8 USE IN SPECIFIC POPULATIONS Lactation: Nursing mothers should be instructed not to breastfeed due to the potential for postnatal HIV transmission. (8.2) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to EVOTAZ during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary Prospective pregnancy data from the Antiretroviral Pregnancy Registry (APR) are not sufficient to adequately assess the risk of birth defects or miscarriage. Cobicistat use in women during pregnancy has not been evaluated; however, atazanavir use during pregnancy has been evaluated in a limited number of women. The pharmacokinetics of EVOTAZ have not been evaluated in pregnant patients. Available data from the APR show no difference in the risk of overall major birth defects for atazanavir compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) [see Data]. In animal reproduction studies, no evidence of adverse developmental outcomes was observed following oral administration of the components of EVOTAZ (atazanavir or cobicistat) to pregnant rats and rabbits [see Data]. During organogenesis in the rat and rabbit, atazanavir exposures (AUC) were similar to those observed at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir), while exposures were up to 1.4 (rats) and 3.3 (rabbits) times human exposures at the maximal recommended human dose (MRHD) of 150 mg [see Data]. 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. Clinical Considerations Dose Adjustment During Pregnancy and the Postpartum Period Dosing recommendations cannot be made because the pharmacokinetics, safety, and efficacy of EVOTAZ cannot be predicted from studies of other atazanavir-containing products in pregnant women. Maternal Adverse Reactions Atazanavir Cases of lactic acidosis syndrome, sometimes fatal, and symptomatic hyperlactatemia have occurred in pregnant women using atazanavir in combination with nucleoside analogues, which are associated with an increased risk of lactic acidosis syndrome. Hyperbilirubinemia occurs frequently in patients who take atazanavir, including pregnant women. Refer to the atazanavir prescribing information for use of atazanavir in pregnancy. Advise pregnant women of the potential risks of lactic acidosis syndrome and hyperbilirubinemia. Fetal/Neonatal Adverse Reactions Atazanavir All infants, including neonates exposed to atazanavir in utero, should be monitored for the development of severe hyperbilirubinemia during the first few days of life. Advise pregnant women of the potential risk to newborn infants. Refer to the atazanavir prescribing information for use of atazanavir in pregnancy. Data Human Data Atazanavir Based on prospective reports from the interim APR of approximately 1600 live births following exposure to atazanavir-containing regimens (including 1037 live births in infants exposed in the first trimester and 569 exposed in second/third trimesters), there was no difference in the overall rate for birth defects for atazanavir (2.3%) compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. Based on prospective reports to the APR, the prevalence of birth defects in live births was 2.1% following first trimester exposure to atazanavir-containing regimens. Cobicistat Insufficient numbers of pregnancies with exposure to cobicistat have been reported to the APR to estimate the rate of birth defects. Animal Data Atazanavir Atazanavir was administered orally to pregnant rats (at 0, 200, 600, and 1920 mg/kg/day) and rabbits (at 0, 4, 15, and 60 mg/kg/day) during organogenesis (on gestation Days 6 through 15 and 7 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with atazanavir at exposures (AUC) approximately 1.2 times higher (rats) and 0.7 times (rabbits) human exposures at the MRHD. In a rat pre- and postnatal developmental study, atazanavir was administered orally at doses of 0, 50, 220, and 1000 mg/kg/day from gestation Day 6 to postnatal Day 20. At a maternal toxic dose (1000 mg/kg/day), atazanavir caused body weight loss or weight gain suppression in the animal offspring at atazanavir exposures (AUC) of approximately 1.3 times higher than human exposures at the MRHD. Cobicistat Cobicistat was administered orally to pregnant rats at doses of 0, 25, 50, 125 mg/kg/day on gestation Day 6 to 17. Maternal toxicity was noted at 125 mg/kg/day and was associated with increases in post-implantation loss and decreased fetal weights. No malformations were noted at doses up to 125 mg/kg/day. Systemic exposures (AUC) at 50 mg/kg/day in pregnant females were 1.4 times higher than the human exposures at the MRHD. In pregnant rabbits, cobicistat was administered orally at doses of 0, 20, 50, and 100 mg/kg/day during the gestation Days 7 to 20. No maternal or embryo/fetal effects were noted at the highest dose of 100 mg/kg/day. Systemic exposures (AUC) at 100 mg/kg/day were 3.3 times higher than exposures at the MRHD. In a pre- and postnatal developmental study in rats, cobicistat was administered orally at doses of 0, 10, 30, and 75 mg/kg from gestation Day 6 to postnatal Day 20, 21, or 22. At doses of 75 mg/kg/day of cobicistat, neither maternal nor developmental toxicity was noted. Systemic exposures (AUC) at this dose were 0.9 times lower than exposures at the MRHD. 8.2 Lactation Risk Summary The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. There is no information regarding the effects of EVOTAZ on the breastfed infant or on milk production. Atazanavir has been detected in human milk. No data are available regarding atazanavir effects on milk production. Cobicistat is present in rat milk [see Data]. There is no information regarding the presence of cobicistat in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for (1) HIV transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant, instruct women not to breastfeed. Data Animal Data Cobicistat: During the prenatal and postnatal development toxicology study at doses up to 75 mg/kg/day, mean cobicistat milk to plasma ratio of up to 1.9 was measured 2 hours after administration to rats on lactation Day 10. 8.4 Pediatric Use Atazanavir, a component of EVOTAZ, is not recommended for use in pediatric patients below the age of 3 months due to the risk of kernicterus. The safety and efficacy of EVOTAZ in pediatric patients 3 months to less than 18 years of age have not been established. 8.5 Geriatric Use Clinical studies with the components of EVOTAZ did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients. In general, appropriate caution should be exercised in the administration and monitoring of EVOTAZ in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)]. 8.6 Renal Impairment EVOTAZ is not recommended for use in HIV-treatment-experienced patients with end-stage renal disease managed with hemodialysis [see Dosage and Administration (2.3), Warnings and Precautions (5.3), and Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment EVOTAZ is not recommended for use in patients with any degree of hepatic impairment [see Dosage and Administration (2.4), Warnings and Precautions (5.7) , and Clinical Pharmacology (12.3)].