ed human dose [MRHD] of 300 mg/day based on area under the curve [AUC] comparisons) prior to mating and up to implantation (gestation Day 6). Treatment of pregnant rats after implantation with dabigatran at the same dose increased the number of dead offspring and caused excess vaginal/uterine bleeding close to parturition. Although dabigatran increased the incidence of delayed or irregular ossification of fetal skull bones and vertebrae in the rat, it did not induce major malformations in rats or rabbits.
Safety and effectiveness of PRADAXA during labor and delivery have not been studied in clinical trials. Consider the risks of bleeding and of stroke in using PRADAXA in this setting [see Warnings and Precautions (5.1)] .
Death of offspring and mother rats during labor in association with uterine bleeding occurred during treatment of pregnant rats from implantation (gestation Day 7) to weaning (lactation Day 21) with dabigatran at a dose of 70 mg/kg (about 2.6 times the human exposure at MRHD of 300 mg/day based on AUC comparisons).
It is not known whether dabigatran is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PRADAXA is administered to a nursing woman.
Safety and effectiveness of PRADAXA in pediatric patients has not been established.
Of the total number of patients in the RE-LY study, 82% were 65 and over, while 40% were 75 and over. The risk of stroke and bleeding increases with age, but the risk-benefit profile is favorable in all age groups [see Warnings and Precautions (5), Adverse Reactions (6.1), and Clinical Studies (14)] .
No dose adjustment of PRADAXA is recommended in patients with mild or moderate renal impairment. Reduce the dose of PRADAXA in patients with severe renal impairment (CrCl 15-30 mL/min) [see Dosage and Administration (2.1)] . Dosing recommendations for patients with CrCl <15 mL/min or on dialysis cannot be provided.
Accidental overdose may lead to hemorrhagic complications. There is no antidote to dabigatran etexilate or dabigatran. In the event of hemorrhagic complications, initiate appropriate clinical support, discontinue treatment with PRADAXA, and investigate the source of bleeding. Dabigatran is primarily excreted in the urine; therefore, maintain adequate diuresis. Dabigatran can be dialyzed (protein binding is low), with the removal of about 60% of drug over 2 to 3 hours; however, data supporting this approach are limited. Consider surgical hemostasis or the transfusion of fresh frozen plasma or red blood cells. There is some experimental evidence to support the role of activated prothrombin complex concentrates (e.g., FEIBA), or recombinant Factor VIIa, or concentrates of coagulation factors II, IX or X; however, their usefulness in clinical settings has not been established. Consider administration of platelet concentrates in cases where thrombocytopenia is present or long-acting antiplatelet drugs have been used. Measurement of aPTT or ECT may help guide therapy [see Clinical Pharmacology (12.2)] .
The chemical name for dabigatran etexilate mesylate, a direct thrombin inhibitor, is β-Alanine, N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl] phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-,ethyl ester, methanesulfonate. The empirical formula is CHNO • CHOS and the molecular weight is 723.86 (mesylate salt), 627.75 (free base). The structural formula is:
Dabigatra
