Pradaxa Approved for Stroke Prevention in Atrial Fibrillation Patients

The Food and Drug Administration approved the direct thrombin inhibitor dabigatran (Pradaxa) on Oct. 19 to prevent stroke and blood clots in people with atrial fibrillation.

It is the first approval of an oral anticoagulant in more than 50 years.

About 2 million Americans have atrial fibrillation, and that condition puts them at a “higher risk of developing blood clots, which can cause a disabling stroke if the clots travel to the brain,” Dr. Norman Stockbridge, director of the division of cardiovascular and renal products in the FDA’s Center for Drug Evaluation and Research, said in a written statement.

Dabigatran, manufactured by Boehringer Ingelheim Pharmaceuticals Inc., will be distributed in 75-mg and 150-mg capsules. Dosage recommendations are based on the patient’s creatinine clearance: For patients with a creatinine clearance greater than 30 mL/min, the recommended dosage is 150 mg twice daily; for those with a level of 15-30 mL/min, the recommended dosage is 75 mg twice daily. There is no dosage recommendation for those with a creatinine clearance below 15 mL/min.

The medication does not require periodic international normalized ratio (INR) testing of patients, as is required for those taking warfarin, Dr. Stockbridge said. Patients converting from warfarin to dabigatran should discontinue warfarin and start dabigatran when their INR is below 2.0, according to the prescribing information.

The approval was based on the results of the Randomized Evaluation of Long Term Anticoagulant Therapy (RE-LY) trial, a noninferiority study of 18,113 patients with nonvalvular atrial fibrillation and at least one other risk factor for stroke. The annual rate of stroke and systemic embolism in RE-LY was 1.5% among the patients on the 110-mg dose and 1.1% among those on the 150-mg dose, compared with 1.7% among those on warfarin, representing risk reductions of 10% and 35% for the 110-mg and 150-mg doses, compared with warfarin. Both doses of dabigatran were considered noninferior to warfarin for preventing stroke and systemic embolism, and the 150-mg dose was more effective than warfarin and the 110-mg dose in preventing stroke and systemic embolism, according to the trial’s sponsor, Boehringer Ingelheim. Both doses were associated with a reduction in hemorrhagic stroke, and compared with warfarin, the higher dose was associated with a reduction in vascular death risk.

The 150-mg dose was associated with a significantly increased risk of major GI bleeding, compared with warfarin, but also with a significant reduction in life-threatening and total bleeding. In a September meeting of the FDA’s Cardiovascular and Renal Drugs Advisory Committee, the panel agreed that the study provided strong evidence that both dabigatran doses studied had clearly been shown to be noninferior to warfarin therapy in the study, and several said they believed the 150-mg dose had been shown to be superior to warfarin. That committee voted unanimously that dabigatran should be approved.

Because dabigatran carries a risk of serious bleeding, a medication guide describing this risk will be given to patients who take it. Other less serious reactions included gastrointestinal symptoms such as dyspepsia, stomach pain, nausea, heartburn, and bloating, the FDA statement said.

The Food and Drug Administration approved the direct thrombin inhibitor dabigatran (Pradaxa) on Oct. 19 to prevent stroke and blood clots in people with atrial fibrillation.

It is the first approval of an oral anticoagulant in more than 50 years.

About 2 million Americans have atrial fibrillation, and that condition puts them at a “higher risk of developing blood clots, which can cause a disabling stroke if the clots travel to the brain,” Dr. Norman Stockbridge, director of the division of cardiovascular and renal products in the FDA’s Center for Drug Evaluation and Research, said in a written statement.

Dabigatran, manufactured by Boehringer Ingelheim Pharmaceuticals Inc., will be distributed in 75-mg and 150-mg capsules. Dosage recommendations are based on the patient’s creatinine clearance: For patients with a creatinine clearance greater than 30 mL/min, the recommended dosage is 150 mg twice daily; for those with a level of 15-30 mL/min, the recommended dosage is 75 mg twice daily. There is no dosage recommendation for those with a creatinine clearance below 15 mL/min.

The medication does not require periodic international normalized ratio (INR) testing of patients, as is required for those taking warfarin, Dr. Stockbridge said. Patients converting from warfarin to dabigatran should discontinue warfarin and start dabigatran when their INR is below 2.0, according to the prescribing information.

