8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary ella is contraindicated for use during an existing or suspected pregnancy. No signal of concern regarding pregnancy complications was found in postmarketing studies [see Data ]. Isolated cases of major malformations in ella-exposed pregnancies were identified; however, the data are not sufficient to determine a risk for birth defects with inadvertent use of ella during pregnancy. Miscarriage was reported in 14% of the known pregnancy outcomes; a rate that is similar to the U.S background rate for miscarriage. 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. In animal reproduction studies, no malformations were observed during repeated administration of ulipristal acetate to pregnant rats, rabbits and monkeys at daily drug exposures ⅓, ½, and 3 times respectively, the human exposure at a dose of 30 mg [see Data ] . Data Human Data ella pregnancy exposure data was collected in the U.S. and Europe from 1999 to 2015 and analyzed post-marketing using data from interventional clinical trials, observational studies and pharmacovigilance reports. Known pregnancy outcomes were available for 462/784 pregnancies in which wome received ella at doses of 30 mg or greater during the conception cycle or during pregnancy. Data of pregnancies with known outcome were analyzed prospectively for 272 cases and retrospectively for 190 cases. Pregnancy outcomes included 302 elective abortions (2 for fetal anomalies including 1 with trisomy 21), 63 spontaneous abortions, and 13 ectopic pregnancies. No maternal or fetal deaths were reported. 84 pregnancies continued until birth, with congenital anomalies reported in 5 infants, including 4 major malformations (2/4 with genetic syndromes). Although these data do not allow estimation of the prevalence rate of congenital anomalies associated with inadvertent use of ella in pregnancy or determination of a causal relationship between reported anomalies and ella, they show that ella-exposed pregnancies were not associated with a pattern of increased risk of adverse outcomes. Animal Data Ulipristal acetate was administered repeatedly to pregnant rats and rabbits during the period of organogenesis. Embryofetal loss was noted in all pregnant rats and in half of the pregnant rabbits following 12 and 13 days of dosing, at daily drug exposures 1/3 and 1/2 the human exposure, respectively, based on body surface area (mg/m2). There were no malformations of the surviving fetuses in these studies. Adverse effects were not observed in the offspring of pregnant rats administered ulipristal acetate during the period of organogenesis through lactation at drug exposures 1/24 the human exposure based on AUC. Administration of ulipristal acetate to pregnant monkeys for 4 days during the first trimester caused pregnancy termination in 2/5 animals at daily drug exposures 3 times the human exposure based on body surface area. 8.2 Lactation Risk Summary Ulipristal acetate and its active metabolite, monodemethyl-ulipristal acetate, are present in human milk in small amounts (see Data). Based on the levels of drug and active metabolite measured in breastmilk, a fully breastfed child would receive a weight-adjusted dosage of approximately 0.8% of ulipristal acetate and monodemethyl-ulipristal acetate on Day 1 of drug administration and an approximate total of 1% of the maternal dose over a 5-day period after drug administration. There is no information on the effects on the breastfed child or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ella and any potential adverse effects on the breastfed child from ella or from the underlying maternal condition Data The breast milk of 12 lactating women following administration of ella was collected in 24-hour increments to measure the concentrations of ulipristal acetate and the active metabolite monodemethyl-ulipristal acetate in breast milk. The mean daily concentrations of ulipristal acetate in breast milk were 22.7 ng/mL [0-24 hours], 2.96 ng/mL [24-48 hours], 1.56 ng/mL [48-72 hours], 1.04 ng/mL [72-96 hours], and 0.69 ng/mL [96-120 hours]. The mean daily concentrations of monodemethyl-ulipristal acetate in breast milk were 4.49 ng/mL [0-24 hours], 0.62 ng/mL [24-48 hours], 0.28 ng/mL [48-72 hours], 0.17 ng/mL [72-96 hours], and 0.10 ng/mL [96-120 hours]. Using these data, a fully breastfed infant would receive approximately 4.1 mcg/kg of ulipristal acetate and monodemethyl-ulipristal acetate on Day 1 following drug administration and approximately 5.2 mcg/kg over a five day period following drug administartion. 8.3 Females and Males of Reproductive Potential Contraception ella and progestin-containing contaceptives may interact and decrease the effectivess of both products. Advise females to use a a reliable barrier method for subsequent acts of intercourse until her next menstrual period and to wait at least 5 days after taking ella to resume oral contraceptives [see Warnings and Precautions (5.5), Drug Interactions (7), and Clinical Pharmaclogy (12.2, 12.3)]. 8.4 Pediatric Use Safety and efficacy of ella have been established in women of reproductive age. The clinical trials of ella enrolled 41 females under age 18, and a post-marketing observational study evaluating effectiveness and safety of ella in adolescents enrolled 279 females under age 18, including 76 under age 16 years. In these studies, the safety and efficacy profile observed in adolescents aged 17 and younger was similar to that in adults. Use of ella before menarche is not indicated. 8.5 Geriatric Use This product is not intended for use in postmenopausal women. 8.6 Race While no formal studies have evaluated the effect of race, a cross-study comparison of two pharmacokinetic studies indicated that exposure in South Asians may exceed that in Caucasians and African Americans. However, no difference in efficacy and safety was observed for women of different races in clinical studies. 8.7 Hepatic Impairment No studies have been conducted to evaluate the effect of hepatic disease on the disposition of ella. 8.8 Renal Impairment No studies have been conducted to evaluate the effect of renal disease on the disposition of ella.