ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: oPeripheral Neuropathy [see Warnings and Precautions (5.1)]oTremor [see Warnings and Precautions (5.2)]oDiarrhea and Weight Loss [see Warnings and Precautions (5.3)]oReductions in Platelet Count [see Warnings and Precautions (5.4)]. oPeripheral Neuropathy [see Warnings and Precautions (5.1)]. oTremor [see Warnings and Precautions (5.2)]. oDiarrhea and Weight Loss [see Warnings and Precautions (5.3)]. oReductions 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 1-800-308-6755 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 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 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 and [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 Gaucher disease patients were treated with miglustat capsules at 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 dose of 50 mg three times daily for up to months in 18 patients [Study 2]. Table 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 CapsulesIncidence of adverse reactionsStudy 1(starting dose 100 mg three times daily)Study 2(50 mg three times daily)Patients entered in Study (n)2818Body System Preferred Term% of patients reporting% of patients reportingGastrointestinal System Diarrhea8989 Flatulence2944 Abdominal pain1850 Nausea1422 Vomiting411 Bloating06 Anorexia70 Dyspepsia70 Epigastric pain not food-related06Metabolic and Nutritional Disorders Weight Decrease3967Central and Peripheral Nervous System Headache2122 Tremor1111 Dizziness011 Leg cramps411 Paresthesia70 Migraine06Vision Disorders Visual Disturbance017Musculoskeletal Disorders Cramps011Platelet, Bleeding, and Clotting Disorders Thrombocytopenia76Reproductive disorders, female Menstrual disorder06In an open-label, active-controlled study, 36 adult type Gaucher disease patients were treated with miglustat, imiglucerase, or miglustat plus imiglucerase [Study 3] for up to 12 months. Table 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 StudyIncidence of adverse reactionsMiglustat Capsules aloneImiglucerase alonePatients entered in Study (n)1212Body System Preferred Term% of patients reporting% of patients reportingGastrointestinal System Diarrhea1000 Abdominal Pain670 Flatulence500 Constipation80 Nausea80 Dry Mouth80Body as Whole Pain08 Generalized weakness170 Abdominal distension80 Back Pain80 Heaviness in Limbs80Metabolic and Nutritional Disorders Weight Decrease670Central and Peripheral Nervous System Tremor170 Dizziness80 Leg cramps80 Unsteady gait80Psychiatric disorders Memory loss80. Table 1: Adverse Reactions in >=5% of Patients in Two Open-Label, Uncontrolled Monotherapy Trials of Miglustat Capsules. Table 2: Adverse Reactions in >=5% of Patients in Open-Label Active Controlled Study.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and/or Pharmacology Histopathology findings in the absence of clinical signs in the central nervous system of the monkey (brain, spine) that included vascular mineralization, in addition to mineralization and necrosis of white matter were observed at >750 mg/kg/day (4 times the human therapeutic systemic exposure based on area-under-the-plasma-concentration curve [AUC] comparisons) in 52-week oral toxicity study using doses of 750 and 2000 mg/kg/d. Vacuolization of white matter was observed in rats dosed orally by gavage at >=180 mg/kg/d (6 times the human therapeutic exposure based on surface area comparisons, mg/m2) in 4-week study using doses of 180, 840, and 4200 mg/kg/d. Vacuolization can sometimes occur as an artifact of tissue processing. Findings in dogs included tremor and absent corneal reflexes at 105 mg/kg/day (10 times the human therapeutic systemic exposure, based on body surface area comparisons, mg/m2) after 4-week oral gavage toxicity study using doses of 35, 70, 105, and 140 mg/kg/d. Ataxia, diminished/absent pupillary, palpebral, or patellar reflexes were observed in dog at >=495 mg/kg/day (50 times the human therapeutic systemic exposure based on body surface area comparisons, mg/m2), in 2-week oral gavage toxicity study using doses of 85, 165, 495, and 825 mg/kg/d. Cataracts were observed in rats at >=180 mg/kg/day (4 times the human therapeutic systemic exposure, based on AUC) in 52-week oral gavage toxicity study using doses of 180, 420, 840, and 1680 mg/kg/d. Gastrointestinal necrosis, inflammation, and hemorrhage were observed in dogs at >=85 mg/kg/day (9 times the human therapeutic systemic exposure based on body surface area comparisons, mg/m2) after 2-week oral (capsule) toxicity study using doses of 85, 165, 495, and 825 mg/kg/d. Similar GI toxicity occurred in rats at 1200 mg/kg/day (7 times the human therapeutic systemic exposure, based on AUC) in 26-week oral gavage toxicity study using doses of 300, 600, and 1200 mg/kg/d. In monkeys, similar GI toxicity occurred at >=750 mg/kg/day (6 times the human therapeutic systemic exposure based on AUC) following 52-week oral gavage toxicity study using doses of 750 and 2000 mg/kg/d.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility CarcinogenesisTwo-year carcinogenicity studies have been conducted with miglustat in CD-1 mice at oral doses up to 500 mg/kg/day and in Sprague Dawley rats at oral doses up to 180 mg/kg/day. Oral administration of miglustat for 104 weeks produced mucinous adenocarcinomas of the large intestine at 210, 420 and 500 mg/kg/day (about 3, and times the recommended human dose, respectively, based on the body surface area) in male mice and at 420 and 500 mg/kg/day (about and times the recommended human dose, based on the body surface area) in female mice. The adenocarcinomas were considered rare in CD-1 mice and occurred in the presence of inflammatory and hyperplastic lesions in the large intestine of both males and females. In rats, oral administration of miglustat for 100 weeks produced increased incidences of interstitial cell adenomas of the testis at 30, 60 and 180 mg/kg/day (about 1, and times the recommended human dose, respectively, based on the body surface area). MutagenesisMiglustat was not mutagenic or clastogenic in battery of in vitro and in vivo assays including the bacterial reverse mutation (Ames), chromosomal aberration (in human lymphocytes), gene mutation in