FDA is updating the label for warfarin to inform physicians and patients about the usefulness of genetic testing before beginning therapy with the anticoagulant, but the agency will wait for data from ongoing studies before adding specific recommendations that tests be conducted or on specific dosing levels based on patients' genetic characteristics.

"The clinical data available today are not sufficient ... to actually alter the recommendations in the label such that we require ... or even strongly encourage ... the use of these tests," Acting Director of the Division of Medical Imaging and Hematology Products Dwaine Rieves explained during an Aug. 16 press conference to unveil the new label.

Requiring the tests would require that they be widely available, and that is not yet the case, Director of Clinical Pharmacology Larry Lesko noted, although all major laboratories offer this service.

He also pointed out that "more studies are needed to explore the precise starting dose" based on genetic factors. Those factors are variants in two genes - CYP2C9 and VKORC1. The former is involved in warfarin metabolism and the latter helps regulate the ability of the drug to prevent blood from clotting.

Currently, prescribing warfarin is a delicate matter as physicians seek a dose that will prevent blood clotting without causing severe bleeding. The proper dose varies by patient based on age, diet, medications being taken, the gene variants and other factors. Genetics can be responsible for 35 to 50 percent of the variability, Lesko said. Patients with the gene variants tend to require lower doses of warfarin, so identification of this factor can prevent overdosing and help get to a maintenance dose faster.

The updated label retains the recommendation that initial dosing begin at 2 mg to 5 mg per day, with adjustments made on the basis of results from the prothrombin time test and how they compare to the International Normalized Ratio for healthy people. Labeling also states, "The lower initiation doses should be considered for patients with certain genetic variations in CYP2C9 and VKORC1 enzymes."

In the precautions section, the label points out that "genetic variations in the CYP2C9 and VKORC1 enzymes" are one of the factors that "may influence the response of the patient to warfarin." The pharmacogenomics section of labeling includes a discussion of studies showing that the gene variants are associated with lower dose requirements.

To get the word out on warfarin and genetics, FDA is working with the American Medical Association and the Critical Path Institute to develop a brochure for patients and physicians, and the Center for Devices and Radiological Health is preparing a video to be put on its Web site. These are expected to be available in the last quarter of 2007, Lesko said.

FDA is supporting research to come up with answers on dosing based on genetics. The agency's Critical Path Initiative is funding research at the University of Utah and the Critical Path Institute to develop genetically based instructions for warfarin dosing and is contributing to a clinical study by Harvard Partners to derive personalized warfarin dosing algorithms for patients new to the drug.

FDA estimates that 2 million people begin warfarin therapy in the U.S. each year to prevent blood clots, heart attacks and stroke. According to NIH, more than 21 million prescriptions for the drug are written annually. Warfarin is the second most common cause of adverse drug reaction-related emergency room visits.

The labeling changes apply to Bristol-Myers Squibb's Coumadin as well as generic versions of warfarin.

-Cathy Dombrowski (c.dombrowski@elsevier.com)

Updated Warfarin Label Notes Genetics’ Impact On Dosing, But Avoids Recommending Test

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