ed malformations were observed after oral administration of tazarotene prior to mating through earlygestation at doses 9 times the MRHD (based on AUC comparison) (see Data).
In animal reproduction studies, increased malformations, including cleft palate and omphalocele, were observed after oraladministration of halobetasol propionate during the period of organogenesis to pregnant rats and rabbits (see Data). The available datado not support relevant comparisons of systemic halobetasol propionate exposures achieved in the animal studies to exposuresobserved in humans after topical use of DUOBRII Lotion.
The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have abackground risk of birth defect, loss, or other adverse outcomes. The background risk in the U.S. general population of major birthdefects is 2 to 4%, and of miscarriage is 15 to 20%, of clinically recognized pregnancies.
Data
Human Data
Available observational studies in pregnant women did not identify a drug-associated risk of major birth defects, preterm delivery, orfetal mortality with the use of topical corticosteroids of any potency. However, when the dispensed amount of potent or very potenttopical corticosteroids exceeded 300 g during the entire pregnancy, maternal use was associated with an increased risk of low birthweight in infants.
Animal Data
Halobetasol propionate has been shown to cause malformations in rats and rabbits when given orally during organogenesis at doses of0.04 to 0.1 mg/kg/day in rats and 0.01 mg/kg/day in rabbits. Halobetasol propionate was embryotoxic in rabbits but not in rats. Cleftpalate was observed in both rats and rabbits. Omphalocele was seen in rats but not in rabbits.
In an embryofetal development study in rats, a tazarotene gel formulation, 0.5% (0.25 mg/kg/day tazarotene ) was topicallyadministered to pregnant rats during gestation days 6 through 17. Reduced fetal body weights and reduced skeletal ossificationoccurred at this dose (11 times the MRHD based on AUC comparison). In an embryofetal development study in rabbits, a tazarotenegel formulation, 0.5%, 0.25 mg/kg/day tazarotene) was topically administered to pregnant rabbits during gestation days 6 through 18.
Single incidences of known retinoid malformations, including spina bifida, hydrocephaly, and heart anomalies were noted at this dose(116 times the MRHD based on AUC comparison).
When tazarotene was given orally to animals, developmental delays were seen in rats; malformations and post-implantation loss wereobserved in rats and rabbits at doses producing 9 and 228 times, respectively, the MRHD (based on AUC comparisons).
In female rats orally administered 2 mg/kg/day of tazarotene from 15 days before mating through gestation day 7, classicdevelopmental effects of retinoids including decreased number of implantation sites, decreased litter size, decreased numbers of livefetuses, and decreased fetal body weights were observed at this dose (16 times the MRHD based on AUC comparison). A lowincidence of retinoid-related malformations was observed at that dose.
In a pre- and postnatal development toxicity study, topical administration of a tazarotene gel formulation (0.125 mg/kg/day) topregnant female rats from gestation day 16 through lactation day 20 reduced pup survival but did not affect the reproductive capacityof the offspring. Based on data from another study, the systemic drug exposur |