mammalian cells (Chinese hamster ovary), and mouse micronucleus assays. Impairment of FertilityMiglustat was administered by oral gavage to male rats at doses of 20, 60, 180 mg/kg/day beginning at least 14 days prior to mating and continuing through mating. Effects on sperm parameters (concentration, motility and morphology) resulting in decreased fertility were observed at all dose levels (the lowest dose level was 0.65 times the human therapeutic dose on mg/m2 basis). Reversibility was demonstrated following weeks of drug withdrawal. Findings of, seminiferous tubule degeneration and atrophy were observed in the testes in rat repeat-dose toxicity studies.Miglustat was administered by oral gavage to female rats at doses of 20, 60, 180 mg/kg/day beginning 14 days before mating and continuing through gestation day 17. There were no effects on mating performance or fertility in female rats at doses up to 180 mg/kg/day. However, increased post implantation loss and decreased embryo-fetal survival were observed at doses >=60 mg/kg/day (>=2 times the human therapeutic dose on mg/m2 basis).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Type Gaucher disease is caused by functional deficiency of glucocerebrosidase, the enzyme that mediates the degradation of the glycosphingolipid glucosylceramide. Miglustat functions as competitive and reversible inhibitor of the enzyme glucosylceramide synthase, the initial enzyme in 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 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.. 12.3 Pharmacokinetics AbsorptionAfter 100 mg oral dose, the time to maximum observed plasma concentration of miglustat (tmax) ranged from to 2.5 hours in Gaucher patients. Plasma concentrations show biexponential decline, characterized by short distribution phase and longer elimination phase. The effective half-life of miglustat is approximately to hours, which predicts that steady-state will be achieved by 1.5 to days following the start of three times daily dosing. Miglustat, dosed at 50 and 100 mg three times daily in Gaucher patients, exhibits dose-proportional pharmacokinetics. The pharmacokinetics of miglustat were not altered after repeated dosing three times daily for up to 12 months. In healthy subjects, co-administration of miglustat with food results in decrease in the rate of absorption of miglustat (maximum plasma concentration [Cmax] was decreased by 36% and tmax delayed h) but had no statistically significant effect on the extent of absorption of miglustat (area-under-the-plasma-concentration time curve [AUC] was decreased by 14%). The mean oral bioavailability of 100-mg miglustat capsule is about 97% relative to an oral solution administered under fasting conditions. The pharmacokinetics of miglustat were similar between adult type Gaucher disease patients and healthy subjects after single dose administration of miglustat 100 mg. DistributionMiglustat does not bind to plasma proteins. Mean apparent volume of distribution of miglustat is 83-105 liters in Gaucher patients. At steady state, the concentration of miglustat in cerebrospinal fluid of six non-Gaucher patients was 31.4-67.2% of that in plasma, indicating that miglustat crosses the blood brain barrier. Metabolism and ExcretionThe major route of excretion of miglustat is via kidney. Following administration of single dose of 100 mg 14C-miglustat to healthy volunteers, 83% of the radioactivity was recovered in urine and 12% in feces. In healthy subjects, 67% of the administered dose was excreted unchanged in urine over 72 hours. The most abundant metabolite in urine was miglustat glucuronide accounting for 5% of the dose. The terminal half-life of radioactivity in plasma was 150 hours, suggesting the presence of one or more metabolites with prolonged half-life. The metabolite accounting for this observation has not been identified, but may accumulate and reach concentrations exceeding those of miglustat at steady state. Specific Populations GenderThere was no statistically significant gender difference in miglustat pharmacokinetics, based on pooled data analysis. RaceEthnic differences in miglustat pharmacokinetics have not been evaluated in Gaucher patients. However, apparent oral clearance of miglustat in patients of Ashkenazi Jewish descent was not statistically different to that in others (1 Asian and 15 Caucasians), based on cross-study analysis. Hepatic ImpairmentNo studies have been performed to assess the pharmacokinetics of miglustat in patients with hepatic impairment. Renal ImpairmentLimited data in non-Gaucher patients with impaired renal function indicate that the apparent oral clearance (CL/F) of miglustat decreases with decreasing renal function. While the number of subjects with mild and moderate renal impairment was very small, the data suggest an approximate decrease in the apparent oral clearance of 40% and 60% respectively, in mild and moderate renal impairment, justifying the need to decrease the dosing of miglustat in such patients dependent upon creatinine clearance levels [see Dosage and Administration (2.2)].Data in severe renal impairment are limited to two patients with creatinine clearances in the range 18-29 mL/min and cannot be extrapolated below this range. These data suggest decrease in CL/F by at least 70% in patients with severe renal impairment [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)].Drug Interaction StudiesMiglustat does not inhibit the metabolism of various substrates of cytochrome P450 enzymes including, CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP4A11 in vitro; consequently, significant interactions via inhibition of these enzymes are unlikely with drugs that are substrates of cytochrome P450 enzymes. Drug interaction between miglustat (miglustat 100 mg orally three times daily) and imiglucerase 7.5 or 15 U/kg/day was assessed in imiglucerase-stabilized patients after one month of co-administration. There was no significant effect of imiglucerase on the pharmacokinetics of miglustat, with the co-administration of imiglucerase and miglustat resulting in 22% reduction in Cmax and 14% reduction in the AUC for miglustat. While miglustat appeared to increase the clearance of imiglucerase by 70%, these results are not conclusive because of the small number of subjects studied and because patients took variable doses of imiglucerase [see Drug Interactions (7)]. Concomitant therapy with loperamide during clinical trials did not appear to significantly alter the pharmacokinetics of miglustat.