Miglustat

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 )

Capsules: 65 mg of miglustat, white opaque hard gelatin capsule with grey opaque cap with “AT2221” printed in black on the body. Capsules: 65 mg (3)

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

Embryo-Fetal Toxicity: May cause embryo-fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for at least 60 days after the last dose. ( 4, 5.1, 8.1, 8.3 ) Risks Associated with Pombiliti: Refer to the Pombiliti Prescribing Information for a description of additional risks for Pombiliti. (5.2)

5.1 Embryo-Fetal Toxicity Based on findings from animal reproduction studies, OPFOLDA in combination with Pombiliti may cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. In a rabbit embryo-fetal development study, great vessel and cardiac malformations were increased in offspring of pregnant rabbits treated with oral miglustat in combination with cipaglucosidase alfa-atga at 3-fold and 16-fold, respectively, the maximum recommended human dose (MRHD) based on plasma AUC exposure. Verify the pregnancy status in females of reproductive potential prior to initiating treatment with OPFOLDA in combination with Pombiliti. Advise females of reproductive potential to use effective contraception during treatment with OPFOLDA in combination with Pombiliti and for at least 60 days after the last dose [see Use in Specific Populations (8.1, 8.3) ] .

5.2 Risks Associated with Pombiliti OPFOLDA must be administered in combination with Pombiliti. Refer to the Pombiliti Prescribing Information for a description of additional risks for Pombiliti including, but not limited to, the warnings and precautions for Pombiliti.

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.

Lactation: Breastfeeding not recommended. (8.2)

8.1 Pregnancy Risk Summary Based on findings from animal reproduction studies, OPFOLDA in combination with Pombiliti may cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. In a rabbit embryo-fetal development study, great vessel and cardiac malformations were increased in offspring of pregnant rabbits treated with miglustat in combination with cipaglucosidase alfa-atga at 3-fold and 16-fold, respectively, the MRHD of OPFOLDA and Pombiliti based on plasma AUC exposure. A No Observed Adverse Effect Level (NOAEL) was not identified for the combination. In a pre- and post-natal development study in rats, increases in pup mortality were seen following maternal treatment with miglustat in combination with cipaglucosidase alfa-atga (400 mg/kg), or with cipaglucosidase alfa-atga (400 mg/kg) alone. The NOAEL for cipaglucosidase alfa-atga alone is 150 mg/kg (5-fold the Pombiliti MRHD margin). A NOAEL for the combination was not identified. Margins at the lowest observed adverse effect level (LOAEL), relative to exposures at the MRHD of OPFOLDA and Pombiliti were 4-fold and 20-fold, respectively, based on plasma AUC exposure ( see Data ). There are no available human data on OPFOLDA in combination with Pombiliti use in pregnant females to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Data Animal Data Reproductive toxicity studies of cipaglucosidase alfa-atga in rats and rabbits included pretreatment with diphenhydramine (DPH) to prevent or minimize hypersensitivity reactions. In a rabbit embryo-fetal development study, 25 mg/kg oral miglustat alone, or in combination with intravenous cipaglucosidase alfa-atga 175 mg/kg, was administered every other day to pregnant females during organogenesis (Gestation Day [GD] 7 through GD 19). Additional experimental groups received cipaglucosidase alfa-atga (30, 70, or 175 mg/kg) with the same dosing frequency during organogenesis. Clusters of great vessel and cardiac malformations were increased in offspring of pregnant rabbits treated with the combination of miglustat and cipaglucosidase alfa-atga at 3-fold and 16-fold the MRHD of OPFOLDA and Pombiliti, respectively, based on plasma AUC exposure. A NOAEL for the combination was not identified. One fetus treated with miglustat alone (25 mg/kg) and one fetus treated with cipaglucosidase alfa-atga alone (175 mg/kg), each showed a similar cluster of these great vessel and cardiac malformations. In a rat embryo-fetal development study, 60 mg/kg oral miglustat alone, or in combination with intravenous cipaglucosidase alfa-atga 400 mg/kg, was administered every other day to pregnant rats during organogenesis (GD 6 through GD 18). Additional experimental groups received cipaglucosidase alfa-atga (75, 150, or 400 mg/kg) with the same dosing frequency during organogenesis. No evidence of adverse effects was noted in pregnant rats or their offspring in any experimental group. The margin at the NOAEL for miglustat (60 mg/kg) was 4-fold the OPFOLDA MRHD based on plasma AUC exposure. The margin at the NOAEL for cipaglucosidase alfa-atga (400 mg/kg) was 20-fold the Pombiliti MRHD based on plasma AUC exposure. In a pre-and post-natal development study in rats, 60 mg/kg oral miglustat alone, or in combination with intravenous cipaglucosidase alfa-atga 400 mg/kg, was administered to pregnant females every other day from GD 6 through GD 18, and from Lactation Day (LD) 1 through LD 19. Additional experimental groups received cipaglucosidase alfa-atga (75, 150, or 400 mg/kg) with the same dosing frequency during pregnancy and lactation. Maternal and pup mortality were increased with the combination, and pup mortality was also increased with cipaglucosidase alfa-atga 400 mg/kg alone. The NOAEL for cipaglucosidase alfa-atga alone is 150 mg/kg (5-fold the Pombiliti MRHD margin). A NOAEL was not identified for the combination, for which LOAEL margins at the MRHD of OPFOLDA and Pombiliti were 4-fold and 20-fold, respectively, based on plasma AUC exposure.

