Miglustat

1 INDICATIONS AND USAGE Miglustat 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 ( 1.1 ). 1.1 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).

2 DOSAGE AND ADMINISTRATION Recommended dosage is 100 mg administered orally three times a day at regular intervals ( 2.1 ). May reduce dosage to 100 mg once or twice a day in some patients due to tremor or diarrhea ( 2.1 ). Adjust in patients with renal impairment ( 2.2 ): 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 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. 2.2 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 ) [see Use in Specific Populations ( 8.6 )].

3 DOSAGE FORMS AND STRENGTHS Capsules: 100 mg of miglustat, hard gelatin capsules with white opaque cap imprinted "NAV" with black ink and white opaque body imprinted "104" with black ink. Capsules: 100 mg ( 3 )

4 CONTRAINDICATIONS None. None ( 4 ).

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: • Peripheral Neuropathy [see Warnings and Precautions ( 5.1 )] • Tremor [see Warnings and Precautions ( 5.2 )] • Diarrhea and Weight Loss [see Warnings and Precautions ( 5.3 )] • Reductions in Platelet Count [see Warnings and Precautions ( 5.4 )] The most common adverse reactions (incidence ≥5%) are diarrhea, weight loss, stomach pain, gas, nausea and vomiting, headache including migraine, tremor, leg cramps, dizziness, weakness, vision problems, thrombocytopenia, muscle cramps, back pain, constipation, dry mouth, heaviness in arms and legs, memory loss, unsteady walking, anorexia, indigestion, paresthesia, stomach bloating, stomach pain not related to food, and menstrual changes ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact ANI Pharmaceuticals, Inc. at 1-855-204-1431 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 capsules 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 capsule treatment in clinical trials was peripheral neuropathy [see Warnings and Precautions ( 5.1 )] . The most commonly reported adverse reactions in patients treated with miglustat capsules (occurring in ≥5%) that were considered related to miglustat are shown in Tables 1 and 2 [see Warnings and Precautions ( 5.2 , 5.3 )] . The most common adverse reactions requiring intervention were diarrhea and tremor [see Warnings and Precautions ( 5.2 , 5.3 )] . In two open-label, uncontrolled monotherapy trials, adult type 1 Gaucher disease patients were treated with miglustat capsules 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 Miglustat Capsules Incidence of adverse reactions Study 1 (starting dose 100 mg three times daily) Study 2 (50 mg three times daily) Patients entered in Study (n) 28 18 Body System - Preferred Term % of patients reporting % of patients reporting Gastrointestinal System Diarrhea 89 89 Flatulence 29 44 Abdominal pain 18 50 Nausea 14 22 Vomiting 4 11 Bloating 0 6 Anorexia 7 0 Dyspepsia 7 0 Epigastric pain not food-related 0 6 Metabolic and Nutritional Disorders Weight Decrease 39 67 Central and Peripheral Nervous System Headache 21 22 Tremor 11 11 Dizziness 0 11 Leg cramps 4 11 Paresthesia 7 0 Migraine 0 6 Vision Disorders Visual Disturbance 0 17 Musculoskeletal Disorders Cramps 0 11 Platelet, Bleeding, and Clotting Disorders Thrombocytopenia 7 6 Reproductive disorders, female Menstrual disorder 0 6 In an open-label, active-controlled study, 36 adult type 1 Gaucher disease patients were treated with miglustat, imiglucerase, or miglustat 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 Incidence of adverse reactions Miglustat Capsules alone Imiglucerase alone Patients entered in Study (n) 12 12 Body System - Preferred Te …

7 DRUG INTERACTIONS 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 [see Clinical Pharmacology ( 12.3 )] . Co-administration of miglustat and imiglucerase may lead to increased clearance of imiglucerase ( 7 ).