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES The efficacy of miglustat in type Gaucher disease has been investigated in two open-label, uncontrolled trials and one randomized, open-label, active-controlled trial with enzyme replacement given as imiglucerase. Patients who received miglustat capsules were treated with doses ranging from 100 to 600 mg day, although the majority of patients were maintained on doses between 200 to 300 mg day. Efficacy parameters included the evaluation of liver and spleen organ volume, hemoglobin concentration, and platelet count. total of 80 patients were exposed to miglustat during the three trials and their extension period. Open-Label Uncontrolled Monotherapy Trials In Study 1, miglustat capsules were administered at starting dose of 100 mg three times daily for 12 months (dose range of 100 once-daily to 200 mg three times daily) to 28 adult patients with type Gaucher disease, who were unable to receive enzyme replacement therapy and who had not taken enzyme replacement therapy in the preceding months. Twenty-two patients completed the trial. After 12 months of treatment, the results showed significant mean percent reductions from baseline in liver volume of 12% and spleen volume of 19%, non-significant increase from baseline in mean absolute hemoglobin concentration of 0.26 g/dL and mean absolute increase from baseline in platelet counts of x 109/L (See Tables 3-6). In Study 2, miglustat capsules were administered at dose of 50 mg three times daily for months to 18 adult patients with type Gaucher disease who were unable to receive enzyme replacement therapy and who had not taken enzyme replacement therapy in the preceding months. Seventeen patients completed the trial. After months of treatment, the results showed significant mean percent reductions from baseline in liver volume of 6% and spleen volume of 5%. There was non-significant mean absolute decrease from baseline in hemoglobin concentration of 0.13 g/dL and non-significant mean absolute increase from baseline in platelet counts of x 109/L (See Tables 3-6). Extension Period Eighteen patients were enrolled in 12-month extension to Study 1. subset of patients continuing in the extension had larger mean baseline liver volumes, and lower mean baseline platelet counts and hemoglobin concentrations than the original study population (See Tables 3-6). After total of 24 months of treatment, there were significant mean decreases from baseline in liver and spleen organ volumes of 15% and 27%, respectively, and significant mean absolute increases from baseline in hemoglobin concentration and platelet count of 0.9 g/dL and 14 109/L, respectively (See Tables 3-6). Sixteen patients were enrolled in 6-month extension to Study 2. After total of 12 months of treatment, there was mean decrease from baseline in spleen organ volume of 10%, whereas the mean percent decrease in liver organ volume remained at 6%. There were no significant changes in hemoglobin concentrations or platelet counts (See Tables 3-6). Liver volume results from Studies and and their extensions are summarized in Table 3: Table 3: Liver Volume Changes in Two Open-Label Uncontrolled Monotherapy Trials of Miglustat Capsules with Extension Period nLiver VolumeAbsolute Mean (L) (2-sided 95% CI)Percent Mean (%) (2-sided 95% CI)Study (starting dose Miglustat Capsules 100 mg three times daily) Baseline (Month 0) 21 2.39 Month 12 Change from baseline-0.28 (-0.38, -0.18) -12.1% (-16.4, 7.9)Study Extension Phase Baseline (Month 0) 12 2.54 Month 24 Change from baseline -0.36 (-0.48, -0.24) -14.5% (-19.3, 9.7)Study (Miglustat Capsules 50 mg three times daily) Baseline (Month 0) 17 2.45 Month Change from baseline -0.14 (-0.25, -0.03) -5.9% (-9.9, -1.9)Study Extension Phase Baseline (Month 0) 13 2.35 Month 12 Change from baseline -0.17 (-0.3, -0.0) -6.2% (-12.0, -0.5)Spleen volume results from Studies and and their extensions are summarized in Table 4: Table 4: Spleen Volume Changes in Two Open-Label Uncontrolled Monotherapy Trials of Miglustat Capsules with Extension Period nSpleen VolumeAbsolute Mean (L) (2-sided 95% CI)Percent Mean (%) (2-sided 95% CI)Study (starting dose Miglustat Capsules 100 mg three times daily) Baseline (Month 0) 181.64 Month 12 Change from baseline -0.32 (-0.42, -0.22)-19.0% (-23.7, -14.3)Study Extension Phase Baseline (Month 0) 101.56 Month 24 Change from baseline -0.42 (-0.53, -0.30)-26.4% (-30.4, -22.4)Study (Miglustat Capsules 50 mg three times daily) Baseline (Month 0) 111.98 Month Change from baseline -0.09 (-0.18, -0.01)-4.5% (-8.2, -0.7)Study Extension Phase Baseline (Month 0) 91.98 Month 12 Change from baseline -0.23 (-0.46, 0.00)-10.1% (-20.1, -0.1)Hemoglobin concentration results from Studies and and their extensions are summarized in Table 5: Table 5: Hemoglobin Concentration Changes in Two Open-Label Uncontrolled Monotherapy Trials of Miglustat Capsules with Extension PeriodnHemoglobin ConcentrationAbsolute Mean (g/dL) (2-sided 95% CI)Percent Mean (%) (2-sided 95% CI)Study (starting dose Miglustat Capsules 100 mg three times daily) Baseline (Month 0) 22 11.94 Month 12 Change from baseline 0.26 (-0.05, 0.57) 2.6% (-0.5, 5.7) Study Extension Phase Baseline (Month 0) 13 11.03 Month 24 Change from baseline 0.91 (0.30, 1.53) 9.1% (2.9, 15.2) Study (Miglustat Capsules 50 mg three times daily) Baseline (Month 0) 17 11.60 Month Change from baseline -0.13 (-0.51, 0.24) -1.3% (-4.4, 1.8) Study Extension Phase Baseline (Month 0) 13 11.94 Month 12 Change from baseline 0.06 (-0.73, 0.85) 1.2% (-5.2, 7.7) Platelet count results from Studies and and their extensions are summarized in Table 6: Table 6: Platelet Count Changes in Two Open-Label Uncontrolled Monotherapy Trials of Miglustat Capsules with Extension PeriodnPlatelet CountAbsolute Mean (109/L) (2-sided 95% CI)Percent Mean (%) (2-sided 95% CI)Study (starting dose Miglustat Capsules 100 mg three times daily) Baseline (Month 0) 22 76.58 Month 12 Change