In a sweeping move to address one of its worst drug safety debacles, the Food and Drug Administration announced Thursday that dozens of widely used prescription painkillers must now carry the government’s strongest warning that they pose risks of heart attacks and strokes.
And one blockbuster painkiller, Bextra, was removed from the market. The FDA said it can cause potentially life-threatening skin reactions in some patients, as well as heart problems.
Bextra, along with Celebrex, have been medications of choice for millions of patients suffering from arthritis and other forms of chronic pain. The two drugs, known as COX-2 inhibitors, belong to a much larger category of medications called nonsteroidal anti-inflammatory drugs, or NSAIDs.
All prescription drugs classified as NSAIDs must now carry the stronger warning label.
In weaker, nonprescription forms such as Advil, Motrin and Aleve, NSAIDs are likely to be found in almost every household in America. The FDA emphasized that these nonprescription versions are safe. But it said they should be taken according to directions and only for limited periods of time.
In other action, the agency made it less likely that another COX-2 inhibitor taken off the market last fall Vioxx will become available again. The FDA said its maker, Merck, must submit a new application for approval and go before an expert advisory panel. It was Merck’s decision to withdraw Vioxx that marked the beginning of cascading concerns about the painkillers.
The FDA’s actions Thursday, which go beyond the steps proposed in February by its scientific advisory committee, suggest the embattled agency has decided to take a tougher approach to the problem of health risks that surface in drugs after they have been approved for market.
Thursday’s action was one of the largest relabeling orders in FDA history.
In recent months, critics in Congress and elsewhere have subjected the agency to criticism for relying too much on drug makers to sound the alarm over potential safety threats that surface after drugs have reached the market and begun to be used by patients.
And the actions were at least partial vindication for agency whistle-blower Dr. David Graham, who had unsuccessfully tried last year to warn of problems with Vioxx. Graham testified in congressional hearings that Bextra should also be withdrawn from the market.
Graham has estimated that of the millions who took Vioxx for arthritis, back pain and other ailments, as many 139,000 Americans may have suffered heart attacks and strokes. Of those, 26,000 to 55,600 may have died, he suggested. The FDA disputes Graham’s calculations and says the total number of fatalities is probably significantly lower, but it does not dispute the seriousness of the problem.
Signaling a more aggressive strategy, Dr. Steven Galson, acting director of the FDA’s Center for Drug Evaluation and Research, said the public can expect further regulatory decisions and information alerts about the risks and benefits of painkillers.
“Let me emphasize now, this announcement is unlikely to be the last word you’ll hear on these drugs,” Galson told reporters on a conference call. “Clinical investigations continue. And in our new spirit of keeping the public informed earlier of emerging drug safety issues we may be providing further modifications as new information comes to light.”
He said the FDA concluded that all prescription NSAID drugs, at least in theory, can increase the risk of heart attacks and strokes.
The tougher approach is in line with demands by congressional and other critics that the FDA become more aggressive in monitoring drugs it has approved for market.
“The FDA took a stand in support of public health,” said Dr. Curt Furberg of Wake Forest University, who had criticized the agency’s handling of safety concerns about Vioxx. “I think patients now can have some hope that the FDA in the future will be the guardian of drug safety.”
Other experts suggested the agency’s action could lead to confusion for patients and doctors, particularly since there is a dearth of hard data on the heart risks of most of the nonsteroidal anti-inflammatory drugs. For example, there is no way at present to know whether some of the drugs are safer than others.
“I am having a very difficult time managing my post-surgery patients,” said Dr. Richard Vanis, an orthopedic surgeon in Arcadia, Calif. Vanis said he has been prescribing narcotic pain relievers for high-risk patients who would have been given Vioxx in the past. Some of the drugs are “horribly addicting,” he said.
On Thursday, Vanis examined a 61-year-old patient with severe arthritis and heart disease who had run out of Vioxx. The patient refused to stop taking the pain reliever when it was recalled last fall.
“I don’t know what I am going to do in his case,” Vanis said.
The FDA said all prescription-strength forms of NSAIDS would now carry a so-called “black-box” warning, the strongest it can impose. The warnings will be printed in bold type and surrounded by a black box at the top of instructions provided to doctors.
Lower-strength over-the-counter versions of the traditional drugs will not carry such a dramatic warning, though patient information will be changed to include details about possible heart and stroke risks.
The FDA sought to reassure patients taking nonprescription painkillers that they face no excessive risks. “The over-the-counter products, when taken according to directions are not an issue, and people should not be concerned,” the FDA’s Galson said.
He also stressed that patients taking aspirin to reduce their risk of having a heart attack should continue to do so. “None of this applies to aspirin,” Galson said. “It has special benefits when taken in low doses.”
The FDA actions were a blow to Pfizer Inc., which makes Bextra and Celebrex, a far more popular prescription drug in the COX-2 family. Touted as a stomach-friendly alternative to aspirin and other drugs, COX-2 inhibitors were heavily advertised by drug companies.
Pfizer said it disagreed with the FDA’s decision to withdraw the drug, but had deferred to the wishes of regulators. The company also agreed to conduct additional long-term studies of the benefits and risks of Celebrex.
More than 500 cases are pending against Merck from patients who claim they were harmed by Vioxx.
A congressional investigation last year revealed that the FDA had downplayed or ignored repeated warnings from its own drug safety reviewers and from academic scientists about the cardiovascular risks of Vioxx. That led lawmakers to call for the creation of a much stronger and more independent drug safety office within the agency.
The stronger warning label on Celebrex is expected to have the effect of sharply restricting its use. As for Vioxx, Dr. Alastair J.J. Wood of Vanderbilt University Medical Center, said, “It seems inconceivable to me that Merck would try to bring it back.”
Wood chaired an expert advisory panel that met for three days earlier this year to hear testimony and weigh the risks and benefits of COX-2 drugs. The panel recommended that Vioxx, Celebrex and Bextra should be available on the market, albeit with black box warnings. Those recommendations led Merck to indicate it might try to bring Vioxx back.
That possibility dimmed as a result of Thursday’s announcements, Wood was suggesting.
Graham, the FDA whistle-blower, said in an interview he was glad the FDA finally agreed with him. But he said the agency’s warning on Celebrex did not go far enough.
“I’m disappointed they didn’t ban the (high) 400-milligram dose of Celebrex,” Graham said. “The benefit of the higher dose doesn’t exceed the risk, and I would challenge the FDA to present evidence to the contrary.”
Agency officials said they are urging patients on Celebrex to take the smallest possible dose for the shortest possible time.
The consumer advocacy group Public Citizen said the FDA should have taken Celebrex off the market as well.
Meantime, a study published in the Journal of Immunology found that COX-2 drugs may have other powerful side effects. Laboratory and animal tests showed the drugs may also suppress the immune system by affecting antibodies that attack invading germs.