Boehringer Ingelheim Announces Plans to Expand Body of Evidence with Novel Cardiovascular Research Supporting Pradaxa^® (dabigatran etexilate mesylate)

Ridgefield, CT, September 3, 2013 – Boehringer Ingelheim Pharmaceuticals, Inc. today confirmed research currently underway for Pradaxa^® (dabigatran etexilate mesylate) in new cardiovascular patient populations, as well as robust plans to gather real-world evidence in patients with non-valvular atrial fibrillation (NVAF). These plans are the cornerstone of an initiative to expand the scientific knowledge of stroke prevention and interventional cardiology with PRADAXA and demonstrate BIPI’s leadership and commitment to innovative solutions for patients and healthcare providers.

Initiating new research will help strengthen understanding of the safety and efficacy profile of dabigatran, the longest studied new oral anticoagulant (NOAC). Since its discovery 20 years ago, dabigatran has been evaluated through the extensive RE-VOLUTION^® clinical trial program, which includes 10 clinical trials involving approximately 40,000 patients in more than 44 countries globally.

“We are proud of PRADAXA’s strong foundation of clinical research and market experience. BI is committed to evaluating PRADAXA in new areas of cardiovascular treatment,” said Sabine Luik, M.D., senior vice president, Medicine & Regulatory Affairs, U.S. Regional Medical Director, Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI). “Our collaborations with experts and regulators to build and launch new clinical programs, and our innovative complementary research on real-world data, will help to deepen our understanding of PRADAXA’s benefit/risk profile, address evolving patient needs and benefit the cardiovascular community as a whole.”

The efficacy and safety of PRADAXA to reduce the risk of stroke and systemic embolism in patients with NVAF was established in the pivotal RE-LY trial, one of the largest stroke prevention clinical studies ever conducted with NVAF patients.

To date, dabigatran research has also been conducted in the following areas:

• Prevention of venous thromboembolism (VTE) in patients undergoing elective total hip and knee replacement surgery
• Acute treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE)
• Prevention of recurrent DVT or PE

The company recently announced it submitted applications to U.S. and EU regulatory authorities to review dabigatran for its use in patients with DVT and PE.

In the U.S., PRADAXA is indicated to reduce the risk of stroke and systemic embolism in patients with NVAF.

Current Dabigatran Research Underway
There are currently 12 Boehringer Ingelheim-sponsored trials of dabigatran in progress. These include studies which investigate dabigatran in patients with impaired renal function, as well as pediatric patients, and studies that explore management strategies for gastrointestinal symptoms. 

The company is also investigating BI 655075, a fully humanized antibody fragment (Fab), to determine its potential to reduce dabigatran-induced anticoagulation. Results from pre-clinical research have led to the initiation of a phase 1 clinical trial to analyze BI 655075 in humans.

Looking to the Future of PRADAXA
Boehringer Ingelheim is engaged in discussions with regulatory authorities worldwide regarding clinical trials to further investigate dabigatran in new patient populations. The company plans to announce details of new clinical programs in the near future.

We also remain focused on gathering real-world evidence on PRADAXA. Boehringer Ingelheim has entered into several research agreements to better understand the use of oral anticoagulants, including PRADAXA, in daily clinical practice. This includes an agreement with Brigham and Women’s Hospital to conduct a long-term study program to assess comparative effectiveness and safety, as well as prescribing patterns, of oral anticoagulants, including PRADAXA, for the reduction of stroke risk in U.S. patients with NVAF. Data from this study program will complement the GLORIATM-AF Registry Program, which Boehringer Ingelheim launched in April 2012. GLORIATM-AF is a worldwide registry with the aim of better understanding the long-term use of antithrombotic therapy in the reduction of NVAF-related stroke risk in a real-world setting, outside of the U.S. The GLORIATM-AF Registry Program is expected to be one of the largest worldwide registries and is actively recruiting patients with the aim of including up to 56,000 patients across 2,200 sites in 35 countries.

Boehringer Ingelheim also has a research agreement with the health insurer Humana to conduct real-world clinical analyses. Further, we are working with several other entities to conduct health economic research, including HealthCore, the health outcomes subsidiary of Wellpoint, and the healthcare research consultancy Trinity Partners to assess data from the Department of Defense.

Current Experience with PRADAXA
Prescribing experience with PRADAXA continues to grow with more than two million patient years of real-world experience to reduce the risk of stroke in patients with NVAF, and six million prescriptions for PRADAXA 150 mg and 75 mg filled for more than 800,000 NVAF patients in the U.S. since its approval in October of 2010. PRADAXA 150mg twice daily is the only medication among the new generation of OACs to demonstrate superior reduction of ischemic stroke compared to warfarin in patients with NVAF. Nearly nine out of 10 strokes caused by atrial fibrillation (AFib) are ischemic strokes. PRADAXA also demonstrated a similar rate of major bleeding events, which are serious and sometimes fatal, in patients with NVAF.

In the U.S., PRADAXA is approved by the FDA to reduce the risk of stroke and systemic embolism in patients with NVAF, and was the first oral anticoagulant approved by the FDA in more than 50 years for this indication. PRADAXA is included on formularies that insure about 95 percent of covered lives in the U.S., through commercial and Medicare Part D plans. PRADAXA is also included in recommendations from three leading U.S. cardiology guidelines for stroke prevention in atrial fibrillation (AFib).

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 II 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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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

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