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You are receiving this message as a subscriber to the FDA HIV/AIDS electronic list serve. The purpose of the list serve is to relay important information about HIV/AIDS-related products and issues, including product approvals, significant labeling changes, safety warnings, notices of upcoming public meetings and alerts to proposed regulatory guidances for comment. . On June 17, 2016, FDA approved updates to the Prezista (darunavir) for use in pregnant women. The major changes are outline below. Section 2: DOSAGE AND ADMINISTRATION is revised with addition of testing and dosing in pregnant women. 2.1 Testing Prior to Initiation of PREZISTA/ritonavir
2.4 Recommended Dosage During Pregnancy The recommended dosage in pregnant patients is PREZISTA 600 mg taken with ritonavir 100 mg twice daily with food. PREZISTA 800 mg taken with ritonavir 100 mg once daily should only be considered in certain pregnant patients who are already on a stable PREZISTA 800 mg with ritonavir 100 mg once daily regimen prior to pregnancy, are virologically suppressed (HIV-1 RNA less than 50 copies per mL), and in whom a change to twice daily PREZISTA 600 mg with ritonavir 100 mg may compromise tolerability or compliance. Section 8.1 Pregnancy and 8.2 Lactation was revised as follows 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to PREZISTA during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) 1-800-258-4263. Risk Summary Available limited data from the 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 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 The recommended dosage in pregnant patients is PREZISTA 600 mg taken with ritonavir 100 mg twice daily with food. PREZISTA 800 mg taken with ritonavir 100 mg once daily should only be considered in certain pregnant patients who are already on a stable PREZISTA 800 mg with ritonavir 100 mg once daily regimen prior to pregnancy, are virologically suppressed (HIV-1 RNA less than 50 copies per mL), and in whom a change to twice daily PREZISTA 600 mg with ritonavir 100 mg may compromise tolerability or compliance. 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 34 pregnant women during the second and third trimesters, and postpartum. 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). Virologic response was preserved throughout the trial period in both arms. No mother to child transmission occurred in the infants born to the 29 subjects who stayed on the antiretroviral treatment through delivery. 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 . Based on prospective reports to the APR (through July 2015) of 532 live births following exposure to darunavir-containing regimens during pregnancy (including 333 exposed in the first trimester and 199 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 2.7% (95% CI: 1.2% to 5.1%) with first trimester exposure to darunavir containing regimens and 1.5% (95% CI: 0.3% 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. 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 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 Specific Populations (8.4)]. 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. Section 12 Clinical Pharmacology was updated as follows: Pregnancy and Postpartum The exposure to total darunavir and ritonavir after intake of PREZISTA/ritonavir 600/100 mg twice daily and PREZISTA/ritonavir 800/100 mg once daily as part of an antiretroviral regimen was generally lower during pregnancy compared with postpartum (see Tables 14, Table 15 and Figure 1).
‡ AUC24h is calculated as AUC12h*2
Pharmacokinetics of total darunavir(mean ±SD)
Due to an increase in the unbound fraction of darunavir during pregnancy compared to postpartum, unbound darunavir exposures were less reduced during pregnancy as compared to postpartum. Exposure reductions during pregnancy were greater for the once daily regimen as compared to the twice daily regimen (see Figure 1). Figure 1: Pharmacokinetic Results (Within-Subject Comparison) of Total and Unbound Darunavir After Administration of PREZISTA/ritonavir at 600/100 mg Twice Daily or 800/100 mg Once Daily as Part of an Antiretroviral Regimen, During the 2nd and 3rd Trimester of Pregnancy Compared to Postpartum
Prezista is a product of Janssen Therapeutics. Complete labeling will be available at Drugs@FDA. Richard Klein Kimberly Struble Steve Morin
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