OPFOLDA

Miglustat is an N-alkylated iminosugar, a synthetic analog of D‑glucose. The pharmacologic class is enzyme stabilizer. The chemical name is 1,5-(butylimino)-1,5-dideoxy-D-glucitol with the molecular weight of 219.28 g/mol, the molecular formula C 10 H 21 NO 4 , and the following chemical structure: Miglustat is a white to off-white crystalline solid (powder). It is highly soluble in water (>1,000 mg/mL as a free base). OPFOLDA (miglustat) capsules each contain 65 mg of miglustat for oral administration. The inactive ingredients are: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, pregelatinized maize starch, and sucralose. The capsule shells include black iron oxide, gelatin, and titanium dioxide. Edible printing ink includes black iron oxide, and shellac. Chemical Structure

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 )

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 [see Use in Specific Populations (8.1, 8.3) ] . 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 <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 [see Clinical Pharmacology (12.3) ] . 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 )

Most common adverse reactions ≥5% are headache, diarrhea, fatigue, nausea, abdominal pain, and pyrexia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Amicus Therapeutics at 1-877-4AMICUS 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. Adverse Reactions from the Pooled Clinical Trials Including Trial 1 The pooled safety analysis from 3 clinical trials included 151 adult patients with late-onset Pompe disease (LOPD) treated with OPFOLDA in combination with Pombiliti including: 85 patients in the randomized, double-blind, active-controlled trial in adults (Trial 1) [see Clinical Studies (14) ] , 37 patients in the open-label extension trial where patients switched from a non‑U.S.‑approved alglucosidase alfa product [see Clinical Studies (14) ] to OPFOLDA in combination with Pombiliti, 29 patients in an open-label trial. The total median duration of exposure in these trials was 21 months, with 120 patients having at least 12 months exposure to OPFOLDA in combination with Pombiliti. In these trials, 78% (n=117) of the patients received previous ERT (ERT‑experienced) with a mean treatment duration of 7.7 years. The most common adverse reactions (≥5%) reported in the pooled safety population of patients treated with OPFOLDA in combination with Pombiliti in the 3 clinical trials were headache, diarrhea, fatigue, nausea, abdominal pain, and pyrexia. Adverse Reactions from Trial 1 Trial 1 (a randomized, double-blind, active-controlled trial) included 123 adult patients with LOPD who were randomized in a 2:1 ratio to receive treatment with OPFOLDA in combination with Pombiliti or a non-U.S.-approved alglucosidase alfa product with placebo [see Clinical Studies (14) ]. The duration of exposure was similar for both treatment groups (overall mean exposure of 12 months). Most patients (77%) were ERT‑experienced, and a majority of patients in both treatment groups had >5 years of prior treatment with ERT (69% and 63% of patients in the OPFOLDA in combination with Pombiliti group and the non-U.S.-approved alglucosidase alfa product with placebo group, respectively). The most common adverse reactions (≥5%) reported in the patients who received OPFOLDA in combination with Pombiliti in Trial 1 were headache and diarrhea. Table 2 summarizes frequent adverse reactions that occurred in patients treated with OPFOLDA in combination with Pombiliti in Trial 1. Trial 1 was not designed to demonstrate a statistically significant difference in the incidence of adverse reactions in the OPFOLDA in combination with Pombiliti and the non-U.S.-approved alglucosidase alfa product with placebo groups. Table 2. Adverse Reactions that Occurred in Adults with LOPD at an Incidence of ≥2% in Trial 1 LOPD: late-onset Pompe disease ∗ Headache included migraine and migraine with aura. † Rash included erythematous rash and macular rash. ‡ Abdominal pain included upper and lower abdominal pain. § Tachycardia included sinus tachycardia. ¶ Urticaria included mechanical urticaria and urticarial rash. Adverse Reaction OPFOLDA in Combination with Pombiliti (n=85) N (%) A Non-U.S.-Approved Alglucosidase alfa Product with Placebo (n=38) N (%) Headache ∗ 7 (8.2) 3 (7.9) Diarrhea 5 (5.9) 2 (5.3) Dizziness 4 (4.7) 2 (5.3) Dyspnea 3 (3.5) 0 Abdominal distention 3 (3.5) 2 (5.3) Pyrexia 3 (3.5) 1 (2.6) Rash † 3 (3.5) 0 Abdominal pain ‡ 2 (2.4) 4 (10.5) Nausea 2 (2.4) 5 (13.2) Chills 2 (2.4) 0 Dysgeusia 2 (2.4) 0 Flushing 2 (2.4) 0 Muscle spasms 2 (2.4) 0 Pruritus 2 (2.4) 2 (5.3) Tachycardia § 2 (2.4) 0 Urticaria ¶ 2 (2.4) 0 Additional adverse reactions reported in at least 2% of patients treated with OPFOLDA in combination with Pombiliti across the 3 clinical trials include: myalgia, arthralgia, increased blood pressure, pain, tremor, dyspepsia, asthenia, constipation, infusion site swelling, flank pain, malaise, paresthesia, somnolence, and decreased platelet count.