The European Medicines Agency (EMA) is the equivalent of the Food & Drug Administration for the countries which comprise the European Union (EU). The EMA was founded in 1995 and is jointly funded by the governments of participating countries as well as the pharmaceutical industry. The organization is focused on safety, scientific inquiry and pharmacovigilance, but does not have a regulatory role equivalent to that of the FDA. The European Medicines Agency is currently responsible for approving approximately 1/3 of the drugs that are marketed globally.
Here is a summary of the key regulatory events that have occurred in Europe with regard to Pradaxa (also known as dabigatran etexilate):
• March 18, 2008 – Pradaxa is approved for the prevention of venous thromboembolic (VTE) events in adult patients who have undergone elective total hip or knee implant surgery.
• August 1, 2011 – Pradaxa is approved for the prevention of strokes and system embolism in adult patients with non-valvular atrial fibrillation. The warning label for the drug in the European Union recommends that doctors check patients for signs of bleeding (without giving any specifics) and to discontinue treatment in patients who experience severe bleeding. The drug is contraindicated in patients who have a history of bleeding problems (such as GI bleeds or ulcers) and in those with a history of severe renal impairment.
• October of 2011 – The Committee for Medicinal Products for Human Use (CHMP) recommended further changes to the warning label and instructions for Pradaxa after learning of several cases of fatal bleeding episodes in Japanese patients taking Pradaxa. The enhanced warning label recommends that all patients have lab work done to determine whether they have any renal impairment prior to initiation of Pradaxa. A recommendation was also made that kidney tests be repeated annually for patients on Pradaxa who are over 75 years of age as well as whenever a Pradaxa patient experiences a change in their renal status. The EMEA reported that these important safety alerts would also be communicated by Boehringer Ingelheim to prescribing physicians in Europe.
• November 6, 2011 – The EMEA reported that it was aware of 256 patients on Pradaxa who had died as a result of serious bleeding events, and that 21 of these adverse events had been reported in the European Union.
• November 18, 2011 – The EMEA issued a press release regarding changes in the warning label and instructions for use of Pradaxa and opined that these new changes (such as kidney testing in certain at-risk patient populations and not prescribing the drugs to patients with pre-existing histories) should be sufficient to stem the tide of Pradaxa-induced bleeding injuries and deaths. The EMEA also promised to continue to closely monitor Pradaxa and reports relating to the safety profile of the drug.
• January of 2012 – The CHMP decided that an in-depth assessment of available data regarding bleeding risks associated with use of Pradaxa was necessary. This announcement followed a number of publications and announcements by regulatory agencies around the world regarding concerns over the safety of Pradaxa. Perhaps, the most noteworthy outcome of this review was the fact that prescribing physicians were informed that Pradaxa is not really appropriate for patients who have renal insufficiency, a condition that inhibits their ability to clear Pradaxa from their system as intended and creates the opportunity for toxic levels of Pradaxa to build up in their bloodstreams.
• March 15, 2012 – The National Institute of Health and Clinical Excellence (NICE) recommended that Pradaxa be prescribed to patients even though Pradaxa is more expensive than other drugs and treatments. NICE’s recommendation is based upon its acceptance of Boehringer’s claims that Pradaxa provides greater protection against strokes than warfarin. In the United Kingdom, Pradaxa is approved for marketing at 110 mg and 150 mg doses, as opposed to the 75 mg and 150 mg doses approved by the FDA in the United States.
• May 24, 2012 – The European Medicines Agency issued a Q&A for patients that emanates from the Agency’s review of bleeding risks associated with Pradaxa. This regulatory body concluded that Pradaxa’s bleeding risks were in line with that associated with other anticoagulant medications, but did at least decide that patients should be given more information. Since lawsuits were first filed over Pradaxa a few months ago, we have seen an enhanced PR and advertising campaign to pump up the benefits of Pradaxa while at the same time minimizing the bleeding risks with claims that this is an unavoidable class effect in this particular category of medications. Apparently, the best opportunity for evaluation of the true risks posed by this dangerous drug will come with the discovery that is already underway in the individual lawsuits filed by Pradaxa victims that are pending in East St. Louis, Illinois.
• June 1, 2012 – The CHMP issued another announcement of a change to the warning label for Pradaxa. This time the changes related to language regarding pre-existing conditions that might predispose a use of Pradaxa to suffer serious injury or death as a result of their use of the product. Examples of such pre-existing conditions include ulcers, history of a GI bleed, recent brain or spinal injury, recent surgery involving the brain, spine, or eyes, intracranial hemorrhage, esophageal varices, arteriovenous (AVM) malformations, vascular aneurysms, and patients with cancer. The warning label was also changed with regard to concurrent use of Pradaxa and other blood thinner, such as Heparin.
• July 19, 2012 – The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency adopted a new contraindication for Pradaxa. This time the labeling for the product was changed to include a warning that Pradaxa may interact inappropriately with dronedarone, another drug for atrial fibrillation that is marketed under the brand name Multaq.
So, with all of the study of Pradaxa and press releases, are patients safer? I suspect not. Unfortunately, it appears that drug regulators in Europe have fallen into the same trap that has befallen the FDA over the past decade. Many dangerous drugs are being permitted to remain on the market, even in the face of serious safety issues, with governmental regulators deciding to issue incessant enhancements to warnings rather than force a defective drug to be recalled or pulled from the market. I suspect that the supposed uniqueness of Pradaxa is perhaps its saving grace for now, and that as newer anticoagulants with better safety records are approved for sale, perhaps Pradaxa will be pulled from the market or at least face a market withdrawal as prescribing physicians and patients make better choices for the treatment of atrial fibrillation.