FDA issues public health advisory on interaction between clopidogrel and omeprazole

Updated: The FDA has issued a public health advisory to highlight updated safety information regarding an interaction between clopidogrel (Plavix) and omeprazole. The label change, which was made on Friday, was reported first by CardioBrief yesterday.

An FDA official explained that the label changes were based on data from a new study performed by the sponsor: Here are the study details as written in the new label:

Omeprazole

In a crossover clinical study, 72 healthy subjects were administered PLAVIX (300-mg loading dose followed by 75 mg/day) alone and with omeprazole (80 mg at the same time as PLAVIX) for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 46% (Day 1) and 42% (Day 5) when PLAVIX and omeprazole were administered together. Mean inhibition of platelet aggregation (IPA) was diminished by 47% (24 hours) and 30% (Day 5) when PLAVIX and omeprazole were administered together. In another study 72 healthy subjects were given the same doses of PLAVIX and omeprazole but the drugs were administered 12 hours apart; the results were similar indicating that administering PLAVIX and omeprazole at different times does not prevent their interaction (see WARNINGS).

The FDA action comes less than two months after the public presentation at TCT by Deepak Bhatt of COGENT, which many experts thought would dispel fears about the interaction issue. At that time, Bhatt said that “the results call into question the exact relationship between ex vivo platelet assays and clinical outcomes, especially with respect to assessing drug interactions.”

The FDA official said that COGENT had “limitations” because it was terminated early and underenrolled. “We are looking at the totality of the evidence,” she said, but “because of the limitations of the data we don’t find it as reassuring as others.”

A joint statement issued by the ACC and the AHA noted that the FDA advisory “is not based on any new published, peer-reviewed clinical trials showing changes in cardiovascular outcomes.”

Sanjay Kaul provided CardioBrief with the following comment:

This study provides evidence of a pharmacodynamic interaction of
clopidogrel with PPIs. The key question whether this is sufficient to
translate into clinical outcomes should await randomized controlled
assesment. (See our previous story for a more detailed comment from Kaul.)

CardioBrief asked the FDA if the timing of the new warning was in any way related to the recent availability of prasugrel, an alternative agent. The FDA, succintly, replied “no.”

Click here to read a more detailed account of the press conference on Medpage Today.

Click here to read a good heartwire story by Sue Hughes, including reactions by many well-known cardiologists.

Click here for the new label posted on the product’s website.

Here is the FDA advisory:

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]

The U.S. Food and Drug Administration (FDA) has new data showing that omeprazole (Prilosec/Prilosec OTC)—a medicine used to reduce stomach acid—reduces the anti-blood clotting effect of clopidogrel (Plavix) by almost half when these two 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. This effect is called a drug interaction and it occurs because omeprazole blocks the conversion of clopidogrel into its active form.

Since clopidogrel can cause bleeding in the stomach, medications like omeprazole may be used in combination to reduce the production of stomach acid, and prevent stomach bleeding. Omeprazole is available by prescription and as an over-the-counter (OTC) medication to treat frequent heartburn

FDA wants to emphasize the following information for patients using clopidogrel:

  • Patients using clopidogrel should consult with their healthcare provider if they are currently taking or considering taking omeprazole, including Prilosec OTC.
  • Both clopidogrel and omeprazole can provide significant benefits to patients, and patients should always consult with their healthcare professional before starting or stopping any medication.
  • It is very important that patients talk with their healthcare professional about any over-the-counter (OTC) drugs they are taking before starting or while using clopidogrel

Patients who use clopidogrel and need a medication to reduce stomach acid can use antacids (such as Maalox or Mylanta) and most acid reducers, such as Zantac (ranitidine), Pepcid (famotidine), or Axid (nizatidine) because the FDA does not believe that these medicines will interfere with the anti-clotting activity of clopidogrel. However, Tagamet and Tagamet HB (cimetidine) should not be used. Ranitidine and famotidine are available by prescription and OTC and antacids are available OTC.

The manufacturers of clopidogrel have agreed to look at other possible drug interactions with clopidogrel. In the meantime, the clopidogrel label will be updated with new warnings on omeprazole and other drugs that could interact with clopidogrel in the same way. When more information becomes available, FDA will communicate any additional recommendations or conclusions on the use of clopidogrel.

Here is the FDA’s information for healthcare professionals:

Information for Healthcare Professionals: Update to the labeling of Clopidogrel Bisulfate (marketed as Plavix) to alert healthcare professionals about a drug interaction with omeprazole (marketed as Prilosec and Prilosec OTC)

[11/17/2009]

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.

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