Three pivotal trials showed PRADAXA as non-inferior to warfarin in reduction of DVT and PE recurrence; fourth pivotal trial showed PRADAXA reduced risk of recurrence by 92 percent compared to placebo
RIDGEFIELD, Conn., April 7, 2014 /PRNewswire/ -- Boehringer Ingelheim Pharmaceuticals, Inc. today announced that the U.S. Food and Drug Administration (FDA) has approved Pradaxa® (dabigatran etexilate mesylate) 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. DVT and PE are collectively referred to as venous thromboembolism (VTE). There are an estimated 900,000 DVT and PE events per year in the U.S., approximately one-third of which result in death from PE.
"Venous thromboembolism is the third most common cardiovascular disease after myocardial infarction and stroke. About one-third of patients with a DVT or PE will suffer a recurrence within 10 years," said Samuel Z. Goldhaber, M.D., Director of Brigham and Women's Hospital's Thrombosis Research Group and Professor of Medicine, Harvard Medical School. "Dabigatran has established efficacy and safety for stroke risk reduction in patients with non-valvular atrial fibrillation. This new FDA approval expands dabigatran's indications to include treatment and the reduction of the risk of recurrence of DVT and PE."
The approval is based on results from four global Phase III studies evaluating the efficacy and safety of PRADAXA in the treatment of DVT and PE.
The RE-COVER® and RE-COVER II® trials, which included patients with DVT and PE who were treated with parenteral anticoagulant therapy for five to 10 days, showed PRADAXA was non-inferior to warfarin in reducing DVT and PE after a median of 174 days of treatment, and was associated with lower rates of overall bleeding and a higher rate of any gastrointestinal (GI) bleeding (3.1 percent vs. 2.4 percent). RE-MEDYSM, which included patients who had been previously treated for an acute DVT and PE with anticoagulant therapy for three to 12 months, showed PRADAXA was non-inferior to warfarin in reducing DVT and PE after a median of 534 days of treatment, and was associated with lower rates of overall bleeding and a higher rate of any GI bleeding (3.1 percent vs. 2.2 percent).
RE-SONATE®, which included patients who had been previously treated for an acute DVT and PE with anticoagulant therapy for six to 18 months, showed PRADAXA reduced the risk of DVT and PE recurrence by 92 percent compared to placebo after a median of 182 days of treatment: 0.4 percent vs. 5.6 percent; HR = 0.08 [CI 0.02, 0.25]. PRADAXA was associated with higher rates of any bleeding (10.5 percent vs. 6.1 percent; HR = 1.77 [CI 1.20, 2.61]), clinically relevant non-major bleeding (5.0 percent vs. 2.0 percent; HR = 2.54 [CI 1.34, 4.82]), and GI bleeding (0.7 percent vs. 0.3 percent) compared to placebo.
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. A PE can be life-threatening and requires urgent treatment.The standard of care for patients with a DVT or PE has been acute treatment with parenteral anticoagulation therapy, such as low-molecular-weight heparin [LMWH]), followed by long-term treatment with an oral vitamin K antagonist (e.g., warfarin).
"Deep vein thrombosis and pulmonary embolism can be life-threatening. Boehringer Ingelheim is pleased that patients will now have a new and efficacious therapeutic option for this complex condition," said Sabine Luik, M.D., senior vice president, Medicine & Regulatory Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. "This approval is a testament to our commitment to evaluate PRADAXA in new areas of cardiovascular treatment, in order to address evolving patient needs."
Current Experience with PRADAXA
PRADAXA is also approved to reduce the risk of stroke in patients with non-valvular atrial fibrillation (NVAF), and eight million prescriptions for PRADAXA 150 mg and 75 mg have been filled for more than 850,000 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. PRADAXA also demonstrated a similar rate of major bleeding events.
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).
About Pradaxa® (dabigatran etexilate mesylate) Capsules
Indications and Usage
Pradaxa® (dabigatran etexilate mesylate) capsules is indicated:
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
PRADAXA is contraindicated in patients with:
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
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
Treatment and Reduction in the Risk of Recurrence of DVT/PE
The most serious adverse reactions reported with PRADAXA were related to bleeding.
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 accompanying full Prescribing Information, including boxed WARNING and Medication Guide.
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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.
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PRADAXA® is a registered trademark of Boehringer Ingelheim Pharma GmBH and Co. KG and used under license.
RE-COVER® and RE-COVER II® are registered service marks of Boehringer Ingelheim International GmBH and used under license. RE-MEDYSM is a registered service mark of Boehringer Ingelheim International GmbH and used under license. RE-SONATE® is a registered trademark of Boehringer Ingelheim International GmbH and used under license.
RE-LY® is a registered service mark of Boehringer Ingelheim International GmbH and used under license.
RE-ALIGN® is a trademark of Boehringer Ingelheim International GmbH (BII) and is used in the US by Boehringer Ingelheim Pharmaceuticals, Inc. under license from BII.
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