If you watch television or read a newspaper you've probably seen the wave of direct-to-consumer advertising for the anticlotting drug Pradaxa (dabigatran). According to Forbes, from approval in October 2010 through this past August, 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.

Unfortunately, reports of serious adverse drug events with Pradaxa also surged and a strong signal for serious bleeding with this new drug was seen in our most recent QuarterWatch report. I previously provided background information about our QuarterWatch program here.  Bleeding seems to be especially problematic for elderly patients.

Pradaxa is approved by FDA for patients with a condition known as "atrial fibrillation," where the two atria or upper pumping chambers of the heart fail to contract rhythmically, and instead flutter, or fail to contract entirely. This is one of the most challenging problems in drug therapy. Atrial fibrillation normally causes only a modest reduction in output of blood from the heart. But in the dead zone of the poorly contracting upper pumping chambers of the heart, blood clots may form and then travel to the brain, where a potentially damaging or life-threatening stroke may occur.

Until Pradaxa became available, Coumadin (warfarin) was used to "thin" the blood to prevent clots. But Coumadin also can cause serious bleeding. In fact, a recent study of emergency hospital admissions for adverse drug reactions for all drugs in patients 65 years of age or older showed that Coumadin alone accounted for a startling 33.3% of all such cases. An advantage with Pradaxa is that it doesn't require frequent lab monitoring or interact with many drugs.
Coumadin requires blood tests every 1 to 4 weeks to establish optimal levels and it also interacts with many other drugs, including drugs frequently used in heart patients. Of course these differences between the two drugs have doctors and patients leaning toward Pradaxa. On the plus side with Coumadin, if an overdose occurs, an antidote (vitamin K) is readily available and highly effective. But there is no antidote for Pradaxa. On the plus side for patients taking Pradaxa, the risk of stroke is 35% less than with Coumadin.

Overall, when we reviewed FDA reports, we found that 932 serious adverse events were linked to Pradaxa during the first quarter last year, including 120 deaths, 25 cases of permanent disability, and 543 cases requiring hospitalization. Of the 932 events, 505 cases involved hemorrhage, more than any other monitored drug including Coumadin, which ranked second with 176 cases of bleeding.

Importantly, a quarter of the adverse events with Pradaxa that were related to bleeding were seen in patients 84 years or older, raising a question regarding safe dosing and monitoring in older patients. Unlike Coumadin, Pradaxa was approved in a "one size fits all" dose of 150 mg twice a day, except for patients with severe kidney impairment. The FDA rejected a lower dose regimen of 110 mg twice daily, which had been sought by Boehringer Ingelheim, the drug's manufacturer, and approved in Canada, Japan, and European countries. This means that not only is the lower 110 mg dose unavailable here, patients are not routinely monitored to see if they are getting too much drug.

A reduction in kidney function occurs in older patients, and it's a related safety issue. In studies of Pradaxa, patients with even mild kidney impairment had blood levels that were 50% higher than patients with normal kidney function. Moderately impaired kidney function could result in dabigatran blood levels three times higher. Pradaxa prescribing information does not recommend dosage adjustment except in cases of "severe" kidney impairment, where a dose of 75 mg twice daily is recommended (www.fda.gov/Drugs/DrugSafety/ucm282724.htm).

These data apparently were also noticed by the FDA which announced in early December 2011 that a safety review of adverse event reports of serious bleeding was being conducted. We believe FDA and the manufacturer should reevaluate dosing in the elderly or those with moderate kidney impairment to determine optimal dosing and monitoring requirements. While further study is needed, we see indications that the "one size fits all" dosing regimen may be resulting in overdoses in some patients, leading to serious and fatal bleeding. A drug that is easier to use because it doesn't require weekly or monthly laboratory tests to individualize doses may be appealing to physicians and patients but less safe for some.

These concerns and recommendations were shared with Boehringer Ingelheim, the manufacturer. While the company had also observed a large volume of serious adverse event reports, a representative noted that the prescribing information already warned about an increased risk of significant and sometimes fatal bleeding. The company attributed the volume of reports to the drug's rapid acceptance and active sales force with extensive physician contact.

The company reported it is working with FDA to provide better guidance to doctors on treating elderly patients, especially those with impaired kidney function. The company declined to comment on whether it would again seek FDA approval for the lower 110 mg dose.

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