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Podcast for Healthcare Professionals: Reduced effectiveness of Plavix in patients who are poor metabolizers of the drug

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Welcome, my name is Chris Jones, a pharmacist in the Division of Drug Information. Today I am updating you about reduced effectiveness of Plavix in patients who are poor metabolizers of the drug.

The U.S. Food and Drug Administration (FDA) has added a Boxed Warning to the drug label for Plavix.

The Boxed Warning in the drug label will include information to:

  • Warn about reduced effectiveness in patients who are poor metabolizers of Plavix.
  • Inform healthcare professionals that tests are available to identify genetic differences in CYP2C19 function.
  • Advise healthcare professionals to consider use of other anti-platelet medications or alternative dosing strategies for Plavix in patients identified as poor metabolizers.

Because Plavix is a pro-drug, it must be converted in the liver to its active form and CYP2C19 is the predominate enzyme responsible for this conversion. Patients who are poor metabolizers of Plavix, do not effectively convert the drug to its active form. In these patients, Plavix has less effect on platelets, and therefore less ability to prevent heart attacks, strokes, and cardiovascular death.

It is estimated that 2 to 14% of the population are poor metabolizers; the rate varies based on racial background.

In May 2009, FDA added information about poor metabolizers of Plavix to the drug label. However, based on additional data reviewed by the agency the Boxed Warning is now being added to highlight the reduced effectiveness of Plavix in these patients.

Pharmacokinetic and antiplatelet tests of the active metabolite of Plavix show that the drug levels and antiplatelet effects differ depending on the genotype of the CYP2C19 enzyme.

The CYP2C19 alleles type *2 and *3have no functional metabolism of Plavix. These two alleles account for most of the reduced function alleles in patients of Caucasian and Asian descent classified as poor metabolizers. A patient with two loss-of-function alleles will have poor metabolizer status.

The pharmacokinetic and antiplatelet responses to Plavix were evaluated in a crossover trial in 40 healthy subjects. Ten subjects in each of the four CYP2C19 metabolizer groups (defined as ultrarapid, extensive, intermediate and poor metabolizers) were randomized to two treatment regimens: the first being300 mg loading dose of Plavix followed by 75 mg per day, or a 600 mg loading dose of Plavix followed by 150 mg per day, each for a total of 5 days. After a washout period, subjects were crossed over to the alternative treatment.

Decreased active metabolite exposure and decreased platelet aggregation were observed in the poor metabolizers compared to the other groups. When poor metabolizers received the 600 mg loading dose of Plavix followed by 150 mg daily, active metabolite exposure and antiplatelet response were greater than with the 300 mg loading dose of Plavix followed by 75 mg per day regimen.

At this time, FDA recommends that healthcare professionals:

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

Thank you for listening. The FDA is committed to keeping healthcare professionals informed of the latest safety information. If you have questions about this safety communication, you can reach the Division of Drug Information at the following email address: druginfo@fda.hhs.gov.

 

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