from baseline 8.28 (1.88, 14.69) 16.0% (-0.8, 32.8) Study Extension Phase Baseline (Month 0) 13 72.35 Month 24 Change from baseline 13.58 (7.72, 19.43) 26.1% (14.7, 37.5) Study (Miglustat Capsules 50 mg three times daily) Baseline (Month 0) 17 116.47 Month Change from baseline 5.35 (-6.31, 17.02) 2.0% (-6.9, 10.8) Study Extension Phase Baseline (Month 0) 13 122.15 Month 12 Change from baseline 14.0 (-3.4, 31.4) 14.7% (-1.4, 30.7) Open-Label Active-Controlled Trial Study was an open-label, randomized, active-controlled study of 36 adult patients with type Gaucher disease, who had been receiving enzyme replacement therapy with imiglucerase for minimum of years prior to study entry. Patients were randomized 1:1:1 to one of three treatment groups, as follows: omiglustat capsules 100 mg three times daily alone oimiglucerase (patients usual dose) alone omiglustat capsules 100 mg three times daily and imiglucerase (usual dose) Patients were treated for months, and 33 patients completed the study. Because miglustat is only indicated as monotherapy, the results for the monotherapy arms are described below. At Month 6, the results showed decrease in mean percent change in liver volume in the miglustat capsule treatment group compared to the imiglucerase alone group. There were no significant differences between the groups for mean absolute changes in liver and spleen volume and hemoglobin concentration. However, there was significant difference between the miglustat capsules alone and imiglucerase alone groups in platelet counts at Month 6, with the miglustat capsules alone group having mean absolute decrease in platelet count of 21.6 109/L and the imiglucerase alone group having mean absolute increase in platelet count of 10.1 109/L (See Tables 7-10).Extension period Twenty-nine patients were enrolled in 6-month extension to Study 3. In the extension phase, all 29 patients had withdrawn from imiglucerase and received open-label miglustat capsules 100 mg three times daily monotherapy. At Month 12, the results showed non-significant decreases in platelet counts from baseline in all the treatment groups (by original randomization). There was significant decrease in platelet counts from Month to Month 12 in the group originally randomized to treatment with imiglucerase, and continued decrease in platelet counts in the group originally randomized to miglustat capsules alone. There were no significant changes in any treatment group for liver volume, spleen volume, or hemoglobin concentration (See Tables 7-10). Liver volume results from Study and extension are summarized in Table 7:Table 7: Liver Volume Changes from Study and Extension PhaseImiglucerase aloneMiglustat Capsules aloneStudy Month Month Change (L) Month % Change Adjusted mean Difference from Imiglucerase (95% CI) n=11 1.81 0.04 3.6%n=10 1.58 -0.05 -2.9% -4.5% (-13.2, 4.2)Extension Phase Month Month 12 Change (L) Month 12 Change n=10 1.94 -0.05 -0.7%n=8 1.60 -0.01 -0.8%All patients received miglustat capsules 100 mg three times daily monotherapy from Month to Month 12.Spleen volume results from Study and extension are summarized in Table 8:Table 8: Spleen Volume Changes from Study and Extension PhaseImiglucerase aloneMiglustat Capsules aloneStudy Month Month Change (L) Month % Change Adjusted Difference from Imiglucerase (95% CI) n=8 0.61 -0.02 -2.1%n=7 0.69 -0.03 -4.8% -5.8% (-22.1, 10.5)Extension Phase Month Month 12 Change (L) Month 12 Change n=7 0.83 0.04 1.5%n=6 0.57 -0.05 -6.1%All patients received miglustat capsules 100 mg three times daily monotherapy from Month to Month 12.Hemoglobin concentration results from Study and extension are summarized in Table 9: Table 9: Hemoglobin Concentration Changes from Study and Extension PhaseImiglucerase aloneMiglustat Capsules aloneStudy Month Month Change (g/dL) Month % Change Adjusted Difference from Imiglucerase (95% CI) n=12 13.18 -0.15 -1.2%n=10 12.44 -0.31 -2.4% -1.9% (-6.4, 2.6)Extension Phase Month Month 12 Change (g/dL) Month 12 Change n=10 13.39 -0.48 -3.1%n=9 12.46 -0.13 -1.1%All patients received miglustat capsules 100 mg three times daily monotherapy from Month to Month 12.Platelet count results from Study and extension are summarized in Table 10:Table 10: Platelet Count Changes from Study and Extension PhaseImiglucerase aloneMiglustat Capsules aloneStudy Month Month Change (109/L) Month % Change Adjusted Difference from Imiglucerase (95% CI) n=12 165.75 15.29 10.1%n=10 170.55 -21.60 -9.6% -17.1% (-32.9, -1.3)Extension Phase Month Month 12 Change (109/L) Month 12 Change n=10 170.05 -3.75 -3.2%n=9 184.83 -27.39-10.4%All patients received miglustat capsules 100 mg three times daily monotherapy from Month to Month 12.Patients with platelet counts above 150 109/L at baseline who were randomized to miglustat treatment had significant decreases in platelet counts at Month 12.. Table 3: Liver Volume Changes in Two Open-Label Uncontrolled Monotherapy Trials of Miglustat Capsules with Extension Period Table 4: Spleen Volume Changes in Two Open-Label Uncontrolled Monotherapy Trials of Miglustat Capsules with Extension Period Table 5: Hemoglobin Concentration Changes in Two Open-Label Uncontrolled Monotherapy Trials of Miglustat Capsules with Extension Period. Table 6: Platelet Count Changes in Two Open-Label Uncontrolled Monotherapy Trials of Miglustat Capsules with Extension Period. omiglustat capsules 100 mg three times daily alone oimiglucerase (patients usual dose) alone omiglustat capsules 100 mg three times daily and imiglucerase (usual dose).