Timeline: Pradaxa (Dabigatran Etexilate)


Timeline Pradaxa (Dabigatran Etexilate)Sept 2008: The European Medicines Agency (EMA) approves Pradaxa for prevention of blood clots in patients who had total hip replacement surgery or total knee replacement surgery, due to an increased risk of venous thromboembolism (VTE)

Oct 2010: The U.S. Food and Drug Administration (FDA) approves Pradaxa for prevention of blood clots and stroke in patients who experience an abnormal heart beat, or atrial fibrillation (AF). The drug is expected to be preferable to Coumadin (warfarin) since it requires less monitoring and has minimal drug and food interactions.

Feb 2011: The Institute for Safe Medication Practices (ISMP), a U.S. non-profit organization, issues a safety alert advising physicians to adjust Pradaxa levels in patients who have a history of kidney problems, or renal impairment. This alert followed reports of a chronic kidney patient who experienced severe gastrointestinal (GI) bleeding while taking Pradaxa.

Aug 2011: The EMA approves Pradaxa for prevention of stroke in patients with nonvalvular atrial fibrillation who have at least one risk factor

Aug 2011: After patients in Japan exhibit GI bleeding, Japanese health regulators urge Pradaxa’s manufacturer, Boehringer Ingelheim, to inform doctors about the deadly untreatable bleeding risk

Oct 2011: The EMA’s Committee for Medicinal Products for Human Use (CHMP) updates Pradaxa safety regulations, requiring doctors to assess a patient’s renal functions before prescribing the drug. Furthermore, renal health must be assessed annually in Pradaxa patients over 75 years old, or when there are signs of failing kidney health in elderly patients. Boehringer complies with the updates.

Nov 2011: A total of 256 Pradaxa-related deaths are reported in EudraVigilance database, 21 of which reported to European Union. The EMA provides a safety update, acknowledging the events and reminding the public about the risks, regulations and contraindications including impaired renal function, severe bleeding, and lower doses in the elderly. The agency suggests that the number of deaths may be associated with the increased use of the drug.

Dec 2011: The FDA initiates a safety review of Pradaxa.

Jan 2012: The ISMP releases report of over 500 cases of Pradaxa-linked hemorrhaging, some of which were fatal. 

Feb 2012: New Zealand hematologists urge for more comprehensive safety measures after a two month review reveals 78 cases of bleeding in connection with Pradaxa.

March 2012: The Journal of Neurosurgery publishes a report that highlights the risk of irreversible bleeding in Pradaxa. The report describes an 83-year old Pradaxa patient who died of a cerebral hemorrhage after a fall.

Mar. 26. 2012: The Archives of Internal Medicine publishes a study showing that Coumadin (warfarin) is fairly effective at preventing stroke in AF patients. The study finds that the rate of residual stroke and systemic embolism to be as low as 1.66 percent.

Apr. 23, 2012: Parker Waichman LLP files a lawsuit on behalf of a Tennessee man who experienced cerebral hemorrhaging following treatment with Pradaxa. The case was filed in U.S. District Court for the District of Connecticut.

May 4, 2012: Dr. Mark Wurster presents preliminary study results comparing Pradaxa and warfarin at the Thrombosis & Hemostasis Summit of North America 2012. The study took place in a real-world setting, where patients switched from warfarin to Pradaxa and drug discontinuation due to complications in a six-month period were analyzed; there was one warfarin-related event (0.88%) that required discontinuation compared to 13 Pradaxa-related events (11.5%).

Jun. 2012: The ISMP QuarterWatch report, which is based off the FDA MedWatch system, finds that there were more reports of Pradaxa fatalities than with any other drug in 2011. According to the report, Pradaxa “accounted for so many reports of serious adverse drug events that was prominent in several different categories”; there were a total of 3,781 reports, with 542 patient deaths, 2,367 cases of hemorrhage, 291 cases of acute renal failure and 644 cases of stroke.

Jul. 2012: MHRA updates the safety label on Pradaxa. The medication now has new contraindications in the UK, and should not be taken in patients who are already at an increased risk of bleeding (i.e. gastrointestinal ulcers, malignant neoplasms, recent or current brain, spine or eye surgery, recent intracranial hemorrhage, etc.). It is now also contraindicated with dronedarone and other anticoagulants “except when switching treatment to or from dabigatran, or with the use of unfractionated heparin for maintenance of venous or arterial catheter patency”

Aug. 8, 2012: The U.S. Judicial Panel on Multidistrict Litigation consolidates Pradaxa lawsuits into an MDL known as the “In Re: Pradaxa (dabigatran etexilate) Products Liability Litigation” (MDL No. 2385). The cases will be litigated in the Southern District of Illinois before U.S. District Court Judge David R. Herndon.

Sept. 2012: The Archives of Internal Medicine publishes a study suggesting that the risks of new-generation oral anticoagulants may outweigh any benefits in patients who experienced acute coronary syndrome (ACS). The authors wrote that anticoagulants such as Pradaxa, Xarelto and Eliquis are “associated with a dramatic increase in major bleeding events, which might offset all ischemic benefits in patients receiving antiplatelet therapy after an ACS.”

Sept. 4, 2012: The Circulation: Cardiovascular Quality and Outcomes journal publishes a study suggesting that Pradaxa has not had much of an effect on the treatment of atrial fibrillation. Although the drug is still mainly used for this condition, the study shows that its off-label uses are on the rise. Researchers concluded that they “did not find evidence that it has increased overall atrial fibrillation treatment rates.”

Sept. 5, 2012: The Journal of the American Medical Association (JAMA) publishes a report highlighting the dangers of expedited approval, using Pradaxa as one of the main examples. The authors said that drugs such as Pradaxa “…raise the question of whether it was good policy to approve three innovative new drugs with significant safety questions unanswered,”

Oct. 2012: Boehringer Ingelheim discontinues first arm of RE-ALIGN trials, where patients were randomized to warfarin or Pradaxa during their hospital stay following a mechanical valve surgery. The trial was stopped due to ““an imbalance in reports of thromboembolic events (primarily strokes).” The second arm, where patients are randomized 3 months after the surgery, has not been affected.