FDA Approves Pradaxa® (dabigatran etexilate mesylate) for Prophylaxis of Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) after Hip Replacement Surgery

RIDGEFIELD, Conn., November 23, 2015 – Boehringer Ingelheim Pharmaceuticals, Inc. today announced that the U.S. Food and Drug Administration (FDA) approved Pradaxa® (dabigatran etexilate mesylate) for the prophylaxis of deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients who have undergone hip replacement surgery. There are an estimated 300,000 total hip replacement surgeries performed in the U.S. each year. Without preventive anticoagulant treatment, the incidence of DVT ranges from 40 to 60 percent for primary elective hip surgery patients.

“This milestone represents the fourth FDA-approved indication for PRADAXA in five years — a testament to the company’s continued leadership in the evolution of anticoagulation care for patients and clinicians,” said Sabine Luik, MD, senior vice president, Medicine & Regulatory Affairs, Boehringer Ingelheim. “PRADAXA has the longest real-world experience of any novel oral anticoagulant, and we are dedicated to ongoing research. Physicians and patients choosing PRADAXA may have added assurance knowing that it is the only novel oral anticoagulant with more than five years of use in clinical practice and a specific reversal agent.”

The FDA approval is based on the results of two randomized, double-blind, phase III trials in patients undergoing total hip replacement, RE-NOVATE™ and RE-NOVATE II™. In RE-NOVATE, 3,494 patients were randomized to three groups receiving prophylactic treatment with one of two doses of PRADAXA (220 mg or 150 mg) once daily or enoxaparin 40 mg once daily for 28 to 35 days. The first PRADAXA group was given a dose of 110 mg on the day of surgery and 220 mg daily thereafter; the second PRADAXA group received a dose of 75 mg on the day of surgery and 150 mg daily thereafter. In RE-NOVATE II, 2,055 patients were randomly assigned prophylactic treatment for 28 to 35 days with PRADAXA 220 mg once daily or enoxaparin 40 mg once daily. Patients receiving PRADAXA were treated with a dose of 110 mg on the day of surgery and 220 mg daily thereafter. The results of RE-NOVATE showed patients taking PRADAXA 220 mg had a lower composite total of venous thromboembolism (VTE, which comprises DVT and PE) and all-cause death (6.0 percent) than those on enoxaparin 40 mg (6.7 percent). In RE-NOVATE II, the composite total of VTE and all-cause death occurred in 7.7 percent of patients in the PRADAXA group vs. 8.8 percent of patients in the enoxaparin group. 

There were higher rates of major bleeding in RE-NOVATE (2.0%, 1.6%) and RE-NOVATE II (1.4%, 0.9%) with 220 mg vs. enoxaparin. In the two studies, the rate of major gastrointestinal bleeds in patients receiving PRADAXA and enoxaparin was the same (0.1%) and for any gastrointestinal bleeds was 1.4% for PRADAXA and 0.9% for enoxaparin. The most common adverse events in both studies were gastrointestinal disorders. Incidence was the same across the PRADAXA and enoxaparin treatment groups (39.5%). Dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort) occurred more frequently among patients receiving PRADAXA (4.1%) compared to enoxaparin (3.8%). Gastritis-like symptoms (including gastritis, GERD, esophagitis, erosive gastritis and gastric hemorrhage) were less common in patients receiving PRADAXA (0.6%) compared to enoxaparin (1.0%). Clinical MI was reported in 2 (0.1%) PRADAXA patients and 6 (0.3%) enoxaparin patients.

“Many Americans will undergo hip replacement surgery each year. Proactive anticoagulation is vital for reducing the risk of VTE in these patients and helping to improve patient outcomes,” said Samuel Z. Goldhaber, MD, Director of Brigham and Women’s Hospital’s Thrombosis Research Group and Professor of Medicine, Harvard Medical School. “The FDA approval of this new indication for PRADAXA will help address an important public health need and provide a new therapeutic option for this large patient population.”

PRADAXA was initially approved by the FDA in 2010 to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF). In 2014, the FDA approved two additional indications for PRADAXA 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.

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.

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. either owns or uses the trademarks Pradaxa® and PRADAXA with associated design®, RE-NOVATE™ and RE-NOVATE II™ under license.

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