Reduced Effect from Clopidogrel [Plavix] in “Poor Metabolizer” Patients

June 12, 2010

Through a new boxed warning, the FDA is alerting healthcare professionals about a subgroup of patients who cannot effectively metabolize the anti-platelet drug Clopidogrel [Plavix].

These patients, called “poor metabolizers,” have little or no activity of the liver enzyme CYP2C19, which converts Clopidogrel [Plavix] to its active form, so they may not experience the full anti-clotting benefits of the drug.

Practitioners should know that tests are available to identify genetic differences in CYP2C19 function and thus identify poor metabolizers. They should consider using other anti-platelet medication or an alternative dosing strategy for these patients. And although raising the dose of Clopidogrel [Plavix] in poor metabolizers can increase anti-platelet response, an appropriate dose regimen has not been established in a clinical trial.

Please find additional information here:

The Original Article

FDA MedWatch Safety Alert. Plavix (clopidogrel): Reduced effectiveness in patients who are poor metabolizers of the drug. March 12, 2010.

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FDA Drug Safety Communication: Reduced effectiveness of Clopidogrel [Plavix] in patients who are poor metabolizers (i.e. carriers of selected CYP2C19 allelic variants) of the drug

March 17, 2010

March 17, 2010 – The U.S. Food and Drug Administration (FDA) has added a Boxed Warning to the label for Clopidogrel [Plavix], the anti-blood clotting medication. The Boxed Warning is about patients who do not effectively metabolize the drug (i.e. “poor metabolizers”, see below) and therefore may not receive the full benefits of the drug.

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

  • Warn about reduced effectiveness in patients who are poor metabolizers of Clopidogrel [Plavix]. Poor metabolizers do not effectively convert Clopidogrel [Plavix] to its active form in the body.
  • 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 Clopidogrel [Plavix] in patients identified as poor metabolizers.

Clopidogrel [Plavix] is given to reduce the risk of heart attack, unstable angina, stroke, and cardiovascular death in patients with cardiovascular disease. Clopidogrel [Plavix] works by decreasing the activity of blood cells called platelets, making platelets less likely to form blood clots.

For Clopidogrel [Plavix] to work, enzymes in the liver (particularly CYP2C19) must convert (metabolize) the drug to its active form. Patients who are poor metabolizers of the drug, do not effectively convert Clopidogrel [Plavix] to its active form. In these patients, Clopidogrel [Plavix] has less effect on platelets, and therefore less ability to prevent heart attack, stroke, and cardiovascular death. It is estimated that 2 to 14% of the population are poor metabolizers; the rate varies based on racial background.

Healthcare professionals should be aware that a subgroup of patients are poor metabolizers and do not metabolize Clopidogrel [Plavix] effectively; this can result in reduced effectiveness of Clopidogrel [Plavix]. Healthcare professionals should consider use of other anti-platelet medications or alternative dosing strategies for Clopidogrel [Plavix] in these patients.

Patients should not stop taking Clopidogrel [Plavix] unless told to do so by their healthcare professional. They should talk with their healthcare professional if they have any concerns about Clopidogrel [Plavix], or to find out if they should be tested for being a poor metabolizer.

In May 2009, FDA added information about poor metabolizers of Clopidogrel [Plavix] to the drug label. However, based on additional data reviewed by the agency (see Data Summary below) the Boxed Warning is now being added to highlight the reduced effectiveness of Clopidogrel [Plavix] in these patients and to recommend that healthcare professionals consider use of other anti-platelet medications or alternative dosing strategies for Clopidogrel [Plavix] in patients identified as poor metabolizers.

Additional Information for Patients and Health Care Providers Alike

Patients currently taking Plavix should:

  • Be aware that some patients do not convert Clopidogrel [Plavix] to its active form as well as other patients. These patients may not get the same benefit from Clopidogrel [Plavix]and are known as poor metabolizers.
  • Not stop taking Clopidogrel [Plavix] unless told to do so by their healthcare professional.
  • Talk with their healthcare professional if they have any concerns about Clopidogrel [Plavix].
  • Talk with their healthcare professional to see if testing to determine their metabolizer status is appropriate.

FDA recommends that healthcare professionals should:

  • Be aware that some patients may be poor metabolizers of Clopidogrel [Plavix]. They do not effectively convert Clopidogrel [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 Clopidogrel [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 Clopidogrel [Plavix] drug label for complete information on the use of Clopidogrel [Plavix].

Scientific Background and Data Summary

The liver enzyme CYP2C19 is primarily responsible for the formation of the active metabolite of Clopidogrel [Plavix]. Pharmacokinetic and antiplatelet tests of the active metabolite of Clopidogrel [Plavix] show that the drug levels and antiplatelet effects differ depending on the genotype of the CYP2C19 enzyme. The following represent the different alleles of CYP2C19 that make up a patient’s genotype:

1. The CYP2C19*1 allele has fully functional metabolism of Clopidogrel [Plavix].

2. The CYP2C19*2 and *3 alleles have no functional metabolism of Clopidogrel [Plavix]. These two alleles account for most of the reduced function alleles in patients of Caucasian (85%) and Asian (99%) descent classified as poor metabolizers.

3. The CYP2C19*4, *5, *6, *7, and *8 and other alleles may be associated with absent or reduced metabolism of Clopidogrel [Plavix], but are less frequent than the CYP2C19*2 and *3 alleles.

A patient who carries two loss-of-function alleles (as defined above) will have poor metabolizer status.

The pharmacokinetic and antiplatelet responses to Clopidogrel [Plavix] were evaluated in a crossover trial in 40 healthy subjects. Ten subjects in each of the four CYP2C19 metabolizer groups (ultrarapid, extensive, intermediate and poor) were randomized to two treatment regimens: a 300 mg loading dose followed by 75 mg per day, or a 600 mg loading dose followed by 150 mg per day, each for a total of 5 days. After a washout period, subjects were crossed over to the alternate treatment. Decreased active metabolite exposure and increased platelet aggregation were observed in the poor metabolizers compared to the other groups. When poor metabolizers received the 600 mg loading dose followed by 150 mg daily, active metabolite exposure and antiplatelet response were greater than with the 300 mg/75 mg regimen. Healthcare professionals should note that an appropriate dose regimen for patients who are poor metabolizers has not been established in clinical outcome trials.


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