Despite the recommendation from a US Food and Drug Administration (FDA) advisory panel in February that the benefits of valdecoxib (BextraR) outweighed its risks, the federal agency Thursday asked Pfizer to withdraw the medication from the market. Pfizer swiftly agreed pending further discussions with the agency.

In another move more closely mirroring the advice of the advisory panel, the FDA called for stricter warnings of all nonsteroidal anti-inflammatory drugs (NSAIDs), a class which includes selective cyclooxygenase-2 (COX-2) inhibitors such as celecoxib as well as over-the-counter (OTC) and prescription non-selective NSAIDs.

The decision is the latest in a chain of events that was set off when Merck conducted a voluntary worldwide withdrawal of Vioxx (rofecoxib) in September 2004.

 

Bye-bye Bextra

Valdecoxib holds "no added advantage" and a special risk of Steven's Johnson Syndrome, the FDA stated. "The panel [was so] closely split on Bextra that it was difficult to finely interpret what they said," Steven K Galson, MD, acting director of the FDA's Center for Drug Evaluation and Research, said in a teleconference. In mid-February, the advisory panel voted 17 to 13 to allow the continued use of valdecoxib, with 2 abstentions. By contrast, all but one of the 32-member panel voted to keep celecoxib on the market.

"What the FDA felt and heard from the discussion is that there wasn't enough long term information on Bextra as compared to others drugs," advisory panel member Steven B. Abramson, MD, rheumatologist and Professor in the Department of Rheumatology/Medicine at New York University School of Medicine, New York, tells CIAOMed.

 

European Union also suspends use of valdecoxib

Pfizer has agreed to suspend of use of valdecoxib in Europe as an interim measure pending a final assessment of COX-2 inhibitors. The European Medicines Agency is conducting an ongoing safety review of the COX-2 class of medicines. Until completion of the review, prescribers are advised to carefully monitor patients being treated with valdecoxib, and not to initiate treatment of new patients.

 

Black box warning for prescription pain killers

According to the FDA, all prescription NSAIDs, including celecoxib (CelebrexR), the lone COX-2 blocker on the market in the US, must revise their labels to include a black box warning highlighting the potential for increased risk of cardiovascular (CV) events and gastrointestinal (GI) bleeding associated with their use. Furthermore, all OTC NSAIDs must include more specific information about their potential CV and GI risks, as well as a warning about potential skin reactions.

"We think these risks apply, based on the information we have now, to all these drugs," Dr. Galson said, though "we don't have enough information to rank [them] in order of risk." The new warnings do not apply to aspirin, which has been found to be particularly beneficial for CV health.

Once the decision had been made to label celecoxib, Dr. Abramson points out, logic demanded that the other NSAIDs receive warnings as well. "The worst case scenario would be that the world interprets this as 'coxibs are dangerous, but other [NSAIDs] are not.' Diclofenac, etodolac and meloxicam had COX-2 selectivity that was overlapping with celebrex, so to label celebrex and not mention this risk in other drugs would be concerning," he tells CIAOMed

Overall, the FDA action is "a very positive move and very similar to what they did for GI class warnings when the coxibs came out," Dr. Abramson says, adding that he is "very pleased that this warning is not limited to coxibs."

 

Et tu naproxen?

Naproxen is, of course, also not immune to the new warnings, even though some contend that this drug has cardioprotective effects. The first suggestion of increased CV risk associated with coxibs came from the Vioxx Gastrointestinal Outcome Research (VIGOR) trial,¹ shortly after rofecoxib was launched. Specifically, VIGOR demonstrated an increased incidence of non-fatal myocardial infarction (MI) in rofecoxib-treated individuals compared to those receiving naproxen.

Critics purport that VIGOR demonstrates the cardiovascular risk of rofecoxib, while others disagree, citing the safety record of rofecoxib in placebo-controlled studies and in studies comparing it to other NSAIDs. They contend that the VIGOR data, in fact, accentuate the cardioprotective effect of naproxen rather than any danger associated with rofecoxib.

