustat 84 mg once daily has not been studied in PMs, however the predicted systemic exposures in these patients are within the range of those observed in clinical studies. Appropriate adverse event monitoring is recommended.1

Common Adverse Effects

The most common adverse reactions (≥10%) are: fatigue, headache, nausea, diarrhea, back pain, pain in extremities, and upper abdominal pain.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

  • Eliglustat is a CYP2D6 and CYP3A substrate. Co-administration of eliglustat with drugs that inhibit CYP2D6 and CYP3A may significantly increase the exposure to eliglustat and result in prolongation of the PR, QTc, and/or QRS cardiac interval, which could result in cardiac arrhythmias. Consider potential drug interactions prior to and during therapy.1

  • CYP2D6 IMs and PMs taking moderate CYP3A inhibitors: not recommended.1

  • CYP2D6 PMs taking weak CYP3A inhibitors: not recommended.1

  • CYP2D6 EMs and IMs taking strong or moderate CYP2D6 inhibitors and CYP2D6 EMs taking strong or moderate CYP3A inhibitors: reduce the dosage to 84 mg once daily.1

  • Eliglustat is an inhibitor of P-gp and CYP2D6. Co-administration with drugs that are substrates for P-gp or CYP2D6 may result in increased concentrations of the other drug.1

  • See Full Prescribing Information for a list of clinically significant drug interactions.1

Actions

Mechanism Of Action

Gaucher disease is caused by a deficiency of the lysosomal enzyme acid β-glucosidase. Acid β-glucosidase catalyzes the conversion of the sphingolipid glucocerebroside into glucose and ceramide. The enzymatic deficiency causes an accumulation of glucosylceramide (GL-1) primarily in the lysosomal compartment of macrophages, giving rise to foam cells or "Gaucher cells." Eliglustat is a specific inhibitor of glucosylceramide synthase (IC50= 10 ng/mL), and acts as a substrate reduction therapy for GD1. In clinical trials eliglustat reduced spleen and liver size, and improved anemia and thrombocytopenia.1

In this lysosomal storage disorder (LSD), clinical features are reflective of the accumulation of Gaucher cells in the liver, spleen, bone marrow, and other organs. The accumulation of Gaucher cells in the liver, spleen, and bone marrow leads to organomegaly and skeletal disease. Presence of Gaucher cells in the bone marrow and spleen lead to clinically significant anemia and thrombocytopenia. 1

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Medication Guide).1

Drug Interactions

Advise patients to discuss all the medications they are taking, including any herbal supplements or vitamins, with their healthcare provider.1

ECG Changes and Potential for Cardiac Arrhythmias

Advise patients to inform their healthcare provider of the following: history of congestive heart failure, recent acute myocardial infarction, bradycardia, heart block, ventricular arrhythmia, or long QT syndrome.1

Advise patients to inform their healthcare provider if they develop new symptoms such as palpitations, fainting, and dizziness.1

Administration Instructions

Advise patients: 1

Swallow capsules whole, preferably with water, and do not crush, dissolve, or open the capsules.1

Eliglustat can be taken with or without food.1

If a dose of eliglustat is missed, take the prescribed dose at the next scheduled time; do not double the next dose.1

Avoid consumption of grapefruit or its juice.1

For patients currently treated with imiglucerase, velaglucerase alfa, or taliglucerase alfa, eliglustat may be administered 24 hours after the last dose of the previous enzyme replacement therapy (ERT).1

Additional Information

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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.

Eliglustat

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsule

84 mg

Cerdelga

Genzyme Corporation

AHFS Drug Information. © Copyright 2016, Selected Revisions September 15, 2016. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Genzyme Corporation. Cerdelga (eliglustat) ORAL prescribing information. 2014 Aug.

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