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Miglustat

Pronunciation

(MIG loo stat)

Index Terms

  • OGT-918

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Zavesca: 100 mg [contains soybean lecithin]

Brand Names: U.S.

  • Zavesca

Pharmacologic Category

  • Enzyme Inhibitor
  • Glucosylceramide Synthase Inhibitor

Pharmacology

Miglustat competitively and reversibly inhibits the enzyme needed to produce glycosphingolipids and decreases the rate of glycosphingolipid glucosylceramide formation. Glucosylceramide accumulates in type 1 Gaucher disease, causing complications specific to this disease.

Distribution

Vd: 83-105 L

Metabolism

No evidence of metabolism in humans

Excretion

Urine (as unchanged drug)

Time to Peak

Plasma: 2-2.5 hours

Half-Life Elimination

6-7 hours

Protein Binding

No binding to plasma proteins

Special Populations: Renal Function Impairment

Limited data suggests that the clearance of miglustat decreases 40% and 60% with mild and moderate renal impairment, respectively; dosage reduction recommended. A decreased clearance of 70% has been suggested in patients with severe renal impairment.

Use: Labeled Indications

Gaucher disease: Treatment of adult patients with mild-to-moderate type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option (eg, due to allergy, hypersensitivity, or poor venous access)

Canadian labeling: Additional use (not in U.S. labeling): Treatment to delay the progression of neurological manifestations in Niemann-Pick type C disease

Contraindications

There are no contraindications listed in the manufacturer’s labeling.

Canadian labeling: Additional contraindications (not in U.S. labeling): Hypersensitivity to miglustat or any component of the formulation; pregnancy

Dosing: Adult

Type 1 Gaucher disease: Oral: 100 mg 3 times daily; dose may be reduced to 100 mg 1-2 times daily in patients with adverse effects (ie, tremor, GI distress)

Niemann-Pick Type C disease (Canadian labeling; not in U.S. labeling): Oral: 200 mg 3 times daily

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Niemann-Pick Type C disease (Canadian labeling (not in U.S. labeling): Oral:

Children <12 years: Note: Children <4 years of age were not included in clinical trials; dose based on body surface area (BSA):

BSA >1.25 m2: Miglustat 200 mg 3 times daily

BSA >0.88-1.25 m2: Miglustat 200 mg 2 times daily

BSA >0.73-0.88 m2: Miglustat 100 mg 3 times daily

BSA >0.47-0.73 m2: Miglustat 100 mg 2 times daily

BSA ≤0.47 m2: Miglustat 100 mg once daily

Children ≥12 years: Refer to adult dosing.

Dosing: Renal Impairment

Gaucher disease: Adults:

CrCl 50-70 mL/minute/1.73 m2: 100 mg twice daily

CrCl 30-50 mL/minute/1.73 m2: 100 mg once daily

CrCl <30 mL/minute/1.73 m2: Not recommended

Niemann-Pick Type C disease: Canadian labeling (not in U.S. labeling):

Children ≥12 years and Adults:

CrCl 50-70 mL/minute/1.73 m2: 200 mg twice daily

CrCl 30-50 mL/minute/1.73 m2: 100 mg twice daily

CrCl <30 mL/minute/1.73 m2: Not recommended

Children <12 years:

CrCl 50-70 mL/minute/1.73 m2: Administer two-thirds of regular dose in 2 equal doses (adjusted for BSA)

CrCl 30-50 mL/minute/1.73 m2: Administer one-third of regular dose in 2 equal doses (adjusted for BSA)

CrCl <30 mL/minute/1.73 m2: Not recommended

Dosing: Hepatic Impairment

No dosage adjustment provided in manufacturer’s labeling (has not been studied). However, dosage adjustment unlikely because miglustat is not metabolized by the liver.

Administration

May be administered with or without food; administration between meals may decrease the incidence of diarrhea. Capsules should be taken at the same time each day at regular intervals. If patient is unable to tolerate or swallow capsule whole and powder is administered, mix powder into a liquid immediately prior to use (do not store); sweetening agents are not expected to interact (data on file [Actelion Pharmaceuticals Ltd, 2011])

Dietary Considerations

May be taken with or without food. Patients with diarrhea should avoid foods with high carbohydrate content.

Storage

Store at 20°C to 25°C (68°F to 77°F). Brief exposure to 15°C to 30°C (59°F to 86°F) permitted. Note: Extended storage information may be available; contact product manufacturer to obtain current recommendations.

