(Last updated: June 7, 2016; last reviewed: June 7, 2016)
Fosamprenavir and amprenavir were neither mutagenic nor clastogenic in a series of in vitro and animal in vivo screening tests. Carcinogenicity studies of fosamprenavir showed an increase in the incidence of hepatocellular adenomas and hepatocellular carcinomas at all doses tested in male mice and at the highest dose tested in female mice. In rats, the incidence of hepatocellular adenomas and thyroid follicular cell adenomas in males (all doses tested) and in females (two highest doses tested) was also increased. Repeat dose studies in rats produced effects consistent with enzyme activation, which predisposes rats, but not humans, to thyroid neoplasms. In rats only, there was an increase in interstitial cell hyperplasia at higher doses and an increase in uterine endometrial adenocarcinoma at the highest dose tested. The incidence of endometrial findings was slightly increased over concurrent controls but was within background range for female rats. Thus, the relevance of the uterine endometrial adenocarcinomas is uncertain. Exposures in the carcinogenicity studies were 0.3- to 0.7 (mice) and 0.7- to 1.4 (rats) times those in humans given 1400 mg twice daily of fosamprenavir alone and were 0.2- to 0.3 (mice) and 0.3- to 0.7 (rats) times those in humans given 1400 mg once daily of fosamprenavir plus 200 mg ritonavir once daily or 0.1- to 0.3 (mice) and 0.3- to 0.6 (rats) times those in humans given 700 mg fosamprenavir plus 100 mg ritonavir twice daily.1
No impairment of fertility or mating was seen in rats at doses providing 3 to 4 times the human exposure to fosamprenavir alone or exposure similar to that with fosamprenavir and ritonavir dosing in humans. No effect was seen on the development or maturation of sperm in rats at these doses.
Human Studies in Pregnancy
Data on fosamprenavir in pregnant women are limited. Fosamprenavir pharmacokinetic (PK) data have been reported in 26 women during pregnancy and postpartum. Following standard dosing with fosamprenavir 700 mg and ritonavir 100 mg, fosamprenavir area under the curve and 12-hour trough concentration were somewhat lower during pregnancy and higher postpartum, compared to historical data. Fosamprenavir exposure during pregnancy appeared to be adequate for patients without protease inhibitor resistance mutations.2 For the postpartum period, potential PK interactions with hormonal contraceptives should be taken into account (see Table 3 in Preconception Counseling and Care).
Placental and Breast Milk Passage
In a small study of women receiving fosamprenavir during pregnancy, the median (range) amprenavir concentration in cord blood was 0.27 (0.09–0.60) µg/mL, and the median (range) ratio of amprenavir concentration in cord blood to that in maternal plasma at the time of delivery was 0.24 (0.06–0.93).2 A second small study in pregnancy yielded a similar mean ratio (95% confidence interval) of amprenavir concentration in cord blood to that in maternal plasma at the time of delivery of 0.27 (0.24, 0.30).3 Whether amprenavir is excreted in human breast milk is unknown.
Two birth defects out of 108 live births with first-trimester exposure and two birth defects out of 36 live births with second- or third-trimester exposure have been reported to the Antiretroviral Pregnancy Registry. These numbers are insufficient to allow conclusions to be drawn regarding the risk of birth defects.4
|Formulation||Dosing Recommendations||Use in Pregnancy|
Lexiva (a prodrug of amprenavir)
Note: Must be combined with low-dose RTV boosting in pregnancy
||Standard Adult Dose
|Low placental transfer to fetus.b
Insufficient data to assess for teratogenicity in humans. Increased fetal loss in rabbits but no increase in defects in rats and rabbits.
Must be given as low-dose RTV-boosted regimen in pregnancy.
a Individual antiretroviral drug dosages may need to be adjusted in renal or hepatic insufficiency (for details, see Adult Guidelines, Appendix B, Table 7).
Key to Abbreviations: ARV = antiretroviral; AUC = area under the curve; EFV = efavirenz; FPV = fosamprenavir; PI = protease inhibitor; PK = pharmacokinetic; RTV= ritonavir