ZAVESCA ® (miglustat capsules, 100 mg) is a glucosylceramide synthase inhibitor, which is a glucosyl transferase enzyme responsible for the first step in the synthesis of most glycosphingolipids. ZAVESCA is an N-alkylated imino sugar, a synthetic analog of D-glucose. The chemical name for miglustat is 1,5-(butylimino)-1,5-dideoxy-D-glucitol with the chemical formula C 10 H 21 NO 4 and a molecular weight of 219.28. Miglustat is a white to off-white crystalline solid and has a bitter taste. It is highly soluble in water (>1000 mg/mL as a free base). ZAVESCA is supplied in hard gelatin capsules each containing 100 mg miglustat for oral administration. Each ZAVESCA 100 mg capsule also contains magnesium stearate, povidone (K30), and sodium starch glycolate. Ingredients in the capsule shell include gelatin and titanium dioxide, and the shells are printed with edible ink consisting of black iron oxide and shellac. Chemical Structure

ZAVESCA is a glucosylceramide synthase inhibitor indicated as monotherapy for treatment of adult patients with mild/moderate type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option

Type 1 Gaucher Disease ZAVESCA 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).

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

Recommended dosage is 100 mg administered orally three times a day at regular intervals. May reduce dosage to 100 mg once or twice a day in some patients due to tremor or diarrhea. Adjust in patients with renal impairment: Renal Impairment Adjusted Creatinine Clearance (in mL/min/1.73 m 2 ) Recommendations Mild 50 – 70 Start dose at 100 mg twice a day Moderate 30 – 50 Start dose at 100 mg once a day Severe <30 Use is not recommended 2.1 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 ZAVESCA 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 ZAVESCA 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 ZAVESCA treatment at a dose of one 100 mg capsule per day. ZAVESCA is not recommended for use in patients with severe renal impairment (creatinine clearance <30 mL/min/1.73 m 2 ) .

Peripheral neuropathy : Perform baseline and follow-up neurological evaluations at 6-month intervals in all patients. Tremor : Reduce dose to ameliorate tremor or discontinue treatment if tremor does not resolve within days of dose reduction. Diarrhea and weight loss : Evaluate for underlying gastrointestinal disease in patients who do not respond to usual interventions (e.g. diet modification). Reductions in Platelet Count : Mild reductions in platelet counts without association with bleeding were observed in some patients. Monitoring of platelet counts is recommended

Peripheral Neuropathy In clinical trials, cases of peripheral neuropathy have been reported in 3% of Gaucher's patients treated with ZAVESCA. All patients receiving ZAVESCA treatment should undergo baseline and repeat neurological evaluations at approximately 6-month intervals. Patients who develop symptoms of peripheral neuropathy such as pain, weakness, numbness and tingling should have a careful re-assessment of the risk/benefit of ZAVESCA therapy, and cessation of treatment may be considered

Tremor Approximately 30% of patients have reported tremor or exacerbation of existing tremor on treatment. These tremors were described as an exaggerated physiological tremor of the hands. Tremor usually began within the first month of therapy and in many cases resolved between 1 to 3 months during treatment. Reduce dose to ameliorate tremor or discontinue treatment if tremor does not resolve within days of dose reduction

Diarrhea and Weight Loss Diarrhea and weight loss were common in clinical studies of patients treated with ZAVESCA, occurring in approximately 85% and up to 65% of treated patients, respectively. Diarrhea appears to be the result of the inhibitory activity of ZAVESCA on intestinal disaccharidases such as sucrase-isomaltase in the gastrointestinal tract leading to reduced absorption of dietary disaccharides in the small intestine, with a resultant osmotic diarrhea. It is unclear if weight loss results from the diarrhea and associated gastrointestinal complaints, a decrease in food intake, or a combination of these or other factors. The incidence of weight loss was most evident in the first 12 months of treatment. Diarrhea decreased over time with continued ZAVESCA treatment, and may respond to individualized diet modification (e.g., reduction of sucrose, lactose and other carbohydrate intake), to taking ZAVESCA between meals, and/or to anti-diarrheal medications, most commonly loperamide. Patients may be instructed to avoid high carbohydrate content foods during treatment with ZAVESCA if they present with diarrhea. Patients with persistent gastrointestinal events that continue during treatment with ZAVESCA, and who do not respond to usual interventions (e.g. diet modification), should be evaluated to determine whether significant underlying gastrointestinal disease is present. The safety of treatment with ZAVESCA has not been evaluated in patients with significant gastrointestinal disease, such as inflammatory bowel disease, and continued treatment of these patients with ZAVESCA should occur only after consideration of the risks and benefits of continued treatment

Reductions in Platelet Count In clinical trials evaluating the use of ZAVESCA for treatment of indications other than type 1 Gaucher disease, mild reductions in platelet counts without association with bleeding were observed in some patients; approximately 40% of patients in this trial had low platelet counts (defined as below 150×10 9 /L) before starting treatment with ZAVESCA. Monitoring of platelet counts is recommended in patients with type 1 Gaucher disease. Mild reductions in platelet counts without association with bleeding were observed in patients with type 1 Gaucher disease who were switched from enzyme replacement therapy (ERT) to ZAVESCA.

While co-administration of ZAVESCA 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 ZAVESCA and imiglucerase may lead to increased clearance of imiglucerase.