Miglustat (Gaucher Disease) (Monograph)

Brand name: Zavesca
Drug class: Enzyme Inhibitors

Medically reviewed by Drugs.com on Apr 10, 2024. Written by ASHP.

Introduction

Glucosylceramide synthase (ceramide glucosyltransferase) inhibitor.

Uses for Miglustat (Gaucher Disease)

Gaucher Disease

Management of mild to moderate nonneuronopathic (type 1) Gaucher disease in patients for whom enzyme replacement therapy is unsuitable (e.g., because of allergy, hypersensitivity, poor venous access).

Designated an orphan drug by FDA for the management of Gaucher disease.

Miglustat (Gaucher Disease) Dosage and Administration

General

• Therapy should be directed by clinicians knowledgeable in the management of Gaucher disease.

Administration

Oral Administration

Administer orally 3 times daily at regular intervals.

If a dose is missed, skip dose and take next dose at usual time.

Dosage

Adults

Gaucher Disease

Oral

100 mg 3 times daily.

Reduce dosage to 100 mg once or twice daily if necessary because of adverse effects.

Special Populations

Renal Impairment

Geriatric Patients

Select dosage with caution because of possible age-related decreases in renal, hepatic, and/or cardiac function and concomitant disease and drug therapy.

Cautions for Miglustat (Gaucher Disease)

Contraindications

• None.

Warnings/Precautions

Warnings

Peripheral Neuropathy

Peripheral neuropathy reported; monitor all patients with neurologic evaluation at baseline and every 6 months while on therapy.

If symptoms (e.g., numbness, tingling) occur, reassess risk versus benefit of therapy; consider discontinuance.

Tremor

Tremor or exaggerated physiologic hand tremor reported in about 30% of patients.

Usually develops within the first month, often resolving between 1–3 months of treatment.

Dosage reduction may ameliorate tremor, usually within days; drug discontinuance occasionally necessary.

Diarrhea and Weight Loss

Diarrhea reported in approximately 85% of patients. Apparently osmotic in nature, resulting from inhibition of disaccharidase; incidence decreases over time with continued use.

Patients should avoid foods with high carbohydrate content.

Weight loss occurred in up to 65% of patients. May result from diarrhea and associated GI complaints, decreased food intake, or a combination of these and other factors.

If persistent GI symptoms occur that do not respond to usual interventions, evaluate for presence of underlying GI disease. Weigh risks versus benefits of continued treatment in patients with substantial GI disease (e.g., inflammatory bowel disease).

Reduction in Platelet Counts

Mild reductions in platelet counts reported; not associated with bleeding.

Monitor platelet counts.

Specific Populations

Pregnancy

Category C.

No adequate and well-controlled studies in pregnant women. Animal studies suggest that the drug may cause fetal harm. Use during pregnancy only if potential benefit justifies potential risk to fetus.

Lactation

Not known whether miglustat is distributed into milk. Discontinue nursing or the drug.

Pediatric Use

Safety and efficacy not established in children <18 years of age.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently from younger adults; select dosage with caution.

Renal Impairment

Dosage adjustments necessary based on degree of renal impairment; do not use in severe renal impairment. (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Diarrhea, flatulence, abdominal pain, abdominal distension with or without gas, nausea, vomiting, bloating, anorexia, dyspepsia, epigastric pain (not related to food), constipation, dry mouth, weight loss, headache, tremor, dizziness, unsteady gait, leg cramps, cramps, back pain, paresthesia, heaviness in limbs, generalized weakness, migraine, visual disturbance, memory loss, thrombocytopenia, menstrual disorder.

Drug Interactions

Drugs Metabolized by Hepatic Microsomal Enzymes

Does not inhibit CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, 3A4, and 4A11 isoenzymes in vitro; clinically important drug interactions unlikely with drugs metabolized by these isoenzymes.

Specific Drugs

Miglustat (Gaucher Disease) Pharmacokinetics

Absorption

Food

Food decreases the rate but not the extent of absorption.

Distribution

Extent

Distributed into extravascular tissues.

Not known whether miglustat crosses the placenta or is distributed into milk.

Plasma Protein Binding

Does not bind to plasma proteins.

Elimination

Elimination Route

Excreted unchanged in urine.

Half-life

6–7 hours.

Special Populations

In patients with mild, moderate, or severe renal impairment, miglustat clearance is reduced by approximately 40, 60, or ≥70%, respectively.

Stability

Storage

Oral

Capsules

20–25°C (may be exposed to 15–30°C).

Actions

• N-alkylated imino sugar; competitive and reversible inhibitor of glucosylceramide synthase, the enzyme responsible for catalyzing the formation of glucocerebroside.

• 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).

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

• Allows residual activity of the deficient enzyme to be more effective; shown to decrease hepatomegaly and splenomegaly but has limited effect on increasing hemoglobin and platelet counts in patients with type 1 Gaucher disease.

Advice to Patients

• Importance of informing patients of risks and benefits of miglustat therapy, and about alternative therapy (e.g., enzyme replacement therapy).

• Importance of advising patients that diarrhea and other adverse GI effects and weight loss are common, and to adhere to dietary instructions.

• Importance of informing clinician of any numbness, pain, or burning in the hands or feet and of the occurrence or worsening of tremor.

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy during therapy and, if pregnancy occurs, to advise the woman of the potential risk to the fetus.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements, as well as any concomitant illnesses.

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

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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.

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