FDA is investigating whether postmarketing reports of serious bleeding events after taking Boehringer Ingelheim GMBH’s Pradaxa (dabigatran) reflect a higher incidence than was anticipated based on clinical trial results, the agency announced Dec. 7.

FDA’s investigation follows recent steps taken by European authorities in the wake of reports that 256 deaths worldwide have been associated with the anticoagulant.

Despite the announcement, FDA maintains support of the drug, which was approved in October 2010 to reduce the risk of stroke in patients with non-valvular atrial fibrillation. “FDA continues to believe that Pradaxa provides an important health benefit when used as directed,” the announcement states, adding that patients with atrial fibrillation should not stop taking Pradaxa without talking to their health care professional.

Furthermore, the agency’s drug safety communication notes that bleeding that may lead to serious or fatal outcomes “is a well-recognized complication of all anticoagulant therapies.”

The agency is evaluating reports of post-market serious bleeding events and comparing them to events reported in the 18,000-patient RE-LY trial that was the basis for approval. In that trial, Pradaxa showed superior efficacy to warfarin, but the anticoagulants had similar bleeding event rates.

BI responded to a query about the data behind the announcement with a statement that it stands behind the safety and efficacy of Pradaxa and cooperates with regulatory agencies around the world to ensure they have the most up to date information.

The first anticoagulant to enter the market since warfarin was approved in the 1950s, FDA cleared Pradaxa because it showed superior efficacy in a trial powered for non-inferiority. But while Pradaxa proved superior to warfarin at preventing strokes it carries the potential for bleeding events that is a concern for all anticoagulants. Its Medication Guide contains strong language about the risk of bleeding death and about compliance. Because Pradaxa has a short half life, missing one of the twice daily doses could increase stroke risk. Still, the convenience for patients and health care providers of getting away from the carefully controlled regimen required for warfarin made Pradaxa a welcome option Also see "FDA Pradaxa Approval Balances Efficacy And Bleeding Risk" - Pink Sheet, 25 October, 2010..

European Medicines Agency Takes Steps In Face Of Excess Bleeding Deaths

In November, EMA released a safety update on Pradaxa in which it notes that as of Nov. 6, 2011, “a worldwide total of 256 spontaneous case reports of serious bleeding resulting in death” had been associated with dabigatran in the EudraVigilance database. Of those, 21 were reported in the European Union. The number of reports has to be seen in light of the “rapidly increasing use of Pradaxa worldwide” as a result of the drug being approved for the atrial fibrillation indication in several regions, as well as increased awareness of the drug, regulators cautioned.

EMA took the same stance as FDA, stating that it will closely monitor event reports and the overall safety profile of Pradaxa. In Europe, Pradaxa has been approved since March 2008 for prevention of venous thromboembolic events in adults who have elective total hip replacement or total knee replacement surgery. In August 2011, it also gained the atrial fibrillation claim.

But EMA had already taken action on Pradaxa. The Committee for Medicinal Products for Human Use acted in October after reports of fatal bleeding came from Japan, and the worldwide mortality data became worrisome. CHMP recommended that Pradaxa labeling be updated to advise testing for renal function in all patients before starting treatment and that while on treatment their renal function should be assessed at least once a year in patients over 75 years of age and whenever a decline in renal function is suspected in patients of any age. BI sent a letter out to health care providers carrying the recommendation.

Weighing Bleeding Risk Against Efficacy

Pradaxa is cleared through the kidneys, and exposure to Pradaxa increases with the severity of renal function impairment. U.S. labeling for the drug provides a 75 mg dose for patients with impaired renal functioning. BI had proposed a 110 mg option for other patients at high risk of bleeding and for the elderly, but in the end FDA supported a 150 mg dose as the only other option because it was the one that proved superior to warfarin in RE-LY, while the 110 mg dose was barely non-inferior Also see "FDA Plays It Safe With Boehringer Ingelheim's Pradaxa By Approving A Single Dosing Option" - Pink Sheet, 20 October, 2010..

BI has enjoyed a first mover advantage in the anticoagulant market, but a host of other novel high-profile, and possibly safer, oral anticoagulants are on now on its heels.

FDA approved Johnson & Johnson/Bayer AG’s Xarelto (rivaroxaban) in July for prevention of deep vein thrombosis; the approval carries no risk management requirement Also see "Xarelto Approval For DVT Bodes Well For Coming Indications" - Pink Sheet, 5 July, 2011.. Other indications are being pursued. And Bristol-Myers Squibb Co./Pfizer Inc.’s Eliquis (apixaban) has been granted a priority review of its initial application, for the atrial fibrillation indication, suggesting the agency believes it offers a major treatment advance over both Pradaxa and Xarelto Also see "BMS/Pfizer’s Eliquis On Priority Review Path Toward March 2012 Approval" - Pink Sheet, 29 November, 2011..

Pradaxa Bleeding Deaths Spur FDA Concerns, European Label Changes

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