8  USE IN SPECIFIC POPULATIONS

8.1  Pregnancy

Teratogenic Effects, Pregnancy Category C.
Investigation of fertility and early embryonic development with tipranavir disodium was performed in rats, teratogenicity studies were performed in rats and rabbits, and pre- and post-natal development were explored in rats.

No teratogenicity was detected in reproductive studies performed in pregnant rats and rabbits up to dose levels of 1000 mg/kg/day and 150 mg/kg/day tipranavir, respectively, at exposure levels approximately 1.1-fold and 0.1-fold human exposure. At 400 mg/kg/day and above in rats, fetal toxicity (decreased sternebrae ossification and body weights) was observed, corresponding to an AUC of 1310 μM•h or approximately 0.8-fold human exposure at the recommended dose. In rats and rabbits, fetal toxicity was not noted at 40 mg/kg/day and 150 mg/kg/day, respectively, corresponding accordingly to Cmax/AUC0-24h levels of 30.4 μM/340 μM•h and 8.4 μM/120 μM•h. These exposure levels (AUC) are approximately 0.2-fold and 0.1-fold the exposure in humans at the recommended dose.

In pre- and post-development studies in rats, tipranavir showed no adverse effects at 40 mg/kg/day (~0.2-fold human exposure), but caused growth inhibition in pups and maternal toxicity at dose levels of 400 mg/kg/day (~0.8-fold human exposure). No post-weaning functions were affected at any dose level.

There are no adequate and well-controlled studies in pregnant women for the treatment of HIV-1 infection. APTIVUS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Antiretroviral Pregnancy Registry
To monitor maternal-fetal outcomes of pregnant women exposed to APTIVUS, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling (800) 258-4263.

8.3  Nursing Mothers

The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV-1. Because of both the potential for HIV-1 transmission and any possible adverse effects of APTIVUS, mothers should be instructed not to breast-feed if they are receiving APTIVUS.

8.4  Pediatric Use

The safety, pharmacokinetic profile, and virologic and immunologic responses of APTIVUS oral solution and capsules were eva luated in HIV-1 infected pediatric patients age 2 to 18 years [see Adverse Reactions (6.2) and Clinical Studies (14.2)].

The most frequent adverse reactions (grades 2-4) were similar to those described in adults. However, rash was reported more frequently in pediatric patients than in adults [see Warnings and Precautions (5.6) and Adverse Reactions (6.2)].

The risk-benefit has not been established in pediatric pat