Difamilast

8.1 Pregnancy Risk Summary The available data on the use of topical difamilast during pregnancy are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal reproduction studies, difamilast administered subcutaneously to pregnant rats and rabbits during the period of organogenesis produced no fetal structural abnormalities at doses up to 30 and 3 times the maximum recommended human dose (MRHD), respectively. Difamilast induced increased post-implantation loss, decreased fetal weight, retarded ossification and increased visceral abnormalities in rats at subcutaneous dose 263 times the MRHD.

Difamilast induced increased skeletal variations in rabbits at subcutaneous doses 14 times the MRHD ( see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, and other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an embryo-fetal development study, pregnant rats were dosed subcutaneously during the period of organogenesis with up to 100 mg/kg/day difamilast (263 times the MRHD based on AUC comparison).

Increased post-implantation loss, decreased fetal weight, retarded ossification, and increased visceral abnormalities (membranous ventricular septum defect) were noted at 100 mg/kg/day (263 times the MRHD based on AUC comparison). No embryo-fetal toxicity was observed at 10 mg/kg/day (30 times the MRHD based on AUC comparison). In an embryo-fetal development study in rabbits, pregnant does were dosed subcutaneously during the period of organogenesis with up to 3 mg/kg/day difamilast (14 times the MRHD based on AUC comparison). Increased skeletal variations (increased supernumerary lumbar vertebra) were observed at 3 mg/kg/day (14 times the MRHD based on AUC comparison).

No embryo-fetal toxicity was observed at 1 mg/kg/day (3 times the MRHD based on AUC comparison). In a pre- and post-natal development study in rats, dams were dosed subcutaneously with up to 3 mg/kg/day difamilast during the periods of organogenesis and lactation. No treatment-related adverse effects on reproductive functions of dams, or pre- and post-natal development of offspring were observed at 3 mg/kg/day (13 times the MRHD based on AUC comparison).