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FDA Updates Plavix Label with PGx Data, but Does Not Provide Dosing Recommendations

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This article has been updated from a prior version to include comments from the FDA and Aetna.

The US Food and Drug Administration has updated the label for Plavix with pharmacogenetic data informing doctors and patients of diminished response to the drug and increased risk of heart attack in patients with reduced CYP2C19 function.

"Based on literature data, patients with genetically reduced CYP2C19 function have lower systemic exposure to the active metabolite of clopidogrel and diminished antiplatelet responses, and generally exhibit higher cardiovascular event rates following myocardial infarction than do patients with normal CYP2C19 function," the agency states in the new label for Plavix, commonly known as clopidogrel.

According to FDA's drug database, the agency updated the label for Plavix, a popular anti-platelet drug marketed by Bristol-Myers Squibb and Sanofi-Aventis, on May 5.

The new label acknowledges that "CYP2C19 poor metabolizer status is associated with diminished response to clopidogrel," and notes that "pharmacogenetic testing can identify genotypes associated with variability in CYP2C19 activity." However, the agency does not specify PGx-guided dosing and does not explicitly "require" or "recommend" genetic testing prior to administration of the drug.

"The optimal dose regimen for poor metabolizers has yet to be determined," the new label states.

The FDA did not disclose to Pharmacogenomics Reporter why the new label does not provide PGx-guided dosing information or whether it was looking at PGx dosing studies that might provide this information in the future.

"We revised the labeling based upon what information we thought [was] sufficiently established at the time the labeling was amended," an agency spokesperson told Pharmacogenomics Reporter without elaborating.

Without PGx-guided dosing information, it is unclear whether genetic testing to gauge Plavix response will go the same way as genetic testing for warfarin.

When FDA updated the labeling for the anticoagulant with genetic-risk data in 2007, the agency did not require doctors to genetically test patients for genetic abnormalities prior to initiating the therapy. Many industry observers have noted that adoption of PGx-guided warfarin dosing has been negatively impacted due to lack of stronger labeling language from FDA.

At least one national insurer, Aetna, feels that the FDA did not provide enough information in the updated Plavix label to warrant coverage for the intervention.

"At this point, we would consider CYP2C19 genotyping as experimental for assessing response to Plavix," Robert McDonough, Aetna's head of clinical policy research & development, told Pharmacogenomics Reporter this week.

"Although the FDA-approved labeling indicates that CYP2C19 metabolizer status is associated with poor response to Plavix, the labeling makes no specific recommendations on how this testing should be used," McDonough said. "Clinical studies demonstrating improved outcomes for patients prospectively managed according to genotype are needed to inform clinical practice."

In light of the labeling update, however, at least one direct-to-consumer genomics firm, 23andMe, is already offering screening for SNPs linked to Plavix response under its $399 Personal Genome Service.

New Labeling Language

The updated Plavix label notes that the CYP2C19*1 allele is associated with "fully functional [drug] metabolism," and the CYP2C19*2 and CYP2C19*3 alleles are linked to "reduced metabolism" of clopidogrel.

The CYP2C19*2 and CYP2C19*3 alleles account for 85 percent of reduced function alleles in whites and 99 percent in Asians. Other alleles linked to poor metabolism include CYP2C19*4, *5, *6, *7, and *8, "but these are less frequent in the general population," the labeling states.

The FDA notes in the label that there may be genetic variants of other CYP450 enzymes linked to clopidogrel metabolism.

Shortly after the agency forecast its intention to update Plavix's label last year, two studies published in the New England Journal of Medicine reported that patients with reduced-function alleles of CYP2C19 who had been treated with clopidogrel experienced diminished platelet inhibition and a higher rate of major cardiovascular events compared to clopidogrel-treated patients without the alleles [see PGx Reporter 12-31-2008].

These two studies, by Simon et al. and Mega et al., and five other clinical trials are cited in the updated label for the drug.

The FDA notes that the impact of CYP2C19 genotype on the pharmacokinetics of clopidogrel's active metabolite has been evaluated in 227 subjects from seven reported studies. Meanwhile, the reduced antiplatelet response has been associated with intermediate and poor CYP2C19 metabolizers in 21 reported studies involving more than 4,500 patients.

"The relative difference in antiplatelet response between genotype groups varies across studies depending on the method used to evaluate response, but is typically greater than 30 percent," according to the label.

In addition, data from two post-hoc clinical trial analyses of CLARITY-TIMI 28 (Clopidogrel as Adjunctive Reperfusion Therapy — Thrombolysis in Myocardial Infarction 28) and TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel — Thrombolysis in Myocardial Infarction 38) and five cohort studies link CYP2C19 genotype and clopidogrel treatment outcomes.

According to the label, in CLARITY-TIMI 28 and one of the cohort studies, cardiovascular event rates did not differ significantly by genotype. In TRITON-TIMI 38 and three of the cohort studies, intermediate and poor metabolizers had a higher rate of cardiovascular events, including death, myocardial infarction, and stroke or stent thrombosis compared to extensive metabolizers. In the fifth cohort study of 2,208 patients, researchers observed an increased event rate only in poor CYP2C19 metabolizers.

Market Impact

If CYP2C19 testing for clopidogrel response and increased cardiovascular risk takes hold, the market size for the drug will certainly be reduced. This may be good news for pharmaceutical firms making competing antiplatelet treatments, since clopidogrel goes off patent in 2011.

Daiichi Sankyo and Eli Lilly are codevelopers of the anti-platelet prasugrel (Effient), which is currently under review at the FDA and stands to compete with Plavix.

In TRITON-TIMI 38, a head-to-head study of Effient and Plavix, Effient was found to be more efficacious than clopidogrel in preventing deaths from blood clots, non-fatal heart attacks, and non-fatal strokes in patients receiving stents.

However, analysis by Mega et al. showed that carriers of CYP2C19 reduced-function alleles treated with clopidogrel had a 53 percent increase in the risk of death from cardiovascular causes, myocardial infarction, or stroke, as compared with noncarriers, and an increase by a factor of 3 in the risk of stent thrombosis.

Genetic tests for CYP2C19 metabolism are available from various national labs, at academic centers, and certain hospitals. Laboratory Corporation of America offers CYP2C19 PGx testing with Roche's AmpliChip. El Camino Hospital's Genomic Medicine Institute in Silicon Valley also offers testing for the genetic risk associated with CYP2C19 metabolism and Plavix response.

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