Five years ago, the FDA approved the blood thinner Pradaxa in the absence of an antidote that could thicken the blood and prevent patients from bleeding uncontrollably. Since then, the drug has been named as primary suspect in thousands of reports about patient deaths.
Now, the FDA is saying what some doctors have long argued: there are times when the ability to reverse Pradaxa’s effects can be a matter of life or death.
“[T]here are situations where reversal of the drug’s effects is medically necessary,” Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in an FDA news release Friday. Pazdur cited “emergency or life-threatening situations when bleeding can’t be controlled.”
The FDA issued those comments as it announced that it was approving a long-awaited antidote for Pradaxa.
The announcement came one day after the Project On Government Oversight published a report detailing a series of questionable judgments in the FDA’s oversight of Pradaxa, including the agency’s decision to approve the drug in the absence of an antidote and its failure to require conspicuous warnings about the lack of a reversal agent.
“The result was to accommodate a pharmaceutical company by easing a drug’s passage to market and then deflecting questions about its safety once the product had won approval,” POGO’s report said. “The issues ranged from what standards to demand from the manufacturer-sponsored clinical trial used to secure the drug’s approval to what warnings to give patients about potential hazards and what claims to allow in ads for the product.”
The agency’s handling of Pradaxa called into question the reliability of a crucial regulatory system, POGO wrote.
Pradaxa is prescribed to prevent blood clots and strokes in patients with atrial fibrillation, a heart condition that affects millions of people in the United States.
Warfarin, the decades-old anticoagulant that Pradaxa was meant to replace, can be reversed with Vitamin K.
The FDA said it granted the Pradaxa antidote “accelerated approval.” That designation allows the agency to vet drugs based on reduced standards of evidence. In a June editorial in The New England Journal of Medicine (paywall), Kenneth A. Bauer, a professor at Harvard Medical School, wrote that test results were convincing that the antidote immediately neutralized Pradaxa.
The approval of the antidote, known by the brand name Praxbind and the generic name idarucizumab, makes Pradaxa the first in its class of new generation oral anticoagulants to have a reversal agent. Like Pradaxa, the other new blood thinners—Xarelto, Eliquis, and Savaysa—were approved by the FDA without antidotes.
That raises a new question: If the FDA now deems the ability to reverse Pradaxa’s effects “medically necessary” in “emergency or life-threatening situations,” what about the ability to reverse the effects of Xarelto, Eliquis, and Savaysa?
The FDA addressed that issue in a commentary posted on its website.
“With reversal agents now available for Pradaxa and warfarin, we have been asked if FDA should continue to allow marketing of anticoagulant drugs that do not have a reversal agent,” Ellis F. Unger, an official in the FDA’s Center for Drug Evaluation and Research, said. “The short answer to that question is yes.”
Unger wrote that the drugs were worthy of FDA approval. Eliquis and Savaysa caused less bleeding in clinical trials than warfarin, and all four drugs caused fewer intra-cranial hemorrhages than warfarin, he said.
“We recognize, however, that patients with severe, life-threatening bleeding require immediate therapy, and these patients might benefit from a reversal agent,” Unger added. “[T]here is much interest in developing such agents for the other drugs in this class.”
When the FDA approved Pradaxa in 2010, Unger gave a different assessment of how Pradaxa compared to warfarin. Unger wrote that it was “important” for the FDA not to say Pradaxa was superior to warfarin, “because it would imply that even those well-treated with warfarin should be switched to dabigatran. Clearly, that is not the case.”
Both Pradaxa and its antidote are produced by drug-maker Boehringer Ingelheim.
“While we anticipate that Praxbind® will be rarely used in clinical practice, the availability of a specific reversal agent has the potential to give physicians and patients added confidence in choosing Pradaxa®,” Boehringer Ingelheim vice president Jorg Kreuzer said in a company news release.
The company said the antidote is to be used when reversing the blood-thinning effects of Pradaxa “is needed for emergency surgery/urgent procedures or in life-threatening or uncontrolled bleeding.”
Read our report, “Drug Problems: Dangerous Decision-Making at the FDA”
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