FDA Alters Warfarin Label to Reflect Gene Tests for Bleeding Risks

ROCKVILLE, Md., Aug. 16 -- The FDA today changed the label for warfarin (Coumadin) to make clinicians aware of two tests for gene variants that may affect the risk of bleeding after initial dosing.

Agency officials cited data indicating that the 30% to 35% of patients who carry the CYP2C9 gene variants probably need a lower initial dose of warfarin.

At the same time, said the officials, certain single nucleotide polymorphisms in the VKORC1 gene (especially the -1639G>A allele) have been associated with lower dose requirements for warfarin in about 30% of patients.

One-time-only tests for the gene variants cost from to , depending on where they are obtained, the FDA officials said.

Although the agency held a press conference promoting a new age of individualized genetic testing, and it changed the drug's label, it did not recommend or urge that patients starting on warfarin be tested, leaving that decision to clinicians. The agency officials explained that the availability of the tests was not sufficiently widespread for a stronger message and the clinical data showing benefit was too sparse.

The FDA officials said they hoped to have clinical data within two years that would allow it to make a firmer recommendation on testing. "The labeling change highlights the opportunity for healthcare providers to use genetic tests to improve their initial estimate of what is a reasonable warfarin dose for individual patients," said the FDA. "Testing may help optimize the use of warfarin and lower the risk of bleeding complications from the drug."

The label changes said that "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, the new label language said, have been reported in Asian patients."

The agency offered no dosing algorithm. It said that some exist but it declined to endorse any.

The new label cited a meta-analysis of nine qualified studies including 2,775 patients (99% Caucasian) that was performed to examine the clinical outcomes associated with CYP2C9 gene variants in warfarin-treated patients.

Three of the studies assessed bleeding risks and eight assessed daily dose requirements. The analysis 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," the label said. "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," the new label continued, "the risk of achieving INR >3 during the first three weeks of warfarin therapy was determined in 219 Swedish patients retrospectively grouped by CYP2C9 genotype. The relative risk of over anticoagulation as measured by INR >3 during the first two weeks of therapy was approximately doubled for those patients classified as *2 or *3 compared to patients who were homozygous for the *1 allele."

The new label also said that "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."

The FDA estimated that two million persons start taking warfarin in the United States every year to prevent blood clots, heart attacks and stroke. Warfarin is the second most common drug -- after insulin -- implicated in emergency room visits for adverse drug events.