Since its approval in the United States in October 2010 dabigatran (Pradaxa) has been prescribed 3.2 million times to more than 600,000 patients with nonvalvular atrial fibrillation (AF), according to its manufacturer, Boehringer Ingelheim. The company also announced that, based on the pivotal RE-LY trial, the “Clinical Studies” section of the drug’s prescribing information now includes the statement that 150 mg twice daily of dabigatran “was superior in reducing ischemic and hemorrhagic strokes relative to warfarin.”
But the news about dabigatran is not entirely upbeat. According to new data compiled by QuarterWatch (PDF), in 2011 the FDA received more safety reports about dabigatran than any other drug. The data are not entirely unexpected, since the bleeding complications of dabigatran are well known and physicians are more likely to report adverse events associated with new drugs. The drug that dabigatran was designed to replace, warfarin (Coumadin), was the second most reported drug, and has been high on the FDA list for many years.
Dabigatran was the subject of 3,781 serious adverse events reported to the FDA in 2011. This included 542 patient deaths and 2,367 hemorrhages. Warfarin was the subject of 1,106 serious adverse events, including 72 deaths.
QuarterWatch noted that the difference between the two anticoagulants “could be at least partly explained by differences in the reporting rate for an older generic drug with many manufacturers, and a newly launched brand name drug being promoted by a large sales force.” But, according to QuarterWatch:
“What is clear, however, is that the FDA’s system is receiving a strong signal about this safety issue. A large share of dabigatran reports (79%) come from health professionals, suggesting that despite this well-known drug risk the bleeding was unexpected or unusually severe.”
QuarterWatch notes that the rapid uptake of dabigatran is probably due to its ease of use– no frequent INR tests are required– and the lack of drug interactions. One likely source of complications is the use of the standard 150 mg dose in older patients or those with renal dysfunction. The label now recommends that physicians “assess renal function during therapy as clinically indicated” but QuarterWatch wonders “whether this modest language will lead to safer use.”
Here is the press release from Boehringer-Ingelheim:
Pradaxa ® (dabigatran etexilate mesylate) U.S. Label Now Affirms Superior Reduction in Ischemic and Hemorrhagic Stroke Versus Warfarin in Patients with Non-Valvular Atrial Fibrillation
PRADAXA continues strong market performance 20 months after U.S. FDA approval
Ridgefield, CT, June 6, 2012 – Boehringer Ingelheim Pharmaceuticals, Inc. today announced that the Pradaxa ® (dabigatran etexilate mesylate) capsules prescribing information has been updated to affirm that “PRADAXA 150mg twice daily was superior in reducing ischemic and hemorrhagic strokes relative to warfarin.” The update to the “Clinical Studies” section is based on the results of the pivotal RE-LY ® trial conducted in 18,000 patients with non-valvular atrial fibrillation (NVAF).
Clinical experience with PRADAXA continues to grow with more than 3.2 million prescriptions for PRADAXA 150mg and 75mg written for more than 600,000 NVAF patients in the U.S. since its approval in October 2010. Additionally, nearly 20,000 cardiologists and more than 90,000 other specialists or primary care physicians have prescribed PRADAXA through April 2012.
“PRADAXA is an important treatment option for many patients with NVAF as it is the only treatment compared to warfarin that provides a superior reduction in ischemic and hemorrhagic stroke, which is the main goal of anticoagulation treatment,” said John Smith, M.D., Ph.D., senior vice president for clinical development and medical affairs, Boehringer Ingelheim Pharmaceuticals, Inc. “The inclusion of specific wording about the superiority of PRADAXA over warfarin in the prescribing information is important in defining the benefit it provides when physicians are considering treatment options for this patient population.”
The launch of PRADAXA has been the most successful in Boehringer Ingelheim history and is among the pharmaceutical industry’s top launches in the last decade. Formulary uptake has been strong for PRADAXA, which is now included on formularies that insure about 90 percent of covered lives in the U.S. PRADAXA also is on formulary with all 50 of the top heart and heart surgery hospitals in the U.S., as identified by U.S. News and World Report.
Boehringer Ingelheim remains focused on patient safety and is committed to further investigating PRADAXA through research such as the long-term safety study RELY-ABLE, which will be presented later this year. Additionally, Boehringer Ingelheim recently launched phase II of the GLORIA-AF patient registry, which is designed to better characterize the use of antithrombotic treatments to reduce the risk of stroke in patients with NVAF.
“Boehringer Ingelheim is committed to the AFib community and is continuing the work and support of educating healthcare professionals about the benefits and risks associated with PRADAXA,” said Greg Behar, president and CEO, Boehringer Ingelheim Pharmaceuticals, Inc. “It is important for physicians and patients to discuss the important clinical benefit of superior stroke risk reduction with PRADAXA versus warfarin when considering treatment options.”
In the RE-LY trial, PRADAXA 150mg twice daily was superior in reducing ischemic and hemorrhagic stroke compared to warfarin in patients with NVAF. The risk of major bleeds was similar with PRADAXA 150mg and warfarin across major subgroups with the exception of age, where there was a trend towards a higher incidence of major bleeding with PRADAXA for patients ≥75 years of age. There were higher rates of major gastrointestinal (GI) bleeding and total GI bleeding with PRADAXA 150mg than warfarin. The incidence of intracranial bleeding, or bleeding inside the skull, was 59 percent lower with PRADAXA 150mg than warfarin in this patient population.
About Pradaxa ® (dabigatran etexilate mesylate) Capsules
Indications and Usage
PRADAXA is indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.
IMPORTANT SAFETY INFORMATION ABOUT PRADAXA
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 AND 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.
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.
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.
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.
For full PRADAXA prescribing information, please visit www.pradaxa.com or contact Boehringer Ingelheim’s Drug Information Unit at 1-800-542-6257.
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About Boehringer Ingelheim Pharmaceuticals, Inc.
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 145 affiliates and more than 44,000 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.
As a central element of its culture, Boehringer Ingelheim pledges to act socially responsible. Involvement in social projects, caring for employees and their families, and providing equal opportunities for all employees form the foundation of the global operations. Mutual cooperation and respect, as well as environmental protection and sustainability are intrinsic factors in all of Boehringer Ingelheim’s endeavors.
In 2011, Boehringer Ingelheim achieved net sales of about $17.1 billion (13.2 billion euro). R&D expenditure in the business area Prescription Medicines corresponds to 23.5% of its net sales.