8 USE IN SPECIFIC POPULATIONS Safety and effectiveness in pediatric patients below the age of 6 months have not been established. (8.4) 8.1 Pregnancy Risk Summary There are no studies with the use of SKLICE Lotion in pregnant women. Epidemiologic studies with the use of oral ivermectin during pregnancy are insufficient to inform a drug-associated risk of adverse developmental outcomes, because either the timing of administration during gestation was not accurately ascertained or the administration occurred only during the second trimester (see Data). However, systemic exposure from topical use of ivermectin is much lower than that from oral use [see Clinical Pharmacology (12.3)]. In animal reproduction studies, ivermectin induced adverse developmental outcomes when orally administered to pregnant mice, rats and rabbits during the period of organogenesis only at or near doses that were maternally toxic to the pregnant females [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, 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% to 4% and 15% to 20%, respectively. Data Human Data Four published epidemiology studies, all performed in rural Africa to treat soil-transmitted helminths, evaluated pregnancy outcomes in a total of 744 women exposed to oral ivermectin in various stages of pregnancy. In the largest of these studies, 397 women in their second trimester of pregnancy were treated open-label with single doses of oral ivermectin, or ivermectin plus albendazole, for soil-transmitted helminths and compared with a pregnant, non-treated population. No differences in pregnancy outcomes were observed between treated and untreated populations. These studies cannot definitively establish or exclude the absence of any drug-associated risk during pregnancy, because either the timing of administration during gestation was not accurately ascertained or the administration occurred only during the second trimester. Animal Data No comparisons of animal exposure with human exposure are made due to the low systemic exposure noted in the clinical pharmacokinetic study [see Clinical Pharmacology (12.3)]. Systemic embryofetal development studies were conducted in mice, rats and rabbits. Oral doses of ivermectin at 0.1, 0.2, 0.4, 0.8, and 1.6 mg/kg/day were administered during the period of organogenesis to pregnant female mice. Maternal death occurred at 0.4 mg/kg/day and above. Cleft palate occurred in the fetuses from the 0.4, 0.8, and 1.6 mg/kg/day groups. Exencephaly was seen in the fetuses from the 0.8 mg/kg group. Oral doses of ivermectin at 2.5, 5, and 10 mg/kg/day were administered during the period of organogenesis to pregnant female rats. Maternal death and pre-implantation loss occurred at 10 mg/kg/day. Cleft palate and wavy ribs were seen in fetuses from the 10 mg/kg/day group. Oral doses of ivermectin at 1.5, 3, and 6 mg/kg/day were administered during the period of organogenesis to pregnant female rabbits. Maternal toxicity and abortion occurred at 6 mg/kg/day. Cleft palate and clubbed forepaws occurred in the fetuses from the 3 and 6 mg/kg groups. These teratogenic effects were found only at or near doses that were maternally toxic to the pregnant female. Therefore, ivermectin does not appear to be selectively fetotoxic to the developing fetus. 8.2 Lactation Risk Summary There is information available on the presence of ivermectin in human milk in 4 lactating women after a single 150 mcg/kg oral dose of ivermectin. However, there is insufficient information from this study to determine the effects of ivermectin on the breastfed infant or the effects of ivermectin on milk production. Topical ivermectin systemic exposure is much lower than that for oral ivermectin [see Clinical Pharmacology (12.3)]. Furthermore, the amount of ivermectin present in human milk after topical application of SKLICE to lactating women has not been studied. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for SKLICE Lotion and any potential adverse effects on the breastfed infant from SKLICE Lotion or from the underlying maternal condition. Clinical Considerations Advise a lactating woman to avoid accidental transfer of SKLICE Lotion to breast area where the infant might directly ingest the drug. 8.4 Pediatric Use The safety and effectiveness of SKLICE Lotion have been established for pediatric patients 6 months of age and older [see Clinical Pharmacology (12.3) and Clinical Studies (14)]. The safety of SKLICE Lotion has not been established in pediatric patients below the age of 6 months. SKLICE Lotion is not recommended in pediatric patients under 6 months of age because of the potential increased systemic absorption due to a high ratio of skin surface area to body mass and the potential for an immature skin barrier and risk of ivermectin toxicity. 8.5 Geriatric Use Clinical studies of SKLICE Lotion did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.