ESC Hot Line: Data Reports NVAF Patients Taking Pradaxa^® (dabigatran etexilate mesylate) Experienced Slower Decline in Kidney Function Compared to Those on Warfarin

Ridgefield, CT, September 2, 2014 – Boehringer Ingelheim Pharmaceuticals, Inc. today announced results from a new post-hoc sub-analysis of the pivotal phase III RE-LY^® trial assessing renal function change in patients with non-valvular atrial fibrillation (NVAF) treated with Pradaxa^® (dabigatran etexilate mesylate) compared to warfarin. The findings suggest that patients treated with PRADAXA experienced a slower decline in kidney function compared to those being treated with warfarin, with the slower decline most marked in patients treated with PRADAXA who had mild kidney impairment at the start of the RE-LY trial. The results were presented today during the European Society of Cardiology (ESC) Congress 2014.

“Kidney function depends on various health factors and naturally declines as we age, but research suggests the use of warfarin or other vitamin K antagonists could be associated with increased calcification of renal arteries, which may accelerate that decline,” said lead investigator Michael Böhm, MD, professor of internal medicine and cardiology and director of internal medicine at Saarland University, Homburg, Germany. “The findings suggesting that the decline in kidney function is slower in patients taking PRADAXA are thought-provoking and require further investigation to determine their clinical relevance, particularly with regards to patients who may already have mild kidney impairment.”

The new findings were based on a post-hoc sub-analysis of data collected from 18,113 NVAF patients who participated in RE-LY. Kidney function assessments were conducted at baseline; at three, six and 12 months; and annually thereafter or at the final physician visit. Patient kidney function was estimated by using blood levels of creatinine, a body waste product, to calculate the “glomerular filtration rate” (GFR) – or the amount of blood that passes through the kidney’s filtering units (glomeruli) per minute. Normal GFR values are 90 mL/min or greater.

Results were more pronounced the longer the study continued and were different at 30 months (3.68 mL/min for warfarin vs. 2.46 mL/min for PRADAXA 150 mg). More patients treated with warfarin had a 20 percent or greater decline in kidney function after one year than patients on PRADAXA (hazard ratio [HR] 0.84, 95 percent confidence interval [CI] 0.73-0.98). Patients treated with warfarin who were more frequently above the INR range showed a sharper decline as early as six months, which continued through the remainder of the study.

The researchers noted it is unclear why patients on PRADAXA showed an early decline in renal function relative to warfarin and cited the following study limitations:

• Retrospective hypothesis-generating analysis
• Only 40 percent of patients had kidney function values at 30 months, which could cause bias in the analysis
• Time-dependent interaction between treatment groups, including a delay in the ability to detect differences

“This post-hoc sub-analysis of data from the pivotal phase III RE-LY trial is the first pivotal phase III data analysis evaluating the effects of a newer oral anticoagulant compared to warfarin on the effect of kidney function in NVAF patients over an average follow-up of two or more years,” said Sabine Luik, M.D., senior vice president, Medicine & Regulatory Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. “This post-hoc sub-analysis is part of Boehringer Ingelheim’s overall commitment to address the needs of patients, particularly NVAF patients who have co-existing medical conditions that may negatively impact their kidney function, such as diabetes, high blood pressure and vascular disease.”

Current Experience with PRADAXA
PRADAXA is approved to reduce the risk of stroke and systemic embolism in patients with NVAF, for the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients who have been treated with a parenteral anticoagulant for five to 10 days and to reduce the risk of recurrent DVT and PE in patients who have been previously treated. Eight million prescriptions for PRADAXA 150 mg and 75 mg have been filled for more than 850,000 NVAF patients in the United States since its approval in October of 2010.

PRADAXA 150 mg twice daily is the only oral anticoagulant to demonstrate superior reduction of ischemic stroke compared to warfarin in patients with NVAF. PRADAXA also demonstrated a similar rate of major bleeding events. Ischemic strokes are the most common type of stroke that NVAF patients experience.

The efficacy and safety of PRADAXA in NVAF were established in the RE-LY^® trial, one of the largest stroke prevention clinical studies ever conducted with NVAF patients. The 18,113-patient RE-LY trial showed that, compared to well-controlled warfarin (N=6,022), PRADAXA 150 mg (N=6,076) significantly reduced the risk of stroke and systemic embolism by 35 percent (primary efficacy endpoint: 134 [2.2%] vs. 202 [3.4%] events, HR: 0.65, 95% CI [0.52, 0.81], P=0.0001), ischemic stroke by 25 percent (103 [1.7%] vs. 134 [2.2%] events, HR: 0.75, 95% CI [0.58, 0.97], P=0.0296) and hemorrhagic stroke by 74 percent (12 [0.2%] vs. 45 [0.8%] events, HR: 0.26, 95% CI [0.14, 0.49], P<0.0001). The rate of all-cause mortality was lower with PRADAXA 150 mg than with warfarin (3.6 percent per year versus 4.1 percent per year). PRADAXA had a higher rate of total gastrointestinal bleeds (6.1% vs. 4.0%) and major GI bleeds (1.6% vs. 1.1%; 50 percent increased risk with the 150 mg dose compared to warfarin). Treatment with PRADAXA 150 mg led to a 59 percent reduction in intracranial hemorrhage, compared to warfarin (38 vs. 90), and showed numerically lower rates of fatal and life-threatening bleeds (28 vs. 39 and 179 vs. 218, respectively).

Through the PradaxaLink^™ program, patients, caregivers and healthcare providers can access a variety of valuable resources and 24-hour support regarding PRADAXA medication.

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.

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 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.

PradaxaLink^™ is a trademark of Boehringer Ingelheim Pharmaceuticals, Inc.

PX629810PR