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

November 18, 2009

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.

Health Canada: Important New Safety Information on Potential Interactions of Proton Pump Inhibitors (PPIs) with Clopidogrel [Plavix]

August 21, 2009

August 21, 2008 –  From a new posting on Health Canadas’s website, we learn that in collaboration with Health Canada,  Sanofi-Aventis Canada Inc. and Bristol Myers Squibb Canada Co. have informed Canadian healthcare professionals and patients alike of important new safety information regarding the potential interaction of Proton Pump Inhibitors (PPIs) with Clopidogrel [Plavix]. This potential interaction could lead to a reduction in the level of Clopidogrel’s [Plavix] active metabolite and therefore, it is conceivable that the therapeutic response to Clopidogrel [Plavix ] may be affected. This information is summarized as follows:

Clopidogrel [Plavix] is a prodrug metabolized by the liver, partly by cytochrome P450 2C19 (CYP2C19), before it can be biologically active in preventing atherothrombotic events. Healthcare professionals should be aware of a potential interaction between PPIs or other drugs that inhibit CYP2C19 and Clopidogrel [Plavix] leading to a potential reduction in the clinical activity of Clopidogrel [Plavix].

Administration of PPIs or of other drugs that inhibit CYP2C19 should be discouraged in patients taking Clopidogrel [Plavix]. The risk-benefit relationship of continuing treatment with a PPI should be considered by the prescribing physician taking into account that other gastro-protective agents are available.

Healthcare professionals should continue to prescribe and patients should continue to take Clopidogrel [Plavix] as directed, because Clopidogrel [Plavix] has demonstrated benefits in preventing life-threatening atherothrombotic events that could lead to myocardial infarction or stroke.

PPIs are drugs used to prevent and treat peptic ulcer and gastroesophageal reflux and may inhibit, to some degree, the activity of CYP2C19. Recent reports in the literature suggest a potential interaction with PPIs through CYP2C19 that may reduce the efficacy of Clopidogrel [Plavix]. Although the evidence for CYP2C19 inhibition varies within the class, the effect is possibly related to all members of the PPI class.

Sanofi-Aventis Canada Inc. and Bristol Myers Squibb Canada Co. are currently working with Health Canada on this topic to integrate the new safety information in the Canadian Product Monograph. In addition to updating the Product Monograph for Clopidogrel [Plavix], Sanofi-Aventis and Bristol Myers Squibb are currently conducting studies to further characterize this potential interaction to provide additional information to healthcare professionals.

Managing marketed health product-related adverse reactions depends on healthcare professionals and consumers reporting them. Reporting rates determined on the basis of spontaneously reported post-marketing adverse reactions are generally presumed to underestimate the risks associated with health product treatments. Any case of serious drug interaction with a PPI or a drug known to inhibit CYP2C19 or other serious or unexpected adverse reactions in patients receiving Clopidogrel [Plavix] should be reported to Sanofi-Aventis Canada Inc. or Health Canada at the following addresses: sanofi-aventis Canada Inc., 2150 St. Elzear Blvd. West Laval, Quebec, H7L 4A8, Telephone: 1-800-265-7927.

The Product Monograph and a copy of this Important Safety Information can be accessed online at  sanofi-aventis Canada Inc. or at Bristol-Myers Squibb Canada Co.

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