Delgocitinib

8.1 Pregnancy Risk Summary The available data on the use of topical delgocitinib during pregnancy is insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal reproduction studies, oral administration of delgocitinib to pregnant rats and rabbits during the period of organogenesis did not result in adverse developmental effects at doses 120 or 193 times, respectively, the maximum recommended human dose (MRHD) based on AUC comparison (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%-4% and 15%-20%, respectively. Data Animal Data In embryofetal development studies, delgocitinib was administered orally to pregnant rats or rabbits during the period of organogenesis at doses of 3, 10, and 30 mg/kg/day in rats, and 1, 3 and 10 mg/kg/day in rabbits, respectively. In rats, no significant maternal toxicity was noted at doses up to 30 mg/kg/day (1446 times the MRHD based on AUC comparison).

Decreases in fetal weight and skeletal variations were observed at doses ≥10 mg/kg/day (512 times the MRHD based on AUC comparison). An increase in post-implantation loss was observed at 30 mg/kg/day (1446 times the MRHD based on AUC comparison). No embryofetal toxicity was noted at 3 mg/kg/day (120 times the MRHD based on AUC comparison). In rabbits, no significant maternal toxicity was noted at doses up to 10 mg/kg/day (992 times the MRHD based on AUC comparison). An increase in post-implantation loss, reduced number of live fetuses, and decrease in fetal weights were observed at 10 mg/kg/day (992 times the MRHD based on AUC comparison).

No embryofetal toxicity was noted at 3 mg/kg/day (193 times the MRHD based on AUC comparison). In a pre- and post-natal development study in pregnant rats, delgocitinib was orally administered at doses of 3, 10, and 30 mg/kg/day from gestation day 7 to lactation day 20. No significant maternal toxicity was noted at 30 mg/kg/day (1555 times the MRHD based on AUC comparison). Extended gestation period, a decrease in the birth index, and an increase in the number of dead newborns were observed at 30 mg/kg/day (1555 times the MRHD based on AUC comparison). Decreased fetal viability and reduced pup weights were noted during the early postnatal period at 30 mg/kg/day…