Drug Interactions

There are no known significant interactions.

Adverse Reactions

Percentages reported from open-label, uncontrolled monotherapy trials.

>10%:

Central nervous system: Headache (21% to 22%), dizziness (up to 11%)

Gastrointestinal: Diarrhea (89% to 100%), weight loss (39% to 67%), abdominal pain (18% to 67%), flatulence (29% to 50%), nausea (8% to 22%), vomiting (4% to 11%)

Neuromuscular & skeletal: Tremor (11% to 30%), weakness (17%), leg cramps (4% to 11%)

Ocular: Visual disturbances (up to 17%)

1% to 10%:

Central nervous system: Memory impairment (8%), migraine (up to 6%)

Endocrine & metabolic: Menstrual disorder (up to 6%)

Gastrointestinal: Abdominal distension (8%), constipation (8%), xerostomia (8%), bloating (up to 6%), anorexia (up to 7%), dyspepsia (up to 7%), epigastric pain (up to 6%)

Hematologic: Thrombocytopenia (6% to 7%)

Neuromuscular & skeletal: Back pain (8%), gait instability (8%), paresthesia (up to 7%)

Warnings/Precautions

Concerns related to adverse effects:

• Diarrhea: Observed in the majority of patients, many also reported weight loss (within first 12 months of treatment). Incidence decreases over time; foods with high carbohydrate content should be avoided. If symptoms persist, patients should be evaluated for underlying GI disease.

• Peripheral neuropathy: Has been reported; neurologic monitoring is required. Weigh risk versus benefit of therapy if patient develops numbness and tingling; treatment discontinuation may be necessary.

• Platelet counts decreased: Mild decrease in platelet counts (without bleeding) has been observed in patients with type 1 Gaucher disease switched from enzyme replacement therapy or in patients with Niemann-Pick type C disease (not an approved use in the U.S.); monitor platelet counts during therapy.

• Tremor: Exacerbations of existing tremor or tremor may occur. Tremor typically begins within the first month of treatment and may resolve over time (1-3 months) or respond to dosage reduction. Treatment discontinuation may be necessary.

Disease-related concerns:

• Renal impairment: Use with caution in patients with renal impairment; dosage adjustments recommended. Not recommended in patients with severe impairment.

• Severe type 1 Gaucher disease: Safety and efficacy have not been established in severe type 1 Gaucher disease.

Concurrent drug therapy issues:

• Imiglucerase: Miglustat increases the clearance of imiglucerase; however, the clinical significance of this is not known; combination therapy is not indicated.

Other warnings/precautions:

• Experienced physician: Should be administered under the supervision of a physician experienced in treatment of Gaucher disease.

• Registry: A registry has been established and all patients with Gaucher disease, and physicians who treat Gaucher disease are encouraged to participate. Information on the International Collaborative Gaucher Group (ICGG) Gaucher Registry may be obtained at https://www.registrynxt.com or by calling 1-800-745-4447 (ext.15500).

Monitoring Parameters

Neurologic evaluations baseline and repeated every 6 months; adverse effects; weight; platelet count; renal function

Canadian labeling: Additional monitoring parameters (not in U.S. labeling): pregnancy test prior to therapy in women of reproductive age; disease status (eg, spleen and liver volumes and hematologic analysis); growth [in pediatric patients]; follow-up in patients with a history or presence of cataracts; vitamin B12

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. In addition, adverse effects on spermatogenesis and reduced fertility were observed in male animal studies; however, no effect on sperm was observed in healthy male patients. Uncontrolled type 1 Gaucher disease is associated an increased risk of spontaneous abortion; maternal hepatosplenomegaly and thrombocytopenia may also occur and lead to adverse pregnancy outcomes.

The Canadian manufacturer recommends that women of reproductive potential should use effective contraception during therapy and male patients should use reliable contraception during therapy and for 3 months following treatment. The Canadian labeling also recommends that all women have a pregnancy test prior to initiation of therapy; use is contraindicated in women who are or may become pregnant.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience dizziness, abdominal pain, heartburn, nausea, vomiting, flatulence, dry mouth, back pain, constipation, leg cramps, muscle cramps, lack of appetite, bloating, loss of strength and energy, weight loss, sensation of heaviness in extremities, or menstrual irregularities. Have patient report immediately to prescriber severe diarrhea, burning or numbness feeling, vision changes, bruising, bleeding, memory impairment, severe headache, tremors, or abnormal gait (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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