FDA Perspective Published in the New England Journal of Medicine Reinforces Safety of Pradaxa (dabigatran etexilate mesylate)

RIDGEFIELD, Conn., March 18, 2013 /PRNewswire/ -- A new perspective from the U.S. Food and Drug Administration (FDA) states the agency has not changed its recommendations regarding Pradaxa^® (dabigatran etexilate mesylate) capsules, following the November 2012 Mini-Sentinel evaluations. The FDA stated that bleeding rates associated with new use of PRADAXA do not appear to be higher than those with new use of warfarin, which is consistent with observations from the pivotal RE-LY^® trial. The perspective was published online on March 13, 2013 in the New England Journal of Medicine (NEJM).

The Mini-Sentinel evaluated information about the risk of serious bleeding associated with the use of blood thinners (anticoagulants): PRADAXA and warfarin. The FDA investigated the rates of bleeding occurring in the stomach and intestines (gastrointestinal bleeding) and a type of bleeding in the brain (intracranial hemorrhage) for new users of PRADAXA compared to new users of warfarin. This assessment was done using insurance claims and administrative data from the FDA's ongoing Mini-Sentinel pilot of the Sentinel Initiative.

"We are encouraged that this article in NEJM provides important context about the safety of PRADAXA, reaffirming the findings from the pivotal RE-LY trial and the important health benefit of PRADAXA when used as directed," said Sabine Luik, M.D., Sr. Vice President, Medicine & Regulatory Affairs, U.S. Regional Medical Director, Boehringer Ingelheim Pharmaceuticals, Inc. 

About Pradaxa^® (dabigatran etexilate mesylate) Capsules

Indications and Usage
Pradaxa^® (dabigatran etexilate mesylate) capsules is indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.

IMPORTANT SAFETY INFORMATION ABOUT PRADAXA

CONTRAINDICATIONS
PRADAXA is contraindicated in patients with:

• Active pathological bleeding
• A known serious hypersensitivity reaction to PRADAXA (e.g., anaphylactic reaction or anaphylactic shock)
• A mechanical prosthetic heart valve 

WARNINGS & PRECAUTIONS 
Risk of Bleeding

PRADAXA increases the risk of bleeding and can cause significant and, sometimes, fatal bleeding. Promptly evaluate any signs or symptoms of blood loss (e.g., a drop in hemoglobin and/or hematocrit or hypotension). Discontinue PRADAXA in patients with active pathological bleeding.

Risk factors for bleeding include concomitant use of medications that increase the risk of bleeding (e.g., anti-platelet agents, heparin, fibrinolytic therapy, and chronic use of NSAIDs). PRADAXA's anticoagulant activity and half-life are increased in patients with renal impairment. 

A specific reversal agent for dabigatran is not available. Hemodialysis can remove dabigatran; however clinical experience for hemodialysis as a treatment for bleeding is limited. Activated prothrombin complex concentrates, recombinant Factor VIIa, or concentrates of factors II, IX or X may be considered but their use has not been evaluated. Protamine sulfate and vitamin K are not expected to affect dabigatran anticoagulant activity. Consider administration of platelet concentrates where thrombocytopenia is present or long-acting antiplatelet drugs have been used. 

Thromboembolic and Bleeding Events in Patients with Prosthetic Heart Valves
The safety and efficacy of PRADAXA in patients with bileaflet mechanical prosthetic heart valves (recently implanted or implanted more than 3 months prior to enrollment) was evaluated in the phase 2 RE-ALIGN trial. RE-ALIGN was terminated early because of significantly more thromboembolic events (valve thrombosis, stroke, transient ischemic attack, and myocardial infarction) and an excess of major bleeding (predominantly post-operative pericardial effusions requiring intervention for hemodynamic compromise) for PRADAXA vs warfarin. Therefore, the use of PRADAXA is contraindicated in patients with mechanical prosthetic valves.

Use of PRADAXA for the prophylaxis of thromboembolic events in patients with atrial fibrillation and other forms of valvular heart disease, including bioprosthetic heart valve, has not been studied and is not recommended.

Temporary Discontinuation of  PRADAXA
Discontinuing PRADAXA for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of stroke. Minimize lapses in therapy.

Effect of P-gp Inducers & Inhibitors on Dabigatran Exposure
The concomitant use of PRADAXA with P-gp inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided. P-gp inhibition and impaired renal function are major independent factors in increased exposure to dabigatran. Concomitant use of P-gp inhibitors in patients with renal impairment is expected to increase exposure of dabigatran compared to either factor alone.

For patients with moderate renal impairment (CrCl 30-50 mL/min), consider reducing the dose of PRADAXA to 75 mg twice daily when dronedarone or systemic ketoconazole is coadministered with PRADAXA.

For patients with severe renal impairment (CrCl 15-30 mL/min), avoid concomitant use of PRADAXA and P-gp inhibitors.

ADVERSE REACTIONS
In the pivotal trial comparing PRADAXA to warfarin, the most frequent adverse reactions leading to discontinuation of PRADAXA were bleeding and gastrointestinal (GI) events. PRADAXA 150 mg resulted in a higher rate of major GI bleeds and any GI bleeds compared to warfarin. In patients >75 years of age, the risk of major bleeding may be greater with PRADAXA than with warfarin. Patients on PRADAXA 150 mg had an increased incidence of GI adverse reactions. These were commonly dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort) and gastritis-like symptoms (including GERD, esophagitis, erosive gastritis, gastric hemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis, and GI ulcer). Drug hypersensitivity reactions were reported in <0.1% of patients receiving PRADAXA.

Other Measures Evaluated
In the pivotal trial, a higher rate of clinical myocardial infarction was reported in patients who received PRADAXA (0.7 per 100 patient-years for 150 mg dose) than in those who received warfarin (0.6).

Click here for full PRADAXA prescribing information and medication guide.

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