Annotation of Health Canada Santé Canada (HCSC) label information
for warfarin and CYP2C9, VKORC1

Actionable PGx

Summary

The product monograph for warfarin (COUMADIN) notes that patients carrying one or two copies of the CYP2C9*2 or *3 alleles may require a decreased mean daily warfarin dose, and have an increased bleeding risk, as compared to those homozygous for the CYP2C9*1 allele. Additionally, variations in the VKORC1 gene, such as -1639G>A, are also associated with changes in the dose requirement of warfarin.

Annotation

Warfarin (COUMADIN) is an anticoagulant. Excerpts from the warfarin (COUMADIN) product monograph:

A meta-analysis of 9 qualified studies including 2775 patients (99% Caucasian)...suggested an increased bleeding risk for patients carrying either the CYP2C9*2 or CYP2C9*3 alleles. Patients carrying at least one copy of the CYP2C9*2 allele required a mean daily warfarin dose that was 17% less than the mean daily dose for patients homozygous for the CYP2C9*1 allele. For patients carrying at least one copy of the CYP2C9*3 allele, the mean daily warfarin dose was 37% less than the mean daily dose for patients homozygous for the CYP2C9*1 allele.

In an observational study...in 219 Swedish patients...The relative risk of over anticoagulation as measured by INR >3 during the first 2 weeks of therapy was approximately doubled for those patients classified as *2 or *3 compared to patients who were homozygous for the *1 allele.

Certain single nucleotide polymorphisms in the VKORC1 gene (especially the -1639G>A allele) have been associated with lower dose requirements for warfarin. In 201 Caucasian patients treated with stable warfarin doses, genetic variations in the VKORC1 gene were associated with lower warfarin doses. In this study, about 30% of the variance in warfarin dose could be attributed to variations in the VKORC1 gene alone; about 40% of the variance in warfarin dose could be attributed to variations in VKORC1 and CYP2C9 genes combined. About 55% of the variability in warfarin dose could be explained by the combination of VKORC1 and CYP2C9 genotypes, age, height, body weight, interacting drugs and indication for warfarin therapy in Caucasian patients. Similar observations have been reported in Asian patients.

For the complete product monograph text with sections containing pharmacogenetic information highlighted, see the warfarin product monograph.

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