Anticoagulant (Thrombin Inhibitor)
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 dabigatran etexilate in human pregnancy have been located. The animal data suggest moderate risk, but the absence of human pregnancy experience prevents a more complete assessment of the embryo–fetal risk. Until such data are available, other anticoagulants, such as the low-molecular-weight heparins, appear to be a better choice in pregnancy.
FETAL RISK SUMMARY
Dabigatran etexilate is a direct thrombin inhibitor that is given orally. It is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. After oral dosing, dabigatran etexilate is converted to dabigatran, the active agent. Dabigatran is further metabolized to four different acyl glucuronides, all of which have similar activity to dabigatran. Plasma protein binding is about 35% and the half-life is 12–17 hours (1).
Reproduction studies have been conducted in rats and rabbits. In pregnant rats, a dose that was about 2.6–3 times the human exposure from the maximum recommended dose of 300 mg/day based on AUC (MRHD) given after implantation resulted in an increase in dead offspring and caused excess vaginal/uterine bleeding close to parturition. This dose also increased the incidence of delayed or irregular ossification of fetal skull bones and vertebrae. However, the drug did not induce major malformations in the rat or rabbit (dose in rabbits not specified). The number of implantations was decreased when dabigatran was given to male and female rats before mating and up to implantation at the above dose (1).
In 2-year studies, dabigatran was not carcinogenic in mice and rats. The drug was not mutagenic in multiple assays. No adverse effects on male and female rat fertility were observed, but, as noted above, the drug decreased the number of implantations when given up to implantation (gestation day 6) (1).
It is not known if dabigatran etexilate or dabigatran crosses the human placenta. The molecular weights of the parent compound and dabigatran (about 628 and 499 for the free bases), low plasma protein binding, and the long elimination half-life suggest that it will cross to the embryo–fetus. However, without referencing, a 2010 review of new oral anticoagulants stated that dabigatran does not cross the placenta (2).
BREASTFEEDING SUMMARY
No reports describing the use of dabigatran etexilate during human lactation have been located. The molecular weight of the parent compound (about 628 for the free base), low plasma protein binding (about 35%), and the long elimination half-life (12–17 hours) suggest that the drug and its active metabolites will be excreted into breast milk. The effect of the exposure on a nursing infant is unknown, but the drug is absorbed orally. Until such data are available, use of other anticoagulants, such as the low-molecular-weight heparins, should be considered.
References
1.Product information. Pradaxa. Boehringer Ingelheim Pharmaceuticals, 2011.
2.Huisman MV. Further issues with new oral anticoagulants. Curr Pharm Des 2010;16:3487–9.