FDA Warns on Painkillers; Drug Pulled
Moving to address one of its worst drug safety debacles, the Food and Drug Administration announced Thursday that dozens of widely used prescription painkillers must carry the government’s strongest warning that they posed risk of heart attack and stroke.
And one blockbuster painkiller, Bextra, was removed from the market. The FDA said the drug could cause potentially life-threatening skin reactions in some patients as well as heart problems.
Bextra, along with Celebrex, both made by Pfizer Inc., 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 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 most American households. The FDA emphasized that these nonprescription versions were safe. But it said they should be taken according to directions and only for limited periods of time.
In another action, the agency made it less likely that another Cox-2 inhibitor taken off the market in the fall -- Vioxx -- would become available again. The FDA said the maker of Vioxx, Merck & Co., 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 beleaguered 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 persistent 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 are being used by patients.
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 Graham testified in congressional hearings that Bextra should also be withdrawn from the market.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 deaths is probably significantly lower, but the agency 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 could 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, could 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.”
The consumer advocacy group Public Citizen said the FDA should have taken Celebrex off the market as well.
Critics of the agency said Thursday’s actions fell short of fixing the larger problem of the government’s oversight of the drugs the FDA approves as “safe and effective.”
New drugs are tested on a few thousand patients at most, and side effects may not emerge until after a drug reaches the market, when tens of thousands of people begin using it, the critics said. If the side effect is a relatively common problem such as a heart attack, it may not stand out even then.
“The increased risk of a common problem like a heart attack will not be picked up from our current reporting system,” said Alastair J.J. Wood of Vanderbilt University Medical Center. “Yet increasing the risk of common problems can have a cumulatively great public health impact, affecting tens of thousands of people.”
Other experts suggested the agency’s action could lead to confusion for patients and doctors, particularly because there is a dearth of hard data on the heart risks of most of the NSAID painkillers. For example, there is no way at present to know whether some of the drugs are safer than others.
“The bottom line,” said Dr. Bruce Psaty of the University of Washington, “is that we are in the difficult position of trying to make public health decisions in the absence of good evidence from large, long-term trials.”
Dr. Richard Vanis, an orthopedic surgeon in Arcadia, said: “I am having a very difficult time managing my post-surgery patients.” Vanis said he had 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 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 faced 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,” said Galson. “It has special benefits when taken in low doses.”
The FDA actions were a blow to pharmaceutical giant Pfizer, the marketer of Bextra and Celebrex, a far more popular prescription drug in the Cox-2 family. Promoted 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.
Matt Zapt, a product liability lawyer at the Chicago firm Goldberg Kahn, predicted a “stampede” of lawsuits against Pfizer over Bextra. Indeed, class action lawyers already were trolling for clients Thursday on the Internet.
Zapt said suits would focus on whether patients were adequately warned about the risks of Bextra. “Pfizer is likely to try its best to distinguish Bextra from Vioxx,” Zapt said.
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, 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 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 suggested.
The FDA’s Galson said that at least in theory all NSAIDs, including the Cox-2 drugs, posed heart risks.
“We think these risks apply to all these drugs. Yes, there may be differences [among them] but we don’t have enough information to rank them in order of risk.” Patients taking the medications should consult with their doctors and weigh their options. “It is really an individualized answer,” Galson said.
Some experts said extending the black-box warning to so many drugs might have the unintended consequence of glossing over problems with Celebrex.
A study by the National Cancer Institute last year found that patients taking Celebrex were more susceptible to heart attacks and strokes, although the drug showed promise in preventing colon cancer. “It would be unfortunate if the widespread use of the black-box warning is used to trivialize the warning on Celebrex,” said Wood.
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,” said Graham. “The benefit of the higher dose doesn’t exceed the risk, and I would challenge the FDA to present evidence to the contrary.”
Officials said they were urging patients on Celebrex to take the smallest possible dose for the shortest possible time.
A leading congressional critic of the agency, Sen. Charles E. Grassley (R-Iowa) said he hoped Thursday’s action would be a turning point indicating that the FDA was taking a more assertive role. But he said the agency’s continued defense of its handling of problems with Vioxx rang hollow.
“FDA officials repeatedly say that Vioxx was handled properly, and that they would act no differently today,” said Grassley. “It’s hard to see how this squares with suspending the sale of Bextra and increasing the warning level for Celebrex. The FDA needs to chart a steady course for its customers, the American public.”
Meanwhile, a study published in the Journal of Immunology found that Cox-2 drugs might have other powerful side effects. Laboratory and animal tests showed the drugs might also suppress the immune system by affecting antibodies that attack invading germs.
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Chronology
Key events involving the safety of Bextra, Vioxx, Celebrex and other painkillers:
December 1998: Food and Drug Administration approved Pfizer Inc.’s Celebrex, the first Cox-2 inhibitor. It is a nonsteroidal anti-inflammatory drug (NSAID).
May 1999: FDA approved Merck & Co.’s Vioxx, a Cox-2 inhibitor.
June 2000: Merck released study results to the FDA that showed Vioxx increased the risk of heart attack. November 2001: Pfizer’s Bextra, also a Cox-2 inhibitor, approved by the FDA.
April 2002: The FDA changed the warning label on Vioxx to reflect increased risk of heart attacks and strokes.
September 2004: Merck said Vioxx showed increased risk of heart attacks and strokes and withdrew it from the market.
February: An FDA panel concluded Vioxx, Celebrex and Bextra posed heart risks, but should be available to consumers.
Thursday: Pfizer withdrew Bextra from the market at the request of the FDA. The FDA also said all NSAID drugs should carry a warning about cardiovascular risks.
Source: Associated Press