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information) Information for PatientsoAdvise patients that the most common serious adverse reaction reported with miglustat is peripheral neuropathy. Advise patients to promptly report any numbness, tingling, pain, or burning in the hands and feet [see Warnings and Precautions (5.1)].oAdvise patients that other adverse reactions include tremor and reductions in platelet counts. Advise patients to promptly report the development of tremor or worsening in an existing tremor [see Warnings and Precautions (5.2 and 5.4)].oAdvise patients that other serious adverse reactions include diarrhea and weight loss. Advise patients to adhere to dietary instructions [see Warnings and Precautions (5.3)].oAdvise patients to take the next miglustat capsule at the next scheduled time if dose is missed.oInform patients of the potential risks and benefits of miglustat and of alternative modes of therapy. PregnancyAdvise pregnant women and females of reproductive potential of the potential risk to fetus, based on animal data. Advise patients who may become pregnant to inform their healthcare provider of known or suspected pregnancy [see Use in Specific Populations (8.1)].LactationAdvise women not to breastfeed if they are taking miglustat capsules [see Use in Specific Populations (8.2)].Manufactured by:Suzhou Amerigen Pharmaceutical Co. Ltd.Jiangsu, China 215006Distributed by:ANI Pharmaceuticals, Inc.Baudette, MN 5662310344 Rev 01/21. oAdvise patients that the most common serious adverse reaction reported with miglustat is peripheral neuropathy. Advise patients to promptly report any numbness, tingling, pain, or burning in the hands and feet [see Warnings and Precautions (5.1)].. oAdvise patients that other adverse reactions include tremor and reductions in platelet counts. Advise patients to promptly report the development of tremor or worsening in an existing tremor [see Warnings and Precautions (5.2 and 5.4)].. oAdvise patients that other serious adverse reactions include diarrhea and weight loss. Advise patients to adhere to dietary instructions [see Warnings and Precautions (5.3)].. oAdvise patients to take the next miglustat capsule at the next scheduled time if dose is missed.. oInform patients of the potential risks and benefits of miglustat and of alternative modes of therapy.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility CarcinogenesisTwo-year carcinogenicity studies have been conducted with miglustat in CD-1 mice at oral doses up to 500 mg/kg/day and in Sprague Dawley rats at oral doses up to 180 mg/kg/day. Oral administration of miglustat for 104 weeks produced mucinous adenocarcinomas of the large intestine at 210, 420 and 500 mg/kg/day (about 3, and times the recommended human dose, respectively, based on the body surface area) in male mice and at 420 and 500 mg/kg/day (about and times the recommended human dose, based on the body surface area) in female mice. The adenocarcinomas were considered rare in CD-1 mice and occurred in the presence of inflammatory and hyperplastic lesions in the large intestine of both males and females. In rats, oral administration of miglustat for 100 weeks produced increased incidences of interstitial cell adenomas of the testis at 30, 60 and 180 mg/kg/day (about 1, and times the recommended human dose, respectively, based on the body surface area). MutagenesisMiglustat was not mutagenic or clastogenic in battery of in vitro and in vivo assays including the bacterial reverse mutation (Ames), chromosomal aberration (in human lymphocytes), gene mutation in mammalian cells (Chinese hamster ovary), and mouse micronucleus assays. Impairment of FertilityMiglustat was administered by oral gavage to male rats at doses of 20, 60, 180 mg/kg/day beginning at least 14 days prior to mating and continuing through mating. Effects on sperm parameters (concentration, motility and morphology) resulting in decreased fertility were observed at all dose levels (the lowest dose level was 0.65 times the human therapeutic dose on mg/m2 basis). Reversibility was demonstrated following weeks of drug withdrawal. Findings of, seminiferous tubule degeneration and atrophy were observed in the testes in rat repeat-dose toxicity studies.Miglustat was administered by oral gavage to female rats at doses of 20, 60, 180 mg/kg/day beginning 14 days before mating and continuing through gestation day 17. There were no effects on mating performance or fertility in female rats at doses up to 180 mg/kg/day. However, increased post implantation loss and decreased embryo-fetal survival were observed at doses >=60 mg/kg/day (>=2 times the human therapeutic dose on mg/m2 basis).. 13.2 Animal Toxicology and/or Pharmacology Histopathology findings in the absence of clinical signs in the central nervous system of the monkey (brain, spine) that included vascular mineralization, in addition to mineralization and necrosis of white matter were observed at >750 mg/kg/day (4 times the human therapeutic systemic exposure based on area-under-the-plasma-concentration curve [AUC] comparisons) in 52-week oral toxicity study using doses of 750 and 2000 mg/kg/d. Vacuolization of white matter was observed in rats dosed orally by gavage at >=180 mg/kg/d (6 times the human therapeutic exposure based on surface area comparisons, mg/m2) in 4-week study using doses of 180, 840, and 4200 mg/kg/d. Vacuolization can sometimes occur as an artifact of tissue processing. Findings in dogs included tremor and absent corneal reflexes at 105 mg/kg/day (10 times the human therapeutic systemic exposure, based on body surface area comparisons, mg/m2) after 4-week oral gavage toxicity study using doses of 35, 70, 105, and 140 mg/kg/d. Ataxia, diminished/absent pupillary, palpebral, or patellar reflexes were observed in dog at >=495 mg/kg/day (50 times the human therapeutic systemic exposure based on body surface area comparisons, mg/m2), in 2-week oral gavage toxicity study using doses of 85, 165, 495, and 825 mg/kg/d. Cataracts were observed in rats at >=180 mg/kg/day (4 times the human therapeutic systemic exposure, based on AUC) in 52-week oral gavage toxicity study using doses of 180, 420, 840, and 1680 mg/kg/d. Gastrointestinal necrosis, inflammation, and hemorrhage were observed in dogs at >=85 mg/kg/day (9 times the human therapeutic systemic exposure based on body surface area comparisons, mg/m2) after 2-week oral (capsule) toxicity study using doses of 85, 165, 495, and 825 mg/kg/d. Similar GI toxicity occurred in rats at 1200 mg/kg/day (7 times the human therapeutic systemic exposure, based on AUC) in 26-week oral gavage toxicity study using doses of 300, 600, and 1200 mg/kg/d. In monkeys, similar GI toxicity occurred at >=750 mg/kg/day (6 times the human therapeutic systemic exposure based on AUC) following 52-week oral gavage toxicity study using doses of 750 and 2000 mg/kg/d.