8.1Pregnancy Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to fosamprenavir during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary Limited data are available for use of fosamprenavir in pregnancy. Fosamprenavir 700 mg twice daily taken with ritonavir 100 mg twice daily should only be considered in pregnant patients who are already on a stable twice-daily regimen of fosamprenavir/ritonavir 700 mg/100 mg prior to pregnancy, and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) (see Clinical Considerations and Data ).
There are insufficient human data on the use of fosamprenavir during pregnancy to adequately assess a drug-associated risk for birth defects and miscarriage. Given the limited number of pregnancies exposed to fosamprenavir-based regimens, no conclusions can be drawn on the safety of fosamprenavir in pregnancy. The background risk for major birth defects and miscarriage for the indicated population is unknown. The background rate for major birth defects in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) is 2.7% (see Data ) .
The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. In animal reproduction studies, no evidence of major adverse developmental outcomes was observed following oral administration of fosamprenavir. Systemic exposure to amprenavir (the active ingredient) was less than (rabbits) or up to 2 times (rats) those in humans at the maximum recommended human dose (MRHD) with or without ritonavir.
In contrast, oral administration of amprenavir was associated with abortions in pregnant rabbits at doses that produced approximately one-twentieth the human exposure at the MRHD. In the rat pre- and postnatal development study, toxicities to the offspring, including reduced survival and reproductive performance, were observed at maternal systemic exposures (AUC) to amprenavir that were approximately 2 times the exposure in humans at the MRHD of fosamprenavir alone or approximately the same as those seen in humans following administration of the MRHD of fosamprenavir in combination with ritonavir (see Data ).
Clinical Considerations Virologic Monitoring During Pregnancy and the Postpartum Period Based on limited data on the use of fosamprenavir during pregnancy, no dosage adjustments are required for pregnant patients who are already on a stable twice-daily regimen of fosamprenavir 700 mg taken with ritonavir 100 mg prior to pregnancy, and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) [see Dosage and Administration (2.3) , Clinical Pharmacology (12.3) ] .
In a clinical trial of 10 HIV-1–infected pregnant women treated with fosamprenvir 700 mg taken with ritonavir 100 mg twice daily through postpartum, total amprenavir exposures were lower during pregnancy compared with the postpartum period. Therefore, viral load should be monitored closely to ensure viral suppression is maintained [see Data , Dosage and Administration (2.2) , Clinical Pharmacology (12.3) ] . Pregnancy data with other dosage regimens of fosamprenavir (with or without ritonavir) are not available.
Data Human Data Fosamprenavir 700 mg taken with ritonavir 100 mg twice daily in combination with a background regimen was evaluated in a clinical trial of 10 HIV-1–infected pregnant women during the second and third trimesters and postpartum. Subjects initiated fosamprenavir/ritonavir during pregnancy at a median of 19 weeks’ gestation; 4 had undetectable HIV-1 RNA viral load (less than 50 copies/mL) at the time of initiation.
Amprenavir pharmacokinetics and placental transfer were studied during the second trimester (n = 6) or third trimester (n = 9) and postpartum (n = 9). Pregnancy outcomes were available for all 10 subjects, among which 1 twin pregnancy was included. Compared to the postpartum period, geometric mean amprenavir AUC was 35% lower in the second trimester and 25% lower in the third trimester. The amprenavir geometric mean ratio (95% CI) of fetal cord to maternal peripheral plasma concentration (n = 7) was 0.27 (0.24 to 0.30) [see Clinical Pharmacology (12.3) ].
At delivery, 9 subjects had HIV-1 viral load less than 50 copies/mL, and 1 subject had a viral load of 111 copies/mL. All 11 infants born had test results that were negative for HIV-1 at the time of delivery and through 12 months postpartum. There were no new safety findings compared with the known safety profile of fosamprenavir/ritonavir in HIV-1–infected adults. Based on prospective reports to the APR of approximately 146 live births following exposure to fosamprenavir-containing regimens, there were 2 birth defects reported in 109 first trimester exposures and 2 birth defects reported in 36 second and third trimester exposures.
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 fosamprenavir are compared with the U.S. background major birth defect rate. Methodological limitations of the APR include the use of 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 Fosamprenavir was administered orally to pregnant rats (300, 820, or 2,240 mg per kg per day) and rabbits (74.8, 224.3, or 672.8 mg per kg per day) on Gestation Days 6 to 17 and Days 7 to 20, respectively. No major adverse effects on embryo-fetal development were observed at these dose levels, resulting in exposures (AUC 0-24 h ) approximately 2 times (rats) and 0.8 times (rabbits) human exposures at the MRHD of fosamprenavir alone or 0.7 times (rats) and 0.3 times (rabbits) human exposures at the MRHD of fosamprenavir in combination with ritonavir.
However, increased incidence of abortion was observed in rabbits administered a maternally toxic dose of fosamprenavir (672.8 mg per kg per day). In a study where amprenavir was administered orally to pregnant rabbits (25, 50, or 100 mg per kg per day) on Gestation Days 8 to 20, increased abortions and an increased incidence of minor skeletal variations (deficient ossification of the femur, humerus, and trochlea) were observed at doses that produced approximately one-twentieth the exposure seen at the MRHD.
In the rat pre- and postnatal development study, fosamprenavir was administered orally (300, 820, or 2,240 mg per kg per day) on Gestation Day 6 to Lactation/Postpartum Day 20. Fosamprenavir caused a reduction in pup survival and body weights. In surviving female offspring from the high-dose group, an increased time to successful mating, an increased length of gestation, a reduced number of uterine implantation sites per litter, and reduced gestational body weights were observed.
Systemic exposure (AUC 0-24 h ) to amprenavir in rats was approximately 2 times the exposures in humans at the MRHD of fosamprenavir alone or approximately the same as those seen in humans at the MRHD of fosamprenavir in combination with ritonavir.
