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FDA Drug Safety Communication: Safety review of post-market reports of serious bleeding events with the anticoagulant Pradaxa (dabigatran etexilate mesylate)

The FDA has issued new information about this safety issue, see the FDA Drug Safety Communications issued 5/13/2014 and 11-02-2012.
 

Safety Announcement
Additional Information for Patients
Additional Information for Healthcare Professionals
Data Summary 
 

Safety Announcement

[12-7-2011] The U.S. Food and Drug Administration (FDA) is evaluating post-marketing reports of serious bleeding events in patients taking Pradaxa (dabigatran etexilate mesylate). Pradaxa is a blood thinning (anticoagulant) medication used to reduce the risk of stroke in patients with non-valvular atrial fibrillation (AF), the most common type of heart rhythm abnormality.

Facts about Pradaxa
(dabigatran etexilate mesylate)

  • A blood thinner (anticoagulant) known as a direct thrombin inhibitor.
  • Approved to reduce the risk of stroke and blood clots (systemic embolism) in patients with non-valvular atrial fibrillation.
  • Available as 75 mg and 150 mg oral capsules.
  • From approval in October 2010 through August 2011, a total of approximately 1.1 million Pradaxa prescriptions were dispensed and approximately 371,000 patients received Pradaxa prescriptions from U.S. outpatient retail pharmacies.1

At this time, FDA continues to believe that Pradaxa provides an important health benefit when used as directed and recommends that healthcare professionals who prescribe Pradaxa follow the recommendations in the approved drug label (See Additional Information for Healthcare Professionals).   

Patients with AF should not stop taking Pradaxa without talking to their healthcare professional. Stopping use of blood thinning medications can increase their risk of stroke. Strokes can lead to permanent disability and death.

Bleeding that may lead to serious or even fatal outcomes is a well-recognized complication of all anticoagulant therapies. The Pradaxa drug label contains a warning about significant and sometimes fatal bleeds. In a large clinical trial (18,000 patients) comparing Pradaxa and warfarin, major bleeding events occurred at similar rates with the two drugs.  

FDA is working to determine whether the reports of bleeding in patients taking Pradaxa are occurring more commonly than would be expected, based on observations in the large clinical trial that supported the approval of Pradaxa. (See Data Summary). FDA is working closely with the manufacturer of Pradaxa (Boehringer Ingelheim) to evaluate the post-market reports of bleeding.

FDA will communicate any new information on the risk of bleeding and Pradaxa when it becomes available.


Additional Information for Patients 

  • Pradaxa is an anticoagulant medicine that reduces the risk of blood clots forming in your body and causing a stroke. Having a stroke can cause permanent disability and death.
  • Do not stop taking Pradaxa without talking to your healthcare professional. Stopping use of your blood thinner suddenly can put you at risk of a stroke.
  • Be aware that while taking Pradaxa you may bruise more easily and it may take longer for any bleeding to stop.
  • Call your healthcare professional and seek immediate care if you develop any signs or symptoms of bleeding such a

      • unusual bleeding from the gums

      • nose bleeding that happens often

      • menstrual or vaginal bleeding that is heavier than normal

      • bleeding that is severe or you cannot control

      • pink or brown urine

      • red or black stools (looks like tar)

      • bruises that happen without a known cause or that get larger

      • coughing up blood or blood clots

      • vomiting blood or vomit that looks like coffee grounds.

  • Discuss any questions or concerns about Pradaxa with your healthcare professional.

  • Report any side effects you experience to your healthcare professional and the FDA MedWatch program using the information in the “Contact Us” box at the bottom of the page. 
     

Additional Information for Healthcare Professionals 

  • If you prescribe Pradaxa, carefully follow the approved indication and other recommendations, such as dosage and administration, in the professional drug label.
  • Make sure your patients know the signs and symptoms of bleeding and when to seek care.
  • Pradaxa is eliminated by the kidneys, therefore:
    • Renal function should be assessed prior to treatment with Pradaxa to determine the appropriate dose.
    • Renal function should be reassessed during treatment with Pradaxa if clinically indicated (fluctuating renal function, diuretic use, hypovolemia), and the dose should be adjusted following recommendations in the label.
  • There is no need for dosage adjustment in patients with mild to moderate renal impairment (creatinine clearance [CrCl] > 30 mL/min). These patients should be given a dose of Pradaxa 150 mg orally twice daily.

  • For patients with severe renal impairment, follow the recommended doses:
    • For patients with CrCl 15-30 mL/min, the recommended dose is 75 mg orally twice daily.
    • Dosing recommendations for patients with a CrCl <15 mL/min or on dialysis cannot be provided.
  • Report adverse events involving Pradaxa to the FDA MedWatch program, using the information in the “Contact Us” box at the bottom of the page.
     

Data Summary  

Bleeding that may lead to serious or even fatal outcomes is a well-recognized complication of all anticoagulant therapies. In a large clinical trial (18,000 patients) comparing Pradaxa (dabigatran etexilate mesylate) and warfarin, major bleeding events occurred at similar rates with the two drugs. At present, the FDA is evaluating the post-marketing reports of serious bleeding in patients taking Pradaxa submitted to the Adverse Events Reporting System (AERS) database. While serious, even fatal events have been reported, the FDA is analyzing the events to determine whether the reports of bleeding in patients taking Pradaxa are occurring more commonly than would be expected, based on observations in the large clinical trial that supported the approval of Pradaxa. 

Complicating this analysis, many factors can influence whether or not adverse effects are reported, particularly the length of time a drug has been marketed, whether or not the adverse effect is described in the drug label, and the amount of publicity about an event or safety concern.

For patients with non-valvular AF, the main alternative to Pradaxa is warfarin. Because warfarin has been marketed for over 50 years and is well-known to cause bleeding, patients and healthcare professionals are not likely to report bleeding in association with warfarin. Thus, a simple comparison between Pradaxa and warfarin with respect to the numbers of post-marketing reports of bleeding is of limited value.

FDA is working with the manufacturer, Boehringer Ingelheim, to analyze the post-market reports for evidence of inappropriate dosing, use of interacting drugs, or other clinical factors that might lead to a bleeding event.

FDA is also using its Mini-Sentinel1 active surveillance system to compare new users of Pradaxa and warfarin with respect to the likelihood of being hospitalized for bleeding. 

At this time, FDA believes the benefits of Pradaxa continue to exceed the potential risks when the drug is used appropriately following the approved drug label. FDA recommends that healthcare professionals continue to prescribe Pradaxa following the recommendations in the drug label. 

References
1. Source: SDI, Vector One: National (VONA) and Total Patient Tracker (TPT). October 2010 to August 2011. Extracted October 2011.  

 

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