Avoid Coadministration of Clopidogrel [Plavix] and Omeprazole [Prilosec] or Esomeprazole [Nexium]

Last Updated on November 18, 2009 by Joseph Gut – thasso

November 17, 2009 – Today, the US Food and Drug Administration (FDA) informed on new data showing that the proton pump inhibitor (PPI) Omeprazole [Prilosec] or [Prilosec OTC] reduces the anti-blood clotting effect of Clopidogrel [Plavix] by almost half when these 2 medicines are taken by the same patient. Patients at risk for heart attacks or strokes who use Clopidogrel [Plavix] to prevent blood clots will not get the full effect of this medicine if they are also taking Omeprazole [Prilosec]; therefore, the FDA recommends that the coadministration of Omeprazole [Prilosec] and Clopidogrel [Plavix] be avoided.

The new recommendations, updated from a January 2009 Early Communication, are based on study results from the manufacturers of Clopidogrel [Plavix]. The studies confirm that coadministration of Omeprazole [Prilosec] with Clopidogrel [Plavix] results in decreased levels of Clopidogrel [Plavix]’s active metabolite, reducing Clopidogrel [Plavix]’s anticlotting effect.

Omeprazole [Prilosec] inhibits the drug-metabolising enzyme CYP2C19, which is responsible for the conversion of Clopidogrel [Plavix] into its active metabolite with anticlotting activity. The new studies compared the amount of Clopidogrel [Plavix]’s active metabolite in the blood and its effect on platelets in patients who took Clopidogrel [Plavix] plus Omeprazole [Prilosec] versus those who took Clopidogrel [Plavix] alone. A reduction in active metabolite levels of about 45% was found in those who received Clopidogrel [Plavix] with Omeprazole [Prilosec] compared with those taking Clopidogrel [Plavix] alone. The effect of Clopidogrel [Plavix] on platelets was reduced by as much as 47% in patients receiving Clopidogrel [Plavix] and Omeprazole [Prilosec] together. These reductions were seen whether the drugs were given at the same time or 12 hours apart.

Since the level of inhibition among other PPIs varies, it is unknown to what amount other PPIs may interfere with Clopidogrel [Plavix]. However, Esomeprazole [Nexium], a PPI that is the S-enantiomer of omeprazole and as such also contained in Omeprazole [Prilosec], inhibits CYP2C19 and should also be avoided in combination with Clopidogrel [Plavix].

Other stomach acid-reducing drugs, such as Ranitidine [Zantac], Famotidine [Pepcid], Nizatidine [Axid], or antacids, are not expected to interfere with the anticlotting activity of Clopidogrel [Plavix] because they do not inhibit CYP2C19 enzyme activity. However, Cimetidine [Tagamet] or [Tagamet HB] does inhibit CYP2C19 activity and should also not be used together with Clopidogrel [Plavix].

In addition to Cimetidine [Tagamet], other drugs that are potent inhibitors of the CYP2C19 enzyme would be expected to have a similar effect and should be avoided in combination with Clopidogrel [Plavix]. These include Fluconazole [Diflucan], Ketoconazole [Nizoral], Voriconazole [VFEND], Etravirine [Intelence], Felbamate [Felbatol], Fluoxetine, as [Prozac], [Sarafem], or  [Symbyax], Fluvoxamine [Luvox], and Ticlopidine [Ticlid].

Sanofi-aventis and Bristol-Myers Squibb, the makers of Plavix (Clopidogrel [Plavix]), are updating this drug’s label with the details of the studies and are conducting follow-up studies to further explore drug interactions with Clopidogrel [Plavix].

Until further information is available, FDA recommends the following:

• The concomitant use of Omeprazole [Prilosec] and Clopidogrel [Plavix] should be avoided because of the effect on Clopidogrel [Plavix]’s active metabolite levels and anticlotting activity. Patients at risk for heart attacks or strokes, who are given Clopidogrel [Plavix] to prevent blood clots, may not get the full protective anticlotting effect if they also take prescription drug Omeprazole [Prilosec] or Omeprazole [Prilosec OTC], its over the counter (OTC) form.

• Separating the dose of Clopidogrel [Plavix] and Omeprazole [Prilosec] in time will not reduce this drug interaction.

• Other drugs that should be avoided in combination with Clopidogrel [Plavix] because they may have a similar interaction include Esomeprazole [Nexium],  Cimetidine [Tagamet], Fluconazole [Diflucan], Ketoconazole [Nizoral], Voriconazole [VFEND], Etravirine [Intelence], Felbamate [Felbatol], Fluoxetine, as [Prozac], [Sarafem], or  [Symbyax], Fluvoxamine [Luvox], and Ticlopidine [Ticlid].

• At this time the FDA does not have sufficient information about drug interactions between Clopidogrel [Plavix] and PPIs other than Omeprazole [Prilosec] and Esomeprazole [Nexium] to make specific recommendations about their coadministration. Healthcare professionals and patients should consider all treatment options carefully before beginning therapy.

• There is no evidence that other drugs that reduce stomach acid, such as most H2 blockers Ranitidine [Zantac], Famotidine [Pepcid], Nizatidine [Axid] (except Cimetidine [Tagamet] or [Tagamet HB], which is potent CYP2C19 enzyme inhibitor), or antacids interfere with the anticlotting activity of Clopidogrel [Plavix]. Ranitidine and Famotidine are available by prescription and OTC to relieve and prevent heartburn and antacids are available OTC to relieve heartburn.

• Talk with your patients about the OTC medicines they take. Be aware that patients may be taking nonprescription forms of Omeprazole [Prilosec] and Cimetidine [Tagamet]. Likewise, patients are urged to inform their physicians if they take any of these OTC medicines.

The FDA will continue to investigate other drug interactions with Clopidogrel [Plavix]. The FDA plans on presenting this issue at the next meeting of the FDA’s Drug Safety Oversight Board in November. The Agency will communicate any further recommendations or conclusions once additional information is available.

Phamacogenetic considerations (added by the blog author)

Patients should be aware that even without taking any of the aforementioned  CYP2C19 enzyme-inhibiting co-medications, monozygote carriers of the loss of function CYP2C19*2, CYP2C19*3,  CYP2C19*4, and CYP2C19*5 allelic variants may experience a considerably reduced transformation of Clopidogrel [Plavix] to its pharmacologically active metabolite responsible for the anti-clotting activity. This may also be true for patients who are compound heterozygote carriers of such alleles, for example  CYP2C19*2/CYP2C19*3, etc. More information on this aspect can be found here and here.

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Ph.D.; Professor in Pharmacology and Toxicology. Senior expert in theragenomic and personalized medicine and individualized drug safety. Senior expert in pharmaco- and toxicogenetics. Senior expert in human safety of drugs, chemicals, environmental pollutants, and dietary ingredients.

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