1. Aschenbrenner, Diane S. MS, APRN, BC

Article Content

In what the Food and Drug Administration (FDA) describes as a step toward "personalized medicine," the label of the commonly used anticoagulant warfarin (Coumadin) has been revised to indicate that patients who do not readily clear the drug have a higher risk of possibly life-threatening bleeding. Warfarin is metabolized by the hepatic cytochrome P-450 (CYP) isoenzyme system, including the isoenzyme CYP2C9. Particular genetic variants of CYP2C9 can significantly decrease the metabolism of warfarin, thereby increasing the amount of active drug in the body and the risk of bleeding. Patients who have these genetic variations must take a lower dose of the drug to avoid the adverse effect. Clinical trials indicate that, depending on the patient's specific genetic variations, the safe, effective dose of warfarin is 17% to 37% lower than a typical dose.


Another genetic variation that increases the risk of bleeding with warfarin involves the vitamin K cycle. Vitamin K is essential for clotting. Warfarin inhibits a multiprotein enzyme complex, vitamin K epoxide reductase (VKOR), thereby reducing the regeneration of vitamin K from vitamin K epoxide. Patients with variations in the VKORC1 gene require a lower dose of warfarin to obtain a therapeutic effect.


Genetic testing can determine whether a patient has any of the genetic variations and permit physicians to make lower-and safer-estimates of the proper dosage. The new label information reflects the increasing importance of pharmacogenomics, which can predict a patient's response to a drug on the basis of her or his genetic constitution.


The revised label does not state that patients should be tested for genetic variations or indicate how to adjust the drug dose in patients who have them. Additional research, some of it sponsored by the National Heart, Lung, and Blood Institute, is being planned to determine safe and effective dosages for new patients on the basis of their genetic test results. If genetic testing is performed, the results should also be considered by the prescriber when estimating the initial dosage. Nurses should be aware that genetic testing may be performed in some patients before beginning therapy with warfarin, or in some patients already taking it. At this time, however, warfarin's label still states that the dose must be determined by comparing the patient's prothrombin time with the international normalized ratio.


U.S. Food and Drug Administration. FDA news: FDA approves updated warfarin (Coumadin) prescribing information. 16 Aug 2007. http://www.fda.bbs/topics/NEWS/2007NEW01684.html; Bristol-Meyers Squibb Company. Coumadin tablets (warfarin sodium tablets, USP) crystalline; Coumadin for injection (warfarin sodium for injection, USP).