Bextra and Celebrex: Prescription Drug Labeling

To further evaluate the potential for increased CV risk, all sponsors of non-selective NSAIDs will be asked to conduct and submit to FDA a comprehensive review and analysis of pertinent available controlled clinical trial databases.

In addition, FDA is requesting labeling changes for prescription and OTC non-selective NSAIDs. Because the use and labeling for the prescription products is different from those available without a prescription, they are addressed separately.

Prescription Non-Selective NSAIDs
Based on the available data, the FDA will request the manufacturers of all prescription products containing non-selective NSAIDs to revise their product labeling to include:

•A boxed warning regarding the potential serious adverse CV events and the serious, and potentially life-threatening GI adverse events associated with the use of this class of drugs.

•A contraindication for use in patients who have recently undergone coronary artery bypass surgery.

•A Medication Guide for patients to help make them aware of the potential for CV and GI adverse events associated with the use of this class of drugs. The Medication Guide will inform patients of the need to discuss with their doctor the risks and benefits of using NSAIDs and the importance of using the lowest effective dose for the shortest duration possible if treatment with an NSAID is warranted in an individual patient.

OTC Non-Selective NSAIDs
The available data do not appear to suggest an increased risk of serious CV events for the short-term, low-dose use of the NSAIDs available over the counter. FDA will request changes to the label to better inform consumers regarding the safe use of these products.

FDA will ask the manufacturers of all non-prescription products containing ibuprofen (Motrin, Advil, Ibu-Tab 200, Medipren, Cap-Profen, Tab-Profen, Profen, Ibuprohm), naproxen (Aleve), and ketoprofen (Orudis, Actron) to revise their labeling to include:

•More specific information about the potential CV and GI risks,

•Instructions about which patients should seek the advice of a physician before using these drugs,

•Stronger reminders about limiting the dose and duration of treatment in accordance with the package instructions unless otherwise advised by a physician, and

•A warning about potential skin reactions.

3. What information did FDA review to arrive at its decisions?
FDA's Center for Drug Evaluation and Research (CDER) considered the risk/benefit profile for each of the drugs Cox-2 selective drugs, and the CV risks of NSAIDs as a class. We reviewed the regulatory histories and NDA databases of the various NSAIDs, FDA and sponsor background documents prepared for the joint Advisory Committee meeting, all materials and data submitted by other stakeholders to the Advisory Committee meeting, presentations made at the joint meeting, the discussions held by the Committee members during the meeting, and the specific votes and recommendations of the joint Committee.

4. What offices within the Center for Drug Evaluation and Research had input into the decisions?
Participants in the CDER decision-making process included staff from the Office of New Drugs (i.e., the Division of Anti-Inflammatory, Analgesic, and Ophthalmic Drug Products, the Division of Over-the-Counter Drug Products, and the Offices of Drug Evaluation II and V), the Office of Drug Safety, Office of Pharmacoepidemiology and Statistical Science, the Office of Medical Policy, the Office of Regulatory Policy, and the Office of the Center Director.

5. Does the Office of Drug Safety agree with the Office of New Drugs and the Divisions?
The management of the Offices of Drug Safety and New Drugs are in full agreement regarding the actions announced by FDA today.

6. Why has FDA requested Pfizer to voluntarily withdraw Bextra from the market?
We have concluded that, from a public health perspective, we must assume that Bextra has an increased risk of CV events with long-term use. This conclusion is strongly supported by the significant increase in CV risk seen in those patients who had just undergone heart surgery and the fact that other COX-2 selective NSAIDs have demonstrated such increased CV risk in long-term studies. What is not known is how large that risk is in outpatient long-term use, because the studies have not been done. However, the CV risk is likely to be no less than that of other Cox-2 selective inhibitors. In addition, Bextra already carries a boxed warning related to its increased risk of serious, life-threatening skin reactions, which have been reported at a much higher rate than for other COX-2 selective inhibitors. Finally, there are no data to suggest that Bextra has benefits that would outweigh these risks (e.g., GI safety or better efficacy). Bextra has not been shown to offer any advantages over other existing NSAIDs. Therefore, we have concluded that the overall risk versus benefit profile of Bextra is unfavorable.

7. The Advisory Committee votes were split on Bextra. Why didn't FDA go with the recommendation of the majority?
The Advisory Committees were closely divided on whether Bextra should remain on the market (17 voted yes, 13 voted no, with 2 abstentions). Advisory Committee votes are recommendations to FDA, and are not binding on the agency. In all cases, but particularly in cases where its Advisory Committees are closely divided, FDA has the responsibility to weigh all the evidence and determine what, if any, regulatory action is appropriate. After weighing all the evidence, as described in question 6 above, FDA decided to seek the withdrawal of Bextra from the market.

8. It was reported in the New York Times that the members of the FDA Arthritis and Drugs Safety and Risk Management Advisory Committees reviewing the safety risks of COX-2 inhibitors were not obligated to disclose their potential conflicts of interest. Were there any conflicts of interest for any of the members, and did this have an effect on the members' recommendations?
For each advisory committee meeting, the Center for Drug Evaluation and Research (CDER) collects financial interest information for advisory committee members and consultants prior to their participation in order to determine whether the members or consultants have any financial interests that pose conflicts of interest.

All members of this joint committee and consultants who participated as discussants and/or voted at the meeting responded to detailed questions regarding their interests in all entities with a financial interest in the meeting topic. After conducting a review of the potential conflicts of interest for all of the members on the advisory committee examining COX-2 inhibitors, conflicts of interest were found. However, these conflicts were not deemed to be of sufficient magnitude to outweigh the need for the members' and consultants' expertise for this meeting. Waivers were written and approved consistent with the federal ethics and conflict of interest laws for 19 participants.

We do not believe that any of the conflicts of interest affected members' recommendations.

U.S. Food and Drug Administration (FDA)
Department of Health and Human Services
Center for Drug Evaluation and Research
April 7, 2005