FDA files supplemental New Drug Application for Boehringer Ingelheim’s Pradaxa (dabigatran etexilate mesylate) for the prophylaxis of deep venous thrombosis and pulmonary embolism after hip replacement surgery

Ridgefield, CT, April 6, 2015 – Boehringer Ingelheim Pharmaceuticals, Inc. today announced that the U.S. Food and Drug Administration (FDA) filed a supplemental New Drug Application (sNDA) for Pradaxa® (dabigatran etexilate mesylate) for the prophylaxis of deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients who have had primary elective total hip replacement surgery. If approved, this will become the fourth indication for PRADAXA.

It is estimated that nearly 300,000 total hip replacement surgeries are performed each year in the United States. Without prophylaxis (e.g., anticoagulation treatment to prevent blood clots), the incidence of DVT detected by venography (x-ray visualization of the veins after administering injectable contrast dye) ranges from 40 percent to 60 percent of primary elective hip surgery patients, and fatal PE occurs in approximately one of 500 patients.

“Total hip replacement is a common procedure, and preventive anticoagulant treatment is recommended because of the potential for DVT and PE, which can be life-threatening for some patients,” said Sabine Luik, MD, senior vice president, Medicine & Regulatory Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. “The acceptance of this sNDA is another step toward expanding the therapeutic uses for PRADAXA to improve patient outcomes in this population.”

The submission to the FDA is based on the results of two randomized, double-blind, phase III trials, RE-NOVATE^TM and RE-NOVATE^TM II. The studies compared the efficacy and safety of PRADAXA to enoxaparin in preventing venous thromboembolism (VTE) and death in patients undergoing total hip replacement surgery.

In RE-NOVATE, 3,494 patients having primary elective total hip replacement 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. The enoxaparin group was given a dose of 40 mg the day before surgery and daily thereafter.

The results showed patients taking PRADAXA 220 mg had a lower composite total of VTE (VTE comprises DVT and PE) and all-cause death (6.0 percent) than those on PRADAXA 150 mg (8.6 percent) and on enoxaparin 40 mg (6.7 percent). There was no significant difference in the rates of major bleeding among all treatment groups: 2.0 percent for PRADAXA 220 mg, 1.3 percent for PRADAXA 150 mg and 1.6 percent for enoxaparin 40 mg. The most common adverse events were gastrointestinal disorders, with similar frequencies in all treatment groups (PRADAXA 220 mg, 44.2 percent; PRADAXA 150 mg, 44.0 percent; enoxaparin 40 mg, 44.8 percent). Treatment with PRADAXA resulted in higher rates of wound secretion than enoxaparin (8.9 percent with PRADAXA 220 mg and 8.3 percent with PRADAXA 150 mg vs. 5.5 percent with enoxaparin).

In RE-NOVATE II, 2,055 patients undergoing primary elective total hip replacement 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 enoxaparin group was given a dose of 40 mg the day before surgery and daily thereafter. The results showed 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 was no difference in major bleeding rates between the two treatments (1.4 percent for patients on PRADAXA and 0.9 percent for patients on enoxaparin). Gastrointestinal disorders were the most frequent adverse events in the study, and were similar in both treatment groups (35.8 percent of PRADAXA patients vs. 35.7 percent of enoxaparin patients). The incidence of wound secretion was slightly higher for patients on PRADAXA (2.7 percent) than on enoxaparin (1.2 percent).

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

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.

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 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 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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About Boehringer Ingelheim Pharmaceuticals, Inc.

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Pradaxa® and PRADAXA with associated design® are registered trademarks of Boehringer Ingelheim Pharma GmbH and Co. KG and used under license.