Prezista Use In Pregnancy & Lactation

Pregnancy: Risk Summary: Available limited data from the Antiretroviral Pregnancy Registry (APR) show no difference in rate of overall birth defects for darunavir (2.7%) 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]. The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks gestation.
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 15-20%. The background risk of major birth defects and miscarriage for the indicated population is unknown.
Studies in animals did not show evidence of developmental toxicity. Exposures (based on AUC) in rats were 3-fold higher, whereas in mice and rabbits, exposures were lower (less than 1-fold) than human exposures at the recommended daily dose [see Data].
Clinical Considerations: No dose adjustment is required for darunavir/ritonavir during pregnancy and postpartum. PREZISTA/ritonavir should be used during pregnancy only if the potential benefit justifies the potential risk.
Data: Human Data: PREZISTA/ritonavir (600/100 mg twice daily or 800/100 mg once daily) in combination with a background regimen was evaluated in a clinical trial of 36 pregnant women during the second and third trimesters, and postpartum. Eighteen subjects were enrolled in each BID and QD treatment arms. Twenty-nine subjects completed the trial through the postpartum period (6-12 weeks after delivery) and 7 subjects discontinued before trial completion, 5 subjects in the BID arm and 2 subjects in the QD arm.
The pharmacokinetic data demonstrate that exposure to darunavir and ritonavir as part of an antiretroviral regimen was lower during pregnancy compared with postpartum (6-12 weeks). Exposure reductions during pregnancy were greater for the once daily regimen as compared to the twice daily regimen [see Pharmacology: Pharmacokinetics under Actions].
Virologic response was preserved. In the BID arm, the proportion of subjects with HIV‑1 RNA <50 copies/mL were 39% (7/18) at baseline, 61% (11/18) through the third trimester visit, and 61% (11/18) through the 6-12 week postpartum visit. Virologic outcomes during the third trimester visit showed HIV-1 RNA ≥50 copies/mL for 11% (2/18) of subjects and were missing for 5 subjects (1 subject discontinued prematurely due to virologic failure). In the QD arm, the proportion of subjects with HIV-1 RNA <50 copies/mL were 61% (11/18) at baseline, 83% (15/18) through the third trimester visit, and 78% (14/18) through the 6‑12 week postpartum visit. Virologic outcomes during the third trimester visit showed HIV-1 RNA ≥50 copies/mL for none of the subjects and were missing for 3 subjects (1 subject discontinued prematurely due to virologic failure).
PREZISTA/ritonavir was well tolerated during pregnancy and postpartum. There were no new clinically relevant safety findings compared with the known safety profile of PREZISTA/ritonavir in HIV-1-infected adults.
Among the 31 infants with HIV test results available data, born to the 31 HIV-infected pregnant women who completed trial through delivery or postpartum period, all 31 infants had test results that were negative for HIV-1 at the time of delivery and/or through 16 weeks postpartum. All 31 infants received antiretroviral prophylactic treatment containing zidovudine.
Based on prospective reports to the APR of 615 live births following exposure to darunavir-containing regimens during pregnancy (including 385 exposed in the first trimester and 230 exposed in the second/third trimester), there was no difference in rate of overall birth defects for darunavir compared with the background rate for major birth defects in a U.S. reference population of the MACDP.
The prevalence of birth defects in live births was 2.6% (95% CI: 1.2% to 4.7%) with first trimester exposure to darunavir containing regimens and 1.7% (95% CI: 0.5% to 4.4%) with second/third trimester exposure to darunavir containing regimens.
Animal Data: Reproduction studies conducted with darunavir showed no embryotoxicity or teratogenicity in mice (doses up to 1000 mg/kg from gestation day (GD) 6-15 with darunavir alone) and rats (doses up to 1000 mg/kg from GD 7-19 in the presence or absence of ritonavir) as well as in rabbits (doses up to 1000 mg/kg/day from GD 8-20 with darunavir alone). In these studies, darunavir exposures (based on AUC) were higher in rats (3-fold), whereas in mice and rabbits, exposures were lower (less than 1-fold) compared to those obtained in humans at the recommended clinical dose of darunavir boosted with ritonavir.
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 are no data on the presence of darunavir in human milk, the effects on the breastfed infant, or the effects on milk production. Darunavir is present in the milk of lactating rats [see Data]. Because of the potential for (1) HIV transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants) and (3) serious adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving PREZISTA [see Use in Children under Precautions].
Data: Animal Data: Studies in rats (with darunavir alone or with ritonavir) have demonstrated that darunavir is secreted in the milk. In the rat pre- and postnatal development study, a reduction in pup body weight gain was observed due to exposure of pups to drug substances via milk. The maximal maternal plasma exposures achieved with darunavir (up to 1000 mg/kg with ritonavir) were approximately 50% of those obtained in humans at the recommended clinical dose with ritonavir.
Females and Males of Reproductive Potential: Contraception: Use of PREZISTA may reduce the efficacy of combined hormonal contraceptives and the progestin only pill. Advise patients to use an effective alternative (non-hormonal) contraceptive method or add a barrier method of contraception. For co-administration with drospirenone, clinical monitoring is recommended due to the potential for hyperkalemia [see Interactions].