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Eliglustat Tartrate

Class: Other Miscellaneous Therapeutic Agents
Chemical Name: N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1- hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)octanamide (2R,3R)-2,3-dihydroxysuccinate
Molecular Formula: C23H36N2O4+½(C4H6O6)
CAS Number: 491833-29-5
Brands: Cerdelga

Introduction

Glucosylceramide synthase (ceramide glucosyltransferase) inhibitor.1 3 4 5 6 7 8 9

Uses for Eliglustat Tartrate

Gaucher Disease

Long-term treatment of nonneuronopathic (type 1) Gaucher disease in patients who are extensive, intermediate, or poor metabolizers of CYP2D6.1 3 4 5 6 7 8 9

Patient selection and dosing based on CYP2D6 metabolizer status; determine patient's CYP2D6 genotype with an FDA-cleared test prior to initiating therapy.1 4 10

Ultrarapid CYP2D6 metabolizers may not achieve adequate plasma concentrations to achieve a therapeutic effect.1 A specific dosage cannot be recommended for patients whose CYP2D6 genotype cannot be determined (indeterminate metabolizers).1

Designated an orphan drug by FDA for treatment of type 1 Gaucher disease.2

Eliglustat Tartrate Dosage and Administration

Administration

Oral Administration

Administer orally without regard to meals.1 Swallow capsules whole, preferably with water; do not crush, dissolve, or open.1

Avoid consumption of grapefruit or grapefruit juice.1

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

Dosage

Available as eliglustat tartrate; dosage expressed in terms of eliglustat.1

Adults

Gaucher Disease
Oral

Dosage based on CYP2D6 metabolizer status.1

Extensive or intermediate CYP2D6 metabolizers: 84 mg twice daily.1

Poor CYP2D6 metabolizers: 84 mg once daily; monitor for adverse effects.1

Indeterminate metabolizers: Manufacturer states a specific dosage cannot be recommended.1

In patients currently receiving imiglucerase, velaglucerase alfa, or taliglucerase alfa, may administer eliglustat 24 hours after last dose of enzyme replacement therapy.1

Concomitant Use with CYP2D6 and CYP3A Inhibitors
Oral

Concomitant use with drugs that inhibit CYP2D6 or CYP3A may require dosage adjustments depending on the patient's CYP2D6 metabolizer status.1 (See Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes under Interactions.)

Extensive or intermediate CYP2D6 metabolizers receiving a potent or moderate CYP2D6 inhibitor: Reduce dosage to 84 mg once daily.1

Extensive CYP2D6 metabolizers receiving a potent or moderate CYP3A inhibitor: Reduce dosage to 84 mg once daily.1

Special Populations

Renal Impairment

No dosage adjustment is required for patients with mild renal impairment.1 Not evaluated in patients with moderate to severe renal impairment or end-stage renal disease.1

Cautions for Eliglustat Tartrate

Contraindications

  • Extensive or intermediate CYP2D6 metabolizers who are receiving a potent/moderate CYP2D6 inhibitor and a potent/moderate CYP3A inhibitor concomitantly.1

  • Intermediate or poor CYP2D6 metabolizers who are receiving concomitant treatment with a potent CYP3A inhibitor.1

Warnings/Precautions

Concomitant Use of CYP2D6 and CYP3A Inhibitors

Concomitant use of drugs that inhibit CYP2D6 (e.g., paroxetine, terbinafine) and/or CYP3A (e.g., ketoconazole, fluconazole) may substantially increase eliglustat exposure and result in prolongation of the PR, corrected QT (QTc), and/or QRS intervals, possibly resulting in cardiac arrhythmias.1 (See Interactions.)

Cardiovascular Effects

May prolong PR, QTc, and/or QRS intervals at substantially elevated plasma concentrations.1 Use not recommended in patients with preexisting cardiac conditions (e.g., congestive heart failure, recent MI, bradycardia, heart block, ventricular arrhythmia).1 Use also not recommended in patients with long QT syndrome or in patients receiving concomitant treatment with class IA (e.g., quinidine, procainamide) or class III (e.g., amiodarone, sotalol) antiarrhythmic agents.1

Specific Populations

Pregnancy

Category C.1

Use during pregnancy only if potential benefit justifies potential risk to fetus.1

Lactation

Not known whether eliglustat is distributed into human milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.1 Clinical experience has not identified differences in responses between geriatric and younger patients.1

Hepatic Impairment

Not studied in patients with hepatic impairment.1 Use not recommended in patients with cirrhosis or any degree of hepatic impairment.1

Renal Impairment

Not studied in patients with moderate, severe, or end-stage renal disease; use not recommended.1 (See Renal Impairment under Dosage and Administration.)

