MIGLUSTAT: 759 Adverse Event Reports & Safety Profile

YARGESA (miglustat capsules) is an inhibitor of the enzyme glucosylceramide synthase, which is a glucosyl transferase enzyme responsible for the first step in the synthesis of most glycosphingolipids. YARGESA 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 (greater than 1000 mg/mL as a free base). YARGESA is supplied in hard gelatin capsules each containing 100 mg miglustat for oral administration. Each YARGESA 100 mg capsule also contains sodium starch glycolate (type A, potato), povidone (K-29/32), and magnesium stearate. Ingredients in the capsule shell include gelatin and titanium dioxide, and the shells are printed with edible ink consisting of black iron oxide, shellac, and propylene glycol. structure

AND USAGE OPFOLDA is indicated, in combination with Pombiliti, for the treatment of adult patients with late-onset Pompe disease (lysosomal acid alpha-glucosidase [GAA] deficiency) weighing ≥40 kg and who are not improving on their current enzyme replacement therapy (ERT). OPFOLDA is an enzyme stabilizer indicated, in combination with Pombiliti, a hydrolytic lysosomal glycogen-specific enzyme, for the treatment of adult patients with late-onset Pompe disease (lysosomal acid alpha-glucosidase [GAA] deficiency) weighing ≥40 kg and who are not improving on their current enzyme replacement therapy (ERT). ( 1 )

AND ADMINISTRATION Verify pregnancy status in females of reproductive potential prior to initiating treatment. (2.1) Administer OPFOLDA in combination with Pombiliti. (2.2) Recommended OPFOLDA dosage (based on actual body weight), administered orally every other week, is: (2.2) 260 mg for patients weighing ≥50 kg. 195 mg for patients weighing ≥40 kg to <50 kg. Start OPFOLDA in combination with Pombiliti 2 weeks after the last ERT dose. (2.2) Take OPFOLDA with an unsweetened beverage approximately 1 hour before the start of Pombiliti infusion; do not consume other beverages or food for at least 2 hours prior to and 2 hours after taking OPFOLDA. (2.2) Missed dose: If the OPFOLDA dosage is missed, Pombiliti should not be administered and treatment should be rescheduled at least 24 hours after OPFOLDA was last taken. If OPFOLDA in combination with Pombiliti are both missed, re-start treatment as soon as possible. (2.2) See full prescribing information for recommended OPFOLDA dosage in patients with renal impairment. (2.3)

2.1 Pregnancy Evaluation Prior to Initiating Treatment Verify the pregnancy status of females of reproductive potential prior to initiating OPFOLDA in combination with Pombiliti <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1, 8.3) ]</span> .

2.2 Recommended Dosage and Administration OPFOLDA must be administered in combination with Pombiliti (see Figure 1 for the dosing timeline). Refer to the Pombiliti Prescribing Information for Pombiliti dosage and administration recommendations. The recommended dosage of OPFOLDA is based on actual body weight. For patients weighing: ≥50 kg, the recommended dosage is 260 mg orally every other week. ≥40 kg to &lt;50 kg, the recommended dosage is 195 mg orally every other week. Start OPFOLDA in combination with Pombiliti 2 weeks after the last ERT dose. Take OPFOLDA approximately 1 hour before intravenous administration of Pombiliti. Swallow the OPFOLDA capsules whole only with unsweetened beverages (e.g., water, tea or coffee with no cream, sugar, or sweeteners). Do not consume other beverages or food for at least 2 hours prior to and 2 hours after administration of OPFOLDA.

Missed

Dose If the OPFOLDA dosage is missed, Pombiliti should not be administered and treatment should be rescheduled at least 24 hours after OPFOLDA was last taken. If OPFOLDA in combination with Pombiliti are both missed, re-start treatment as soon as possible.

Figure

1.

Dosing Timeline Figure

1

2.3 Recommended Dosage in Patients with Renal Impairment The recommended dosage of OPFOLDA in patients with moderate or severe renal impairment is shown in Table 1 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .

Table

1. Recommended OPFOLDA Dosage in Patients with Moderate or Severe Renal Impairment ∗ Renal function classified by CLcr (creatinine clearance) based on the Cockcroft-Gault equation.

Patient Weight Moderate Renal

Impairment∗(CLcr 30-59 mL/minute)

Severe Renal

Impairment∗ (CLcr 15-29 mL/minute) ≥50 kg 195 mg 195 mg ≥40 kg to <50 kg 130 mg 130 mg For patients with mild renal impairment (creatinine clearance based on the Cockcroft-Gault equation, CLcr 60-89 mL/minute), the recommended OPFOLDA dosage is the same as for patients with normal renal function.

OPFOLDA in combination with Pombiliti is contraindicated in Pregnancy [see Use in Specific Populations (8.1 )] Pregnancy. ( 4, 5.1, 8.1 )

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 ≥ to 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 Edenbridge Pharmaceuticals, LLC at 1-877-381-3336 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 capsules 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 ≥ to 5%) that were considered related to miglustat capsules 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 ≥ to 5% of patients.

Table

1: Adverse Reactions in greater than or equal to 5% of Patients in Two Open-Label, Uncontrolled Monotherapy Trials of miglustat capsules Incidence of adverse reactions Study 1 (starting dose 100mg three times daily)

Study

2 (50mg 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 capsules, imiglucerase, or miglustat capsules plus imiglucerase [Study 3] for up to 12 months.

Table

2 lists adverse reactions that occurred during the trial in greater than or equal to 5% of patients.

Table

2: Adverse Reactions in greater than or equal to 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 Term % of patients reporting % of patients reporting Gastrointestinal System Diarrhea 100 0 Abdominal Pain 67 0 Flatulence 50 0 Constipation 8 0 Nausea 8 0 Dry Mouth 8 0 Body as Whole Pain 0 8 Generalized weakness 17 0 Abdominal distension 8 0 Back pain 8 0 Heaviness in limbs 8 0 Metabolic and Nutritional Disorders Weight Decrease 67 0 Central Peripheral Nervous System Tremor 17 0 Dizziness 8 0 Leg cramps 8 0 Unsteady gait 8 0 Psychiatric disorders Memory loss 8 0

AND PRECAUTIONS

• Peripheral neuropathy: Perform baseline and follow-up neurological evaluations at 6-month intervals in all patients ( 5.1 ).
• Tremor: Reduce dose to ameliorate tremor or discontinue treatment if tremor does not resolve within days of dose reduction ( 5.2 ).
• Diarrhea and weight loss: Evaluate for underlying gastrointestinal disease in patients who do not respond to usual interventions (e.g. diet modification) ( 5.3 ).
• Reductions 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 Gaucher‘s patients treated with miglustat capsules. All patients receiving miglustat capsules 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 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 1 to 3 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 capsules, 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 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 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 capsules if they present with diarrhea. Patients with persistent gastrointestinal events that continue during treatment with miglustat capsules, 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 capsules has not been evaluated in patients with significant gastrointestinal disease, such as inflammatory bowel disease, and continued treatment of these patients with miglustat capsules 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 capsules 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 miglustat capsules. 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 miglustat capsules.

INTERACTIONS While co-administration of miglustat capsules 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 YARGESA and imiglucerase may lead to increased clearance of imiglucerase ( 7 ).