A genetic test for sensitivity to the drug warfarin (Coumadin) received marketing clearance from the U.S. Food and Drug Administration (FDA) last month. This lab test identifies individuals who metabolize warfarin more slowly than normal. As a result of slow metabolism, the “blood-thinning” drug, when administered in normal doses, can accumulate in the body of such individuals. Slow metabolizers face a greater risk of severe bleeding. This test could be used to identify such individuals even before they start warfarin and assure that the starting dose is chosen to reflect their slow metabolism of the drug.

Each year, about 2 million people begin warfarin therapy to prevent or treat blood clots, and emergency rooms handle about 43,000 cases with warfarin-related problems. Only insulin is implicated in more adverse drug events than warfarin.

Consequently, healthcare providers are cautious when prescribing warfarin. To estimate the right dose, they look at many factors, including the person’s age, diet, weight and height, other health problems, and medications. They order frequent blood tests (PT and INR) to monitor patients who are taking warfarin, and then raise or lower the dose to make the warfarin work as intended. They are especially careful with people over age 65 and during the first several weeks of therapy, when adverse reactions like bleeding are more likely. Even so, determining an effective but safe dose for this widely prescribed drug involves trial and error.

Genes Tell of Slow Metabolism
About one third of those taking warfarin process it more slowly than typically expected. Recent studies have shown that variations of two genes—CYP2C9 and VKORC1— lead to slower metabolism of drugs like warfarin. People with those genetic variations are at risk of accumulating too much warfarin and developing complications if given “normal” doses. They require lower starting doses and lower maintenance doses than most people. Once the genetic test identifies someone as a slow metabolizer and lower doses are established for them, the PT/INR test is used regularly to monitor their warfarin therapy.

Although some university and commercial laboratories can currently test for these genetic variations, the marketing of the newly approved test and its workstation will allow many more labs to offer this test.

It is hoped that wider availability and use of the new test will lead to better dosing and reduce the number of emergency room visits due to complications from this drug.

Smarter Dose Decisions
The FDA wants those prescribing warfarin to know that people’s genetic makeup may influence how they respond to the drug. In an August 16 press release, the agency announced that the labeling and prescribing information for warfarin must tell healthcare providers that genetic tests may support their initial estimate of a reasonable dose of warfarin for individual patients.

The genetic information may be a useful supplement to other clinical tools and evaluations to better establish the right starting dose and maintenance doses for individuals. Clinical trials are needed to establish the best ways in which to use this information.

Steps To Take
Your healthcare provider may discuss or suggest warfarin sensitivity testing when prescribing warfarin for you or you can ask if such testing may be useful or appropriate in your case. Information from the National Library of Medicine can tell you more about the conditions for which this medication is prescribed. The test results may show that you should start with or change to a lower dose. You can ask if this testing is available in your area and find out if Medicare or your health plan pays for it.

Sources

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Critical Path Initiative: warfarin dosing. US Food and Drug Administration. On the Internet: http://www.fda.gov/oc/initiatives/criticalpath/warfarin.html. Accessed 5 Sep 2007.

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Drug information: Warfarin. Last revised 1 Jan 2007. MedlinePlus; National Library of Medicine. On the Internet: http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a682277.html. Accessed 4 Sep 2007.

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FDA approves updated warfarin (Coumadin) prescribing information. 16 Aug 2007. US Food and Drug Administration. On the Internet: http://www.fda.gov/bbs/topics/NEWS/2007/NEW01684.html. Accessed 4 Sep 2007.

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FDA clears genetic lab test for warfarin sensitivity. 17 Sep 2007. US Food and Drug Administration. On the Internet: http://www.fda.gov/bbs/topics/NEWS/2007/NEW01701.html. Accessed 26 Sep 2007.

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Nanosphere announces first FDA cleared genetic test for warfarin sensitivity and nanotechnology-based molecular diagnostics platform. 18 Sep 2007. Nanosphere, Inc. Northbrook, Ill. Available online. Accessed 24 Sep 2007.

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Questions and answers on new labeling for warfarin (marketed as Coumadin). US Food and Drug Administration. On the Internet: http://www.fda.gov/cdre/drug/infopage/warfarin/qa.html. Accessed 4 Sep 2007.

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Ray, T. 16 Aug 2007. FDA updates warfarin label to explain genetic links to response; says change not meant as ‘directive’ for doctors. GenomeWeb Daily News. On the Internet: http://www.genomeweb.com/issues/news/141730-1.html. Accessed 9 Sep 2007.

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Teleconference on an important drug labeling change.16 Aug 2007. Woodcock, J, Lesko L, Weiss K, and Rieves D. US Food and Drug Administration. Washington, DC.