Poor CYP2D6 Metabolizers

Eliglustat 84 mg once daily not studied in poor CYP2D6 metabolizers; however, predicted systemic exposures are within the range of those observed in clinical studies.1 Monitor for adverse events in such patients.1

Common Adverse Effects

Headache,1 5 6 fatigue,1 6 nausea,1 5 6 diarrhea,1 5 6 back pain,1 6 extremity pain,1 6 upper abdominal pain.1

Interactions for Eliglustat Tartrate

Metabolized principally by CYP2D6 and, to a lesser extent, by CYP3A.1 Inhibitor of CYP2D6 and a weak inhibitor of CYP3A in vitro.1

Substrate and inhibitor of P-glycoprotein (P-gp).1

Does not appear to be a substrate for organic anion-transporting polypeptide (OATP).1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

CYP2D6 and CYP3A inhibitors: May substantially increase eliglustat exposure and cause prolongation of PR, QTc and/or QRS intervals, possibly resulting in cardiac arrhythmias.1 Avoid concomitant use or approach with caution.1 9 (See Contraindications under Cautions.) Dosage adjustments may be required depending on the patient's CYP2D6 metabolizer status.1 9 (See Concomitant Use with CYP2D6 and CYP3A Inhibitors under Dosage and Administration.)

Potent CYP3A inhibitors: Contraindicated in patients who are intermediate or poor CYP2D6 metabolizers; reduce dosage to 84 mg once daily in extensive CYP2D6 metabolizers.1

Moderate CYP3A inhibitors: Not recommended in patients who are intermediate or poor CYP2D6 metabolizers; reduce dosage to 84 mg once daily in extensive CYP2D6 metabolizers.1

Weak CYP3A inhibitors: Not recommended in patients who are poor CYP2D6 metabolizers.1

Potent CYP2D6 inhibitors: Reduce dosage to 84 mg once daily in extensive or intermediate CYP2D6 metabolizers.1

Moderate CYP2D6 inhibitors: Reduce dosage to 84 mg once daily in extensive or intermediate CYP2D6 metabolizers.1

Potent/moderate CYP2D6 inhibitor concomitantly with a potent/moderate CYP3A inhibitor: Contraindicated in extensive and intermediate CYP2D6 metabolizers.1

Potent CYP3A inducers: May substantially decrease eliglustat exposure; therefore, not recommended in extensive, intermediate, or poor CYP2D6 metabolizers.1

CYP2D6 substrates: May increase concentrations of the CYP2D6 substrate.1 Manufacturer recommends therapeutic drug monitoring or dosage reduction (and subsequent titration to clinical effect) of the substrate drug as indicated.1

Drugs Affecting or Affected by P-glycoprotein

P-gp substrates: May increase concentrations of the P-gp substrate.1 Therapeutic drug monitoring or dosage reduction (and subsequent titration to clinical effect) of the substrate drug is recommended as indicated.1

P-gp inhibitors: Effect on eliglustat exposure not evaluated clinically.1

Drugs Affecting Gastric pH

No clinically important effect on eliglustat exposure.1

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Antacids (e.g., aluminum and magnesium hydroxides, calcium carbonate)

Clinically important interaction not observed1

Antiarrhythmic agents, class IA (e.g., quinidine, procainamide) or class III (e.g., amiodarone, sotalol)

Possible prolongation of PR, QTc and/or QRS intervals and increased risk of cardiac arrhythmias1

Concomitant use not recommended1

Carbamazepine

Potential decreased eliglustat exposure1

Concomitant use not recommended in extensive, intermediate, or poor CYP2D6 metabolizers1

Colchicine

Potential increased colchicine exposure1

Consider therapeutic drug monitoring or dosage reduction of colchicine (and titration to clinical effect) as indicated1

Dabigatran

Potential increased dabigatran exposure1

Consider therapeutic drug monitoring or dosage reduction of dabigatran (and titration to clinical effect) as indicated1

Digoxin

Potential increased peak plasma concentrations and exposure of digoxin1

Measure serum digoxin concentrations before initiating eliglustat therapy, and reduce digoxin dosage by 30% upon initiation of eliglustat; continue to monitor digoxin concentrations1

Fluconazole

Possible increased peak plasma concentrations and exposure of eliglustat; may result in prolongation of PR, QTc and/or QRS intervals and increase risk of cardiac arrhythmias1

Concomitant use not recommended in intermediate or poor CYP2D6 metabolizers; reduce eliglustat dosage to 84 mg once daily in extensive CYP2D6 metabolizers1