The approval was based on the results of the Randomized Evaluation of Long Term Anticoagulant Therapy (RE-LY) trial, a noninferiority study of 18,113 patients with nonvalvular atrial fibrillation and at least one other risk factor for stroke. The annual rate of stroke and systemic embolism in RE-LY was 1.5% among the patients on the 110-mg dose and 1.1% among those on the 150-mg dose, compared with 1.7% among those on warfarin, representing risk reductions of 10% and 35% for the 110-mg and 150-mg doses, compared with warfarin. Both doses of dabigatran were considered noninferior to warfarin for preventing stroke and systemic embolism, and the 150-mg dose was more effective than warfarin and the 110-mg dose in preventing stroke and systemic embolism, according to the trial’s sponsor, Boehringer Ingelheim. Both doses were associated with a reduction in hemorrhagic stroke, and compared with warfarin, the higher dose was associated with a reduction in vascular death risk.

The 150-mg dose was associated with a significantly increased risk of major GI bleeding, compared with warfarin, but also with a significant reduction in life-threatening and total bleeding. In a September meeting of the FDA’s Cardiovascular and Renal Drugs Advisory Committee, the panel agreed that the study provided strong evidence that both dabigatran doses studied had clearly been shown to be noninferior to warfarin therapy in the study, and several said they believed the 150-mg dose had been shown to be superior to warfarin. That committee voted unanimously that dabigatran should be approved.

Because dabigatran carries a risk of serious bleeding, a medication guide describing this risk will be given to patients who take it. Other less serious reactions included gastrointestinal symptoms such as dyspepsia, stomach pain, nausea, heartburn, and bloating, the FDA statement said.

The Food and Drug Administration approved the direct thrombin inhibitor dabigatran (Pradaxa) on Oct. 19 to prevent stroke and blood clots in people with atrial fibrillation.

It is the first approval of an oral anticoagulant in more than 50 years.

About 2 million Americans have atrial fibrillation, and that condition puts them at a “higher risk of developing blood clots, which can cause a disabling stroke if the clots travel to the brain,” Dr. Norman Stockbridge, director of the division of cardiovascular and renal products in the FDA’s Center for Drug Evaluation and Research, said in a written statement.

Dabigatran, manufactured by Boehringer Ingelheim Pharmaceuticals Inc., will be distributed in 75-mg and 150-mg capsules. Dosage recommendations are based on the patient’s creatinine clearance: For patients with a creatinine clearance greater than 30 mL/min, the recommended dosage is 150 mg twice daily; for those with a level of 15-30 mL/min, the recommended dosage is 75 mg twice daily. There is no dosage recommendation for those with a creatinine clearance below 15 mL/min.

The medication does not require periodic international normalized ratio (INR) testing of patients, as is required for those taking warfarin, Dr. Stockbridge said. Patients converting from warfarin to dabigatran should discontinue warfarin and start dabigatran when their INR is below 2.0, according to the prescribing information.

The approval was based on the results of the Randomized Evaluation of Long Term Anticoagulant Therapy (RE-LY) trial, a noninferiority study of 18,113 patients with nonvalvular atrial fibrillation and at least one other risk factor for stroke. The annual rate of stroke and systemic embolism in RE-LY was 1.5% among the patients on the 110-mg dose and 1.1% among those on the 150-mg dose, compared with 1.7% among those on warfarin, representing risk reductions of 10% and 35% for the 110-mg and 150-mg doses, compared with warfarin. Both doses of dabigatran were considered noninferior to warfarin for preventing stroke and systemic embolism, and the 150-mg dose was more effective than warfarin and the 110-mg dose in preventing stroke and systemic embolism, according to the trial’s sponsor, Boehringer Ingelheim. Both doses were associated with a reduction in hemorrhagic stroke, and compared with warfarin, the higher dose was associated with a reduction in vascular death risk.

The 150-mg dose was associated with a significantly increased risk of major GI bleeding, compared with warfarin, but also with a significant reduction in life-threatening and total bleeding. In a September meeting of the FDA’s Cardiovascular and Renal Drugs Advisory Committee, the panel agreed that the study provided strong evidence that both dabigatran doses studied had clearly been shown to be noninferior to warfarin therapy in the study, and several said they believed the 150-mg dose had been shown to be superior to warfarin. That committee voted unanimously that dabigatran should be approved.

Because dabigatran carries a risk of serious bleeding, a medication guide describing this risk will be given to patients who take it. Other less serious reactions included gastrointestinal symptoms such as dyspepsia, stomach pain, nausea, heartburn, and bloating, the FDA statement said.