Miglustat Drug Information

Type 1 Gaucher Disease Miglustat is 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).

Instructions for Administration Therapy should be directed by physicians who are knowledgeable in the management of Gaucher disease. The recommended dose for the treatment of adult patients with type 1 Gaucher disease is one 100 mg capsule administered orally three times a day at regular intervals. If a dose is missed, the next miglustat capsule should be taken at the next scheduled time.

It may be necessary to reduce the dose to one 100 mg capsule once or twice a day in some patients due to adverse reactions, such as tremor or diarrhea.

Patients with Renal Insufficiency

In patients with mild renal impairment (adjusted creatinine clearance 50–70 mL/min/1.73 m 2 ), initiate miglustat treatment at a dose of 100 mg twice per day. In patients with moderate renal impairment (adjusted creatinine clearance of 30–50 mL/min/1.73 m 2 ), initiate miglustat treatment at a dose of one 100 mg capsule per day. Miglustat is not recommended for use in patients with severe renal impairment (creatinine clearance <30 mL/min/1.73 m 2 ).

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 miglustat at doses ranging from 50 mg 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 miglustat treatment in clinical trials was peripheral neuropathy. The most commonly reported adverse reactions in patients treated with miglustat (occurring in ≥5%) that were considered related to miglustat are shown in Tables 1 and 2.

The most common adverse reactions requiring intervention were diarrhea and tremor. Table 1 below lists adverse reactions that occurred during the trials in ≥5% of patients. Table 2 lists adverse reactions that occurred during the trial in ≥5% of patients.

While co-administration of miglustat appeared to increase the clearance of imiglucerase by 70%, these results are not conclusive because of the small number of patients studied and because patients took variable doses of imiglucerase. Co-administration of miglustat and imiglucerase may lead to increased clearance of imiglucerase.

Pregnancy Risk Summary Based on findings from animal reproduction studies, miglustat may cause fetal harm when administered to a pregnant woman. Available data from postmarketing case reports with miglustat use in pregnancy are insufficient to assess a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks associated with symptomatic Type I Gaucher disease in pregnancy, including hepatosplenomegaly and thrombocytopenia (see Clinical Considerations ).

Advise pregnant women of the potential risks to the fetus. In animal reproduction studies, miglustat was maternally toxic in rabbits at exposures near the expected human therapeutic dose and caused embryo-fetal toxicities in rats at doses twice the recommended human dose. No adverse developmental outcomes were observed with administration of miglustat to pregnant rats at dose levels 6 times the recommended human dose. (see Data ).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Clinical Considerations Disease-associated Maternal and Embryo-Fetal Risk Pregnancy may exacerbate existing Type 1 Gaucher disease symptoms or result in new disease manifestations. Type 1 Gaucher disease manifestations may lead to adverse pregnancy outcomes including, hepatosplenomegaly which can interfere with the normal growth of a pregnancy and thrombocytopenia which can lead to increased bleeding and possible hemorrhage. Delayed and prolonged parturition with decreased live births were observed at doses ≥60 mg/kg/day (≥2 times the human therapeutic dose on a mg/m 2 basis).

The 15 mg/kg/day dose level was 0.97 times the human therapeutic dose on a mg/m 2 basis. There was no effect on behavioral and learning assessments, sexual maturation or reproductive performance of the offspring at doses up to 180 mg/kg/day (about 6 times the human therapeutic dose on a mg/m 2 basis).

Pediatric Use The safety and effectiveness of miglustat in pediatric patients have not been established. In a combined clinical trial safety data set of 45 patients less than 18 years of age exposed to miglustat in indications other than type 1 Gaucher disease, the median weight and height percentiles adjusted for age and gender decreased during the first year of treatment but then stabilized. The mean length of exposure in these studies ranged from 2 to 2.6 years; some pediatric patients were exposed for up to 4 years.

However, the effect of miglustat on long-term gain in weight and height in pediatric patients is unclear.