Editorial - SAGE Journals

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lion people and is second only to insulin in contributing ... drug to list specific pharmacoge- ... Director, Kansas University Medical Center, Kansas City, Kansas.
Hospital Pharmacy Volume 42, Number 10, p 882 2007 Wolters Kluwer Health, Inc.

Editorial Personalized Medicine? An Update on Warfarin (Coumadin) Labeling Allison King, PharmD* and Joyce Generali, MS, RPh, FASHP†

n August 16, 2007, the Food and Drug Administration (FDA) approved updated warfarin (Coumadin) prescribing information to include a statement regarding the use of genetic testing in estimating a reasonable starting dose. According to the FDA, warfarin is used by an estimated 2 million people and is second only to insulin in contributing to emergency room visits related to adverse drug events. Therapy with warfarin may be complicated by difficulty in dosing appropriately and a narrow therapeutic window.1 The dose of this medication can vary 20-fold and is influenced by several known factors (eg, age, gender, ethnicity, body mass index, drug-drug and drug-food interactions, infections, ingestion of vitamin K, heart failure, liver-function impairment, genetic make-up).2,3 Two genes, CYP2C9 and vitamin K epoxide reductase complex subunit 1 (VKORC1), are responsible for 35% to 50% of the variability in warfarin doses.4 Warfarin is a racemic mixture of R- and S-enantiomers, which differ in potency and metabolism. S-warfarin is 5-fold more potent than R-warfarin. In addition, Swarfarin is metabolized by CYP2C9 whereas R-warfarin is metabolized by CYP3A4, 1A2, and 1A1. Patients with polymorphisms

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in CYP2C9, specifically CYP2C9*2 and CYP2C9*3, have demonstrated a need for a reduced dose of warfarin.5 Patients with polymorphisms of the VKORC1 gene have demonstrated a spectrum of responses to warfarin, ranging from resistance to reduced dosage need.2,5 Warfarin is a specific inhibitor of the vitamin K epoxide reductase (VKOR), which is encoded by VKORC1 gene.5 Some patients may possess both polymorphisms, leading to severe over anticoagulation if not treated properly. The approved new labeling marks the start of a new era of pharmacy, pharmacogenomics or personalized medicine. The FDA started a new program 3 years ago called Critical Path Initiative that “is [the] FDA’s effort to stimulate and facilitate a national effort to modernize the sciences through which FDA-regulated products are developed, evaluated, and manufactured.”6 Warfarin is the second drug to list specific pharmacogenetic details relating to dosing within its labeling; the first was irinotecan (Camptosar), a drug used to treat colon cancer.4 Several other oncology drugs also generally mention genetic information in their labels. According to the FDA, the new labeling changes do not change current practice but merely suggest

*Clinical Assistant Professor, Drug Information Specialist; †Clinical Professor, Drug Information Director, Kansas University Medical Center, Kansas City, Kansas.

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genetic testing as an option. Dr. Dwaine Rieves, acting director of the FDA’s division of medical imaging and hematology products, Center for Drug Evaluation and Research, stated, “...this label change...highlights the availability of these tools for the physician to test their patient,” but also went one step further to say: “if a patient has the allele genotype with these gene variations, then it behooves, it’s logical [for], the physician to use the lower initial dose.”4 Current practice standards do not address requirements for genetic testing, (which can cost between $125 and $500).4 Currently, the FDA’s Critical Path Initiative is conducting research to develop guidelines for genetically-based warfarin dosing, but until completed, practitioners everywhere struggle with the question to recommend testing. Hospital Pharmacy is interested in feedback regarding how various health care settings are planning to incorporate this new information into practice. REFERENCES 1. U.S. Food and Drug Administration. FDA News. FDA approves updated warfarin (Coumadin) prescribing information. http://www.fda.gov/bbs/topics/ NEWS/2007/NEW01684.html. Accessed August 22, 2007. 2. Schalekamp T, Brassé BP, Roijers JFM, et al. VKORC1 and CYP2C9 genotypes and acenocoumarol anticoagulation status: interaction between both genotypes affects overanticoagulation. Clin Pharmacol Ther. 2006;80(1):13-22.

Editorial

3. Wadelius M, Chen LY, Eriksson N, et al. Association of warfarin dose with genes involved in its action and metabolism. Hum Genet. 2007;127(1):23-34. 4. Wood S. New warfarin labeling reminds physicians about genetic tests to

help guide initial warfarin dosing. h t t p : / / w w w. t h e h e a r t . o r g / a r t i cle/807123.do. Accessed August 28, 2007. 5. Yin T, Miyata T. Warfarin dose and the pharmacogenomics of CYP2C9 and

VKORC1 - rationale and perspectives. Thromb Res. 2007;120(1):1-10. 6. U.S. Food and Drug Administration. Critical Path Initiative. http://www. fda.gov/oc/initiatives/criticalpath/. Accessed August 27, 2007. 

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