April 7, 2005 -- The popular arthritis drug Bextra will be pulled from the U.S. market under a decision issued by the FDA Thursday.
Pfizer agreed to suspend sales and marketing of Bextra in the U.S. But a company statement says it "respectfully disagrees" with the FDA's view of Bextra's risks and benefits. And Pfizer says it will talk with the FDA about ways to let the company restore Bextra's availability to doctors and patients.
Celebrex, a closely related drug also made by Pfizer, from the class of pain relievers known as Cox-2 inhibitors, will be allowed to remain on the market. But it will be forced to carry strict new warnings alerting doctors and patients that it elevates the risk of heart attacks and strokes, the FDA says.
Aspirin, Tylenol Not Included
Officials also say they are ordering new label warnings for all nonsteroidal anti-inflammatory drugs (NSAIDs)new label warnings for all nonsteroidal anti-inflammatory drugs (NSAIDs) except aspirin, including the widely sold drugs ibuprofen and naproxen.
Although aspirin is not included in this warning, regular use does increase the risk of stomach ulcer bleeding. Acetaminophen (Tylenol) is not an anti-inflammatory drug and is not included in the warnings.
Prescription forms of the drugs will now carry "black box" alerts warning of heart disease and stroke risk. Over-the-counter brands -- usually taken at lower doses and for a shorter amount of time -- must alter their labels to include more risk information. At the same time, the FDA stresses that they do not see any new increased risks associated with as-needed or short-term use of over-the-counter painkillers.
The decision is the culmination of more than seven months of public controversyculmination of more than seven months of public controversy surrounding Cox-2 drugs sparked last fall when the drug company Merck pulled Vioxx from the market because of elevated heart risks. The decision led to a broad FDA review of Cox-2 drugs and related pain relievers, including three days of scientific hearings in front of an expert advisory panel in February.
Officials Thursday said they concluded that all NSAID drugs potentially pose an elevated heart risk but that additional reports of dangerous skin reactions with Bextra effectively tipped the scales against its continued sale.
Bextra Has Special Risk
Nearly every study of Cox-2 drugs has shown that they relieve pain no better than older NSAIDs. But the drugs became popular because they are less likely than the older drugs to cause stomach bleeding.
Only a few studies have looked directly at Bextra's heart safety. One trial released in December suggested that the drug raised the risk of heart attacks in patients undergoing heart bypass surgery. Meanwhile, the FDA said it had received an abnormally high number of reports implicating Bextra in dangerous skin reactionsdangerous skin reactions including toxic epidermal necrolysis and Stevens-Johnson syndrome.
"It has the same cardiovascular problem, no specific benefit, and this added worse skin risk," says Steven K. Galson, acting director of FDA's Center for Drug Evaluation and Research. "Bextra has a special risk in addition to the class risk."
Doctors wrote nearly 24 million prescriptions for Celebrex and 13 million for Bextra in 2004, according to FDA figures.
Along with stricter warnings, patients receiving Celebrex or other prescription anti-inflammatory drugs will now also receive medication guides outlining the risks and benefits of the drugs, Galson says. The additional warnings will begin appearing with the drugs within a few weeks, he says.
But the decision appeared to make it likely that Celebrex will be the only Cox-2 drug available to U.S. patients. Regulators said that Pfizer would have to provide significant new data showing Bextra's safety before the drug is allowed to return to the market.
"There would be a lot of factors that would have to go in their favor to do that," Galson said.
Vioxx Unlikely to Return
Officials from Merck told the FDA in February that they would likely move to return Vioxx to the market, despite a narrow 17-15 vote by an FDA advisory panel on whether the drug should be sold. FDA officials said Thursday that the company will be required to resubmit the drug, sold since 1998, for a new FDA approval before it can be marketed again.
Merck and makers of unmarketed Cox-2 drugs will also have to show "significant new safety data" before the drugs can be sold, Galson says.
Warnings for All
Data presented to experts in February suggested that some of the more than 20 nonsteroidal anti-inflammatory drugs (NSAIDs),more than 20 nonsteroidal anti-inflammatory drugs (NSAIDs), including naproxen, may carry a lower heart risk. But the FDA declined to designate any of the drugs as a less hazardous alternative, saying reviewers did not have enough evidence to rank the remaining drugs in terms of their safety.
