eliglustat

General

Genetic Implications: Genetic Implications

Pronunciation:
e-lig-lu-stat


Trade Name(s)

  • Cerdelga

Ther. Class.
orphan drugs

Pharm. Class.
glucosylceramide synthase inhibitors

Indications

Genetic implicationLong term treatment of adults with Gaucher disease type 1 who have been tested to be extensive metabolizers (EMs), intermediate metabolizers (IMs) or poor metabolizers (PMs) of the CYP2D6 enzyme system.

Action

Acts as a specific inhibitor of glucosylceramide synthase, thereby reducing the substrate that accumulates in Gaucher disease type 1.

Therapeutic Effect(s):

Improvement in symptoms of Gaucher's disease (anemia, thrombocytopenia, bone disease, splenomegaly, and hepatomegaly).

Pharmacokinetics

Absorption: EMs–5% absorbed following oral administration (due to extensive first-pass metabolism).

Distribution: Distributes mainly into plasma.

Metabolism and Excretion: Extensively metabolized, primarily by the CYP2D6 enzyme system, with some metabolism by CYP3A4; 41.8% excreted in urine and 51.4% in feces mostly as metabolites.

Half-life: EMs–6.5 hr; PMs–8.9 hr.

TIME/ACTION PROFILE (blood levels)

ROUTEONSETPEAKDURATION
POunknown1.5–2 hr (EMs), 3 hr (PMs)12–24 hr

Contraindication/Precautions

Contraindicated in:

  • CYP2D6 ultra-rapid metabolizers (may not achieve effective concentrations)
  • Concurrent use of strong or moderate CYP2D6 inhibitors in patients who are CYP2D6 EMs or IMs (↑ risk of adverse cardiac events)
  • Concurrent use of strong CYP3A inhibitors in patients who are CYP2D6 PMs or IMs (↑ risk of adverse cardiac events)
  • History of cardiac disease, long QT syndrome, or concurrent use of Class IA or Class III antiarrhythmics
  • Concurrent ingestion of grapefruit/grapefruit juice
  • Moderate or severe renal impairment
  • Hepatic impairment;
  • Lactation: Discontinue eliglustat or discontinue breastfeeding.

Use Cautiously in:

  • CYP2D6 indeterminate metabolizers (dose not known)
  • OB: Use only if potential maternal benefit justifies risk to fetus
  • Pedi: Safety and effectiveness not established.

Adverse Reactions/Side Effects

CNS: fatigue, headache, dizziness

CV: palpitations

GI: diarrhea, flatulence, nausea, oropharyngeal pain, upper abdominal pain, constipation, reflux

Derm: rash

MS: arthralgia, back pain, extremity pain

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

General

Drug-Drug

  • Concurrent use of strong CYP3A inducers including carbamazepine, phenobarbital, phenytoin, and rifampin may ↓ blood levels and effectiveness; concurrent use not recommended.
  • May ↑ blood levels and effects/risk of toxicity with P-gp substrates including digoxin (↓ digoxin dose by 30% and monitor digoxin levels), colchicine, dabigatran, and phenytoin (monitor drug levels, consider dose reduction/titration).
  • May ↑ blood levels and effects/risk of toxicity with CYP2D6 substrates including metoprolol, tricyclic antidepressants , and phenothiazines; monitor drug levels, consider dose ↓/titration.
  • Concurrent use of Class IA antiarrhythmics (including procainamide and quinidine) or Class III antiarrhythmics (including amiodarone and sotalol) ↑ risk of potentially serious adverse cardiac events; concurrent use not recommended.

Drug-Natural Products:

St. John's wort ↓ blood levels and may ↓ effectiveness; concurrent use not recommended.

Drug-Food:

Grapefruit/grapefruit juice ↑ risk of potentially serious adverse cardiac events; concurrent ingestion contraindicated.