Grapefruit juice

Possible increased eliglustat exposure1

Avoid concomitant use1

Ketoconazole

Increased peak plasma concentrations and exposure of eliglustat; may result in prolongation of PR, QTc and/or QRS intervals and increase risk of cardiac arrhythmias1

Concomitant use contraindicated in intermediate or poor CYP2D6 metabolizers; reduce eliglustat dosage to 84 mg once daily in extensive CYP2D6 metabolizers1

Metoprolol

Possible increased peak plasma concentrations and exposure of metoprolol1

Consider therapeutic drug monitoring or dosage reduction of metoprolol (and titration to clinical effect) as indicated1

Oral contraceptives

Pharmacokinetic interaction unlikely; no effect on norethindrone or ethinyl estradiol exposure1

Pantoprazole

Clinically important interaction not observed1

Paroxetine

Possible increased peak plasma concentrations and exposure of eliglustat; may result in prolongation of PR, QTc and/or QRS intervals and increase risk of cardiac arrhythmias1

Reduce eliglustat dosage to 84 mg once daily in extensive or intermediate CYP2D6 metabolizers1

Phenobarbital

Potential decreased eliglustat exposure1

Concomitant use not recommended in extensive, intermediate, or poor CYP2D6 metabolizers1

Phenothiazines (e.g., chlorpromazine, perphenazine)

Possible increased exposure to the phenothiazine1

Consider therapeutic drug monitoring or dosage reduction of the phenothiazine (and titration to clinical effect) as indicated1

Phenytoin

Potential decreased eliglustat exposure1

Potential increased phenytoin exposure1

Concomitant use not recommended in extensive, intermediate, or poor CYP2D6 metabolizers; if concomitant use necessary, consider therapeutic drug monitoring and/or dosage reduction (and titration to clinical effect) of phenytoin1

Ranitidine

Possible increased peak plasma concentrations and exposure of eliglustat; may result in prolongation of PR, QTc and/or QRS intervals and increase risk of cardiac arrhythmias1

Concomitant use not recommended in poor CYP2D6 metabolizers1

Rifampin

Potential decreased eliglustat exposure1

Concomitant use not recommended in extensive, intermediate, or poor CYP2D6 metabolizers1

St. John's wort (Hypericum perforatum)

Potential decreased eliglustat exposure1

Concomitant use not recommended in extensive, intermediate, or poor CYP2D6 metabolizers1

Terbinafine

Possible increased peak plasma concentrations and exposure of eliglustat; may result in prolongation of PR, QTc and/or QRS intervals and increase risk of cardiac arrhythmias1

Reduce eliglustat dosage to 84 mg once daily in extensive or intermediate CYP2D6 metabolizers1

Tricyclic antidepressants (e.g., amitriptyline, imipramine, nortriptyline)

Potential increased exposure to the tricyclic antidepressant1

Consider therapeutic drug monitoring or dosage reduction of the tricyclic antidepressant (and titration to clinical effect) as indicated1

Eliglustat Tartrate Pharmacokinetics

Absorption

Bioavailability

Low (<5%) in extensive CYP2D6 metabolizers due to substantial first-pass metabolism.1

Food

Administration with a high-fat meal resulted in a 15% decrease in peak plasma concentrations and no change in AUC; are not considered clinically important.1

Plasma Concentrations

Systemic exposure dependent on CYP2D6 genotype.1

In extensive and intermediate CYP2D6 metabolizers, eliglustat exposure increases in a greater than dose-proportional manner.1 Following multiple oral doses of 84 mg twice daily in extensive CYP2D6 metabolizers, systemic exposure increased up to about 2 times that observed after the first dose.1

In extensive CYP2D6 metabolizers, median time to peak plasma concentrations is 1.5–2 hours following multiple doses of 84 mg twice daily.1

In poor CYP2D6 metabolizers, pharmacokinetics expected to be linear and time-independent.1 Compared with extensive CYP2D6 metabolizers, systemic exposure at steady state is sevenfold to ninefold higher in poor metabolizers.1 Median time to peak plasma concentrations is 3 hours following multiple doses of 84 mg twice daily in poor metabolizers.1

Distribution

Extent

In blood, mainly distributes into plasma and not RBCs.1

Appears to be widely distributed into tissues.1

Crosses the blood-brain barrier, but is immediately transported back out of the CNS by P-gp.4

Not known whether eliglustat is distributed into human milk.1

Plasma Protein Binding

76–83%.1

Elimination

Metabolism

Extensively metabolized, principally by CYP2D6 and to a lesser extent by CYP3A.1

Primary metabolic pathways involve sequential oxidation of the octanoyl moiety followed by oxidation of the 2,3-dihydro-1,4-benzodioxane moiety, or a combination of the two pathways, resulting in multiple oxidative metabolites; no active metabolites identified.1

