Information for Health Care Professionals: Update to the Labeling of Clopidogrel Bisulfate (Marketed as Plavix) to Alert Health Care Professionals About a Drug Interaction With Omeprazole (Marketed as Prilosec and Prilosec OTC)

FDA is alerting the public to new safety information concerning an interaction between clopidogrel (Plavix), an anti-clotting medication, and omeprazole (Prilosec/Prilosec OTC), a proton pump inhibitor (PPI) used to reduce stomach acid. New data show that when clopidogrel and omeprazole are taken together, the effectiveness of clopidogrel is reduced. 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. The updated label for clopidogrel will contain details of new studies submitted by Sanofi-Aventis and Bristol-Myers Squibb, the manufacturer of Plavix (clopidogrel).

Omeprazole inhibits the drug metabolizing enzyme (CYP2C19) which is responsible for the conversion of clopidogrel into its active form (active metabolite). The new studies compared the amount of clopidogrel's active metabolite in the blood and its effect on platelets (anti-clotting effect) in people who took clopidogrel plus omeprazole versus those who took clopidogrel alone. A reduction in active metabolite levels of about 45% was found in people who received clopidogrel with omeprazole compared to those taking clopidogrel alone. The effect of clopidogrel on platelets was reduced by as much as 47% in people receiving clopidogrel and omeprazole together. These reductions were seen whether the drugs were given at the same time or 12 hours apart.

Other drugs that are potent inhibitors of the CYP 2C19 enzyme would be expected to have a similar effect and should be avoided in combination with clopidogrel. These include: cimetidine, fluconazole, ketoconazole, voriconazole, etravirine, felbamate, fluoxetine, fluvoxamine, and ticlopidine. Since the level of inhibition among other PPIs varies, it is unknown to what amount other PPIs may interfere with clopidogrel. However, esomeprazole, a PPI that is a component of omeprazole, inhibits CYP2C19 and should also be avoided in combination with clopidogrel.

FDA is aware there are studies, such as the Clopidogrel and Optimization of Gastrointestinal Events (COGENT) study, that might provide information about the effect of this interaction on clinical outcome. Although the FDA has not fully reviewed the study results, the applicability of these data is limited because of the study design and follow-up. Therefore, based on the current scientific information, the clopidogrel label has been updated with new warnings on omeprazole and other drugs that inhibit the CYP2C19 enzyme that could interact with clopidogrel in the same way. In addition, the manufacturer of Plavix (clopidogrel) is conducting follow-up studies to explore this and other drug interactions.

Considerations for Healthcare Professionals

• The concomitant use of omeprazole and clopidogrel should be avoided because of the effect on clopidogrel's active metabolite levels and anti-clotting activity. Patients at risk for heart attacks or strokes, who are given clopidogrel to prevent blood clots, may not get the full protective anti-clotting effect if they also take prescription omeprazole or the OTC form (Prilosec OTC).
• 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 (Nexium), cimetidine (which is available by prescription Tagamet and OTC as Tagamet HB), fluconazole (Diflucan), ketoconazole (Nizoral), voriconazole (VFEND), etravirine (Intelence), felbamate (Felbatol), fluoxetine (Prozac, Serafem, Symbyax), fluvoxamine (Luvox), and ticlopidine (Ticlid).
• At this time FDA does not have sufficient information about drug interactions between clopidogrel and PPIs other than omeprazole and esomeprazole to make specific recommendations about their co-administration. 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 anti-clotting 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 non prescription forms omeprazole and cimetidine.

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

Related Information

• Information on Clopidogrel Bisulfate (marketed as Plavix)
• Public Health Advisory: Updated Safety Information about a drug interaction between Clopidogrel Bisulfate (marketed as Plavix) and Omeprazole (marketed as Prilosec and Prilosec OTC)
  11/17/2009
• Follow-Up to the January 26, 2009, Early Communication about an Ongoing Safety Review of Clopidogrel Bisulfate (marketed as Plavix) and Omeprazole (marketed as Prilosec and Prilosec OTC)
  11/17/2009
• Early Communication about an Ongoing Safety Review of clopidogrel bisulfate (marketed as Plavix)
  1/26/2009

Labeling and Regulatory History From Drugs@FDA

• Clopidogrel Bisulfate (marketed as Plavix) -- Prescribing and Label Information