Plavix label gets black box warning about poor metabolizers 1

The FDA announced today that it had added a boxed warning to the Plavix (clopidogrel) label, warning patients and doctors that the drug may be less effective in people who are unable to metabolize the drug and convert it to its active form.

The FDA said that healthcare professionals “should consider use of other anti-platelet medications or alternative dosing strategies for Plavix in these patients.” The FDA said that patients should not stop taking Plavix without talking to their physician.

Harlan Krumholz provided the following comment to CardioBrief:

Unfortunately the FDA has taken the step of warning people about a harm that has yet to be established. This warning could lead to non-compliance, unnecessary testing and increased cost without benefiting patients. The recommendation is based on platelet activation studies and not on clinical outcomes studies. To this point we do not know if a strategy of testing patients before prescribing will provide them a net benefit.

Here are the FDA recommendations for healthcare professionals:

  • Be aware that some patients may be poor metabolizers of Plavix. They do not effectively convert Plavix to its active form because of low CYP 2C19 activity. The effectiveness of Plavix as a preventive therapy is reduced in these patients.
  • Be aware that tests are available to determine patients’ CYP2C19 status.
  • Consider use of other anti-platelet medications or alternative dosing strategies for Plavix in patients who have been identified as poor metabolizers.
  • Be aware that although a higher dose regimen (600 mg loading dose followed by 150 mg once daily) in poor metabolizers increases antiplatelet response, an appropriate dose regimen for poor metabolizers has not been established in a clinical outcome trial.
  • Review the newly approved Plavix drug label for complete information on the use of Plavix

Click here for the FDA’s complete communication.

Here is the FDA press release:

FDA Announces New Boxed Warning on Plavix
Alerts patients, health care professionals to potential for reduced effectiveness

The U.S. Food and Drug Administration today added a boxed warning to the anti-blood clotting drug Plavix (clopidogrel), alerting patients and health care professionals that the drug can be less effective in people who cannot metabolize the drug to convert it to its active form.

Plavix reduces the risk of heart attack, unstable angina, stroke, and cardiovascular death in patients with cardiovascular disease by making platelets less likely to form blood clots. 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.

“We want to highlight this warning to make sure health care professionals use the best information possible to treat their patients,” said Mary Ross Southworth, Pharm.D., 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.

It is estimated that 2 percent to 14 percent of the U.S. population are poor metabolizers. The FDA recommends that health care 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 health care professional. They should talk with their health care professional if they have any concerns about Plavix.

Plavix is made under a Bristol-Myers Squibb – Sanofi Pharmaceuticals partnership.

For information:
FDA Drug Safety Communication: Reduced effectiveness of Plavix (clopidogrel) in patients who are poor metabloizers of the drug

http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm203888.htm

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One comment

  1. If a patient’s perspective is OK, I have this question:

    Is anyone aware of any studies of significant resistance to Plavix _developing_ over months on tx?

    Following a PCI, I began Plavix and, for five months, I had “nuisance bleeds” daily.. Suddenly, it stopped–actually reversed–so that, at six months, I could not “buy a bleed.”

    This was “convenient,” but a little concerning. There were no changes in meds, diet, supplements, etc. that correlated with the shift.

    Has anyone seen this or know of studies?

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