8.2 Lactation Risk Summary There are no data on the presence of miglustat, alone or in combination with cipaglucosidase alfa-atga, in human milk, the effects on the breastfed infant, or the effects on milk production. Miglustat is present in animal milk (see Data ) . When a drug is present in animal milk, it is likely that the drug will be present in human milk. Based on findings in animal studies, the use of OPFOLDA in combination with Pombiliti may lead to serious adverse reactions in breastfed infants. Advise females that breastfeeding is not recommended while on treatment with OPFOLDA in combination with Pombiliti. Data Evaluation of milk in rats from the pre- and post-natal development study of miglustat in combination with cipaglucosidase alfa-atga (60 mg/kg and 400 mg/kg, respectively) showed secretion of miglustat and excretion of cipaglucosidase alfa-atga in rat milk. In this study, the ratio of miglustat exposure in rat milk to the miglustat exposure in rat plasma was 1.7, and the ratio of cipaglucosidase alfa-atga exposure in rat milk to the cipaglucosidase alfa-atga exposure in rat plasma was <4%. The concentration of drug in animal milk does not necessarily predict the concentration of drug in human milk.

8.3 Females and Males of Reproductive Potential OPFOLDA in combination with Pombiliti may cause embryo-fetal harm when administered to a pregnant female [see Use in Specific Populations (8.1) ] . Pregnancy Testing Verify the pregnancy status in females of reproductive potential prior to initiating treatment with OPFOLDA in combination with Pombiliti. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with OPFOLDA in combination with Pombiliti and for at least 60 days after the last dose. Infertility Females Based on preimplantation loss observed in female rats treated with oral miglustat (60 mg/kg) in combination with intravenous cipaglucosidase alfa-atga (400 mg/kg) every other day for 14 days prior to mating and continuing through GD 7, OPFOLDA in combination with Pombiliti may impair human female fertility. A NOAEL for the combination was not identified. The LOAEL margins are 4-fold and 27-fold the MRHD for OPFOLDA and Pombiliti, respectively. It is not known whether this preimplantation loss in female rats would be sustained if dosing with the combination were discontinued prior to mating [see Nonclinical Toxicology (13.1) ] . Males Based on reversible increases in preimplantation loss in male rats treated with the combination every other day for 28 days prior to mating, OPFOLDA in combination with Pombiliti may impair human male fertility. A NOAEL for the combination was not identified. The LOAEL margins are 4-fold and 27-fold the MRHD for OPFOLDA and Pombiliti, respectively [see Nonclinical Toxicology (13.1) ] . For additional information about male fertility with the use of Pombiliti, see the Pombiliti Prescribing Information.

8.4 Pediatric Use Safety and effectiveness of OPFOLDA in combination with Pombiliti have not been established in pediatric patients with late-onset Pompe disease.

8.5 Geriatric Use Of the total number of patients treated with OPFOLDA in combination with Pombiliti in clinical trials for LOPD, 17 (11%) were 65 to 74 years of age, and none were 75 years of age and older [see Clinical Studies (14) ] . Clinical trials of OPFOLDA in combination with Pombiliti did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

8.6 Renal Impairment Plasma concentrations of miglustat increased in patients with renal impairment [see Clinical Pharmacology (12.3) ] . […]

Miglustat binds with, stabilizes, and reduces inactivation of cipaglucosidase alfa-atga in the blood after infusion. The bound miglustat is dissociated from cipaglucosidase alfa-atga after it is internalized and transported into lysosomes. Miglustat alone has no pharmacological activity in cleaving glycogen.