Committee Approval Date: September 12, 2014 Next Review Date: September 2015

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1 Medication Policy Manual Policy No: dru361 Topic: Pradaxa, dabigatran Date of Origin: September 12, 2014 Committee Approval Date: September 12, 2014 Next Review Date: September 2015 Effective Date: November 1, 2014 IMPORTANT REMINDER This Medical Policy has been developed through consideration of medical necessity, generally accepted standards of medical practice, and review of medical literature and government approval status. Benefit determinations should be based in all cases on the applicable contract language. To the extent there are any conflicts between these guidelines and the contract language, the contract language will control. The purpose of medical policy is to provide a guide to coverage. Medical Policy is not intended to dictate to providers how to practice medicine. Providers are expected to exercise their medical judgment in providing the most appropriate care. Description Dabigatran (Pradaxa) is an anticoagulant that helps prevent blood clots in some patients. Blood clots may lead to a variety of complications such as heart attack or stroke. dru361.0 Page 1 of 5

2 Policy/Criteria I. Most contracts require prior authorization approval of dabigatran (Pradaxa) prior to coverage. Dabigatran (Pradaxa) may be considered medically necessary in patients requiring anticoagulation when criteria A and B below are met: A. Apixaban (Eliquis) has been not tolerated, or is contraindicated AND B. Rivaroxaban (Xarelto) has been not tolerated, or is contraindicated II. Administration, Quantity Limitations, and Authorization Period A. RegenceRx considers dabigatran (Pradaxa) to be a self-administered medication. B. When prior authorization is approved, dabigatran (Pradaxa) may be authorized in quantities of 60 tablets per month. C. Authorization may be reviewed at least yearly to confirm that current medical necessity criteria are met and that the medication is effective. Position Statement Apixaban (Eliquis) and rivaroxaban (Xarelto) have the greatest number of clinical uses for which they have been proven safe and effective, and are the best value branded oral anticoagulants for RegenceRx members. Clinical Efficacy Atrial Fibrillation - The efficacy of dabigatran (Pradaxa) versus warfarin for anticoagulation in atrial fibrillation was evaluated in one trial in 18,113 patients which assessed the composite primary endpoint of reduction of stroke or systemic embolism. [1] Both the dabigatran (Pradaxa) 110 mg and 150 mg doses were shown to be noninferior to warfarin [relative risk vs warfarin 0.90; 95% confidence interval (CI): 0.74, 1.10; p < and 0.65; 95% CI: 0.52, 0.81; p < 0.001, respectively], and the 150 mg dose was shown to be superior (p < 0.001) with regard to the primary endpoint. Dabigatran (Pradaxa) 110 mg was associated with lower rates of major hemorrhage as compared to warfarin, while rates of major hemorrhage with the 150 mg dose were similar to those seen with warfarin. This trial was of low confidence due to its open-label design, a large number of drop-outs, and due to the allowance of other medications that may have affected blood clotting (e.g. aspirin, clopidogrel). dru361.0 Page 2 of 5

3 In addition, currently available strengths of dabigatran (Pradaxa) do not include the 150 mg dose evaluated in this trial, but do include the 110 mg dose as well as a 75 mg dose, which was not evaluated in this trial. While it is likely that dabigatran (Pradaxa) is at least as effective as warfarin, its superiority is uncertain. - There is insufficient evidence to determine the relative efficacy of branded oral anticoagulants including apixaban (Eliquis), dabigatran (Pradaxa), and rivaroxaban (Xarelto) for prevention of stroke or systemic embolism in atrial fibrillation due to lack of comparative data. [2] In one low quality systematic review and meta-analyses which evaluated interventions for stroke prevention in atrial fibrillation, the authors concluded that the branded oral anticoagulants may reduce stroke and bleeding events in patients with non-valvular atrial fibrillation compared to warfarin, and apixaban (Eliquis) shows promise in patients who are not candidates for warfarin. This review was of low quality as conclusions of superiority versus warfarin were made based on evidence appraised as less than high confidence due to high attrition and treatment crossover. In addition, while a conclusion of superiority was made, results of the meta-analysis indicated dabigatran (Pradaxa) and rivaroxaban (Xarelto) were non-inferior to warfarin for the primary outcome of stroke prevention, and rivaroxaban (Xarelto) showed similar rates of major bleeding relative to warfarin. There is no direct comparative evidence evaluating the branded oral anticoagulants relative to each other for prevention of stroke or systemic embolism in atrial fibrillation. Other Conditions Requiring Anticoagulation - The branded oral anticoagulants including apixaban (Eliquis), dabigatran (Pradaxa), and rivaroxaban (Xarelto), have been studied in a variety of other conditions requiring anticoagulation such as deep vein thrombosis prophylaxis following hip or knee replacement. - The data is suggestive that all three branded anticoagulants are effective in these conditions and because comparative evidence is limited to indirect comparison, a conclusion that one is more effective than another cannot be made. Safety - As with other anticoagulants used in atrial fibrillation, bleeding was among the most common adverse events (> 15%) reported in clinical trials with dabigatran (Pradaxa). Other common adverse events (> 15%) included gastritis-like symptoms. [3] dru361.0 Page 3 of 5

