BI Launches Observational Study on Management of DVT

First patient enrolled in RE-COVERY DVT/PE™, an observational study on blood thinning treatment for acute DVT and PE
Involving 14,000 patients worldwide, the study will collect real-world data on reducing the risk of DVT and PE with PRADAXA

Ridgefield, Conn., March 23, 2016 – Boehringer Ingelheim Pharmaceuticals, Inc. today announced the enrollment of the first patient in RE-COVERY DVT/PE™, a global observational study on the management of blood clots in the legs (deep vein thrombosis, DVT) and in the lungs (pulmonary embolism, PE). The new study will provide insights into how patients with DVT and PE are being treated in real-world clinical practice, and will add to the growing body of data on the effectiveness and safety of Pradaxa® (dabigatran etexilate mesylate) compared to warfarin.

“Large pivotal randomized trials have revolutionized our strategies to manage and reduce the risk of deep vein thrombosis (DVT) and pulmonary embolism (PE). However, it remains uncertain whether the results of these trials impact everyday clinical practice in the ‘real world.’ We are launching RE-COVERY DVT/PE, an exciting new global prospective observational cohort study, to learn more about DVT and PE patient treatments and outcomes,” said Professor Samuel Z. Goldhaber, MD, Professor of Medicine at Harvard Medical School, Section Head of Vascular Medicine at Brigham and Women’s Hospital, and Chair of the RE-COVERY DVT/PE Steering Committee.

A DVT occurs when a blood clot blocks the normal flow of blood through a vein, usually in the leg or pelvis, which may lead to swelling or pain in the affected leg. A PE occurs when a DVT, or part of it, breaks off and travels through the bloodstream to the lungs, blocking a vessel. The symptoms of a PE include shortness of breath and chest pain. It may also cause other symptoms like cough, rapid heart rate and dizziness. Treatment for patients with DVT and/or PE includes anticoagulation therapy, like novel oral anticoagulants, low-molecular-weight heparin or vitamin K antagonists such as warfarin, which are used to reduce the risk of blood clots recurring and existing ones from growing. There are an estimated 900,000 VTE events per year in the U.S., approximately one-third of which result in death from PE.

PRADAXA was approved for the treatment of DVT and 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.

The overall Boehringer Ingelheim research program for PRADAXA, which includes the RE-COVERY DVT/PE study, will involve more than 120,000 patients worldwide across cardiovascular-related therapy areas, including stroke risk reduction in atrial fibrillation. The aim of the research program is to deepen the science behind effective clot prevention and provide everyday support for patient management.

About RE-COVERY DVT/PE™
RE-COVERY DVT/PE will enroll up to 14,000 DVT/PE patients. Following a DVT or PE diagnosis, patients will be categorized according to the anticoagulant treatment they receive. Those receiving either dabigatran 110mg or 150mg twice daily or warfarin will be followed for up to one year. In addition to collecting data on patient characteristics including patient history and treatment patterns, RE-COVERY DVT/PE will evaluate the incidence of bleeding rates and recurrent symptomatic DVT/PE.

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
for the prophylaxis of deep vein thrombosis and pulmonary embolism in patients who have undergone hip replacement surgery

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 and restart PRADAXA as soon as medically appropriate.

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 (idarucizumab) for dabigatran is available when reversal of the anticoagulant effect of dabigatran is needed:
- For emergency surgery/urgent procedures
- In life-threatening or uncontrolled bleeding

Hemodialysis can remove dabigatran; however clinical experience for hemodialysis as a treatment for bleeding is limited. Prothrombin complex concentrates or recombinant Factor VIIa 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), reduce 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 & Prophylaxis of DVT/PE Following Hip Replacement Surgery

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 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 in PRADAXA patients [1 (0.32/100 patient-years)] vs placebo [1 (0.34/100 patient-years)]
GI adverse reactions were similar in patients receiving PRADAXA 150 mg vs warfarin. They were 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)

DVT/PE After Hip Replacement Surgery

Rate of major GI bleeds in patients receiving PRADAXA 220 mg and enoxaparin was the same; rate of any GI bleeds was higher in patients receiving PRADAXA 220 mg vs enoxaparin
GI adverse reactions were the same in patients receiving PRADAXA 220 mg vs enoxaparin. These were 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)
Clinical MI was reported in 2 (0.1%) patients who received PRADAXA 220 mg and 6 (0.3%) patients who received enoxaparin

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
Boehringer Ingelheim Pharmaceuticals, Inc., based in Ridgefield, CT, is the largest U.S. subsidiary of Boehringer Ingelheim Corporation.

Boehringer Ingelheim is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, the company operates globally with 146 affiliates and more than 47,000 employees. Since its founding in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel treatments for human and veterinary medicine.

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Boehringer Ingelheim Pharmaceuticals, Inc. either owns or uses the trademarks Pradaxa®, RE-COVERY™, RE-LY®, RE-COVER®, RE-COVER II™ and RE-MEDY™ under license.

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