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics AbsorptionAfter 100 mg oral dose, the time to maximum observed plasma concentration of miglustat (tmax) ranged from to 2.5 hours in Gaucher patients. Plasma concentrations show biexponential decline, characterized by short distribution phase and longer elimination phase. The effective half-life of miglustat is approximately to hours, which predicts that steady-state will be achieved by 1.5 to days following the start of three times daily dosing. Miglustat, dosed at 50 and 100 mg three times daily in Gaucher patients, exhibits dose-proportional pharmacokinetics. The pharmacokinetics of miglustat were not altered after repeated dosing three times daily for up to 12 months. In healthy subjects, co-administration of miglustat with food results in decrease in the rate of absorption of miglustat (maximum plasma concentration [Cmax] was decreased by 36% and tmax delayed h) but had no statistically significant effect on the extent of absorption of miglustat (area-under-the-plasma-concentration time curve [AUC] was decreased by 14%). The mean oral bioavailability of 100-mg miglustat capsule is about 97% relative to an oral solution administered under fasting conditions. The pharmacokinetics of miglustat were similar between adult type Gaucher disease patients and healthy subjects after single dose administration of miglustat 100 mg. DistributionMiglustat does not bind to plasma proteins. Mean apparent volume of distribution of miglustat is 83-105 liters in Gaucher patients. At steady state, the concentration of miglustat in cerebrospinal fluid of six non-Gaucher patients was 31.4-67.2% of that in plasma, indicating that miglustat crosses the blood brain barrier. Metabolism and ExcretionThe major route of excretion of miglustat is via kidney. Following administration of single dose of 100 mg 14C-miglustat to healthy volunteers, 83% of the radioactivity was recovered in urine and 12% in feces. In healthy subjects, 67% of the administered dose was excreted unchanged in urine over 72 hours. The most abundant metabolite in urine was miglustat glucuronide accounting for 5% of the dose. The terminal half-life of radioactivity in plasma was 150 hours, suggesting the presence of one or more metabolites with prolonged half-life. The metabolite accounting for this observation has not been identified, but may accumulate and reach concentrations exceeding those of miglustat at steady state. Specific Populations GenderThere was no statistically significant gender difference in miglustat pharmacokinetics, based on pooled data analysis. RaceEthnic differences in miglustat pharmacokinetics have not been evaluated in Gaucher patients. However, apparent oral clearance of miglustat in patients of Ashkenazi Jewish descent was not statistically different to that in others (1 Asian and 15 Caucasians), based on cross-study analysis. Hepatic ImpairmentNo studies have been performed to assess the pharmacokinetics of miglustat in patients with hepatic impairment. Renal ImpairmentLimited data in non-Gaucher patients with impaired renal function indicate that the apparent oral clearance (CL/F) of miglustat decreases with decreasing renal function. While the number of subjects with mild and moderate renal impairment was very small, the data suggest an approximate decrease in the apparent oral clearance of 40% and 60% respectively, in mild and moderate renal impairment, justifying the need to decrease the dosing of miglustat in such patients dependent upon creatinine clearance levels [see Dosage and Administration (2.2)].Data in severe renal impairment are limited to two patients with creatinine clearances in the range 18-29 mL/min and cannot be extrapolated below this range. These data suggest decrease in CL/F by at least 70% in patients with severe renal impairment [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)].Drug Interaction StudiesMiglustat does not inhibit the metabolism of various substrates of cytochrome P450 enzymes including, CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP4A11 in vitro; consequently, significant interactions via inhibition of these enzymes are unlikely with drugs that are substrates of cytochrome P450 enzymes. Drug interaction between miglustat (miglustat 100 mg orally three times daily) and imiglucerase 7.5 or 15 U/kg/day was assessed in imiglucerase-stabilized patients after one month of co-administration. There was no significant effect of imiglucerase on the pharmacokinetics of miglustat, with the co-administration of imiglucerase and miglustat resulting in 22% reduction in Cmax and 14% reduction in the AUC for miglustat. While miglustat appeared to increase the clearance of imiglucerase by 70%, these results are not conclusive because of the small number of subjects studied and because patients took variable doses of imiglucerase [see Drug Interactions (7)]. Concomitant therapy with loperamide during clinical trials did not appear to significantly alter the pharmacokinetics of miglustat.

PREGNANCY SECTION.

8.1 Pregnancy Risk Summary Based on findings from animal reproduction studies, miglustat capsules may cause fetal harm when administered to pregnant woman. Available data from postmarketing case reports with miglustat use in pregnancy are insufficient to assess drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks associated with symptomatic Type 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 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 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 Gaucher disease symptoms or result in new disease manifestations. Type Gaucher disease manifestations may lead to adverse pregnancy outcomes including, hepatosplenomegaly which can interfere with the normal growth of 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 mg/m2 basis). Miglustat was also administered to pregnant rats by oral gavage at doses of 20, 60, 180 mg/kg/day from gestation day 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 mg/m2 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 mg/m2 basis. In 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 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 mg/m2 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 times the human therapeutic dose on mg/m2 basis).

