Rockville, MD - The FDA is updating the label for warfarin to include information in the "precautions" section to remind physicians that people with variations in two known genes may require a lower initial dose of the drug [1,2]. Experts say this new labeling is a sign of things to come in the dawning era of pharmacogenetics.

Genetic variants of the CYP2C9 and VKORC1 genes are individually responsible for anywhere from 35% to 50% of the variable dose response to warfarin, Dr Larry Lesko, director of the FDA's Office of Clinical Pharmacology, said during a press teleconference. Someone carrying variants of both genes might be even more susceptible to adverse effects of the drug. One gene is involved in drug metabolism such that certain variations permit the drug to remain active in the blood for longer; the other represents the site of action of warfarin such that gene variants could affect patient sensitivity to the drug. Currently, physicians rely predominantly on factors like age, body weight, body size, gender, and environmental factors to estimate an appropriate starting dose for warfarin, which ranges from 2 mg to 5 mg.

Importantly, however, the new labeling does not dictate how physicians should change the dosage: directives of this sort require the backing of clinical trials, and no such adequate studies have yet shown that using a genetic test to determine initial warfarin dosing actually has an impact on the safety or efficacy of the drug. One such trial planned by the FDA in collaboration with Kaiser Permanente was never completed; while several companies offer tests for the two genes in question, none are FDA approved.

"This labeling does not change how physicians alter their dosage," Dr Dwaine Rieves, acting director of the FDA's division of medical imaging and hematology products, Center for Drug Evaluation and Research, explained. "None of the recommendations [for dosing] have changed in the label. What this label change does is it highlights the availability of these tools for the physician to test their patients. If a patient has the allele genotype with these gene variations, then it behooves, it's logical, the physician to use the lower initial dose. . . . The practice of medicine in the dosing of warfarin involves a great deal of subjectivity, and you have a sizable number of adverse bleeding events that are related to the challenges of selecting this initial dose. The genetic testing impacts the choice of the initial dose; that is an important consideration in the very first few days of starting warfarin therapy."

Tests for the two genes are widely available, but not universally—another factor taken into account when the FDA was deciding on the labeling change. Tests for the genetic variances cannot be mandatory if they are not available to every physician needing to prescribe warfarin. According to Lesko, his inquiries into price of the test—and most laboratories offer the tests in combination—suggest that it may cost between $125 and $500.

But some physicians fear that including the tests in the labeling may leave them open to litigation if they do not order a test and a patient subsequently experiences adverse events. Asked about this during the press briefing, FDA officials emphasized that there simply are not enough clinical data to make this test mandatory.

"There is a considerable amount of information available to date to suggest that the presence of these variances importantly impacts the choice of the initial warfarin dose, as well as the propensity for bleeding. On the other hand, the clinical data today are not sufficient in our judgment to alter the recommendations in the label such that we require or even strongly encourage—beyond what we have described in the current label—the use of these tests, Rieves said. "Subsequent clinical tests may actually prove that these tests are essential, and if the data do turn out that way, we anticipate that the labeling will be changed to reflect that. But for now, we're balancing some of the considerations that we know right now impact the safety of this with what we don't know about the test. . . . We're not quite to the point where we can say that doctors must perform these tests. Doctors can still practice good medicine without using these tests."

Inclusion of genetic information on drug labeling, in general, is not new: several oncology drugs already make mention of genetic information. But warfarin is only the second drug in which specific pharmacogenetic details have been listed in the label relating to drug dosing, the first drug being the colon cancer drug irinotecan (Camptosar, Pharmacia & Upjohn). FDA spokespeople, however, point out that this is the first time that a widely used agent has included these types of genetic details; currently warfarin is taken by an estimated two million people in the US and, after insulin, is the second most likely drug to send people to the emergency room with drug-related side effects.

Warfarin's new labeling is a sign of things to come in personalized medicine, or pharmacogenetics. Three years ago the FDA launched its Critical Path initiative focused on tailoring drug development to genetics. The initiative has funded research being conducted at the University of Utah and the Critical Path Institute of Tucson, AZ, to develop genetically based instructions for warfarin dosing and is coordinating with the National Heart, Lung and Blood Institute to fund trials elsewhere addressing the pharmacogenetics and dose algorithms for warfarin as well as for other widely used or investigational drugs.

Commenting on the FDA announcement to heartwire, Dr Eric Topol (Scripps Translational Science Institute, La Jolla, CA) stated: "I fully support the FDA's stance on the value of genetic information in dosing of warfarin. It is a major step in the right direction of individualized medicine in the future. While it will take years before the final, definitive proof that genotyping the two genes—CYP2C9 and VKORC1—will change the outcomes of bleeding via randomized trials, getting this information today is remarkably inexpensive and harmless, and, at the very least, can accelerate the time it takes for a patient to be properly anticoagulated and markedly improves the convenience features. This is a big step for the FDA and for the field of individualized medicine, just the beginning."