Amprenavir (Agenerase, APV)
Amprenavir is classified as FDA pregnancy category C and is no longer available in the United States.
In vitro screening tests for carcinogenicity have been negative. An increase in benign hepatocellular adenomas and hepatocellular carcinomas was observed in male mice and rats at the highest doses evaluated, which produced systemic exposures in mice 2-fold and in rats 4-fold higher than systemic exposure in humans receiving therapeutic doses of amprenavir. Female mice and rats were not affected.
No effect has been seen on reproductive performance, fertility, or embryo survival in rats at exposures about twice those of human therapeutic exposure.
Teratogenicity/Adverse Pregnancy Outcomes
In pregnant rabbits, administration of amprenavir resulting in systemic exposures about one-twentieth of that observed with human therapeutic exposure was associated with abortions and an increased incidence of minor skeletal variations resulting from deficient ossification of the femur, humerus trochlea, and humerus. In rat fetuses, thymic elongation and incomplete ossification of bones were also attributed to amprenavir at systemic exposures about one-half that associated with the recommended human dose. Reduced body weights of approximately 10% – 20% were observed in offspring of rodents administered amprenavir from Day 7 of gestation to Day 22 of lactation (exposures approximately twice that observed with the human therapeutic dose). However, the subsequent development of the offspring, including fertility and reproductive performance, was not affected by maternal administration of amprenavir.
Placental and Breast Milk Passage
Whether amprenavir crosses the placenta is unknown. Amprenavir is excreted in the milk of lactating rats; it is not known if it is excreted in human milk.
Human Studies in Pregnancy
There have been limited studies of amprenavir in pregnant women and no studies in neonates. Amprenavir oral solution contains high levels of excipient propylene glycol in the oral solution vehicle; this is not true for the capsular formulation. Propylene glycol is metabolized by the alcohol and aldehyde dehydrogenase enzyme pathway. Some patients, including infants and children below the age of 4 years, pregnant women, patients with hepatic or renal failure, and patients treated with disulfiram or metronidazole, are not able to adequately metabolize and eliminate propylene glycol, thereby leading to its accumulation and potential adverse events. Thus, while the capsule formulation of amprenavir may be used in pregnancy, amprenavir oral solution is contraindicated in pregnant women and infants and in children under the age of 4 years.