Boehringer Ingelheim Initiates U.S. Sites in First-Ever Global Phase III Trial of Investigational Antidote in Patients Taking PRADAXA^®(dabigatran etexilate mesylate)

Ridgefield, CT, November 10, 2014 – Boehringer Ingelheim Pharmaceuticals, Inc. today announced the initiation of U.S. sites of the RE-VERSE AD^™ trial (NCT02104947), a phase III global study investigating idarucizumab* in actual clinical settings where Pradaxa^® (dabigatran etexilate mesylate) patients may require emergency intervention or experience an uncontrolled or life-threatening bleeding event. Idarucizumab is an investigational humanized antibody fragment (Fab) being studied as a specific antidote for PRADAXA. This is the first-ever trial to investigate an antidote in patients actively being treated with a newer oral anticoagulant.

“Studies of idarucizumab in animal models and in healthy human volunteers suggest that administration of idarucizumab results in immediate, complete and sustained reversal of the anticoagulant effects of PRADAXA,” said Dr. Charles Pollack, Professor of Emergency Medicine at the Perelman School of Medicine at the University of Pennsylvania, Chairman of Emergency Medicine at Pennsylvania Hospital in Philadelphia and lead investigator of the patient study. “RE-VERSE AD will help further inform the effects of idarucizumab in real-world situations where the antidote could be a potential therapeutic option in very specific, and typically rare, clinical settings involving patients treated with PRADAXA.”

Based on the low rates of life-threatening bleeding observed in the RE-LY^® trial, and as seen in post-marketing safety data, Boehringer Ingelheim anticipates enrollment may take an extended period. As a result, RE-VERSE AD is being conducted in more than 35 countries and will aim to enroll a total of 250 patients.

“This trial is the next step in the development of idarucizumab, which began prior to regulatory approval of PRADAXA in 2010,” said Sabine Luik, M.D., senior vice president, Medicine & Regulatory Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. “While PRADAXA’s favorable risk-benefit profile has been well-established in clinical trials and reinforced through real-world analyses without an antidote, BI is committed to offering healthcare providers an additional therapeutic option to be considered should a patient require emergency intervention or if a patient experiences uncontrolled bleeding.”

High-level data from the first study in healthy human volunteers, presented at the American Heart Association’s (AHA) Scientific Sessions in November 2013, showed that intravenous administration of idarucizumab resulted in immediate, complete and sustained reversal of the anticoagulation effects of PRADAXA. In a placebo-controlled study, idarucizumab did not cause any clinically relevant side effects. No pro-thrombotic effect was observed after the administration of idarucizumab and no return of anticoagulant activity of PRADAXA was seen over time at adequate doses.

In June 2014, the U.S. Food and Drug Administration granted Breakthrough Therapy Designation to idarucizumab. Boehringer Ingelheim plans to present additional data analyses from healthy human volunteer trials at the upcoming AHA Scientific Sessions and American Society of Hematology Annual Meeting in November and December 2014.

About Idarucizumab
Idarucizumab is a humanized antibody fragment, or Fab, being investigated as a specific antidote for the anticoagulant effect of PRADAXA. Pre-clinical studies indicate idarucizumab binds specifically to and inhibits dabigatran with no other expected interactions.

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;
• for the treatment of deep venous thrombosis and pulmonary embolism in patients who have been treated with a parenteral anticoagulant for 5-10 days;
• to reduce the risk of recurrence of deep venous thrombosis and pulmonary embolism in patients who have been previously treated

IMPORTANT SAFETY INFORMATION ABOUT PRADAXA

WARNING: (A) PREMATURE DISCONTINUATION OF PRADAXA INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA

(A) PREMATURE DISCONTINUATION OF PRADAXA INCREASES THE RISK OF THROMBOTIC EVENTS
Premature discontinuation of any oral anticoagulant, including PRADAXA, increases the risk of thrombotic events. If anticoagulation with PRADAXA is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant  
(B) SPINAL/EPIDURAL HEMATOMA
Epidural or spinal hematomas may occur in patients treated with PRADAXA who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include:

• use of indwelling epidural catheters
• concomitant use of other drugs that affect hemostasis, such as non-steroidal anti‑inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants
• a history of traumatic or repeated epidural or spinal punctures
• a history of spinal deformity or spinal surgery
• optimal timing between the administration of PRADAXA and neuraxial procedures is not known

Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.  Consider the benefits and risks before neuraxial intervention in patients who are or will be anticoagulated.

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 Thrombotic Events after Premature Discontinuation
Premature discontinuation of any oral anticoagulant, including PRADAXA, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events.  If PRADAXA is discontinued for a reason other than pathological bleeding or completion of a course of therapy, 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.
• Reversal of Anticoagulant Effect: 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 use of PRADAXA is contraindicated in patients with mechanical prosthetic valves due to a higher risk for thromboembolic events, especially in the post-operative period, and an excess of major bleeding for PRADAXA vs. warfarin. 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
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.
Reduction of Risk of Stroke/Systemic Embolism in NVAF

• 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.

Treatment and Reduction in the Risk of Recurrence of DVT/PE

• For patients with CrCl <50 mL/min, avoid use of PRADAXA and concomitant P-gp inhibitors

ADVERSE REACTIONS
The most serious adverse reactions reported with PRADAXA were related to bleeding.

Other Measures Evaluated
In NVAF patients, a higher rate of clinical MI was reported in patients who received PRADAXA (0.7/100 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.

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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 142 affiliates and more than 47,400 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.

Social responsibility is a central element of Boehringer Ingelheim's culture. 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 2013, Boehringer Ingelheim achieved net sales of about $18.7 billion (14.1 billion euro). R&D expenditure in the Prescription Medicines business corresponds to 19.5% 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.

RE-LY^® is a registered trademark of Boehringer Ingelheim International GmbH and used under license.

* Idarucizumab is the proposed International Nonproprietary Name (pINN).

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