4 - All branded oral anticoagulants, including dabigatran (Pradaxa) have a boxed warning that discontinuation puts patients at an increased risk of blood clots. [3-5] - Both the FDA and the European Medicines Agency have issued safety communications with regard to dabigatran (Pradaxa), the most recent of which reported on an observational cohort study using claims data from Medicare patients in the U.S. [6-9] Findings from this study indicate that patients taking dabigatran (Pradaxa) were at a lower risk for stroke and death, but at higher risk for gastrointestinal bleeding versus warfarin. The risk of MI was similar between the two groups. Limitations of this study include the potential for baseline differences between groups as subjects were not randomized, and potential confounding due to treatment differences between groups. - No safety communications have been issued regarding apixaban (Eliquis) and rivaroxaban (Xarelto) to date; however, dabigatran (Pradaxa) has the longest track record of clinical safety experience. - In July 2014, a feature article was published in The BMJ stating that the manufacturer of dabigatran (Pradaxa) withheld information regarding the potential benefits of monitoring anticoagulant activity and adjusting the dose to make sure the drug is working as safely and effectively as possible. [10] The manufacturer s analysis showed that a relatively small difference in kidney function may have a large effect (up to a fivefold variation per dose) on the plasma level of dabigatran (Pradaxa). An optimum plasma level was determined via this analysis; however, to achieve this level would require monitoring of plasma levels and subsequent dose adjustments. - There is currently no commercially available test to determine the plasma level of dabigatran (Pradaxa). Cross References N/A Codes Number Description N/A dru361.0 Page 4 of 5

5 Appendix 1: Summary of Branded Oral Anticoagulant Approvals and Published Data apixaban (Eliquis) dabigatran (Pradaxa) rivaroxaban (Xarelto) Mechanism of action Factor Xa inhibitor Direct thrombin inhibitor Factor Xa inhibitor Indication Atrial fibrillation Post hip/knee surgery Medically ill Acute coronary syndrome Treatment of VTE VTE = venous thromboembolism U.S. (12/2012) Europe (9/2012) U.S. (3/2014) Europe (5/2011) U.S. (08/2014) Europe Approval Status U.S. (10/2010) Europe (4/2011) U.S. Europe (3/2008) No published data No published data U.S. (4/2014) Europe U.S. (11/2011) Europe (9/2011) U.S. (7/2011) Europe (7/2008) U.S. Europe (6/2013) U.S. (11/2012) Europe (1/2012) References 1. Connolly, SJ, Ezekowitz, MD, Yusuf, S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. United States, p Lopes, RD, Crowley, MJ, Shah, BR, et al. Stroke Prevention in Atrial Fibrillation. Rockville (MD), Eliquis [package insert]. Princeton, New Jersey: Bristol-Myers Squibb Company; 03/ Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 04/ Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 03/ FDA Drug Safety Communication: FDA study of Medicare patients finds risks lower for stroke and death but higher for gastrointestinal bleeding with Pradaxa (dabigatran) compared to warfarin. [cited 08/02/2014]; Available from: 7. FDA Safety Communication: Update on the risk for serious bleeding events with the anticoagulant Pradaxa (dabigatran). [cited 02/7/2013]; Available from: 8. FDA Drug Safety Communication: Pradaxa (dabigatran etexilate mesylate) should not be used in patients with mechanical prosthetic heart valves. [cited 02/11/2013]; Available from: 9. Questions and answers on the review of bleeding risk with Pradaxa (dabigatran etexilate). [cited 02/07/2013]; Available from: Cohen, D. Dabigatran: how the drug company withheld important analyses. BMJ. 2014;349:g4670. PMID: dru361.0 Page 5 of 5