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Pregnancy: Risk Summary: There are no adequate data from the use of Afinitor in pregnant women. The potential risk for humans is unknown. Studies in animals have shown reproductive toxicity effects including embryo-toxicity and feto-toxicity. Afinitor should not be given to pregnant women unless the potential benefit outweighs the potential risk to the fetus.
Animal Data: Oral doses of everolimus in female rats at ≥0.1 mg/kg (approximately 4% the AUC0-24h in patients receiving the 10 mg daily dose) resulted in increased incidence of pre-implantation loss. Everolimus crossed the placenta and was toxic to the conceptus. In rats, everolimus caused embryo/feto-toxicity at systemic exposure below the therapeutic level. This was manifested as mortality and reduced fetal weight. The incidence of skeletal variations and malformations (e.g. sternal cleft) was increased at 0.3 and 0.9 mg/kg. In rabbits, embryotoxicity was evident via an increase in late resorptions that occurred at an oral dose of 0.8 mg/kg (9.6 mg/m2), approximately 1.6 times either the 10 mg daily dose in adults or the median dose administered to SEGA patients, and 1.3 times the median dose for patients with TSC and refractory seizures, on a body surface area basis. In rats, there was no evidence of adverse effects by treating males with everolimus on embryo-fetal parameters.
Human data: There have been reports of exposure to everolimus during pregnancy, some due to exposure via the mother and some via the father (pregnancy in a female partner of a male patient while under treatment with everolimus). There were no reports of congenital abnormalities. In some cases the pregnancies progressed uneventfully with delivery of healthy, normal babies.
Lactation: Risk Summary: It is not known whether everolimus is transferred in human breast milk. There are no reported cases of exposure to everolimus during breast-feeding in humans. However, in animal studies everolimus and/or its metabolites readily passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum.
Women taking Afinitor should therefore not breast-feed during treatment and for 2 weeks after the last dose.
Females and males of reproductive potential: Contraception: Females of reproductive potential should be advised that animal studies have been performed showing Afinitor to be harmful to the developing fetus. Sexually-active females of reproductive potential should use effective contraception (one that results in an annual pregnancy rate <1% when used correctly) while receiving Afinitor, and for up to 8 weeks after ending treatment. Male patients taking Afinitor should not be prohibited from attempting to father children (see PHARMACOLOGY: TOXICOLOGY: NON CLINICAL SAFETY DATA under ACTIONS).
Infertility: Females and Males: Animal data: In animal reproductive studies, female fertility was not affected. However, pre-implantation losses were observed. In male rats, testicular morphology was affected at 0.5 mg/kg and above, and sperm motility, sperm head count, and plasma testosterone levels were diminished at 5 mg/kg, which is within the range of therapeutic exposure (52 ng.hr/mL and 414 ng.hr/mL respectively compared to 560 ng.hr/mL human exposure at 10 mg/day) and which caused a reduction in male fertility. There was evidence of reversibility.
Human data: Both male and female fertility may be compromised by treatment with everolimus (see PHARMACOLOGY: TOXICOLOGY: NON CLINICAL SAFETY DATA under ACTIONS). Menstrual irregularities, secondary amenorrhea and associated luteinizing hormone (LH)/follicle stimulating hormone (FSH) imbalance have been observed in female patients receiving everolimus. Blood levels of FSH and LH increased, blood levels of testosterone decreased, and azoospermia have been observed in male patients receiving everolimus.
