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Fertility: Preclinical data about peri- and post-natal toxicity of ENBREL and of effects of ENBREL on fertility and general reproductive performance are not available.
Pregnancy: The effects of etanercept on pregnancy outcomes have been investigated in two observational cohort studies. One pregnancy registry compared rates of major birth defects in liveborn infants of mothers with rheumatic diseases or psoriasis exposed to ENBREL in the first trimester (n=319) versus those unexposed to ENBREL during pregnancy (n=144). The all-inclusive adjusted odds ratio for major birth defects was 2.77 (95% CI 1.04-7.35) and when chromosomal and known genetic disorders were removed was 2.49 (95% CI 0.92-6.68). The findings showed no increased rate of minor malformations, and no pattern of major or minor malformations. In addition, there was no increase in rates of intrauterine or post-natal growth deficits or delayed post-natal development. In a second observational multi-country registry study comparing the risk of adverse pregnancy outcomes in women exposed to etanercept (n=522) to those exposed to non-biologic drugs (n=3508), there was no observed increased risk of major birth defects (adjusted odds ratio 0.96, 95% CI 0.58-1.60). This study also showed no increased risks of minor birth defects, preterm birth, stillbirth or infections in the first year of life for infants born to women exposed to etanercept during pregnancy. ENBREL should only be used during pregnancy if the potential benefits to the mother outweigh the potential risks to the foetus.
The use of ENBREL in pregnant women is not recommended and the women of child-bearing potential should be advised not to get pregnant during ENBREL therapy.
Developmental toxicity studies have been performed in rats and rabbits. The AUC-based systemic exposures of etanercept in rats and rabbits are 21- to 25-times higher than in humans at the usual human therapeutic dose of 50 mg weekly, and are approximately 10- to 13-times higher than in humans at the maximum recommended human dose of etanercept of 50 mg twice weekly (for psoriasis). No evidence of harm to the foetus in rats or rabbits or neonatal rats due to etanercept was observed. There are, however, no studies in pregnant women. Animal studies are not always predictive of human response.
Etanercept crosses the placenta and has been detected in the serum of infants born to female patients treated with ENBREL during pregnancy. The clinical impact of this is unknown; however, infants may be at increased risk of infection. Administration of live vaccines to infants for 16 weeks after the mother's last dose of ENBREL is generally not recommended.
Lactation: In lactating rats, following subcutaneous administration etanercept was excreted in the milk and detected in the serum of the pups. Limited information from the published literature indicates etanercept has been detected at low levels in human milk. Etanercept could be considered for use during breastfeeding taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
While systemic exposure in a breastfed infant is expected to be low because etanercept is largely degraded in the gastrointestinal tract, limited data regarding systemic exposure in the breastfed infant are available. Therefore, the administration of live vaccines (e.g., BCG) to a breastfed infant when the mother is receiving etanercept could be considered 16 weeks after stopping breastfeeding (or at an earlier time point if the infant etanercept serum levels are undetectable).
