Miglustat

Miglustat is used to treat Gaucher's disease (a condition in which a certain fatty substance is not broken down normally in the body and instead builds up in some organs and causes liver, spleen, bone, and blood problems). Miglustat is in a class of medications called enzyme inhibitors. It works by preventing the body from producing the fatty substance so that less of it will build up in the body and cause symptoms.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• tremor or uncontrolled shaking, especially in your hands;
• numbness, tingling, or burning pain in your hands or feet;
• severe diarrhea and weight loss; or
• easy bruising or bleeding (nosebleeds, bleeding gums).

Common side effects may include:

• diarrhea, constipation, bloating;
• nausea, vomiting, stomach pain, indigestion;
• dry mouth;
• dizziness, weakness;
• headache (including migraine);
• back pain, muscle cramps;
• pain or heavy feeling in your arms or legs;
• memory problems, feeling unsteady, loss of balance;
• vision problems; or
• changes in your menstrual periods.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

No information provided.

Miglustat may reduce the formation of the protein glucosylceramide in the body. Individuals with type 1 Gaucher disease (a hereditary disorder) are missing an enzyme to break down glucosylceramide in the body. Therefore, it may build up in the tissues and cause problems. Untreated Gaucher disease may result in anemia (low level of red blood cells), thrombocytopenia (low level of platelets), bone disease, hepatomegaly (enlargement of the liver), or splenomegaly (enlargement of the spleen).

Miglustat is used in the treatment of mild to moderate type 1 Gaucher disease by people who cannot receive enzyme replacement therapy.

Miglustat may also be used for purposes other than those listed here.

There are no restrictions on food, beverages, or activity during treatment with miglustat unless otherwise directed by your doctor.

The following serious adverse reactions are described below and elsewhere in the labeling:

• Peripheral Neuropathy [see WARNINGS AND PRECAUTIONS]
• Tremor [see WARNINGS AND PRECAUTIONS]
• Diarrhea and weight loss [see WARNINGS AND PRECAUTIONS]
• Reductions in platelet count [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure of 80 patients with type 1 Gaucher disease in two open-label, uncontrolled, monotherapy trials, one open-label, active-controlled trial, and two extensions, who received Zavesca at doses ranging from 50mg to 200 mg three times daily. Patients were aged 18 to 69 years at first treatment. The population was evenly distributed by gender.

The most common serious adverse reaction reported with Zavesca treatment in clinical trials was peripheral neuropathy [see WARNINGS AND PRECAUTIONS].

The most commonly reported adverse reactions in patients treated with Zavesca (occuring in ≥ 5%) that were considered related to Zavesca are shown in Tables 1 and 2. [see WARNINGS AND PRECAUTIONS].

The most common adverse reactions requiring intervention were diarrhea and tremor. [see WARNINGS AND PRECAUTIONS].

In two open-label, uncontrolled monotherapy trials, adult type 1 Gaucher disease patients were treated with Zavesca at a starting dose of 100 mg three times daily (dose range 100 to 200 mg three times daily) for up to 12 months in 28 patients [Study 1], or at a dose of 50 mg three times daily for up to 6 months in 18 patients [Study 2]. Table 1 below lists adverse reactions that occurred during the trials in ≥ 5% of patients.

Table 1: Adverse Reactions in ≥ 5% of Patients in Two Open-Label, Uncontrolled Monotherapy Trials of Zavesca

In an open-label, active-controlled study, 36 adult type 1 Gaucher disease patients were treated with Zavesca, imiglucerase, or Zavesca plus imiglucerase [Study 3] for up to 12 months. Table 2 lists adverse reactions that occurred during the trial in ≥ 5% of patients.

Table 2: Adverse Reactions in ≥ 5% of Patients in Open-Label Active Controlled Study

Read the entire FDA prescribing information for Zavesca (Miglustat)

Miglustat may be found in some form under the following brand names:

• Zavesca

Take this medication exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The dose your doctor recommends may be based on the following:

• the condition being treated
• other medical conditions you have
• how you respond to this medication

The recommended dose of miglustat is 100 mg three times daily. The dose may be reduced in patients who experience side effects or who have kidney problems.

