Pradaxa® (dabigatran etexilate mesylate) capsules is indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.
In non-valvular atrial fibrillation (NVAF)
The clinical evidence for the efficacy of PRADAXA was derived from the RE-LY (Randomized Evaluation of Long-term anticoagulant therapY) trial2,3
Objective2
- To determine if PRADAXA was non-inferior to warfarin in reducing the occurrence of the composite endpoint, stroke (ischemic and hemorrhagic) and systemic embolism
- Statistical superiority was also analyzed
Inclusion Criteria2,3
- Non-valvular AF documented by electrocardiogram on the day of screening or within 6 months
- Paroxysmal, persistent, or permanent AF
- One or more of the following additional risk factors:
- Previous stroke, transient ischemic attack (TIA), or systemic embolism
- Left ventricular ejection fraction <40%
- Symptomatic heart failure, ≥New York Heart Association Class 2
- Age ≥75 years
- Age ≥65 years and one of the following: diabetes mellitus, coronary artery disease (CAD), or hypertension
Patient Population2,3
- Mean age was 71.5 years and mean CHADS2 score was 2.1
- Demographics: 64% male, 70% Caucasian, 16% Asian, and 1% black
- Comorbidities: 20% history of a stroke or TIA, 79% hypertension, 23% diabetes, and 28% CAD
- At baseline, 40% were on aspirin and 6% were on clopidogrel
- 50% were warfarin naive, defined as less than 2 months total lifetime exposure to warfarin
- 32% had never been exposed to warfarin
- 21% of patients in the RE-LY trial had valve disease that was not severe enough to meet the criterion of being hemodynamically relevant4
- Patients were not expected to need surgical intervention over the course of the trial
- Patients were excluded from the RE-LY trial if they had a prosthetic valve or had hemodynamically relevant valve disease
Study Design2,3
- Prospective, multicenter, randomized, parallel-group trial
- 2 blinded doses of PRADAXA were compared to open-label warfarin adjusted locally to an international normalized ratio (INR) of 2.0 to 3.0, with the INR measured at least monthly
- Primary efficacy outcome: stroke or systemic embolism; primary safety outcome: major hemorrhage
- Patients were followed for a median of 2 years
Time in Therapeutic Range (TTR)2,3
- Mean percentage of time in therapeutic range (INR 2.0-3.0) was 64% for patients randomized to warfarin
- Mean percentages of time INR measurements were greater than 4.0 or less than 1.5 were 2% and 5%, respectively
- Median percentage of time in therapeutic range was 67% for patients randomized to warfarin
*Although studied in the pivotal trial, PRADAXA 110 mg dose is not approved for use.
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.
IMPORTANT SAFETY INFORMATION ABOUT PRADAXA
CONTRAINDICATIONS
PRADAXA is contraindicated in patients with active pathological bleeding and patients with a known serious hypersensitivity reaction (e.g., anaphylactic reaction or anaphylactic shock) to PRADAXA.
WARNINGS & PRECAUTIONS: 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, such as a drop in hemoglobin and/or hematocrit or hypotension. Discontinue PRADAXA in patients with active pathological bleeding
- Risk factors for bleeding include 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
- A specific reversal agent for dabigatran is not available. Dabigatran can be dialyzed (removal of about 60% of drug over 2-3 hours) but data supporting this 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
WARNINGS & PRECAUTIONS: Temporary Discontinuation of PRADAXA
Discontinuing PRADAXA for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of stroke. Minimize lapses in therapy.
WARNINGS & PRECAUTIONS: Effect of P-gp Inducers & Inhibitors on Dabigatran Exposure
The 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.
- 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
ADVERSE REACTIONS
In the pivotal trial comparing PRADAXA to warfarin, the most frequent adverse reactions leading to discontinuation of PRADAXA were bleeding and gastrointestinal (GI) events. PRADAXA 150 mg resulted in a higher rate of major GI bleeds and any GI bleeds compared to warfarin. In patients ≥75 years of age, the risk of major bleeding may be greater with PRADAXA than with 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). Drug hypersensitivity reactions were reported in <0.1% of patients receiving PRADAXA.
Other Measures Evaluated
The risk of myocardial infarction was numerically greater in patients who received PRADAXA 150 mg than in those who received warfarin.
Please click here to read the full Prescribing Information and Medication Guide for PRADAXA.
This information is intended for the U.S. only.
REFERENCES:
- Wann LS, Curtis AB, Ellenbogen KA, et al; writing on behalf of the 2006 ACC/AHA/ESC Guidelines for the Management of Patients With Atrial Fibrillation Writing Committee. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (update on dabigatran): A report of the American College of Cardiology Foundation /American Heart Association task Force on Practice Guidelines. J Am Coll Cardiol. 2011; 57:1330-1337.
- Pradaxa [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; January 2012.
- Connolly SJ, Ezekowitz MD, Yusuf S, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-1151.
- Data on file. Boehringer Ingelheim Pharmaceuticals, Inc.
PRADAXA® is a registered trademark of Boehringer Ingelheim Pharma GmbH and Co. KG and used under license.
RE-LY® is a registered service mark of Boehringer Ingelheim International GmbH and used under license.
Copyright © 2012 Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved.
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01/2012 PX176804PROF
Pradaxa Important Safety Information
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.
IMPORTANT SAFETY INFORMATION ABOUT PRADAXA
CONTRAINDICATIONS
PRADAXA is contraindicated in patients with active pathological bleeding and patients with a known serious hypersensitivity reaction (e.g., anaphylactic reaction or anaphylactic shock) to PRADAXA.
WARNINGS & PRECAUTIONS: 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, such as a drop in hemoglobin and/or hematocrit or hypotension. Discontinue PRADAXA in patients with active pathological bleeding
- Risk factors for bleeding include 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
- A specific reversal agent for dabigatran is not available. Dabigatran can be dialyzed (removal of about 60% of drug over 2-3 hours) but data supporting this 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
WARNINGS & PRECAUTIONS: Temporary Discontinuation of PRADAXA
Discontinuing PRADAXA for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of stroke. Minimize lapses in therapy.
WARNINGS & PRECAUTIONS: Effect of P-gp Inducers & Inhibitors on Dabigatran Exposure
The 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.
- 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
ADVERSE REACTIONS
In the pivotal trial comparing PRADAXA to warfarin, the most frequent adverse reactions leading to discontinuation of PRADAXA were bleeding and gastrointestinal (GI) events. PRADAXA 150 mg resulted in a higher rate of major GI bleeds and any GI bleeds compared to warfarin. In patients ≥75 years of age, the risk of major bleeding may be greater with PRADAXA than with 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). Drug hypersensitivity reactions were reported in <0.1% of patients receiving PRADAXA.
Other Measures Evaluated
The risk of myocardial infarction was numerically greater in patients who received PRADAXA 150 mg than in those who received warfarin.
Please click here to read the full Prescribing Information and Medication Guide for PRADAXA.
This information is intended for the U.S. only.