Drug companies have produced no data on heart safety for many of the older NSAID drugs, while some drugs have shown limited evidence of an increased risk.
Officials suggested the higher dosage normally seen with prescription drugs led them to place strong black box warnings on those products while ordering somewhat weaker alerts for over-the-counter forms.
The decision will cause some drugs sold in both forms, including naproxen, to carry different warnings depending if they're prescription or nonprescription.
"We don't see any data that would suggest that short-term use of low doses of the products that are currently sold over the counter increase the risk of serious cardiovascular events," says John Jenkins, MD, director of the FDA's Office of New Drugs.
Still, officials say they are planning to ask all NSAID manufacturers to review safety data surrounding their drugs and submit the findings to the FDA.
The agency also asked Pfizer to conduct a broad new safety study of Celebrex in an effort to settle conflicting data on the drug's heart safety. Several studies, including one halted late last year at the National Institutes of Health, suggested increased heart risks for patients taking Celebrex,increased heart risks for patients taking Celebrex, while others suggested that patients taking lower doses of the drug had no increased risk.
"We think it's very important to do a new, well-designed study to really try to nail down the question about whether Celebrex itself has a unique risk," Jenkins said.
Standing Up for Patient Safety
The FDA's decision on Bextra went against the February recommendations of the FDA's advisors, who voted 17 to 13, with two abstentions, to allow the drug to stay on the market. Galson said that the decision reflected a conservative approach to the panel's largely split recommendations on Bextra and other drugs.
Curt D. Furberg, MD, a member of the panel who also led the January Bextra study, praised the agency for "standing up for patient safety" with Thursday's decision.
"If you were on a plane and 17 pilots said it was safe to fly, and 13 said it was not safe, and then two abstained, would you fly?" Furberg, professor of pubic health sciences at the Wake Forest University School of Medicine, says in an interview.
He added that the agency's order for new warnings for all NSAID drugs will also likely influence drugmakers to conduct new safety studies. "You now have an incentive to show you're different from the others," Furberg says.
But Elizabeth Tindall, MD, president of the American College of Rheumatology, tells WebMD she was "shocked" by the FDA's decision to pull Bextra and extend heart risk warnings to all NSAIDs. Many patients will now be afraid to take the drugs despite severe pain, she warns.
"I don't know how else to deal with it except on a patient-by-patient basis," taking into account individuals' risk factors, says Tindall, who is a professor of medicine at the Oregon Health and Sciences University in Portland.
"It's a matter of going to every patient and talking with them about what is the most appropriate course. I'm reeling. I'm really very, very surprised," she says.
The news about Bextra is "surprising and a little bit aggravating," says Stephen Lindsey, MD, chairman of the rheumatology department at the Ochsner Clinic Foundation in Baton Rouge, La.
Lindsey says he wishes more leeway had been given to use Bextra and Vioxx in patients without heart and stroke risks. "A lot of our patients are young women with rheumatism who are 25, 30 years old, who benefit a lot from this kind of medicine," says Lindsey. "There are a lot of 'weekend warriors' who use [the drugs] for a couple of weeks."
He says many people might be able to take the drugs with no problems if they took them intermittently, which hasn't been studied. "The studies were long-term studies with older folks," he says.
Lindsey says his patients taking Bextra and similar drugs have already been screened for any heart or stroke risk. That started six months ago, when the controversy began, so he doesn't plan to take anyone off Celebrex, which is still on the market.
"My job is to help people function better, have less pain, [be able to do] daily activities and have fun without hurting them. You have to think about benefits and risks," says Lindsey.
Risks Are Real
"I think it's probably true that all of these medications probably have risks," says Lindsey. "Physicians and patients have to get together [and decide] what's the best risk/benefit ratio for them. We need better information about how to use these drugs appropriately and safely."
"They may take everything off the market, and you'll have nothing, and that won't be a pretty picture," he says, predicting an increase in narcotic use for pain relief.
Lindsey advises people who have no risk of heart problems or stroke and who have been tolerating their drugs well to "stay with the medicine until they get to their doctor and discuss what they're going to try next."
Scott Zashin, MD a rheumatologist in private practice in Dallas, says that placing strict warnings on all prescription NSAIDs was appropriate. "We've known that these drugs increase risk, but most doctors will put patients on these drugs and not even check blood pressure after a couple of weeks," he says.