Warfarin (Coumadin®) dsoe is sometimes difficult to adjust. The labeling for a popular formulation of warfarin was revised in August 2007 and February 2010 to include information about how the three most widely studied pharmacogenetic mutations (CYP2C9*2, CYP2C9*3, and VKORC1 -1639G>A) affect dose requirements (NDA 9-218/S-105). The Warfarin-Sensitivity test idendifies that most common mutations that affect warfarin metabolism. ?CYP2C9 genotype accounts for up to 18% of the variability in warfarin dosing ?VKORC1 genotype accounts for up to 29% of the variability in warfarin dosing ?Combining genotypes with clinical factors may account for 50-70% of variability in warfarin dosing.
Approval was based on a study involved 896 participants with an average age of 65 who were members of prescription benefit plans managed by Medco. Hospitalization rates for this group were matched against a historical control group of 2,688 individuals. Researchers collected DNA from either blood or buccal cells and determined patients’ genotypes for the CYP2C9 and VKORC genetic variants. Mutations in the CYP2C9 gene have been associated with decreased warfarin metabolism, while mutations in the VKORC1 gene are associated with warfarin sensitivity. Based on each individual’s genotype, clinicians used a dosing algorithm to determine that person’s initial dose. The study followed patients for 6 months after the start of their treatment. Compared with the control group, the genotyped patients had 31% fewer hospitalizations overall and 28% fewer hospitalizations for bleeding or thromboembolism during the follow-up period. The study results were first reported at the American College of Cardiology’s annual meeting in March of 2010 and are available online: J Am Coll Cardiol (doi:10.1016/j.jacc.2010.03.009).
This is the relevant information form the label for Warfarin: "
The dose of COUMADIN must be individualized by monitoring the PT/INR. Not all factors causing warfarin dose variability are known. The maintenance dose needed to achieve a target PT/INR is influenced by:
Clinical factors including age, race, body weight, sex, concomitant medications, and comorbidities and
Genetic factors (CYP2C9 and VKORC1 genotypes).
Select the starting dose based on the expected maintenance dose, taking into account the above factors. Routine use of loading doses is not recommended as this may increase hemorrhagic and other complications and does not offer more rapid protection against clot formation. If the patient's CYP2C9 and VKORC1 genotypes are not known, the initial dose of COUMADIN is usually 2 to 5 mg per day. Modify this dose based on consideration of patient-specific clinical factors. Consider lower initiation doses for elderly and/or debilitated patients. (See CLINICAL PHARMACOLOGY and PRECAUTIONS).
The patient's CYP2C9 and VKORC1 genotype information, when available, can assist in selection of the starting dose. Table 5 describes the range of stable maintenance doses observed in multiple patients having different combinations of CYP2C9 and VKORC1 gene variants. Consider these ranges in choosing the initial dose."
Food and Drug Administration. New labeling information for Coumadin. Approved 1/22/2010.
Anderson JL, Horne BD, Stevens SM et al. Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation 2007;116:2563-70.
The International Warfarin Pharmacogenetics Consortium. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med2009;360:753-64.
Gage B, Eby C, Johnson J, Deych E et al. Use of Pharmacogenetic and Clinical Factors to Predict the Therapeutic Dose of Warfarin. Clinical Pharmacology & Therapeutics 2008: 84, 326–331