SPL PATIENT PACKAGE INSERT SECTION.

Patient Information Miglustat Capsules(mi gloo stat)Read this Patient Information before you start taking miglustat capsules and each time you get refill. There may be new information.What are Miglustat Capsules Miglustat capsules are prescription medicine used alone to treat adults with mild to moderate type Gaucher disease. Miglustat capsules are used only in people who cannot be treated with enzyme replacement therapy. It is not known if miglustat capsules are safe and effective in children under 18 years of age.Before taking Miglustat Capsules, tell your healthcare provider about all of your medical conditions, including if you:ohave kidney problems oare pregnant or plan to become pregnant. Miglustat capsules may harm your unborn baby. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with miglustat capsules.oare breastfeeding or plan to breastfeed. It is not known if miglustat can pass into your breast milk and may harm your baby. Do not breastfeed during treatment with miglustat capsules. Talk to your healthcare provider about the best way to feed your baby during treatment with miglustat capsules.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Miglustat capsules may affect how other medicines work.How should take Miglustat Capsules oTake miglustat capsules exactly as your healthcare provider tells you to.oTake miglustat capsules at the same time each day. oIf you miss dose of miglustat capsules, skip that dose. Take the next miglustat capsule at the usual time.What are the possible side effects of Miglustat Capsules Miglustat Capsules may cause serious side effects including: oNumbness, tingling, pain, or burning in your hands or feet (peripheral neuropathy). Call your healthcare provider right away if you get numbness, tingling, pain, or burning in your hands or feet. oYour healthcare provider may test your nerves (neurological exam) before you start miglustat and during treatment with miglustat capsules.oNew or worsening hand tremors (shaky movements). Tremors are common with miglustat and may begin within the first month of starting treatment. Sometimes the tremors may go away between to months with continued treatment. Your healthcare provider may lower your dose or stop miglustat capsules if you develop new or worsening hand tremors. Call your healthcare provider right away if you get new hand tremors during treatment with miglustat capsules or if the hand tremors you already have get worse.oDiarrhea is common with miglustat and sometimes can be serious. Your healthcare provider may prescribe another medicine (anti-diarrheal) to treat diarrhea if it is problem for you and may recommend changes to your diet, such as avoiding foods high in carbohydrates. Talk with your healthcare provider about your diet if you have diarrhea.oWeight loss is common with miglustat and sometimes can be serious. You may lose weight when you start treatment with miglustat capsules. oLow platelet count is common with miglustat and can be serious. Your healthcare provider may do blood tests to monitor your blood platelet count during treatment with miglustat capsules.The most common side effects of miglustat capsules include:oWeight loss oStomach pain oGas oNausea and vomiting oHeadache, including migraineoBack pain oConstipation oDry mouth oHeaviness in arms and legs oMemory loss oUnsteady walkingoLeg cramps oDizziness oWeakness oVision problems oMuscle crampsoLoss of appetite oIndigestion oNumbness, tingling, pain, or burning of your skin oStomach bloating oStomach pain not related to food oMenstrual changesThese are not all the possible side effects of miglustat capsules. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store Miglustat Capsules oStore miglustat capsules at room temperature between 68o to 77o (20oC to 25oC). Keep miglustat capsules and all medicines out of the reach of children.General information about the safe and effective use of miglustat capsules. Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use miglustat capsules for condition for which it was not prescribed. Do not give miglustat capsules to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about miglustat capsules that is written for health professionals.What are the ingredients in Miglustat Capsules Active ingredient: miglustat Inactive ingredients: magnesium stearate. The capsule shell contains: gelatin and titanium dioxide; the edible printing ink contains black iron oxide, propylene glycol, potassium hydroxide and shellac.Manufactured by: Suzhou Amerigen Pharmaceutical Co. Ltd., Jiangsu, China 215006Distributed by: ANI Pharmaceuticals, Inc. Baudette, MN 56623For more information about miglustat capsules call 1-800-308-6755 or go to www.anipharmaceuticals.com.This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: 1/2021. ohave kidney problems oare pregnant or plan to become pregnant. Miglustat capsules may harm your unborn baby. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with miglustat capsules.. oare breastfeeding or plan to breastfeed. It is not known if miglustat can pass into your breast milk and may harm your baby. Do not breastfeed during treatment with miglustat capsules. Talk to your healthcare provider about the best way to feed your baby during treatment with miglustat capsules.. oTake miglustat capsules exactly as your healthcare provider tells you to.. oTake miglustat capsules at the same time each day. oIf you miss dose of miglustat capsules, skip that dose. Take the next miglustat capsule at the usual time.. oNumbness, tingling, pain, or burning in your hands or feet (peripheral neuropathy). Call your healthcare provider right away if you get numbness, tingling, pain, or burning in your hands or feet. oYour healthcare provider may test your nerves (neurological exam) before you start miglustat and during treatment with miglustat capsules.. oNew or worsening hand tremors (shaky movements). Tremors are common with miglustat and may begin within the first month of starting treatment. Sometimes the tremors may go away between to months with continued treatment. Your healthcare provider may lower your dose or stop miglustat capsules if you develop new or worsening hand tremors. Call your healthcare provider right away if you get new hand tremors during treatment with miglustat capsules or if the hand tremors you already have get worse.. oDiarrhea is common with miglustat and sometimes can be serious. Your healthcare provider may prescribe another medicine (anti-diarrheal) to treat diarrhea if it is problem for you and may recommend changes to your diet, such as avoiding foods high in carbohydrates. Talk with your healthcare provider about your diet if you have diarrhea.. oWeight loss is common with miglustat and sometimes can be serious. You may lose weight when you start treatment with miglustat capsules. oLow platelet count is common with miglustat and can be serious. Your healthcare provider may do blood tests to monitor your blood platelet count during treatment with miglustat capsules.. oWeight loss oStomach pain oGas oNausea and vomiting oHeadache, including migraine. oBack pain oConstipation oDry mouth oHeaviness in arms and legs oMemory loss oUnsteady walking. oLeg cramps oDizziness oWeakness oVision problems oMuscle cramps. oLoss of appetite oIndigestion oNumbness, tingling, pain, or burning of your skin oStomach bloating oStomach pain not related to food oMenstrual changes. oStore miglustat capsules at room temperature between 68o to 77o (20oC to 25oC).