Invirase Pregnancy and Lactation label updates

December 19, 2019 The INVIRASE (saquinavir mesylate) tablet label was updated to include revisions to Section 8; USE IN SPECIFIC POPULARIONS: subsections 8.1, Pregnancy and 8.2 Lactation as follows: 8             USE IN SPECIFIC POPULATIONS 8.1          Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to antiretrovirals 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 APR are not sufficient to adequately assess a drug-associated risk of birth defects or fetal outcomes. Limited number of reports on the use of saquinavir during pregnancy has been submitted to the APR and the number of exposures to saquinavir is insufficient to make a risk assessment compared to a reference population. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background rate for major birth defects is 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The estimated rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in the U.S. general population is 15–20%. In animal reproduction studies with saquinavir, no evidence of adverse developmental effects were observed at the highest achievable plasma exposures (AUC) in both rats and rabbits, resulting in exposures approximately 25% of those obtained in humans at the recommended human dose (RHD) combined with ritonavir. Saquinavir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus (see Data). Data Human Data Based on prospective reports to the APR following exposure to saquinavir-containing regimens, there were 7 birth defects reported in 183 first trimester exposures and 9 birth defects reported in 221 second and third trimester exposures. Insufficient numbers of pregnancies with exposure to saquinavir have been reported to the APR to calculate the prevalence (95% CI) or for a detailed assessment about the risk of saquinavir with regard to birth defects in this population. The background rate for major birth defects is 2.7% in a U.S. reference population of the MACDP. Prospective reports from the APR of overall major birth defects in pregnancies exposed to saquinavir are compared with the U.S. background major birth defect rate. Methodological limitations of the APR include the use of the MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations as well as confounding due to the underlying disease. Animal Data In animal reproduction studies, no evidence of harm to the fetus was detected when saquinavir was administered orally to pregnant rats and rabbits twice-daily during the period of organogenesis at dose levels up to 1200 (rats) or 1000 (rabbits) mg/kg/day. However, because of limited bioavailability of saquinavir in animals and/or dosing limitations, plasma exposures (AUC) in these species were only 29% (rat) and 21% (rabbits) of those obtained in humans at the RHD combined with ritonavir. In a pre- and postnatal development study, saquinavir was administered orally to pregnant rats (up to 1600 mg/kg/day) from gestation day 15 to post-partum day 20. No adverse effects were observed in the offspring exposed daily from before birth through lactation at maternal exposures (AUC) approximately 27% of those obtained in humans at the RHD combined with ritonavir. 8.2          Lactation The Centers for Disease Control and Prevention recommends that HIV‑infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1. There are no data available regarding the presence of saquinavir in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants) and (3) adverse reactions in breastfed infants similar to those seen in adults, instruct mothers not to breastfeed if they are receiving INVIRASE.

The updated label will soon be available at Drugs@FDA or DailyMed Kimberly Struble Division of Antivirals Food and Drug Administration Elizabeth Thompson Division of Antivirals Food and Drug Administration Michael Stanfield Jr. Division of Antivirals Food and Drug Administration