Warfarin (Coumadin) is an anticoagulant used as a prophylaxis and to treat venous thrombosis, pulmonary embolism, thromboembolic complications from atrial fibrillationa and cardiac valve replacement, and to reduce the recurrence of myocardial infarction. Pharmacogenomics-related dosing information for CYP2C9 and VKORC1 variants is provided within the label. The drug label notes that deficiency in protein C (PROC) or protein S (PROS1) have been associated with tissue necrosis following warfarin administration.
The VKORC1:G-1639A polymorphism is associated with lower dose requirements for warfarin in Caucasian and Asian patients. Increased bleeding risk and lower initial warfarin dose requirements have been associated with the CYP2C9*2 and CYP2C9*3 alleles. Approximately 30% of the variance in warfarin dose could be attributed to genetic variation in VKORC1, and about 40% of dose variance could be explained taking into consideration both VKORC1 and CYP2C9 genetic polymorphisms. Accounting for genetic variation in both VKORC1 and CYP2C9, age, height, body weight, interacting drugs, and indication for warfarin therapy explained about 55% of the variability in warfarin dose. The drug label also notes that hereditary or acquired deficiency of protein C (encoded by the PROC gene) or protein S (PROS1) have been associated with tissue necrosis following administration of warfarin.
Excerpts from the warfarin drug label:
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.
Known or suspected deficiency in protein C mediated anticoagulant response: Hereditary or acquired deficiencies of protein C or its cofactor, protein S, have been associated with tissue necrosis following warfarin administration.
For the complete drug label text with sections containing pharmacogenetic information highlighted, see the warfarin drug label. Pharmacogenomics-related dosing information is found in Table 5 on page 27.
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