8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no studies of ADDYI in pregnant women to inform whether there is a drug-associated risk in humans. In animals, fetal toxicity only occurred in the presence of significant maternal toxicity including reductions in weight gain and sedation. Adverse reproductive and developmental effects consisted of decreased fetal weight, structural anomalies and increases in fetal loss at exposures greater than 15 times exposures achieved with the recommended human dosage [see Data]. Animal studies cannot rule out the potential for fetal harm. In the general population (not taking ADDYI), the estimated background risk of major birth defects is 2% to 4% of live births, and the estimated background risk of miscarriage of clinically recognized pregnancies is 15% to 20%. Data Animal Data Pregnant rats were administered flibanserin at doses of 0, 20, 80 and 400 mg/kg/day (3, 15 and 41 times clinical exposures at the recommended human dose based on AUC) during organogenesis. The highest dose was associated with significant maternal toxicity as evidenced by severe clinical signs and marked reductions in weight gain during dosing. In the litters of high-dose dams, there were decreased fetal weights, decreased ossification of the forelimbs and increased number of lumbar ribs, and two fetuses with anophthalmia secondary to severe maternal toxicity. The no adverse effect level for embryofetal toxicity was 80 mg/kg/day (15 times clinical exposure based on AUC). Pregnant rabbits were administered flibanserin at doses of 0, 20, 40 and 80 mg/kg/day (4, 8 and 16 times the clinical exposure at the recommended human dose) during organogenesis. Marked decreases in maternal body weight gain (>75%), abortion and complete litter resorption were observed at 40 and 80 mg/kg/day indicating significant maternal toxicity at these doses. Increases in resorptions and decreased fetal weights were observed at ≥ 40 mg/kg/day. No treatment-related teratogenic effects were observed in fetuses at any dose level. The no adverse effect level for maternal and embryofetal effects was 20 mg/kg/day (3-4 times clinical exposure based on AUC). Pregnant rats were administered flibanserin at doses of 0, 20, 80 and 200 mg/kg/day (3, 15 and ~ 20 times clinical exposures at the recommended human dose) from day 6 of pregnancy until day 21 of lactation to assess for effects on peri- and postnatal development. The highest dose was associated with clinical signs of toxicity in pregnant and lactating rats. All doses resulted in sedation and decreases in body weight gain during pregnancy. Flibanserin prolonged gestation in some dams in all dose groups and decreased implantations, number of fetuses and fetal weights at 200 mg/kg/day. Dosing dams with 200 mg/kg also decreased pup weight gain and viability during the lactation period and delayed opening of the vagina and auditory canals. Flibanserin had no effects on learning, reflexes, fertility or reproductive capacity of the F1 generation. The no adverse effect level for maternal toxicity and peri/postnatal effects was 20 mg/kg/day [see Nonclinical Toxicology (13.1)]. 8.2 Lactation Risk Summary Flibanserin is excreted in rat milk. It is unknown whether flibanserin is present in human milk, whether ADDYI has effects on the breastfed infant, or whether ADDYI affects milk production. Because of the potential for serious adverse reactions including sedation in a breastfed infant, breastfeeding is not recommended during treatment with ADDYI. Reference ID: 4865026