Boehringer Ingelheim announces comprehensive settlement of U.S. Pradaxa® (dabigatran etexilate mesylate) litigation

Ridgefield, CT, May 28, 2014 – Boehringer Ingelheim (BI) announced today that it has reached a comprehensive settlement of state and federal cases in the U.S. litigation regarding Pradaxa® (dabigatran etexilate mesylate) in the amount of $650 million.

"Time and again, the benefits and safety of PRADAXA have been confirmed," said Desiree Ralls-Morrison, senior vice president and general counsel, Boehringer Ingelheim USA Corporation. "BI stands resolutely behind PRADAXA and believed from the outset that the plaintiffs’ claims lacked merit. Notwithstanding our strong belief that we would prevail in these lawsuits, this settlement allows BI to avoid the distraction and uncertainty of lengthy litigation and focus on our mission of improving patients’ lives."

BI is proud of its employees who have worked for years to research, develop and offer to patients such an important medication as PRADAXA. PRADAXA was the first oral anticoagulant approved by FDA in more than 50 years to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF).

"This settlement does not change the facts about PRADAXA or its importance to patients. From the time PRADAXA launched, BI properly advised doctors and patients about its benefits and safety, working closely with FDA, European Medicines Agency (EMA) and other regulators to ensure doctors and patients had the information they needed," said Desiree Ralls-Morrison.

There are approximately 4,000 claims that the company seeks to resolve with this settlement. BI expects most, if not all, of the plaintiffs to accept the terms of the settlement and BI will vigorously defend against those who do not.

PRADAXA is the only oral anticoagulant shown to be superior to warfarin in reducing ischemic strokes, with a similar rate of major bleeding events. Ischemic strokes account for nearly nine out of every 10 strokes caused by atrial fibrillation. PRADAXA’s efficacy and safety was established in the pivotal RE-LY® trial, one of the largest stroke prevention clinical studies ever conducted in patients with NVAF.

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 NVAF patients. On May 13, 2014, FDA once again reaffirmed PRADAXA’s positive benefit-risk profile when it issued a Drug Safety Communication that included results from a Medicare study comparing new users of PRADAXA and warfarin who had received a diagnosis of atrial fibrillation. This included more than 134,000 Medicare patients, who were 65 years or older. The new study found that, among new users of blood-thinning drugs, PRADAXA was associated with a lower risk of clot-related strokes, bleeding in the brain and death compared to warfarin. The study also found an increased risk of major gastrointestinal bleeding with use of PRADAXA as compared to warfarin, but unlike in RE-LY, no increased risk of MI compared to warfarin.

As with any anticoagulant, there needs to be a balanced consideration of stroke risk reduction and bleeding risk. Patients should not stop taking their anticoagulant medication without first talking to their health care providers. Discontinuing anticoagulation therapy puts a patient at increased risk of stroke.

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 vein 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 vein 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 Stroke with Discontinuation of PRADAXA
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.

Spinal/Epidural Anesthesia or Puncture
When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulants are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis. To reduce potential risk of bleeding with concurrent use of dabigatran and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of dabigatran. Placement/removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of dabigatran is low but exact timing to reach a sufficiently low anticoagulant effect in each patient is unknown. If anticoagulation is administered with epidural or spinal anesthesia/analgesia or lumbar puncture, monitor frequently for signs/symptoms of neurological impairment, i.e., midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to immediately report if they experience any of the above signs/symptoms. If spinal hematoma is suspected, initiate urgent diagnosis and treatment; consider spinal cord decompression even though it may not prevent or reverse neurological sequelae.

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
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.
NVAF

• Most frequent adverse reactions leading to discontinuation of PRADAXA were bleeding & gastrointestinal (GI) events
• PRADAXA 150 mg resulted in higher rates of major and any GI bleeds compared to warfarin.
• In patients ≥75 years of age, the risk of major bleeding may be greater with PRADAXA vs 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).

DVT/PE

• Rates of any GI bleeds were higher in patients receiving PRADAXA 150 mg vs warfarin and placebo
• In the active-controlled studies, there was a higher rate of clinical myocardial infarction (MI) in PRADAXA patients [20 (0.66/100) patient-years)] vs warfarin [5 (0.17/100 patient-years)]. In the placebo-controlled study, there was similar rate of non-fatal and fatal clinical MI PRADAXA patients [1 (0.32/100 patient-years)] vs warfarin [1 (0.34/100 patient-years)].
• GI adverse reactions were similar in patients receiving PRADAXA 150 mg vs warfarin. They were commonly dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort) and gastritis-like symptoms (including gastritis, GERD, esophagitis, erosive gastritis and gastric hemorrhage).

Drug hypersensitivity reactions were reported in ≤ 0.1% of patients receiving PRADAXA.

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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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 service mark of Boehringer Ingelheim International GmbH and used under license.