FDA adds Boxed Warning to clopidogrel label: drug less effective in poor metabolizers with CYP2C19 gene variant

Genéricos/Novedades | Posted 23/03/2010 post-comment

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Sanofi-aventis and Bristol-Myers Squibb announced on 12 March 2010 revisions to the US prescribing information for its anti-blood clotting drug Plavix (clopidogrel bisulfate).

The US FDA added a Boxed Warning to the label for Plavix, which concerns the diminished effectiveness of the pro-drug clopidogrel in patients who have a genetic variation, leading to reduced formation of the active metabolite. These patients, who are designated as “poor metabolizers”, represent, according to the prescribing information, approximately 2% of whites, 4% of blacks, and 14% of Chinese. The percentage of poor metabolizers is estimated to be approximately 3% of the population, based on published studies. Seven different variants of the CYP2C19 gene are associated with poor metabolism of clopidogrel. According to the FDA, patients with two loss-of-function alleles, which do not have to be identical, will be poor metabolizers. It is estimated that 2–14% of the US population are poor metabolizers.

Plavix does not have its anti-platelet effects until it is metabolized into its active form by the liver enzyme, CYP2C19. People who have reduced functioning of their CYP2C19 liver enzyme cannot effectively convert Plavix to its active form. As a result, Plavix may be less effective in altering platelet activity in those people. These poor metabolizers may not receive the full benefit of Plavix treatment and may remain at risk for heart attack, stroke, and cardiovascular death, states the FDA.

"We want to highlight this warning to make sure healthcare professionals use the best information possible to treat their patients," said Ms Mary Ross Southworth, a Clinical Analyst in the Division of Cardiovascular and Renal Products in the FDA's Center for Drug Evaluation and Research.

In May 2009, the FDA added this warning to the drug's label. After reviewing more data, the agency felt it was important to highlight this risk in a Boxed Warning. The FDA recommends that healthcare professionals consider alternative dosing of Plavix for these patients, or consider using other anti-platelet medications. Tests are available to assess CYP2C19 genotype to determine if a patient is a poor metabolizer. Patients should not stop taking Plavix, unless told to do so by their healthcare professional.

MedPage Today reports that Dr Christopher Cannon, a Cardiologist at Brigham and Women's Hospital and Harvard Medical School in Boston, US, told them in an email that the warning effectively means every patient on clopidogrel needs to be tested, although the new label does not say so directly. Some 25 million prescriptions for clopidogrel were written in 2008, according to ‘www.drugs.com’. Though the FDA recommends that physicians "consider alternative dosing" if patients are found to be poor metabolizers, Dr Cannon stressed that appropriate dosing in poor metabolizers has not yet been established. "We will need more trials of alternate dosing of clopidogrel in ACS [acute coronary syndrome] and other patients or of alternate drugs in the non-ACS patients," he wrote. In addition, testing approaches and treatment alternatives for some groups of patients still need to be worked out. He also told MedPage Today that the cost could be a problem, for like most genetic tests, obtaining a CYP2C19 genotype runs into the hundreds of dollars.

References:

Sanofi-aventis and Bristol-Myers Squibb Announce Important Updates to PLAVIX U.S. Prescribing Information. BMS Press Release. 2010 March 12.

FDA Drug Safety Communication: Reduced effectiveness of Plavix (clopidogrel) in patients who are poor metabolizers of the drug. FDA Press Release. 2010 March 12.

John Gever. Boxed Warning Added to Clopidogrel Label, Testing Suggested. MedPage Today. 2010 March 12.

Lianne Dane. FDA adds boxed warning to Plavix to advise of reduced effectiveness in some patients. FirstWord. 2010 March 12.

Nancy Faigen. Plavix gets US "boxed warning" about poor metabolisers. Scrip News. 2010 March 15.

Source: BMS Press Release; FDA Press Release; MedPage Today; FirstWord; Scrip News

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