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.