Boehringer Ingelheim Pharmaceuticals, Inc. Announces Updates to Prescribing Information for Pradaxa® (dabigatran etexilate mesylate)

Ridgefield, Conn., April 30, 2013 – Boehringer Ingelheim Pharmaceuticals, Inc. today announced three important updates to the U.S. prescribing information for PRADAXA, an oral anticoagulant (OAC) indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF).

• The PRADAXA label now carries a Boxed Warning, similar to the Boxed Warnings in the labels of other new OACs, to advise patients that discontinuing treatment puts them at increased risk of stroke. A similar warning was previously stated in the Pradaxa Prescribing Information (sections 5.3 and 17.1) and Medication Guide.
   
• The postmarketing experience section of the PRADAXA label has been updated to include thrombocytopenia.
   
• The PRADAXA label now includes data from the pivotal RE-LY® trial that showed a lower rate of all-cause death with PRADAXA 150 mg than warfarin (3.6 percent per year versus 4.1 percent per year). The rate of vascular death was lower on PRADAXA compared to warfarin (2.3 percent per year versus 2.7 percent per year). Non-vascular death rates were similar in the treatment arms.

The updated label does not change the positive benefit-risk profile of PRADAXA 150 mg twice daily when used as directed. PRADAXA 150 mg twice daily remains the only anticoagulant to demonstrate superior reduction of ischemic stroke and hemorrhagic stroke compared to warfarin.

“Patient safety is our top priority at Boehringer Ingelheim,” said Sabine Luik, M.D., senior vice president, medicine & regulatory affairs, U.S. regional medical director, Boehringer Ingelheim Pharmaceuticals, Inc. “We have worked closely with the FDA to reinforce the importance of adhering to PRADAXA to reduce the risk of stroke through this updated label. Patients should not stop taking PRADAXA unless directed by a physician.”

The efficacy and safety of PRADAXA was established in the RE-LY trial, one of the largest clinical studies conducted in patients with NVAF. In RE-LY, PRADAXA was proven to be 36 percent better than warfarin at reducing the risk of stroke in patients with NVAF. PRADAXA showed a superior 25 percent reduction of ischemic stroke compared to warfarin and a superior 74 percent reduction in hemorrhagic stroke compared to warfarin.

Additional RE-LY® Trial Details
RE-LY was a global, Phase 3, randomized trial of 18,113 patients enrolled in 951 centers in 44 countries, investigating whether dabigatran etexilate (two blinded doses) was as effective as open label warfarin – INR 2.0 - 3.0 – for stroke prevention. Patients with NVAF and at least one other risk factor for stroke (i.e., previous ischemic stroke; transient ischemic attack or systemic embolism; left ventricular ejection fraction < 40 percent; symptomatic heart failure documented to be New York Heart Association Class ≥ 2; age ≥ 75 years; or age ≥ 65 years and having one of the following: diabetes mellitus, verified coronary artery disease, or hypertension) were enrolled in the study for a mean of approximately two years with a minimum follow-up period of one year.

The primary endpoint of the trial was incidence of stroke (including ischemic and hemorrhagic) and systemic embolism. The primary safety endpoint was major bleeding, defined as a reduction in the hemoglobin level of at least 2.0 g/dL, or leading to transfusion of at least two units of blood, or symptomatic bleeding in a critical area or organ. Other safety endpoints included bleeding events (major and minor), intracerebral hemorrhage, other intracranial hemorrhage, elevations in liver transaminases, bilirubin and hepatic dysfunction and other adverse events.

In the RE-LY trial, clinical endpoints were adjudicated in a blinded manner to assess outcomes for each treatment.

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 

WARNING: DISCONTINUING PRADAXA IN PATIENTS WITHOUT ADEQUATE CONTINUOUS ANTICOAGULATION INCREASES RISK OF STROKE. Discontinuing PRADAXA places patients at an increased risk of thrombotic events. If anticoagulation with PRADAXA must be discontinued for a reason other than pathological bleeding, consider coverage with another anticoagulant.

CONTRAINDICATIONS
PRADAXA is contraindicated in patients with:
- active pathological bleeding;
- known serious hypersensitivity reaction (e.g., anaphylactic reaction or anaphylactic shock) to PRADAXA;
- mechanical prosthetic heart valve

WARNINGS & PRECAUTIONS

Increased Risk of Stroke with Discontinuation of PRADAXA
Discontinuing PRADAXA in absence of adequate alternative anticoagulation increases the risk of thrombotic events. If PRADAXA must be discontinued for a reason other than pathological bleeding, consider coverage with another anticoagulant.

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 AFib in the setting of other forms of valvular heart disease, including bioprosthetic heart valve, has not been studied and is not recommended.

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 higher rates 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 Prescribing Information, including Boxed WARNING, and Medication Guide.

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