Stroke Notes: avoid plavix plus nexium/prevacid

FDA: Avoid Coadministration of Clopidogrel and Omeprazole, Esomeprazole

SILVER SPRING, Md -- November 17, 2009 -- The US Food and Drug Administration (FDA) has new data showing that the proton pump inhibitor (PPI) omeprazole (Prilosec/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 to prevent blood clots will not get the full effect of this medicine if they are also taking omeprazole; therefore, the FDA recommends that the coadministration of omeprazole and clopidogrel be avoided.

The new recommendations, updated from a January 2009 Early Communication, are based on study results from the manufacturers of clopidogrel. The studies confirm that coadministration of omeprazole with clopidogrel results in decreased levels of clopidogrel's active metabolite, reducing clopidogrel's anticlotting effect.

Omeprazole inhibits the drug-metabolising enzyme (CYP2C19), which is responsible for the conversion of clopidogrel into its active metabolite. The new studies compared the amount of clopidogrel's active metabolite in the blood and its effect on platelets in patients who took clopidogrel plus omeprazole versus those who took clopidogrel alone. A reduction in active metabolite levels of about 45% was found in those who received clopidogrel with omeprazole compared with those taking clopidogrel alone. The effect of clopidogrel on platelets was reduced by as much as 47% in patients receiving clopidogrel and omeprazole 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. However, esomeprazole (Nexium), a PPI that is a component of omeprazole, inhibits CYP2C19 and should also be avoided in combination with clopidogrel.

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 because they do not inhibit CYP2C19 activity. However, cimetidine (Tagamet/Tagamet HB) does inhibit CYP2C19 activity and should not be used.

In addition to cimetidine, 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. These include fluconazole (Diflucan), ketoconazole (Nizoral), voriconazole (VFEND), etravirine (Intelence), felbamate (Felbatol), fluoxetine (Prozac, Sarafem, Symbyax), fluvoxamine (Luvox), and ticlopidine (Ticlid).

Sanofi-aventis and Bristol-Myers Squibb, the makers of Plavix (clopidogrel), 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.

Until further information is available, FDA recommends the following:
• The concomitant use of omeprazole and clopidogrel should be avoided because of the effect on clopidogrel's active metabolite levels and anticlotting activity. Patients at risk for heart attacks or strokes, who are given clopidogrel to prevent blood clots, may not get the full protective anticlotting effect if they also take prescription omeprazole or the OTC form.
• Separating the dose of clopidogrel and omeprazole in time will not reduce this drug interaction.
• Other drugs that should be avoided in combination with clopidogrel because they may have a similar interaction include esomeprazole, cimetidine, fluconazole, ketoconazole, voriconazole, etravirine, felbamate, fluoxetine, fluvoxamine, and ticlopidine.
• At this time the FDA does not have sufficient information about drug interactions between clopidogrel and PPIs other than omeprazole and esomeprazole 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 and Tagamet HB - a CYP2C19 inhibitor), or antacids interfere with the anticlotting activity of clopidogrel. 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 and cimetidine.

The FDA will continue to investigate other drug interactions with clopidogrel. 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.

Effectiveness of Clopidogrel May Be Reduced by Common Heartburn Drugs: Presented at SCAI

Certain PPIs Increase Risk of Heart Attacks for Patients on Clopidogrel

SOURCE: US Food and Drug Administration