Latest review of FDA safety reports shows wide use of Pradaxa

QuarterWatch is an Institute for Safe Medication Practices (ISMP) drug surveillance program that regularly monitors all serious, disabling and fatal adverse drug events reported to the US Food and Drug Administration (FDA) by drug manufacturers and the public. The agency releases computer excerpts for research use on a quarterly basis, and these case reports are our primary data source. Our goal is to improve patient safety through identification of "signals" that may represent serious drug safety issues.

We recently looked at FDA reports for all of 2010 as well as for the final quarter last year. We identified 141,829 new cases of serious, disabling, or fatal adverse events reported to FDA, a 21% increase since 2009. The increase (24,736 cases) in 2010 was the largest absolute (raw number) increase between years since 1998. For the 4th quarter alone, reports meeting the QuarterWatch criteria totaled 38,733, an increase of 5.5% compared to the 4th quarter of 2009. You can see the entire report here. Table I shows the drugs most frequently associated with serious events during 2010.

In the current QuarterWatch we provide much more detail about many of the drugs listed in table I, including the surprising finding that Tracleer (bosentin) is at the top of the list. This seemed strange because the drug really isn't used that much. It's for a serious and rather rare condition known as pulmonary arterial hypertension, which occurs in about 15 people per million.

On investigation we discovered a new and dramatic example of an adverse event reporting issue that was troubling, but by no means signaled an emerging drug disaster. It turned out that the manufacturer submitted all reports of death in patients who happened to be on the drug, even when they died from the disease and not the drug. In the case of patient deaths, the FDA requires reporting when "there is a reasonable probability that the drug caused the adverse effect." So thousands of death reports of low quality were placed into the FDA adverse event database without any investigation or information about whether the drug might have played a role in the patient death. Not only do the reports have no value in post-market safety surveillance, they obstruct the assessment of genuine potential threats to the public health by diminishing report quality. We've called upon FDA to look into this matter as soon as possible and make corrections.

Although not listed in table I, one of the interesting findings in this issue of QuarterWatch involves the new drug Pradaxa (dabigatran etexilate). Within weeks of its launch, Pradaxa generated more reports (307) than 98.7% of the other drugs we regularly monitor. The predominant reported adverse effects were equally divided among bleeding or clotting events.

Pradaxa received FDA approval last October for reducing the risk of blood clots and stroke in patients with a heart condition known as atrial fibrillation, which is a quivering of the heart's upper pumping chambers. In some cases the blood stagnates and can form a clot so the drug is used to prevent clotting. Coumadin (warfarin) is another drug used for this purpose. It's less expensive and has been used for many years, and is also associated with bleeding episodes. But unlike Coumadin, an advantage with Pradaxa is that it doesn't require frequent lab monitoring or interact with many drugs. Still, Coumadin does have at least one important advantage: severe bleeding can be more easily reversed with an antidote whereas no specific antidote exists for Pradaxa reversal.

This large number of reports in the 2-3 months after launch illustrates that serious safety issues are likely to grow as the use of Pradaxa increases and forthcoming new alternatives to Coumadin are approved. The large number of reports just weeks after approval show how quickly a new treatment can spread into wide clinical use.

We also found that this new drug was immediately used "off-label," meaning that the FDA has not approved the drug for use in the manner in which it's being prescribed because its risks and benefits have not yet been systematically studied. Only 36% of reports that listed the indication noted that the drug was being used for the approved indication. Another 46% of reports said the drug was being used to prevent blood clots or stroke in general terms, and other reports clearly specified off-label uses, such as the prevention of deep vein thrombosis postoperatively after hip or knee arthroplasty. The data suggest that physicians were substituting Pradaxa for warfarin across a wide spectrum of conditions, despite not having FDA approval.

I plan to look at additional findings from QuarterWatch in a future blog.

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