Anticoagulant
PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
No reports describing the use of apixaban in human pregnancy have been located. The animal reproduction data suggest low risk, but the absence of human pregnancy experience prevents a complete assessment of the embryo–fetal risk. Maternal bleeding during pregnancy and at delivery, as well as fetal or newborn bleeding, is a risk because there is no established way to reverse the anticoagulant effect that may persist for about 24 hours. The treatment of deep venous thrombosis or pulmonary embolism is not an approved indication, and apixaban should not be used as heparin is the treatment of choice for these indications (1). However, if apixaban is the treatment of choice for its approved indication, it should not be withheld because of pregnancy.
FETAL RISK SUMMARY
Apixaban is an oral, reversible, selective active site inhibitor of factor Xa in the same pharmacologic class as rivaroxaban. It is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. The agent is partially metabolized (about 25%) to inactive metabolites. Plasma protein binding is about 87%. The half-life is about 6 hours but, because of prolonged absorption, repeated dosing results in an effective half-life of about 12 hours (2).
Reproduction studies have been conducted in mice, rats, and rabbits. In these species that were given apixaban from implantation to the end of gestation, fetal exposures occurred but were not associated with an increased risk of fetal malformations or toxicity, or maternal or fetal deaths due to bleeding. However, an increased incidence of maternal bleeding in mice, rats, and rabbits was observed at maternal exposures that were 19, 4, and 1 times, respectively, the human exposure of unbound drug based on AUC at the maximum human dose of 5 mg twice daily (MHD) (2).
Two-year studies in mice and rats observed no carcinogenicity. Various assays for mutagenic and clastogenic effects also were negative. No effect on fertility was observed in male or female rats given doses up to 3 and 4 times, respectively, the MHD. In rats given doses up to 5 times the MHD from implantation through the end of lactation, no adverse findings were observed in male offspring. Adverse effects in female offspring were decreased mating and fertility indices (2).
It is not known if apixaban crosses the human placenta. The molecular weight (about 460), partial metabolism, moderate plasma protein binding, and long effective half-life suggest that the drug will cross to the embryo–fetus. The drug does cross the rat placenta and distributes in fetal blood, liver, and kidney (3).
BREASTFEEDING SUMMARY
No reports describing the use of apixaban during human lactation have been located. The molecular weight (about 460), partial metabolism, moderate plasma protein binding (about 87%), and long effective half-life (about 12 hours) suggest that the drug will be excreted into breast milk. The effect of this exposure on a nursing infant is unknown. However, bleeding (e.g., gastrointestinal, intracranial, intraocular) has been reported in adults and is potentially fatal. Therefore, the safest course is to not breastfeed if apixaban is taken.
References
1.Greer IA. Thrombosis in pregnancy: updates in diagnosis and management. Hematol Am Soc Hematol Educ Program 2012;203–7. doi:10.1182/asheducation-2012.1.203.
2.Product information. Eliquis. Bristol-Myers Squibb, 2012.
3.Wang L, He K, Maxwell B, Grossman SJ, Tremaine LM, Humphreys WG, Zhang D. Tissue distribution and elimination of [14C]apixaban in rats. Drug Metab Dispos 2011;39:256–64.