Setting the Record Straight: The Facts about Pradaxa^® (dabigatran etexilate mesylate)

Ridgefield, Conn., February 13, 2014 – Recent media coverage has used very limited and specifically selected fragments of robust internal discussions to inaccurately and incompletely characterize Boehringer Ingelheim and Pradaxa^® (dabigatran etexilate mesylate). PRADAXA is an important treatment that was approved by the U.S. Food and Drug Administration (FDA) after review of the clinical trial data and deemed to be safe and effective when used as directed in the label.

First and foremost, at Boehringer Ingelheim patient health and safety is our top priority. As a company with a deep heritage in, and commitment to, scientific innovation, we pride ourselves on ethical clinical research to produce new medicines that are safe and effective. One key to scientific innovation is peer-reviewed research.

We are deeply concerned that misleading and imbalanced media coverage could compromise the health and safety of people who may benefit from a medication like PRADAXA to reduce their risk of stroke when used as directed.

The following detailed review of the facts shows that Boehringer Ingelheim and its employees acted ethically and responsibly in the clinical development and marketing of PRADAXA.

Understanding the Complete Research and Related Discussions

Selected company documents referenced in media coverage do not represent the complete internal scientific discussions, and thus, have been taken out of context. In truth, the complete internal discussion reflects a legitimate concern that doctors might make dosing decisions without sufficient scientific data to support such decisions, which could lead to unintended negative consequences for patients. For instance, a doctor could inadvertently put a patient at higher risk of stroke by lowering a patient’s dosage based on blood readings alone, when in fact there are more factors at play, including age and kidney function.

Boehringer Ingelheim did not “quash” research; internal medical debates and diversity of opinion reflect the normal course of clinical development. Regarding the Journal of the American Cardiology (JACC) paper referenced in media coverage, which was co-authored by independent researchers from highly-regarded academic institutions, we began with the hope of identifying a therapeutic range of plasma levels that could be used for all patients. As the data was vetted through the scientific process, the authors came to the conclusion that there is no single plasma concentration range that provides optimal benefit-risk for all patients. Any suggestion that Boehringer Ingelheim was resistant to further research for marketing reasons is false.

The Safety and Efficacy Profile of PRADAXA has Been Well-Studied

PRADAXA’s safety and efficacy was established in one of the largest stroke prevention trials. It has been studied in more than 40,000 people worldwide across many patient populations, including the pivotal RE-LY^® trial that enrolled more than 18,000 patients. RE-LY was conducted without the need for regular blood tests.

The FDA has publicly stated that PRADAXA 150 mg twice daily offers a positive benefit-risk profile and provides an important health benefit when used as directed to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF).

Decisions About Anticoagulant Treatment Should be made between Patients and their Doctors

It is known that discontinuing anticoagulation therapy puts a patient at increased risk of stroke. Patients should not stop taking their anticoagulant medication without first talking to their doctors because stopping could increase their risk of stroke.

Boehringer Ingelheim stands behind PRADAXA. The company is completely confident that all of the facts will show that Boehringer Ingelheim acted appropriately and responsibly.

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 ADEQUATECONTINUOUS 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).

Please see full Prescribing Information including Boxed WARNING, and Medication Guide.

About the Boehringer Ingelheim Cares Foundation Patient Assistance Programs
For more than 125 years, Boehringer Ingelheim has been focused on improving the lives of patients. In keeping with the company commitment to do the most good for the most people, Boehringer Ingelheim works hard to ensure its medicines are accessible to everyone who needs them, including senior citizens and families on limited incomes. The Boehringer Ingelheim Cares Foundation Patient Assistance Programs (BI-PAP) make Boehringer Ingelheim medicines available free of charge to patients who are without pharmaceutical insurance coverage, and who meet certain household income levels.

About Boehringer Ingelheim Pharmaceuticals, Inc.
Boehringer Ingelheim Pharmaceuticals, Inc., based in Ridgefield, CT, is the largest U.S. subsidiary of Boehringer Ingelheim Corporation (Ridgefield, CT) and a member of the Boehringer Ingelheim group of companies.

The Boehringer Ingelheim group is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 140 affiliates and more than 46,000 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel medications of high therapeutic value for human and veterinary medicine.

As a central element of its culture, Boehringer Ingelheim has a demonstrated commitment to corporate social responsibility. Involvement in social projects, caring for employees and their families, and providing equal opportunities for all employees form the foundation of the global operations. Mutual cooperation and respect, as well as environmental protection and sustainability are intrinsic factors in all of Boehringer Ingelheim’s endeavors.

In 2012, Boehringer Ingelheim achieved net sales of about $19.1 billion (14.7 billion euro). R&D expenditure in the business area Prescription Medicines corresponds to 22.5% of its net sales.

For more information please visit www.us.boehringer-ingelheim.com/

PRADAXA^® is a registered trademark of Boehringer Ingelheim Pharma GmBH and Co. KG and used under license.

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