Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to EDURANT during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) 1-800-258-4263.

Risk Summary

Available data from the APR show no difference in the overall risk of birth defects for rilpivirine compared with the background rate for major birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population (see Data) . The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The background risk for major birth defects and miscarriage for the indicated population is unknown. Methodologic limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at <20 weeks gestation. In a clinical trial, total rilpivirine exposures were generally lower during pregnancy compared to the postpartum period (see Data) . 

In animal reproduction studies, no adverse developmental outcomes were observed when rilpivirine was administered orally at exposures up to 15 (rats) and 70 (rabbits) times the exposure in humans (≥12 years of age and weighing at least 32 kg) at the recommended dose of 25 mg once daily (see Data) . 

Clinical Considerations

Dosing During Pregnancy and the Postpartum Period

Based on the experience of HIV-1-infected pregnant women who completed a clinical trial through the postpartum period with a rilpivirine-based regimen, no dose adjustments are required for pregnant patients who are already on a stable EDURANT regimen prior to pregnancy and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) [see Dosage and Administration (2.5)]. Lower exposures of rilpivirine were observed during pregnancy, therefore viral load should be monitored closely [see Clinical Pharmacology (12.3)] . 

Data

Human Data

Based on prospective reports to the APR of over 550 exposures to rilpivirine during the first trimester of pregnancy resulting in live births, there was no significant difference between the overall risk of birth defects with rilpivirine compared to the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 1.4% (95% CI: 0.6% to 2.8%) and 1.5% (95% CI: 0.3% to 4.3%) following first and second/third trimester exposure, respectively, to rilpivirine-containing regimens.

Rilpivirine in combination with a background regimen was evaluated in a clinical trial of 19 HIV-1 infected pregnant women during the second and third trimesters and postpartum. Each of the women were on a rilpivirine-based regimen at the time of enrollment. Twelve subjects completed the trial through the postpartum period (6–12 weeks after delivery) and pregnancy outcomes are missing for six subjects. The exposure (C 0hand AUC) of total rilpivirine was approximately 30 to 40% lower during pregnancy compared with postpartum (6 to 12 weeks). The protein binding of rilpivirine was similar (>99%) during second trimester, third trimester, and postpartum period. One subject discontinued the trial following spontaneous termination of the pregnancy at 25 weeks gestation due to suspected premature rupture of membranes. Among the 12 subjects who were virologically suppressed at baseline (less than 50 copies/mL), virologic response was preserved in 10 subjects (83.3%) through the third trimester visit and in 9 subjects (75%) through the 6–12 week postpartum visit. Virologic outcomes during the third trimester visit were missing for two subjects who were withdrawn (one subject was nonadherent to the study drug and one subject withdrew consent). Among the 10 infants with HIV test results available, born to 10 HIV-infected pregnant women, all had test results that were negative for HIV-1 at the time of delivery and up to 16 weeks postpartum. All 10 infants received antiretroviral prophylactic treatment with zidovudine. Rilpivirine was well tolerated during pregnancy and postpartum. There were no new safety findings compared with the known safety profile of rilpivirine in HIV–1-infected adults. 

Animal Data

Rilpivirine was administered orally to pregnant rats (40, 120, or 400 mg per kg per day) and rabbits (5, 10, or 20 mg per kg per day) through organogenesis (on gestation Days 6 through 17, and 6 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with rilpivirine in rats and rabbits at exposures 15 (rats) and 70 (rabbits) times higher than the exposure in humans (≥12 years of age and weighing >32 kg) at the recommended dose of 25 mg once daily. In a pre- and postnatal development study, rilpivirine was administered orally up to 400 mg/kg/day through lactation. No adverse effects were noted in the offspring at maternal exposures up to 63 times the exposure in humans (≥12 years of age and weighing >32 kg) at the recommended dose of 25 mg daily.