8 USE IN SPECIFIC POPULATIONS • Pregnancy : Based on animal data, may cause fetal harm ( 8.1 ). • Lactation : Breastfeeding not recommended ( 8.2 ). 8.1 Pregnancy Risk Summary Based on findings from animal reproduction studies, miglustat capsules 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. Data Animal Data In female rats given miglustat by oral gavage at doses of 20, 60, 180 mg/kg/day beginning 14 days before mating and continuing through gestation day 17 (organogenesis), increased post implantation loss, decreased embryo-fetal survival and decreased fetal and pup weights were observed at doses ≥60 mg/kg/day (≥2 times the human therapeutic dose on a mg/m 2 basis). Miglustat was also administered to pregnant rats by oral gavage at doses of 20, 60, 180 mg/kg/day from gestation day 6 through lactation (postpartum day 20). 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). In pregnant rabbits given miglustat by oral gavage at doses of 15, 30, 45 mg/kg/day during gestation days 6-18 (organogenesis), maternal toxicity, including maternal deaths (all doses), reduced food consumption (30 and 45 mg/kg/day), and decreased body weight gain (15 and 30 mg/kg/day), was observed. The 15 mg/kg/day dose level was 0.97 times the human therapeutic dose on a mg/m 2 basis. In a pre- and postnatal development study in rats, miglustat was administered by oral gavage at doses of 20, 60, 180 mg/kg/day from gestation day 6 through day 20 of lactation, decreased live births were observed in dams, as well as decreased body weight gain in the offspring at doses ≥60 mg/kg/day (≥2 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). 8.2 Lactation Risk Summary There are no available data on the presence of miglustat in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. Based on the physical properties of miglustat, miglustat is likely to be present in breast milk. Because of the potential for serious adverse reactions in breastfed infants, advise women that breastfeeding is not recommended. 8.3 Females and Male …

12.1 Mechanism of Action Type 1 Gaucher disease is caused by a functional deficiency of glucocerebrosidase, the enzyme that mediates the degradation of the glycosphingolipid glucosylceramide. Miglustat functions as a competitive and reversible inhibitor of the enzyme glucosylceramide synthase, the initial enzyme in a series of reactions which results in the synthesis of most glycosphingolipids. Miglustat helps reduce the rate of glycosphingolipid biosynthesis so that the amount of glycosphingolipid substrate is reduced to a level which allows the residual activity of the deficient glucocerebrosidase enzyme to be more effective (substrate reduction therapy). In vitro and in vivo studies have shown that miglustat can reduce the synthesis of glucosylceramide-based glycosphingolipids.

11 DESCRIPTION Miglustat Capsules, 100 mg are a glucosylceramide synthase inhibitor, which is a glucosyl transferase enzyme responsible for the first step in the synthesis of most glycosphingolipids. Miglustat 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). Miglustat capsules are supplied in hard gelatin capsules each containing 100 mg miglustat for oral administration. Each miglustat 100 mg capsule also contains magnesium stearate. Ingredients in the capsule shell include gelatin, sodium lauryl sulfate and titanium dioxide, and the shells are printed with edible ink consisting of black iron oxide, propylene glycol, potassium hydroxide and shellac. structure

16 HOW SUPPLIED/STORAGE AND HANDLING Miglustat capsules are supplied in hard gelatin capsules containing 100 mg of miglustat. Miglustat 100 mg capsules are white opaque cap imprinted "NAV" with black ink and white opaque body imprinted "104" with black ink filled with white to off white powder. Miglustat capsules 100 mg are packed in blister cards. Six blister cards of 15 capsules and four blister cards of 21 capsules are supplied in each carton respectively. NDC 68475-204-02: carton containing 90 capsules NDC 68475-204-01: blister card containing 15 capsules NDC 68475-204-04: carton containing 84 capsules NDC 68475-204-03: blister card containing 21 capsules Storage Store at 20°C to 25°C (68°F to 77°F). Excursions are permitted between 15°C to 30°C (59°F to 86°F), [See USP Controlled Room Temperature]. Keep out of reach of children.