Interactions

For extensive metabolizers (EMs)

Drug-Drug

  • Concurrent use of strong or moderate CYP2D6 inhibitors plus strong or moderate CYP3A inhibitors ↑ risk of potentially serious cardiac events; concurrent use contraindicated.
  • Concurrent use of strong CYP2D6 inhibitors including paroxetine ↑ risk of potentially serious cardiac events; once daily dosing recommended.
  • Concurrent use of moderate CYP2D6 inhibitors including terbinafine ↑ risk of potentially serious cardiac events; once daily dose recommended.
  • Concurrent use of strong CYP3A inhibitors including ketoconazole ↑ risk of potentially serious cardiac events; once daily dose recommended.
  • Concurrent use of moderate CYP3A inhibitors including fluconazole ↑ risk of potentially serious cardiac events; once daily dose recommended.

Interactions

For intermediate metabolizers (IMs)

Drug-Drug

  • Concurrent use of strong or moderate CYP2D6 inhibitors plus strong or moderate CYP3A inhibitors ↑ risk of potentially serious cardiac events; concurrent use contraindicated.
  • Concurrent use of strong CYP3A inhibitors including ketoconazole ↑ risk of potentially serious cardiac events; concurrent use contraindicated.
  • Concurrent use of strong CYP2D6 inhibitors including paroxetine ↑ risk of potentially serious cardiac events; once daily dose recommended.
  • Concurrent use of moderate CYP2D6 inhibitors including terbinafine ↑ risk of potentially serious cardiac events; once daily dose recommended.
  • Concurrent use of moderate CYP3A inhibitors including fluconazole ↑ risk of potentially serious cardiac events; concurrent use not recommended.

Interactions

For poor metabolizers (PMs)

Drug-Drug

  • Concurrent use of strong CYP3A inhibitors including ketoconazole ↑ risk of potentially serious cardiac events; concurrent use contraindicated.
  • Concurrent use of moderate CYP3A inhibitors including fluconazole ↑ risk of potentially serious cardiac events; concurrent use not recommended.
  • Concurrent use of weak CYP3A inhibitors including ranitidine ↑ risk of potentially serious cardiac events; concurrent use not recommended.

Route/Dosage

PO: (Adults) CYP2D6 EMs or IMs–84 mg twice daily; CYP2D6 PMs–84 mg once daily; CYP2D6 EMs or IMs taking strong or moderate CYP2D6 inhibitors or CYP2D6 EMs taking strong or moderate CYP3A inhibitors–84 mg once daily.

Availability

Capsules: 84 mg

Assessment

  • Monitor for an improvement in symptoms including hepatomegaly, splenomegaly, anemia, thrombocytopenia, bone demineralization, and increased appetite and energy level periodically during therapy. Assess liver and spleen size every 6 mo to determine effectiveness of therapy.

Potential Diagnoses

Implementation

  • If taking imiglucerase, taliglucerase, or velaglucerase, administer 24 hr after last dose.
  • PO: Administer without regard to food, preferably with water. Swallow capsules whole; do not open, crush or chew.

Patient/Family Teaching

  • Instruct patient to take eliglustat as directed. Omit missed doses and take next scheduled dose; do not double doses. Advise patient to read Medication Guide before starting therapy and with each Rx refill in case of changes.
  • Advise patient to avoid grapefruit and grapefruit juice during therapy.
  • Inform patient of the purpose of this medication and the importance of treatment at least every 4 wk. Eliglustst helps control the symptoms but does not cure Gaucher's disease. Lifelong therapy may be required.
  • Advise patient to notify health care professional if palpitations, fainting, or dizziness occur.
  • Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications, especially St. John's Wort.
  • Advise female patient to notify health care professional if pregnancy is planned or suspected or if breastfeeding.
  • Emphasize the importance of follow-up examinations and lab tests.

Evaluation/Desired Outcomes

Improvement in symptoms of Gaucher's disease (anemia, thrombocytopenia, bone disease, splenomegaly, and hepatomegaly).

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