Elimination Route

Following oral administration of radiolabeled eliglustat, 41.8 or 51.4% of a dose is excreted in urine or feces, respectively, mainly as metabolites.1

Hemodialysis considered unlikely to remove substantial quantities because of the drug's large volume of distribution.1

Half-life

Extensive CYP2D6 metabolizers: Approximately 6.5 hours.1

Poor CYP2D6 metabolizers: Approximately 8.9 hours.1

Special Populations

Mild renal impairment has no effect on eliglustat pharmacokinetics.1

Gender, body weight, age, and race have no clinically important effect on eliglustat pharmacokinetics.1

Stability

Storage

Oral

Capsules

20–25°C (may be exposed to 15–30°C).1

Actions

  • Specific inhibitor of glucosylceramide synthase, the enzyme responsible for formation of glucocerebroside.1 3 4 5 6 7

  • Gaucher disease is an autosomal recessive lysosomal storage disorder characterized by a deficiency of the enzyme glucocerebrosidase, which results in accumulation of glucocerebroside within the lysosomes of macrophages in the liver, spleen, bone marrow, and other organs; clinical manifestations include hepatosplenomegaly, anemia, thrombocytopenia, and skeletal complications (e.g., osteopenia, osteonecrosis, progressive joint destruction, fractures).1 3 4 5 6 8 9

  • Acts as a substrate reduction therapy; inhibits formation of the substrate (glucocerebroside) for the deficient glucocerebrosidase enzyme in patients with type 1 Gaucher disease.3 4 5 6 7

Advice to Patients

  • Importance of advising patients to read the manufacturer's patient information (medication guide).1

  • Importance of advising patients to swallow eliglustat capsules whole, preferably with water, and to not crush, dissolve, or open the capsules.1

  • Importance of advising patients that if they miss a dose of eliglustat, they should take their prescribed dose at the next scheduled time; do not take a double dose to make up for a missed dose.1

  • Importance of advising patients of important administration instructions, including the need to avoid consuming grapefruit or grapefruit juice.1

  • Risk of ECG changes and cardiac arrhythmias; importance of informing clinicians of any history of congestive heart failure, bradycardia, heart block, ventricular arrhythmia, long QT syndrome, or recent acute MI.1

  • Importance of informing clinicians of any new symptoms of possible heart disease, including palpitations, fainting, or dizziness.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, herbal supplements, and vitamins, and of concomitant medical conditions.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

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 Tartrate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

84 mg (of eliglustat)

Cerdelga

Genzyme

AHFS DI Essentials. © Copyright 2017, Selected Revisions March 21, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Genzyme Ireland, Ltd. Cerdelga (eliglustat) capsules prescribing information. Waterford, Ireland; 2014 Aug.

2. Food and Drug Administration. Orphan designation pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act. (P.L. 97-414). Rockville, MD. From FDA website. Accessed 2015 Nov 16.

3. Bennett LL, Turcotte K. Eliglustat tartrate for the treatment of adults with type 1 Gaucher disease. Drug Des Devel Ther. 2015; 9:4639-47. [PubMed 26345314]

4. Balwani M, Burrow TA, Charrow J et al. Recommendations for the use of eliglustat in the treatment of adults with Gaucher disease type 1 in the United States. Mol Genet Metab. 2015 Sep 7. pii: S1096-7192(15)30050-0. [PubMed 26387627]

5. Mistry PK, Lukina E, Ben Turkia H et al Effect of oral eliglustat on splenomegaly in patients with Gaucher disease type 1: the ENGAGE randomized clinical trial. JAMA. 2015; 313:695-706. [PubMed 25688781]

6. Cox TM, Drelichman G, Cravo R et al. Eliglustat compared with imiglucerase in patients with Gaucher's disease type 1 stabilized on enzyme replacement therapy: a phase 3, randomized, open-label, non-inferiority trial. Lancet. 2015; 385:2355-62. [PubMed 25819691]

7. Lukina E, Watman N, Dragosky M et al. Eliglustat, an investigational oral therapy for Gaucher disease type 1: phase 2 trial results after 4 years of treatment. Blood Cells Mol Dis. 2014; 53:274-6. [PubMed 24835462]

8. Scott LJ. Eliglustat: a review in Gaucher disease type 1. Drugs. 2015; 75:1669-78. [PubMed 26384672]

9. Anon. Eliglustat (Cerdelga): an oral drug for Gaucher disease. Med Lett Drugs Ther. 2015; 57:e100-1.

10. US Food and Drug Administration. Summary Review: BLA# 205494. From FDA website.

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