OPFOLDA (opfolda (miglustat) 65 mg) Dailymed

Verify the pregnancy status of females of reproductive potential prior to initiating OPFOLDA in combination with Pombiliti .

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)].

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.

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)].



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.

OPFOLDA in combination with Pombiliti may cause embryo-fetal harm when administered to a pregnant female .

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.

Carcinogenesis The carcinogenicity of OPFOLDA is based on studies from another miglustat product. Below are findings from the carcinogenicity studies with the other miglustat product. Two-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, 5, and 6-fold the MRHD of OPFOLDA 260 mg, respectively, based on body surface area [BSA]) in male mice and at 420 and 500 mg/kg/day (about 5 and 6-fold the MRHD of OPFOLDA 260 mg, respectively, based on BSA) 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, 2, and 4-fold the MRHD of OPFOLDA 260 mg, respectively, based on BSA). Mutagenesis The mutagenicity of OPFOLDA is based on studies from another miglustat product. Below are findings from the carcinogenicity studies with the other miglustat product. Miglustat was not mutagenic or clastogenic in a 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, in studies with another miglustat product. Impairment of Fertility In a fertility study in rats, oral miglustat (60 mg/kg) was administered alone, or in combination with intravenous cipaglucosidase alfa-atga (400 mg/kg), to male and female rats every other day. Dosing in males was initiated 28 days prior to cohabitation with untreated females. Dosing in females was initiated 14 days prior to cohabitation with untreated males and continued through GD 7. Additional experimental groups received intravenous cipaglucosidase alfa-atga alone (75, 150, or 400 mg/kg/day) with the same frequency over the same pre-mating interval (males) or pre-mating and pregnancy interval (females). There was no effect on male or female rat fertility in any experimental group. Treatment of male rats with the combination was associated with increased preimplantation loss that was reversible. Treatment of female rats with the combination, or with miglustat alone, resulted in preimplantation loss; whether this would be reversible if treatment were discontinued prior to cohabitation is unknown. NOAELs were not identified for the combination in either male or female rats. The LOAEL margins for these doses represent 4-fold and 27-fold the MRHD of OPFOLDA and Pombiliti, respectively, based on plasma AUC exposures. The impact of OPFOLDA on fertility is based, in part, on studies from another miglustat product. Below are findings from the fertility studies with the other miglustat product. Fertility studies conducted with another miglustat product showed that male rats, given 20 mg/kg/day miglustat (exposure less than that expected for the MRHD of OPFOLDA 260 mg, based on BSA comparisons, mg/m2) by oral gavage, 14 days prior to mating, had decreased spermatogenesis with altered sperm morphology and motility and decreased fertility. Decreased spermatogenesis was reversible following 6 weeks of miglustat withdrawal in this study. A higher dose of 60 mg/kg/day (2 times the MRHD of OPFOLDA, based on BSA comparisons, mg/m2) resulted in seminiferous tubule and testicular atrophy/degeneration. Female rats were given oral miglustat gavage doses of 20, 60, and 180 mg/kg/day beginning 14 days before mating and continuing through gestation in this study. Effects observed at 20 mg/kg/day (systemic exposure less than the human therapeutic systemic exposure, based on BSA comparisons) included decreased corpora lutea, increased post-implantation loss, and decreased live births.