FDA advisory on Bextra withdrawal, Celebrex and other NSAIDs

FDA information on Bextra and Celebrex
After several months of discussion and an Advisory Committee meeting, the Food and Drug Administration (FDA) announced its recommendation, on Thursday, April 7, 2005, that Bextra (valdecoxib) should be taken off the market. Bextra, a COX-2 inhibitor commonly used for arthritis and back pain, is manufactured by Pfizer, Inc. The voluntary withdrawal is based on the FDA’s decision that the risk/benefit analysis of Bextra is unfavorable. Pfizer has said it will suspend sales and marketing of Bextra pending further discussions with the FDA.

Bextra’s label was recently changed to include warnings for a potentially fatal skin disease. Combined with the risk of cardiovascular problems (i.e. heart attack and stroke), the FDA determined that the serious risks associated with Bextra are not outweighed by the anti-inflammatory and other benefits for arthritis and back pain patients.

The FDA also stated that Celebrex should remain on the market, but with stronger label warnings about the increased risk of heart attack and stroke. Given the voluntary recall of Vioxx in October 2004 and Bextra in April 2005, the only COX-2 inhibitor brand available in the U.S. is now Celebrex.

All prescription-strength NSAIDs (including Celebrex) will now display “black box” label warnings for the potential risk of cardiovascular events and gastrointestinal bleeding. Celebrex and other prescription NSAIDs are also asked to now include a Medication Guide to help educate patients on the cardiovascular and gastrointestinal side effects associated with the drugs. The FDA also requested that over-the-counter NSAIDs (such as ibuprofen, naproxen) include more information about the potential gastrointestinal and cardiovascular adverse side effects of the drugs, a warning about potential skin reactions, as well as information about safe use of the drugs (such as duration and dosage) (1).

FDA advisory process for COX-2 inhibitors
The Food and Drug Administration (FDA) held a joint meeting of the Drug Safety and Risk Management Advisory Committee and the Arthritis Advisory Committee from February 16 to 18, 2005 regarding the benefits and health risks of non-steroidal anti-inflammatory drugs (NSAIDs). The committee included 32 panelists: 8 rheumatologists, 19 physicians, 8 epidemiologists and biostatisticians, 1 ethicist and several patient and industry representatives (2).

The FDA committee that convened in February discussed the risks and outcomes and possible restrictions for specific COX-2 inhibitor and other NSAID brands. While committee members agreed on warnings and restrictions for COX-2 inhibitors as a class of drugs, there was much less agreement on this information for each specific drug - indicating less confidence in the data at the individual drug level. Historically, the FDA has followed the recommendations of its advisory committees. However, given the close votes on specific COX-2 inhibitors, the call for further studies and the fact that no formal report was issued, it is perhaps not surprising that the FDA broke the trend this time and made some decisions that contradict the committee recommendations.

The Advisory Committee that convened in February issued a vote on specific COX-2 inhibitor brands (Celebrex, Bextra and Vioxx) and also on naproxen, another type of NSAID. The results of the committee’s votes were as follows:

COX-2 inhibitors:

Bextra (valdecoxib): The February committee on NSAIDs voted narrowly in favor of keeping Bextra on the market (17 “yes”, 13 “no”, 2 abstained) (2). This vote indicated a lower amount of confidence with Bextra than with other COX-2 inhibitors. In April 2005, the FDA decided request that Pfizer voluntarily withdraw Bextra from the market, and Pfizer has complied with this request.
Celebrex (celecoxib): The committee voted unanimously in favor of keeping Celebrex on the market, indicating greater confidence of the risk versus benefit analysis for the drug (2). Patients are encouraged to talk with their doctor about the risks and benefits of using Celebrex or any NSAID. They are also advised to use only the lowest effective dose for the shortest duration possible.
Vioxx (rofecoxib): The vote on Vioxx was a close 17 “yes” and 15 “no” to return Vioxx to the market since its withdrawal in September 2004. However, the final decision for whether or not Vioxx becomes available again will be determined by the FDA and Merck, the drug’s manufacturer. Merck has announced that it will petition the FDA for reintroduction of Vioxx, but it is not yet known whether studies will show significant new safety information.

Other NSAIDs:

Naproxen: Experts on the FDA panel raised the issue that the warnings for naproxen (brands include Aleve and Naprosyn) may have been exaggerated and needlessly frightened naproxen users. Some research shows that although naproxen poses some risk for heart attack, it may carry a lower risk than COX-2 inhibitors (2). However, more research testing naproxen against a placebo is necessary. As with all other NSAIDs, the FDA has recommended that naproxen will now carry stronger warnings for adverse side effects.

More research needed on NSAIDs
Additionalinformation is still needed to clearly determine health risks (versus benefits) based on duration of usage and dosages for specific brands of COX-2 inhibitors and NSAIDs. Further research is especially necessary to evaluate specific brands, as not all NSAIDs carry the same risk for heart problems. Based on currently available data, however, some degree of increased risk may be a class effect for all NSAIDs. The FDA Advisory Committee voted in favor of mandating cardiovascular safety studies as a condition for allowing COX-2 inhibitors and older NSAIDs to remain on or enter the market.

Patients should consult a physician to weigh their individual risks and benefits
The FDA advises patients who are or were taking Bextra to discontinue use of the drug and consult their physician. In determining a new treatment option, there is no single course of treatment using COX-2 inhibitors and other NSAIDs that will be optimal for all patients. For patients taking any type of NSAIDs, it remains vital for patients to consult their physician and determine the safest treatment options.

The potential for adverse affects from NSAIDs is thought to increase for high-risk patients (i.e. those with a high risk for heart attack, stroke, recent recipients of heart bypass surgery, and patients with a high risk for gastrointestinal bleeding), as well as with higher dosage and with longer duration of usage. For guidelines for taking NSAIDs and explanation of the FDA’s Public Health Advisory on NSAIDs, please see Safe use of COX-2 inhibitors and other NSAIDs.

As more information becomes available, patients should not hesitate to consult their physician to re-evaluate their treatment options and to weigh their individual risks versus the benefits of Celebrex and other NSAIDs.

By: Doug Hendricks, MD
May 16, 2005

References:

U.S. Food and Drug Administration. FDA News. “FDA Announces Series of Changes to the Class of Marketed Non-Steroidal Anti-Inflammatory Drugs (NSAIDs).” April 7, 2005. http://www.fda.gov/bbs/topics/news/2005/NEW01171.html.
Cush JJ, Kavanaugh A, Matteson EL. “Hotline: American College of Rheumatology. Hotline: The Safety of COX-2 Inhibitors: Deliberations from the February 16-18, 2005, FDA Meeting.” American College of Rheumatology. http://www.rheumatology.org/publications/hotline/0305NSAIDs.asp
U.S. Food and Drug Administration. Questions and Answers “FDA Regulatory Actions for the Cox-2 selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs). http://www.fda.gov/cder/drug/infopage/COX2/COX2qa.htm