Risk Summary

There are no controlled or large-scale epidemiologic studies with Hydrocortisone Butyrate Lotion in pregnant women, and available data on hydrocortisone butyrate use in pregnant women have not identified a drug associated risk for major birth defects, miscarriages, or adverse maternal or fetal outcomes.

In animal reproduction studies, when administered subcutaneously or topically to pregnant rats, rabbits, and mice, hydrocortisone butyrate induced adverse reproductive and developmental outcomes, including abortion, fetal death, malformation, delayed ossification, decrease in fetal weight, and delay in sexual maturation (see Data). The available data do not allow the calculation of relevant comparisons between the systemic exposure of hydrocortisone butyrate observed in animal studies and the systemic exposure that would be expected in humans after topical use of Hydrocortisone Butyrate Lotion. 

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or 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

Systemic embryofetal development studies were conducted in rats and rabbits. Subcutaneous doses of 0.6, 1.8, and 5.4 mg/kg/day hydrocortisone butyrate were administered to pregnant female rats during gestation days 6 – 17. In the presence of maternal toxicity, fetal effects noted at 5.4 mg/kg/day included increased ossification variations and unossified sternebra. No treatment-related embryofetal toxicity or malformation were noted at 5.4 and 1.8 mg/kg/day, respectively.

Subcutaneous doses of 0.1, 0.2 and 0.3 mg/kg/day hydrocortisone butyrate were administered to pregnant female rabbits during gestation days 7 – 20. Increased abortion was noted at 0.3 mg/kg/day. In the absence of maternal toxicity, a dose-dependent decrease in fetal body weight was noted at doses ≥0.1 mg/kg/day. Embryofetal toxicities (reduction in litter size, decreased number of viable fetuses, and increased post-implantation loss) were noted at doses ≥0.2 mg/kg/day. Additional fetal effects included delayed ossification noted at doses ≥0.1 mg/kg/day and increased fetal malformations (primarily skeletal malformations) noted at doses ≥0.2 mg/kg/day. A dose at which no embryofetal toxicity or malformation was observed was not established in this study.

Additional systemic embryofetal development studies were conducted in rats and mice. Subcutaneous doses of 0.1 and 9 mg/kg/day hydrocortisone butyrate were administered to pregnant female rats during gestation days 9 – 15. In the presence of maternal toxicity, an increase in fetal death and fetal resorption and an increase in ossification of caudal vertebrae were noted at 9 mg/kg/day. No treatment-related embryofetal toxicity or malformation was noted at 0.1 mg/kg/day.

Subcutaneous doses of 0.2 and 1 mg/kg/day hydrocortisone butyrate were administered to pregnant female mice during gestation days 7 – 13. In the absence of maternal toxicity, an increased number of cervical ribs and one fetus with clubbed legs were noted at 1 mg/kg/day. No treatment-related embryofetal toxicity or malformation was noted at 1 and 0.2 mg/kg/day.

No topical embryofetal development studies were conducted with hydrocortisone butyrate lotion. However, topical embryofetal development studies were conducted in rats and rabbits with a hydrocortisone butyrate ointment formulation. Topical doses of 1% and 10% hydrocortisone butyrate ointment were administered to pregnant female rats during gestation days 6 – 15 or pregnant female rabbits during gestation days 6 – 18. A dose-dependent increase in fetal resorption was noted in rabbits and fetal resorptions were noted in rats at the 10% hydrocortisone butyrate ointment dose. No treatment-related embryofetal toxicity was noted at the 1% hydrocortisone butyrate ointment dose in rats. A dose at which no embryofetal toxicity was observed in rabbits after topical administration of hydrocortisone butyrate ointment was not established. No treatment-related malformation was noted at a dose of 10% hydrocortisone butyrate ointment in rats or rabbits.

A peri- and post-natal development study was conducted in rats. Subcutaneous doses of 0.6, 1.8 and 5.4 mg/kg/day hydrocortisone butyrate were administered to pregnant female rats from gestation day 6 to lactation day 20. In the presence of maternal toxicity, a dose-dependent decrease in fetal weight was noted at doses ≥1.8 mg/kg/day. No treatment-related fetal toxicity was noted at 0.6 mg/kg/day. A delay in sexual maturation was noted at 5.4 mg/kg/day. No treatment-related effects on sexual maturation were noted at 1.8 mg/kg/day. No treatment-related effects on behavioral development or subsequent reproductive performance were noted at 5.4 mg/kg/day.