Anticoagulant
PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Moderate Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
No reports describing the use of rivaroxaban during human pregnancy have been located. The animal data in one species suggest risk but the adverse embryo–fetal outcomes may have been caused by maternal hemorrhage. Structural malformations were not observed in the animals. Pregnancy-related hemorrhage and/or emergent delivery is a concern because the drug cannot be reliably monitored with standard laboratory testing, and the anticoagulant effect is not readily reversible other than waiting about 24 hours (1). For these reasons, the drug should be avoided in pregnancy (2). In addition, the treatments of deep venous thrombosis or pulmonary embolism are not approved indications and rivaroxaban should not be used as heparin is the treatment of choice for these indications (3). However, if rivaroxaban is the treatment of choice for its approved indications, it should not be withheld because of pregnancy.
FETAL RISK SUMMARY
Rivaroxaban is an oral factor Xa inhibitor in the same pharmacologic class as apixaban. It is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation and for the prophylaxis of deep vein thrombosis which may lead to pulmonary embolism in patients undergoing knee or hip replacement surgery. Rivaroxaban undergoes partial metabolism to inactive metabolites; the parent drug is the predominant moiety in plasma with no major or active circulating metabolites. Plasma protein binding, primarily to albumin, is 92%–95% and the terminal elimination half-life is 5–9 hours in healthy subjects (1).
Reproduction studies with oral rivaroxaban have been conducted in rats and rabbits. Pronounced maternal hemorrhage occurred in rats but the dose was not specified. Decreased fetal body weights were observed with doses that were about 14 times the human exposure of unbound drug based on AUC at the highest recommended dose of 20 mg/day (HE). Maternal hemorrhage also occurred in rabbits given a dose that produced exposures during organogenesis that were about 4 times the HE. At this dose, embryo–fetal toxicity in rabbits included increased resorptions, decreased number of live fetuses, and decreased fetal body weight. Without mentioning the animal species, the manufacturer reported that during labor and delivery a dose about 6 times the HE resulted in maternal bleeding and maternal and fetal death. Rivaroxaban crossed the placenta in both rats and rabbits (1).
Two-year studies for carcinogenesis were negative in mice and rats. Studies for mutagenicity also were negative, as were studies for impaired fertility in male and female rats (1).
As demonstrated by autoradiography, moderate amounts of rivaroxaban cross the human placenta (4). The transfer is consistent with the molecular weight (about 436), limited metabolism, and moderately long elimination half-life. Although the amount crossing has not been determined, it may be limited by the high plasma protein binding.
BREASTFEEDING SUMMARY
No reports describing the use of rivaroxaban during human lactation have been located. A 2012 reference on the treatment of pulmonary embolism in pregnancy, however, stated without further details that the drug is excreted into breast milk (2). This would be consistent with the molecular weight (about 436), limited metabolism, and moderately long elimination half-life (5–9 hours), but the moderately high plasma protein binding (92%–95%) might limit the excretion. The effect of this exposure on a nursing infant is unknown, but hemorrhage is a potential complication. Until additional data on the amount in breast milk are available, the safest course is to not breastfeed when taking this drug.
References
1.Product information. Xarelto. Janssen Pharmaceuticals, 2011.
2.Cutts BA, Dasgupta D, Hunt BJ. New directions in the diagnosis and treatment of pulmonary embolism in pregnancy. Am J Obstet Gynecol 2013;208:102–8.
3.Greer IA. Thrombosis in pregnancy: updates in diagnosis and management. Hematology Am Soc Hematol Educ Program 2012;2012:203–7. doi: 10.1182/asheducation-2012.1.203.
4.Rivaroxaban FDA DDAC document. Available at www.fda.gov. As cited by Huisman MV. Further issues with new oral anticoagulants. Curr Pharm Des 2010;16:3487–9.