FDA Public Health Advisory - Arthritis Drug Valdecoxib (BEXTRA) Removed From Market; Major New Warnings for Other NSAIDs

The Food and Drug Administration (FDA) issued a Public Health Advisory on April 7, 2005 announcing that it had asked Pfizer, Inc. to withdrawn the popular arthritis drug valdecoxib (BEXTRA) from the market for safety reasons. Pfizer has agreed. Sales of valdecoxib have also been halted in Europe and Canada.  

The FDA also requested that a black box warning be added to the professional product labeling, or package inserts, for all nonsteroidal anti-inflammatory drugs (NSAIDS) remaining on the market. A list of these drugs appears below. A black box warning is the strongest type of warning that the FDA can request.

The boxed warning will highlight the potential for increased harm from cardiovascular (CV) adverse events, such as heart attack and stroke, with these drugs as well as the well-described, serious, and potentially life-threatening gastrointestinal (GI) bleeding associated with their use.

We listed valdecoxib as a DO NOT USE drug in the 2002 Companion to Worst Pills, Best Pills. Readers of Worst Pills, Best Pills News were warned in January 2003, over two years ago, not to use valdecoxib because of increased harm due to heart attacks and strokes from the drug. On January 24, 2005, Public Citizen petitioned the FDA to remove both valdecoxib and celecoxib (CELEBREX) from the market.

The FDA is also requiring that the manufacturers of all prescription NSAIDS write Medication Guides for their drugs. The FDA can require Medication Guides for drugs that present significant public health problems. These FDA approved guides are written specifically for consumers and must be distributed with each new and refill prescription for an NSAID. Unfortunately, the overwhelming majority of written drug information now distributed in pharmacies is produced by unregulated commercial information vendors and of low quality. Public Citizen has advocated since 1979 that FDA approved Medication Guides should be distributed with all prescription drugs.  

The FDA’s announcement does not apply to aspirin. Aspirin has clearly been shown to reduce the risk of serious adverse CV events in certain patient populations, though it is associated with an increased risk of GI bleeding.

Specifically, FDA is requesting the following actions:

Valdecoxib (BEXTRA)

The FDA concluded that the overall harm versus benefit profile is unfavorable for this drug and has requested that Pfizer voluntarily withdraw valdecoxib from the market. This request is based on:

• the lack of adequate data on the cardiovascular safety of long-term use of valdecoxib, along with the increased risk of adverse CV events in short-term coronary artery bypass surgery (CABG) trials that the FDA believes may be relevant to the chronic use of this drug.
• Reports of serious and potentially life-threatening skin reactions, including deaths, in patients using valdecoxib. The risk of these reactions in individual patients is unpredictable, occurring in patients with and without a prior history of sulfa drug allergy, and after both short- and long-term use.
• Lack of any demonstrated advantages for valdecoxib compared to other NSAIDs.

Valdecoxib was a drug that clearly should have never been approved in the first place. Both Pfizer and the FDA knew that there was an excess of serious adverse events, including deaths, in patients receiving the drug in one of the CABG trials mentioned above that was analyzed before valdecoxib was approved (see Worst Pills, Best Pills News September 2004).

Celecoxib (CELEBREX)

In a decision with which we do not agree, the FDA concluded that the benefits of celecoxib outweigh its harm in properly selected and informed patients. It is our view that like valdecoxib, there is a lack of any demonstrated advantages of celecoxib compared to other NSAIDs. We first warned Worst Pills, Best Pills News readers not to use celecoxib in April 2001.

The FDA asked Pfizer to take the actions listed below.

Revise the celecoxib professional product label to:

• Include a boxed warning containing the warnings and contraindication (see below) that apply to all NSAIDs (except aspirin, as noted above) about CV and GI risk, plus specific information on the controlled clinical trial data that demonstrated an increased risk of adverse CV events for celecoxib.
• Encourage prescribers to discuss the potential benefits and risks of celecoxib and other treatment options with patients before a decision is made to use celecoxib.
• 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 that pharmacists will be required to distribute when the drug is dispensed. The guide will inform patients of the potential for CV and GI risk associated with NSAIDs in general and celecoxib specifically. It will also inform patients of the need to discuss the risks and benefits of using NSAIDs with their doctor 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 celecoxib 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.

This last point, that Pfizer commit to a long-term study, rings hollow. The FDA does not have the legal authority to require a manufacturer to conduct a study after a drug is approved.

Non-Selective NSAIDs

A number of non-selective NSAIDs, both prescription and nonprescription, are approved for marketing in the U.S.These products, including ibuprofen (MOTRIN) and diclofenac (VOLTAREN), are listed in the box below.

Celecoxib and valdecoxib fall into the category called COX-2 inhibitors because they selectively inhibit the COX-2 enzyme. Others are considered “non-selective” NSAIDs because they do not selectively inhibit either the COX-2 or COX-1 enzyme. However, longterm controlled clinical trials have not been conducted with most nonselective NSAIDs. It is therefore very difficult to draw conclusions about the relative CV harm among the COX-2 selective NSAIDs and non-selective NSAIDs with the data that are currently available. For one of these older drugs, naproxen (ALEVE), a randomized trial showed it was only one-fourth as likely to cause heart attacks as rofecoxib (VIOXX).

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

The FDA says it will work closely with companies and the National Institutes of Health to encourage additional long-term controlled clinical trials of non-selective NSAIDs to further evaluate the potential for increased CV harm.

In addition, the FDA is requesting labeling changes for both prescription and over-the-counter (OTC) nonselective 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

The FDA plans to request that manufacturers of all prescription products containing non-selective NSAIDs 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 regarding the potential for CV and GI adverse events associated with the use of this class of drugs. The Medication Guide will be required to be given to patients at the time each prescription is dispensed. The Medication Guide will also 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 for an individual patient.

OTC Non-Selective NSAIDs

The available data do not suggest an increased risk of serious CV events for the short-term, low-dose use of OTC NSAIDs. The FDA will allow these products to remain on the market, but will request changes to the label to better inform consumers regarding the safe use of these products.

The FDA will ask manufacturers of all OTC products containing ibuprofen, naproxen, and ketoprofen (ORUDIS, ACTRON) to revise their labeling to include:

• More specific information about the potential CV and GI harms;
• Instructions about which patients should seek the advice of a physician physician before using these drugs;
• Stronger reminders about limiting the dose and duration of treatment in accordance with package instructions, unless otherwise advised by a physician; and
• A warning about potential skin reactions.

Aspirin is a special case. It is a nonselective NSAID. However, aspirin is also a platelet inhibitor that prevents blood clots and has been shown in clinical trials to reduce the risk of CV events. Patients taking aspirin to prevent CV events should NOT stop taking the drug, unless specifically advised do so by their physician.

What You Can Do

If you are currently taking celecoxib you should contact your physician to consider alternative NSAID treatment. See the box below for information on how to report adverse reactions to this or any drug to the FDA.

1- This drug is listed as DO NOT USE in the Fourth Edition of Worst Pills, Best Pills.

2 -There are many OTC Combinations with ibuprofen: ADVIL COLD AND SINUS, ADVIL COLD, ADVIL ALLERGY SINUS, CHILDREN’S ADVIL ALLERGY SINUS, IBUPROHM COLD AND SINUS, SINE-AID IB, CHILDREN’S MOTRIN COLD.