Bextra® Withdrawal from the Market - HSS Physicians Reflect on Options for Patients in Pain


Theodore R. Fields, MD, FACP

Attending Physician, Hospital for Special Surgery
Professor of Clinical Medicine, Weill Cornell Medical College

Allan Gibofsky, MD

Attending Physician, Hospital for Special Surgery
Professor of Medicine and Public Health, Weill Cornell Medical College

Joseph A. Markenson, MD

Attending Physician, Hospital for Special Surgery
Professor of Clinical Medicine, Weill Cornell Medical College
Attending Physician, Department of Medicine, Memorial Sloan-Kettering Cancer Center

Michael D. Lockshin, MD

Attending Rheumatologist, Hospital for Special Surgery
Professor of Medicine, Weill Cornell Medical College
Director, Barbara Volcker Center for Women and Rheumatic Disease

Stephen A. Paget, MD, FACP, FACR

Physician-in-Chief Emeritus, Hospital for Special Surgery

Why was Bextra removed from the market?
On April 7, 2005, the FDA requested that Pfizer withdraw Bextra® (valdecoxib) from the market (for further information, click here). Pfizer responded that it "respectfully disagrees with FDA's position regarding the overall risk/benefit profile of Bextra. However, in deference to the agency's views, the company has agreed to suspend sales of the medicine pending further discussions with the FDA."

The FDA is also asking that all prescription NSAIDs (non-steroidal anti-inflammatory drugs), including the COX-2 inhibitor Celebrex (celecoxib), a COX-2 selective NSAID, revise the package insert and include a "black box" warning about possible cardiovascular events with these drugs (in addition to risks of gastrointestinal bleeding). Over-the counter NSAID's (other than aspirin) are also being asked to add these risks to their labeling.

The FDA stated that they have requested the voluntary withdrawal of Bextra® because they decided that the risks of the drug outweighed the benefits. Note that the FDA Advisory Panel, which had met February 16-18, 2005, had recommended that this medication remain on the market. The FDA press release cited four reasons for their decision. First, they remained concerned about two studies showing increased cardiovascular risk with Bextra® in short-term study after coronary artery bypass grafting. Secondly, there was a lack of long-term data on the cardiovascular safety of this drug. Third, life-threatening skin reactions have been reported with Bextra. Finally, they felt that Bextra lacked proven advantages over other NSAIDs.

How does this relate to other COX-2 inhibitors?
With Bextra® removed from the market, the only remaining COX-2 inhibitor is Celebrex®. The FDA decided that the benefits exceeded the risk for Celebrex® and that it may remain on the market. This was consistent with the overwhelmingly positive vote by the FDA Advisory panel to keep this medication available. Celebrex® will require the "black box" warning to be placed on its package insert. Regarding Vioxx®, which Merck had previously voluntarily removed from the market, the FDA noted that in order for the drug to come back on the market, it would first be required that a supplemental new drug application be filed and be subject to public review.

How does this relate to the older anti-inflammatory agents such as naproxen or ibuprofen and to over-the-counter NSAIDs?
The same "black box" warning for Celebrex® is being recommended for all NSAIDs, both prescription and over-the-counter, with the exception of aspirin. The FDA noted that "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." (For further information click here). The FDA also expressed their interest in reviewing data related to all available NSAIDs and their cardiovascular risk, and in encouraging long-term studies of that risk.  Regarding over-the-counter NSAID's, the FDA's opinion was that "the available data do not suggest an increased risk of serious CV events for the short-term, low-dose use of the NSAIDs available over the counter." These products will be kept on the market with warnings as above.

What are the NSAID/COX-2 inhibitor options for patients in pain?
Celebrex® remains the only COX-2 inhibitor on the market. Patients have a choice of non-selective NSAID's (e.g. naproxen, ibuprofen, diclofenac, ketoprofen) and over-the-counter NSAID's (e.g. low-dose naproxen, ibuprofen and ketoprofen). At this time, patients who were doing well on Bextra were advised by the FDA to stop this medication and contact their physician.

Analysis and Comment from HSS Rheumatologists

We had felt strongly that the FDA Advisory Panel had carefully reviewed the voluminous data and considered the needs of patients in their recommendations for Cox-2 Inhibitor Safety. We recognized that patients have different responses to different medications, and each patient has their own set of risk factors. Some patients are at higher risk for gastrointestinal bleeding and some for cardiovascular complications. Also, patients have different levels of pain, different degrees of loss of function, and different levels of willingness to accept risk. We, therefore, felt that with appropriate education and warnings, and careful patient selection, it was preferable to have more rather than fewer drugs available.

As a result, our review of the FDA panel findings had concluded that individual discussion was required in each patient's case to come to the right decision for him or her. We had noted that although smaller doses may be safer and certainly are preferred, if they are effective, full therapeutic NSAID doses may be needed by patients with chronic inflammatory arthritis to achieve the quality of life they seek.

Although we would have preferred that the FDA had left patients and physicians with more options, we do agree that patients need to know all the risks of the medications they use. We agree with the " black box warning" and agree that all NSAIDs need this warning. Patients need to recall that the COX-2 inhibitors are among the very few NSAIDs that have had long-term trials. It is completely unknown whether Orudis® (ketoprofen) or Lodine® (etodolac) or Ansaid® (flurbiprofen), for example, would have similar findings to COX-2 inhibitors if studied for the same length of time.

We would also point out that the skin reactions that the FDA cites regarding Bextra® (Stevens-Johnson syndrome or toxic epidermal necrolysis) are well-known side-effects of sulfonamide drugs, and that this risk is increased, since Bextra has a sulfonamide portion (as does Celebrex). Patients taking Bextra® who have not developed a rash would be very unlikely to get it after prolonged use.

We would also note that in the two short-term studies where the drug was employed after coronary artery bypass graft, the dose of Bextra used was 2-4x as large as the usual dose of the drug (and the patients also received an intravenous drug which was essentially the same as Bextra®). These were the only studies that showed the cardiovascular risk. Also, in the studies of Bextra in arthritis - also not long-term studies - no sign of cardiovascular risk was noted.

At the present time, patients and physicians need to pick their arthritis treatments from those that remain available. No NSAID was ever felt to be without side effect, and now no NSAID (or COX-2 inhibitor) is fully exempt from concern about long-term cardiovascular safety. Lower doses likely are safer, and low-dose naproxen has been looked at over a longer period and may be of lower risk. However, the low dose may be inadequate to control inflammation in many patients. Some patients will prefer to avoid NSAIDs and take analgesics (e.g. acetaminophen such as Tylenol® and others) or codeine, but these may be inadequate or not tolerated. Some will try to use physical measures, such as physical therapy, heat application, and local steroid injections. These are all reasonable in individual cases, but often they are insufficient to restore quality of life. Thus, many arthritis patients will continue to choose NSAIDs, and a good number will likely find that the full therapeutic dose may be required for the effect they need.

The removal of Bextra® from the market only further emphasizes the need for individualized decision-making in each patient's case, in order to strike the proper balance between risk avoidance and the need for an improved quality of life.

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