Bextra

The market withdrawal of valdecoxib and the black box warnings on celecoxib and all other remaining prescription NSAIDs have some physicians fuming and patients worried and confused, experts say.

"The American College of Rheumatology has been getting a lot of e-mails expressing anger and frustration," said ACR President Elizabeth Tindall, M.D. "We still feel that these drugs play an extremely important role. The fallout of this will be that patients either go off their medications without supervision, won't go on them even if indicated, or will be on them and have to listen to well-meaning family and friends telling them to get off. This decision has made caring for these patients even more difficult."

Rheumatologists are not the only physicians expressing alarm, said Dr. Tindall of Oregon Health and Science University, Portland. "The chronic pain societies have also been very concerned. They were rather pointed in their response, saying, 'What is left for pain, other than narcotics?'"

In addition to calling for valdecoxib (Bextra) to be voluntarily removed from the market (which Pfizer agreed to do), the Food and Drug Administration called for a black box warning about serious cardiovascular and gastrointestinal risks to be added to the labels of all prescription NSAIDs, including celecoxib (Celebrex). The FDA has also called for stronger warnings about potential gastrointestinal and cardiovascular risks to be added to the packages of nonprescription NSAID products. Aspirin is exempt from label revision because of its proven cardiac benefits.

"I am not surprised by this decision, but I am disappointed for my patients and the millions of others who have pain and arthritis," said John Cush, M.D., a member of FDA's arthritis drugs and drug safety and risk management advisory committee and chief of rheumatology and clinical immunology at Presbyterian Hospital of Dallas. "It seems their welfare is being put on the back burner. This will definitely have a chilling effect on patients and their doctors who need to use COX-2 drugs or NSAIDs."

He added that including all NSAIDs in the picture may result in unforeseen consequences. "The implications of this announcement on over-the-counter NSAIDs have not been delineated but may be significant."

In asking Pfizer Inc. to remove valdecoxib, the FDA went against the recommendation of its own advisory board. In February, the committee voted 17-13 to keep valdecoxib on the market, with a contraindication against its use in cardiac surgery patients.

During a press conference announcing the agency's decisions, Steven Galson, M.D., acting director of FDA's Center for Drug Evaluation and Research, said that valdecoxib's "unique risk" of severe, life-threatening skin reactions--including toxic erythema necrolysis, Stevens-Johnson syndrome, and erythema multiforme--swayed the FDA's decision.

The agency generally follows its committees' recommendations, and this apparent turnabout rankles some physicians. "The FDA did not follow the advice of the committee, and many of us feel they have overreacted to the issue. To have nonclinicians outweigh clinicians on a clinical matter is inappropriate. The process could definitely use some improvement," Dr. Tindall said in an interview.

John K. Jenkins, M.D., director of FDA's Office of New Drugs, said that adverse event reports have risen since 2004, when the FDA instituted a black box warning on valdecoxib for skin reactions. He didn't release any numbers, but he said they are "significant."

"This information is fraught with uncertainty. It's very difficult to be precise with the numbers, but we think it's clear that the reports [of skin reaction] with Bextra are significantly higher than reports from other products," he said during the press conference.

Despite disagreement with the FDA recommendations, Pfizer did comply with the U.S. market withdrawal, and, in response to requests by European regulators, has also suspended sales in the European Union. The drug has also been withdrawn from the market in Canada and China.

Pfizer will "explore options" that might allow the resumption of sales, according to a statement released by the company.

However, the chance that valdecoxib could make a market comeback look slim, given comments made by Dr. Jenkins. "The path forward--if there is to be one--would have to address the question of bringing the risks and benefits into balance. But these skin reactions are unpredictable, and so it's hard to manage the risks, because you don't know who is at risk."

The future may hold even more restrictions on NSAIDs. "This is unlikely to be the last word you will hear on these drugs. Investigation continues, and in our new spirit of keeping the public informed earlier, we may be providing more recommendations as new information comes to light."

Celecoxib appears safe for the time being; Dr. Jenkins said its risk-benefit profile is satisfactory. But the agency wants a large, long-term randomized controlled safety trial of the drug.

"We have asked Pfizer to make a post-marketing commitment to evaluate Celebrex," Dr. Jenkins said. "There are several studies currently available that show conflicting results. We think it's very important to do a new, well-designed study to nail down whether Celebrex has a unique risk."

So far, the FDA has stopped short of asking other NSAID manufacturers to perform additional studies, but it has asked them to review all available safety data from both short- and long-term studies and look for additional safety signals. Because the NSAIDs' cardiovascular risks appear to be a class effect, there are not enough data to draw absolute conclusions about any differences among the individual drugs' risks, nor to rank the drugs in order of safety, Dr. Galson said.

The FDA has no intention of removing any over-the-counter NSAIDs from the market. "I want to emphasize that our current thinking is that the over-the-counter products, taken at the recommended dose according to the instructions, are not a problem, and people don't have to be concerned about them except for the risks that are already listed and that will be added."

Pfizer announced plans to reimburse patients for unused valdecoxib. Details on the buyback will be available shortly on www.bextra.com.

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With the recent withdrawals of both rofecoxib and valdecoxib, pain relief options are dwindling, said Dr. Tindall.

In light of the changes and the new warnings on all NSAIDs, the American College of Rheumatology is revising its treatment guidelines for osteoarthritis and rheumatoid arthritis. Until those guidelines are finished, Dr. Tindall offers the following tips for managing patients:

* In people who have some risks for GI bleeding, ulcers, or gastritis and for whom celecoxib doesn't work or is contraindicated, use one of the older, nonselective NSAIDS, in combination with a proton pump inhibitor.

* For patients on anticoagulant therapy, select a nonacetylated NSAID, such as salsalate. "It doesn't affect bleeding times, and the incidence of peptic ulcers and gastritis is less with this. But it also isn't very potent."

* For rheumatoid arthritis patients, turn to corticosteroids, "even though patients aren't very happy with that alternative," she said. "After that, we're left with only the pure analgesics--everything from acetaminophen to morphine."

--Michele G. Sullivan

BY MICHELE G. SULLIVAN

Mid-Atlantic Bureau

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