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS oPregnancy: Based on animal data, may cause fetal harm (8.1). oLactation: Breastfeeding not recommended (8.2).. oPregnancy: Based on animal data, may cause fetal harm (8.1). oLactation: 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 pregnant woman. Available data from postmarketing case reports with miglustat use in pregnancy are insufficient to assess drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks associated with symptomatic Type 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 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 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 Gaucher disease symptoms or result in new disease manifestations. Type Gaucher disease manifestations may lead to adverse pregnancy outcomes including, hepatosplenomegaly which can interfere with the normal growth of 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 mg/m2 basis). Miglustat was also administered to pregnant rats by oral gavage at doses of 20, 60, 180 mg/kg/day from gestation day 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 mg/m2 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 mg/m2 basis. In 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 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 mg/m2 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 times the human therapeutic dose on mg/m2 basis). 8.2 Lactation Risk SummaryThere 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 Males of Reproductive Potential InfertilityFindings from small clinical study in seven healthy adult males who received miglustat for six weeks did not indicate effects on male fertility. Studies in male rats have shown that miglustat decreased fertility but findings were reversible. Studies in female rats have shown increased post-implantation loss and decreased embryo-fetal survival [see Use in Specific Populations (8.1), Nonclinical Toxicology (13.1)].. 8.4 Pediatric Use The safety and effectiveness of miglustat in pediatric patients have not been established. In combined clinical trial safety data set of 45 patients less than 18 years of age exposed to miglustat in indications other than type 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 to 2.6 years; some pediatric patients were exposed for up to years. However, the effect of miglustat on long-term gain in weight and height in pediatric patients is unclear.. 8.5 Geriatric Use Clinical studies of miglustat capsules did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, and cardiac function and of concomitant disease or other drug therapy.. 8.6 Renal Impairment Miglustat is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function [see Clinical Pharmacology (12.3)].In patients with mild renal impairment (adjusted creatinine clearance 50-70 mL/min/1.73m2), miglustat capsule administration should commence at dose of 100 mg twice per day. In patients with moderate renal impairment (adjusted creatinine clearance of 30-50 mL/min/1.73m2), miglustat capsule administration should commence at dose of 100 mg once day. Use of miglustat capsules in patients with severe renal impairment (creatinine clearance 30 mL/min/1.73m2) is not recommended. Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. The impact of hemodialysis on the disposition of miglustat has not been investigated.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oPeripheral neuropathy: Perform baseline and follow-up neurological evaluations at 6-month intervals in all patients (5.1). oTremor: Reduce dose to ameliorate tremor or discontinue treatment if tremor does not resolve within days of dose reduction (5.2). oDiarrhea and weight loss: Evaluate for underlying gastrointestinal disease in patients who do not respond to usual interventions (e.g. diet modification) (5.3). oReductions in Platelet Count: Mild reductions in platelet counts without association with bleeding were observed in some patients. Monitoring of platelet counts is recommended. (5.4). oPeripheral neuropathy: Perform baseline and follow-up neurological evaluations at 6-month intervals in all patients (5.1). oTremor: Reduce dose to ameliorate tremor or discontinue treatment if tremor does not resolve within days of dose reduction (5.2). oDiarrhea and weight loss: Evaluate for underlying gastrointestinal disease in patients who do not respond to usual interventions (e.g. diet modification) (5.3). oReductions in Platelet Count: Mild reductions in platelet counts without association with bleeding were observed in some patients. Monitoring of platelet counts is recommended. (5.4). 5.1 Peripheral Neuropathy In clinical trials, cases of peripheral neuropathy have been reported in 3% of Gauchers patients treated with miglustat. All patients receiving miglustat 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 careful re-assessment of the risk/benefit of miglustat therapy, and cessation of treatment may be considered.. 5.2 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 to months during treatment. Reduce dose to ameliorate tremor or discontinue treatment if tremor does not resolve within days of dose reduction.. 5.3 Diarrhea and Weight Loss Diarrhea and weight loss were common in clinical studies of patients treated with miglustat, occurring in approximately 85% and up to 65% of treated patients, respectively. Diarrhea appears to be the result of the inhibitory activity of miglustat on intestinal disaccharidases such as sucrase-isomaltase in the gastrointestinal tract leading to reduced absorption of dietary disaccharides in the small intestine, with resultant osmotic diarrhea. It is unclear if weight loss results from the diarrhea and associated gastrointestinal complaints, decrease in food intake, or 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 miglustat treatment, and may respond to individualized diet modification (e.g., reduction of sucrose, lactose and other carbohydrate intake), to taking miglustat capsules between meals, and/or to anti-diarrheal medications, most commonly loperamide. Patients may be instructed to avoid high carbohydrate content foods during treatment with miglustat if they present with diarrhea.Patients with persistent gastrointestinal events that continue during treatment with miglustat, 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 miglustat has not been evaluated in patients with significant gastrointestinal disease, such as inflammatory bowel disease, and continued treatment of these patients with miglustat should occur only after consideration of the risks and benefits of continued treatment.. 5.4 Reductions in Platelet Count In clinical trials evaluating the use of miglustat for treatment of indications other than type 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 150 109/L) before starting treatment with miglustat. Monitoring of platelet counts is recommended in patients with type Gaucher disease. Mild reductions in platelet counts without association with bleeding were observed in patients with type Gaucher disease who were switched from enzyme replacement therapy (ERT) to miglustat.