ct rate of 2.7% in the U.S. reference population of theMACDP. The preva lence of defects in live births was 3.0% (95% CI: 2.6% to 3.5%) followingfirst trimester exposure to lamivudine-containing regimens and 2.9% (95% CI: 2.5%, 3.3%)following second/third trimester exposure to lamivudine-containing regimens.
Lamivudine pharmacokinetics were studied in pregnant women during 2 clinical trials conductedin South Africa. The trials assessed pharmacokinetics in 16 women at 36 weeks’ gestation usinglamivudine 150 mg twice daily with zidovudine, 10 women at 38 weeks’ gestation usinglamivudine 150 mg twice daily with zidovudine, and 10 women at 38 weeks’ gestation usinglamivudine 300 mg twice daily without other antiretrovirals. These trials were not designed orpowered to provide efficacy information. Lamivudine concentrations were generally similar inmaternal, neonatal, and umbilical cord serum samples. In a subset of subjects, amniotic fluid
specimens were collected following natural rupture of membranes and confirmed thatlamivudine crosses the placenta in humans. Based on limited data at delivery, median (range)amniotic fluid concentrations of lamivudine were 3.9-fold (1.2- to 12.8-fold) greater comparedwith paired maternal serum concentration (n = 8).
Animal Data: Dolutegravir: Dolutegravir was administered orally to pregnant rats and rabbits(up to 1,000 mg/kg/day) on Gestation Days 6 to 17 and 6 to 18, respectively, and also to rats onGestation Day 6 to Lactation/Postpartum Day 20. No adverse effects on embryo-fetal (rats andrabbits) or pre/postnatal (rats) development were observed up to the highest dose tested. Duringorganogenesis, systemic exposures (AUC) to dolutegravir in rabbits were less than the exposure
in humans at the RHD and in rats were approximately 50 times the exposure in humans at theRHD. In the rat pre/postnatal development study, decreased body weight of the developingoffspring was observed during lactation at a maternally toxic dose (approximately 50 timeshuman exposure at the RHD).
Lamivudine: Lamivudine was administered orally to pregnant rats (at 90, 600, and
4,000 mg/kg/day) and rabbits (at 90, 300 and 1,000 mg/kg/day and at 15, 40, and 90 mg/kg/day)during organogenesis (on Gestation Days 7 through 16 [rat] and 8 through20 [rabbit]).
Noevidence of fetal malformations due to lamivudine was observed in rats and rabbits at dosesproducing plasma concentrations (Cmax) approximately 35 times higher than human exposure atthe RHD. Evidence of early embryolethality was seen in the rabbit at systemic exposures (AUC)similar to those observed in humans, but there was no indication of this effect in the rat at plasma concentrations (Cmax) 35 times higher than human exposure at the RHD. Studies in pregnant rats
showed that lamivudine is transferred to the fetus through the placenta. In the fertility/pre- andpostnatal development study in rats, lamivudine was administered orally at doses of 180, 900,and 4,000 mg/kg/day (from prior to mating through Postnatal Day 20). In the study, developmentof the offspring, including fertility and reproductive performance, was not affected by thematernal administration of lamivudine.
8.2 Lactation
Risk Summary
The Centers for Disease Control and Prevention recommends that HIV-1–infected mothers in theUnited States not breastfeed their infants to avoid risking postnatal transmission of HIV-1infection.
Lamivudine, a component of DOVA |
