October 13, 2016

Idarucizumab: The New Dabigatran Reversal Agent

UAMS Reynolds Institute logo - Jan 2016

By Nick Grunewald, PharmD candidate and Lisa Hutchison, PharmD, MPH

Dabigatran is a twice a day oral anticoagulant indicated for stroke prevention in patients having atrial fibrillation and deep vein thrombosis/pulmonary embolism treatment and prevention. These conditions are more prevalent in older and frail adults. Dosage ranges from 110mg twice a day to 150mg twice a day, with 150mg doses noted as having a higher incidence of bleeding.1 Dabigatran becomes therapeutic within 24 hours of administration with continuation of therapy. Studies show that dabigatran is an acceptable alternative to warfarin and has a similar adverse effect profile.2 Dabigatran acts as a direct thrombin inhibitor, and in comparison to warfarin, it does not require frequent monitoring, has a more rapid effect, and fewer drug-drug interactions.

Until now, if a patient on dabigatran had a major bleed, there was no way to quickly reverse its effects. Clinicians (and patients) had to wait until the drug was eliminated from the body for its effect on bleeding to dissipate or sometimes in extreme bleeding situations clinicians might try prothrombin complex concentrate to reverse dabigatran effects. Not having a reversal agent was considered a disadvantage for use of the dabigatran, and clinicians worried about its overall safety in older adults.

Idarucizumab (Praxbind®) has been recently marketed as a reversal agent for dabigatran. It is a humanized monoclonal antibody fragment (Fab) that binds to dabigatran and its metabolites with higher affinity than that of dabigatran’s binding to thrombin, neutralizing its anticoagulant effect. The recommended dose of idarucizumab is 5 g, provided as two doses separated by 15 minutes. Idarucizumab is supplied in vials containing 2.5 g/50 mL.3

In studies of normal volunteers taking dabigatran, after infusion of idarucizumab, immediate and complete reversal of the dabigatran-induced increase in dilute thrombin time (dTT) was reported for all idarucizumab dose groups [ie, dTT was reduced to less than the upper limit of normal (ULN) of 34·9 s and was close to the mean baseline measurement of 32·1 s]. Reversal was sustained (i.e., mean dTT values remained at <ULN for 72 h) with the 2 g, 4 g, and 5 g plus 2·5 g doses. In addition to complete reversal of dabigatran, study data showed that 24 hours after administration of idarucizumb, anticoagulation with dabigatran can be restarted with full therapeutic effect.⁴ ⁵ In summation, study data show that complete reversal of dabigatran is obtained in minutes after administering 2 doses of 2.5mg of idarucizumab.

At present, idarucizumab’s place in therapy as a reversal agent for dabigatran is limited to emergent situations. This may decrease the occurrence of major bleeds due to trauma or surgical intervention. However, careful consideration for its use should be made. The average wholesale price (AWP) cost of idarucizumab is $42/mL, equaling $4200 per administration. Casual use of this agent could cause undue expense to patients and institutions. Therefore, risk benefit should be evaluated in every patient that would be considered for administration of idarucizumab.

References:

1. Boehringer Ingelheim. Pradaxa Full Prescribing Information. Last Accessed on 6/25/16. Available at http://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Pradaxa/Pradaxa.pdf
2. Dabigatran Versus Warfarin In Patients With Atrial Fibrillation, Connolly SJ, N Engl J Med, 2009, 361(12):1139-51[Pubmed 19717844]

3. Boehringer Ingelheim. FDA Approves Praxbind® (idarucizumab), Specific Reversal Agent for Pradaxa® (dabigatran etexilate mesylate). PRAXBIND Full Prescribing Information. Last Accessed on 10/27/15. Available at: http://us.boehringer-ingelheim.com/content/dam/internet/opu/us_EN/documents/Media_Press_Releases/2015/Praxbind.pdf

4. S Glund, J Stangier, M Schmohl, et al. Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial Lancet (2015) published online June 16. Last Accessed on 10/27/15. Available at: http://dx.doi.org/10.1016/S0140-6736(15)60732-2

5. Pollack CV, Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA, Dubiel R, Huisman MV, Hylek EM, Kapmhusien PW, Kreuzer J, Levy JH, Sellke FW, Stangier J, Steiner T, Wang B, Kam CW, Weitz JI 2015) Idarucizumab for dabigatran reversal. N Engl J Med 373:511–520