FDA Public Health Advisory: Bextra (Valdecoxib) and Celebrex (Celecoxib)

Today, the Food and Drug Administration (FDA) is announcing that it has asked Pfizer, Inc. to voluntarily withdraw Bextra (valdecoxib) from the market. Pfizer has agreed to suspend sales and marketing of Bextra in the U.S., pending further discussions with the agency. FDA is also asking manufacturers of all marketed prescription NSAIDs, including Celebrex (celecoxib), a COX-2 selective NSAID, to revise the labeling (package insert) for their products to include a boxed warning and a Medication Guide. The boxed warning will highlight the potential for increased risk of cardiovascular (CV) events with these drugs and the well-described, serious, and potentially life-threatening gastrointestinal (GI) bleeding associated with their use. The Medication Guide will accompany every prescription NSAID at the time it is dispensed to better inform patients about the CV and GI risks. Finally, FDA is asking manufacturers of non-prescription (OTC) NSAIDs to revise their labeling to include more specific information about the potential GI and CV risks, and information to assist consumers in the safe use of the drug. This announcement does not apply to aspirin as it has clearly been shown to reduce the risk of serious adverse CV events in certain patient populations.

In reaching these decisions, FDA has carefully considered the available data on all of the NSAIDs. The Agency has also considered presentations, discussions, and votes from the joint public meeting of the FDA Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee held on February 16, 17, and 18, 2005 to discuss the CV safety concerns for these drugs along with their overall risk-benefit.

Specifically, FDA is requesting the actions listed below and will work closely with the manufacturers to ensure their timely implementation.

BEXTRA (valdecoxib tablets)
FDA has concluded that the overall risk versus benefit profile is unfavorable and has requested that Pfizer, the manufacturer of Bextra, voluntarily withdraw Bextra from the market. This request is based on:

•The lack of adequate data on the cardiovascular safety of long-term use of Bextra, along with the increased risk of adverse CV events in short-term coronary artery bypass surgery (CABG) trials that FDA believes may be relevant to chronic use.

•Reports of serious and potentially life-threatening skin reactions, including deaths, in patients using Bextra. The risk of these reactions in individual patients is unpredictable, occurring in patients with and without a prior history of sulfa allergy, and after both short- and long-term use.

•Lack of any demonstrated advantages for Bextra compared with other NSAIDs.

Pfizer has agreed to suspend sales and marketing of Bextra in the U.S., pending further discussions with the agency.

Patients currently taking Bextra should contact their physicians to consider alternative treatments.

CELEBREX (celecoxib tablets)
FDA has concluded that the benefits of Celebrex outweigh the potential risks in properly selected and informed patients. Accordingly, FDA will allow Celebrex to remain on the market and has asked Pfizer to take the actions listed below.

•Revise the Celebrex label to:

•Include a boxed warning containing the class NSAID warnings and contraindication (see below) about CV and GI risk, plus specific information on the controlled clinical trial data that demonstrate an increased risk of adverse CV events for celecoxib.

•Encourage prescribers to discuss with patients the potential benefits and risks of Celebrex and other treatment options before a decision is made to use Celebrex.

•Encourage practitioners to use the lowest effective dose for the shortest duration consistent with individual patient treatment goals.

•Include a Medication Guide as part of the labeling. It will be required to be given at the time the drug is dispensed to inform patients of the potential for CV and GI risk associated with NSAIDS, in general, and Celebrex specifically. 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.

•Commit to conduct a long-term study to address the safety of Celebrex compared to naproxen and other appropriate drugs. FDA will work with Pfizer to design this long-term study and ensure its timely initiation and completion.

Patients who are taking CELEBREX should discuss questions or concerns about this new information with their physician.

Non-Selective NSAIDs
A number of non-selective NSAIDs (prescription and non-prescription (over-the-counter (OTC)) are approved for marketing in the United States. A list of these products is attached and is also available at http://www.fda.gov/cder/drug/infopage/cox2/default.htm#list.

Long-term controlled clinical trials have not been conducted with most of these NSAIDs. However, the available data suggest that use of these drugs may increase CV risk. It is very difficult to draw conclusions about the relative CV risk among the COX-2 selective and non-selective NSAIDs with the data available.

All sponsors of non-selective NSAIDs will be asked to conduct and submit to FDA a comprehensive review and analysis of available controlled clinical trial databases pertaining to their NSAID product(s) to which they have access to further evaluate the potential for increased CV risk.

FDA will work closely with sponsors and other interested stakeholders (e.g., NIH) to encourage additional long-term controlled clinical trials of non-selective NSAIDs to further evaluate the potential for increased CV risk.

In addition, FDA is requesting labeling changes for both 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.

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