However, the Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT), a 3-year study that randomized participants to celecoxib, naproxen, or placebo, was halted when researchers found that naproxen appeared to increase the risk of CV events.

 

Going behind the counter?

Calling these new warnings "huge", Lee Simon, MD, a rheumatologist and associate clinical professor of medicine at Harvard Medical School in Boston, Massachusetts, tells CIAOMed that "it is amazing how big this warning is. It takes us one step closer to a third class of drugs that are 'behind the counter.'" Such drugs, while not requiring a prescription, would only be available to patients after consultation with a pharmacist.

Dr. Simon suggests that the label warnings may cause some patients to stop using NSAIDs, but that, because of their effectiveness, they will start using them again as they begin to understand the principle of comparing risks and benefits when considering medication.

He suggests that this phenomenon may even lead to the return of rofecoxib. "Vioxx may still return, but it will take a long time," he predicts. The FDA stated it will carefully review any proposal from Merck for resumption of marketing of Vioxx. Peter Kim, MD, the president of Merck Research Laboratories, announced that the company would consider bringing rofecoxib back if the FDA advisory panel decided that the increased CV risk was a class effect.

Dr. Abramson says that "the obstacle to Vioxx coming back is that there was a greater amount of information pointing to toxicity with Vioxx, and I think if it were to come back, it would be with great restrictions." He adds that "I would be surprised if it was allowed back and, all things considered, it's highly unlikely."

 

Front line doctors confused

"I feel somewhat confused by the whole situation because we don't know all the ins-and-outs as to why [the FDA] made these decisions," comments Stephen Lindsey, MD, the head of rheumatology at the Ochsner Clinic Foundation in Baton Rouge, Louisiana. "Six weeks ago, the advisory panel recommended that they not pull these drugs off and then all of a sudden, we wake up today and they decide to take Bextra off the market," he says.

Dr. Lindsey argues that the FDA could have just as simply put a black-box warning on valdecoxib. "I think that would have been more appropriate," he says. "It puts us...in a hard position as physicians, because we are trying to help people function without severe pain, and now patients with no CV risks have no options," he tells CIAOMed.

"We are going to have them stop taking Bextra and discuss celebrex with them. However, most people on Bextra have failed celebrex and Vioxx, so we don't have a lot of good alternatives," Dr. Lindsey says. "They are stuck and will have to use narcotics-and there are problems there too."

He agrees with the decision to place stricter warnings on OTC and prescription non-selective NSAIDS. "No one had ever studied these drugs for any length of time, and it was only until the polyp and Alzheimer's trials that went for years that we picked this [CV safety signal] up," Dr. Lindsey points out. The Adenomatous Polyp Prevention on Vioxx (APPROVE) study,² resulted in Merck & Co. voluntarily pulling rofecoxib from the market. This study found that after 18 months of continuous treatment (but not before), there was an increased risk of confirmed CV events including MI and stroke associated with rofecoxib

Dr. Galson urges calm. "People should not have a concern about continuing to take [NSAIDs] per directions," he said during the teleconference. Instead, patients should consult their physicians about which painkiller is best suited for them, and to take the lowest effective dose. "All these risks we're talking about have already been known," Dr. Galson said. "People should not worry about, from today to tomorrow, stopping the products."

A list of products that will receive the new warnings is available at http://www.fda.gov/cder/drug/infopage/cox2/default.htm#list

References:

FDA Announces Series of Changes to the Class of Marketed Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). Press release issued on April 7, 2005.

European Medicines Agency statement on the suspension of use of Bextra. April 7, 2005 Doc. Ref: EMEA/121637/2005.

1. Bombardier C, Laine L, Reicin A, et al, for the VIGOR Study Group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med. 2000; 343:1520-1528.
2. Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med; published online before print February 15, 2005.