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FDA Updates Warfarin Label to Explain Genetic Links to Response; Says Change Not Meant As 'Directive' for Doctors

NEW YORK (GenomeWeb News) - The US Food and Drug Administration said today that the labeling for the widely prescribed anticoagulant warfarin will be updated to explain how people’s genetics may impact their response to the drug.
“The labeling change highlights the opportunity for healthcare providers to use genetic tests to improve their initial estimate of what is a reasonable warfarin dose for individual patients,” the FDA said in a statement. “Testing may help optimize the use of warfarin and lower the risk of bleeding complications from the drug.”
Clinical studies have shown that patients with variations in the CYP2C9 and VKORC1 genes may need a lower warfarin dose than patients without those variations.
During a call hosted by the FDA today, Larry Lesko, director of the office of clinical pharmacology at the FDA’s Center for Drug Evaluation and Research, hailed the labeling update as a milestone that brings “personalized medicine to the mainstream.”
The warfarin labeling update isn’t the first time the agency updated a drug’s label with genetic testing information. The FDA currently recommends the use of genotypic data to modify doses for patients using the acute lymphatic leukemia drug 6-mercaptopurine and Pfizer’s colorectal cancer agent Camptosar (irinotecan).
“However, this marks the first time that such pharmacogenomic information has been included in a widely used drug,” Lesko said. “This means that personalized medicine is no longer an abstract concept, but has moved into the mainstream, where it is recognized as a factor in a product used by millions of Americans.”
Approximately 2 million people are initiated on warfarin therapy each year to prevent blood clots, heart attacks, and stroke. According to the FDA’s adverse events reporting database, complications from warfarin (Bristol-Myer’s Squibb’s Coumadin) are the second most common reason for patients to go to the emergency room, behind adverse reactions from insulin.
Warfarin dosing is complicated by various factors including a patient’s diet, age, and other medications. Patients who take too much drug can suffer life-threatening bleeding and those who take too little can suffer blood clots. 
In November 2005 the FDA Clinical Pharmacology Subcommittee of Pharmaceutical Science Advisory Committee recommended testing for variations in the CYP2C9 and VKORC1 genes in patients requiring warfarin therapy.
Coumadin's new label states: "It is recommended that Coumadin therapy be initiated with a dose of 2 to 5 mg per day with dosage adjustments based on the results of [prothrombin time/international normalized ratio] determinations. The lower initiation doses should be considered for patients with certain genetic variations in CYP2C9 and VKORC1 enzymes as well as for elderly and/or debilitated patients and patients with potential to exhibit greater than expected PT/INR responses to Coumadin." 
The agency, in making its long-awaited announcement today, clarified that the labeling language does not aim to encourage doctors to genetically test their patients, since current clinical studies do not definitively support such a recommendation.
“I think we’re seeing right now just the early stages of the use of these tests in clinical practice. … We’re not quite to the point where we can say that doctors must perform these tests,” Dwaine Rieves, acting director of the division of medical imaging and hematology products at FDA’s Center for Drug Evaluation and Research, said.
“Doctors can still practice good medicine without doing these tests, but the tests are available and that’s one of the major points we hope to make with making the change there,” Rieves added.
Lesko said that despite using genetic tests, doctors should regularly check if warfarin is working properly by ordering a prothrombin time test to evaluate the blood’s ability to clot properly.
“[International normalized ratio] monitoring should continue to be the cornerstone of anticoagulation monitoring,” he added.
Janet Woodcock, deputy commissioner and chief medical officer of the FDA, further emphasized that this labeling update is “not a directive to doctors” to use genetic tests for warfarin therapy. “We have to wait for outcomes data for that kind of a label,” Woodcock said.
To this end, there are numerous studies currently ongoing looking at outcomes when genetic tests are incorporated into warfarin treatment. The Harvard Partners Center for Genetics and Genomics, Medco and the Mayo Clinic, Clinical Data and PharmaCare, and the University of Utah under the Critical Path Initiative, are all researching the clinical utility of PGx-based warfarin dosing.
The fact that pharmacy-benefit managers like PharmaCare and Medco are involved in this type of research suggests that insurers will also be looking closely at outcomes results to determine whether they should cover such genetic tests. Although few major insurers cover genetic testing for warfarin, the labeling update may change all that.
Large insurers like Aetna have said that the mention of genetic testing in a drug’s label, along with published data in medical journals regarding the value of genetic testing, weigh heavily when deciding whether to reimburse for a genetic test. Genetic tests currently available on the market range between $125 and $500, the FDA said. 

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