Other drugs may interact with miglustat, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Contraindications

• None.1

Warnings/Precautions

Warnings

Peripheral neuropathy reported; monitor all patients with neurologic evaluation at baseline and every 6 months while on therapy.1

If symptoms (e.g., numbness, tingling) occur, reassess risk versus benefit of therapy; consider discontinuance.1

Tremor or exaggerated physiologic hand tremor reported in about 30% of patients.1 24

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

Dosage reduction may ameliorate tremor, usually within days; drug discontinuance occasionally necessary.1

Diarrhea reported in approximately 85% of patients.1 24 Apparently osmotic in nature, resulting from inhibition of disaccharidase; incidence decreases over time with continued use.1

Patients should avoid foods with high carbohydrate content.1

Weight loss occurred in up to 65% of patients.1 May result from diarrhea and associated GI complaints, decreased food intake, or a combination of these and other factors.1

If persistent GI symptoms occur that do not respond to usual interventions, evaluate for presence of underlying GI disease.1 Weigh risks versus benefits of continued treatment in patients with substantial GI disease (e.g., inflammatory bowel disease).1

Mild reductions in platelet counts reported; not associated with bleeding.1

Monitor platelet counts.1

Specific Populations

Category C.1

No adequate and well-controlled studies in pregnant women.1 Animal studies suggest that the drug may cause fetal harm.1 Use during pregnancy only if potential benefit justifies potential risk to fetus.1

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

Safety and efficacy not established in children <18 years of age.1

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently from younger adults; select dosage with caution.1

Dosage adjustments necessary based on degree of renal impairment; do not use in severe renal impairment.1 (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.1 24

Absorption

Food

Food decreases the rate but not the extent of absorption.1

Distribution

Extent

Distributed into extravascular tissues.1

Not known whether miglustat crosses the placenta or is distributed into milk.1

Plasma Protein Binding

Does not bind to plasma proteins.1

Elimination

Elimination Route

Excreted unchanged in urine.1 15

Half-life

6–7 hours.1 15

Special Populations

In patients with mild, moderate, or severe renal impairment, miglustat clearance is reduced by approximately 40, 60, or ≥70%, respectively.1 15

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.

• If you have an allergy to miglustat or any other part of miglustat.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have kidney disease.
• If you are breast-feeding or plan to breast-feed.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take miglustat with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Dizziness.
• Belly pain or heartburn.
• Loose stools (diarrhea).
• Upset stomach or throwing up.
• Gas.
• Dry mouth.
• Back pain.
• Hard stools (constipation).
• Leg cramps.
• Muscle cramps.
• Headache.
• Not hungry.
• Bloating.
• Feeling tired or weak.
• Weight loss.
• Feeling of heaviness in your arms or legs.
• Period (menstrual) changes.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

Type 1 Gaucher Disease

Miglustat is a glucosylceramide synthase inhibitor indicated as monotherapy for the treatment of adult patients with mild to moderate type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option (e.g. due to allergy, hypersensitivity, or poor venous access).

100 mg white opaque hard gelatin capsules with "OGT 918" printed in black on the cap and "100" printed in black on the body.

Gaucher disease: Adults:

CrCl >70 mL/minute/1.73 m2: No dosage adjustment necessary.

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

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

CrCl <30 mL/minute/1.73 m2: Use not recommended

Niemann-Pick Type C disease: (off-label use) (Zavesca Canadian labeling 2012)

Children ≥12 years, Adolescents, and Adults:

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

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

CrCl <30 mL/minute/1.73 m2: Use not recommended

Children <12 years:

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

CrCl 30 to 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

Concerns related to adverse effects:

• Diarrhea: Observed in the majority of patients, many also reported weight loss (within first 12 months of treatment). Diarrhea decreased over time with continued treatment, and may respond to diet modification (eg, reduction of sucrose, lactose and other carbohydrate intake), taking miglustat between meals, and/or to anti-diarrheal medications. If diarrhea occurs during treatment, instruct patients to avoid foods with high carbohydrate content. If symptoms persist, evaluate patients for underlying GI disease.

• Peripheral neuropathy: Peripheral neuropathy has been reported; neurologic monitoring is required. Weigh risk versus benefit of therapy if patient develops symptoms (eg, 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; monitor platelet counts during therapy.

• Tremor: New-onset or exacerbations of existing 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 if tremor does not respond within days of dose reduction.

Disease-related concerns:

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

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 1-888-404-4413.

• 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.

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for dosing related precautions.