Source: New York Times
Date: 8 April 2005

F.D.A. Announces Strong Warnings for Painkillers


ASHINGTON, April 7 - Federal drug regulators issued sweeping warnings Thursday that many popular painkillers could hurt the heart, stomach or skin, and they persuaded Pfizer to withdraw its pain pill Bextra, once a strong seller.

Tough warnings about heart risks will soon dominate the labels for prescription painkillers like Celebrex, Mobic, Naprosyn, Voltaren and more than a dozen other similar drugs, the Food and Drug Administration announced. Even the labels of popular over-the-counter pills like Advil and Aleve will have to cite risks to heart, stomach and skin, the agency said.

Few studies have examined the long-term health effects of most of these medicines, so regulators are groping a bit in the dark. Studies done on Bextra and Celebrex, both from Pfizer, and Vioxx, made by Merck, strongly suggest that they increase the risks of heart attacks and strokes. With those studies in hand and suggestions that older pills may act similarly, F.D.A. officials said that they could not rule out the possibility that all of the drugs in the class known as nonsteroidal anti-inflammatories cause similar problems. Several doctors interviewed said they would now weigh the risks and benefits case by case. [Page C4.]

"We think these risks apply to all of these drugs," said Dr. Steven Galson, acting director of the F.D.A.'s center for drugs. "There may be some differences, but our conclusion is that we don't have enough data to rank-order these risks."

Still, Dr. Galson emphasized that popular over-the-counter pain pills were safe if taken briefly and in low doses, and patients should not suddenly stop taking these medicines because of the F.D.A.'s announcement. Several experts said that naproxen, the medicine found in Naprosyn and Aleve, is probably the safest among the nonsteroidal pain pills.

Neither acetaminophen, sold as Tylenol and other names, nor aspirin are affected by the new warnings, although those medicines are not problem-free. In high doses, aspirin can hurt the stomach and Tylenol can damage the liver. Aspirin, though, protects the heart.

The latest warnings will complicate prescribing decisions for arthritis patients and others in chronic pain. There are hints in the research that the pain pills that are easiest on the stomach may be toughest on the heart, and vice versa. Aspirin, for instance, protects the heart but can irritate the stomach. Naproxen may be mildly protective to the heart but seems especially harsh on the stomach. Vioxx proved easiest on the stomach but probably has the most toxic effects on the heart. All, in rare cases, cause skin reactions.

Doctors must now ask about a patient's heart and stomach risks. Those with cardiovascular problems could get one kind of pill, and those with a history of ulcers may get another. And some drugs have uniquely beneficial effects in some patients, who may prefer to accept a measure of risk to continue taking their favored drug. The difficulties may be particularly acute for the elderly, who are often at risk for stomach and heart problems.

Pfizer said in a statement that it "respectfully disagrees with F.D.A.'s position regarding the overall risk-benefit profile of Bextra," but it agreed to suspend sales of the drug. The company said it would work with the agency to come up with a strongly worded warning for Celebrex.

Pfizer has agreed to undertake a large study of Celebrex's effects on the heart, the agency said. The F.D.A. has asked manufacturers of other pain pills to re-evaluate studies of their pills' effects on the heart. The F.D.A. has no authority to force drug makers to undertake trials of approved medicines.

The F.D.A.'s decision to force Bextra's withdrawal could prove a balm to widespread criticism, arising from a series of drug scandals, that the agency has been too lax. Senator Edward M. Kennedy, a Massachusetts Democrat, praised the agency's action. "No patients should have to worry that the pill they take may put them at unacceptable risk," he said.

Senator Charles E. Grassley, an Iowa Republican who has overseen hearings that were acutely embarrassing to the agency, said that the action would be good news if it "is a turning point and indicates a more independent Food and Drug Administration." Still, Mr. Grassley noted that the agency continued to defend its approval and actions around Vioxx, which he said was "hard to square" with its decision to force Bextra's withdrawal. Merck withdrew Vioxx in September after a study showed that it more than doubled the risk of heart attacks and stroke.

Merck has said it may ask to start selling Vioxx again; the F.D.A. has said any such application would be reviewed by an advisory committee.

Dr. Galson said that information about drugs evolves as studies are completed "and we feel very strongly that we have taken account of these as quickly as possible."

"The medical and public health community should have confidence in the F.D.A. in light of these changes," Dr. Galson said.

F.D.A. officials have acknowledged that they are almost entirely unable to discover whether popular drugs cause common problems like heart attacks, which can arise from a variety of causes. Dr. Paul Seligman, a top F.D.A. drug safety official, said that the agency was trying to improve, but uncovering such effects was a challenge.

Celebrex, Bextra and Vioxx were, as recently as last year, among the top drugs in the world in sales. All are part of a new class of drugs called cox-2 inhibitors that were supposed to be safer on the stomach than older pain pills. But Celebrex and Bextra never proved any safer to the stomach, and some researchers say they believe that all three drugs were designed in ways that make them especially toxic to the heart. None of the three has been proved to ease pain any better than older pills.

In February, the F.D.A. asked a committee of experts whether it should force the withdrawal of Bextra and Celebrex and keep Vioxx off the market.

The committee voted overwhelmingly to keep Celebrex on the market but only narrowly supported continued sales of Bextra and Vioxx. Dr. Galson said that the agency's decision to press Pfizer to withdraw Bextra was "consistent with the views of many people on the panel."

Dr. Galson explained that the F.D.A. pushed for the withdrawal of Bextra largely because the drug causes a rare, life-threatening skin reaction more often than other pain pills and had no other unique benefits. This explanation surprised many on the panel, whose deliberations focused almost entirely on Bextra's effects on the heart and largely ignored its rare but serious effects on the skin.

Dr. Alastair Wood, the panel's chairman, said that F.D.A. officials told him and others early Thursday morning that the agency asked for the withdrawal of Bextra because of its effects on the heart, not the skin.

Dr. Wood also said he worried that the agency's decision to require tough warnings on all prescription painkillers might suggest to some physicians and patients that the worries about Celebrex were not unusual.

"By labeling everything, you might be trivializing the label on Celebrex," Dr. Wood said.

Physicians and patients should largely avoid Celebrex, Dr. Wood said, because the evidence is clear that it causes heart problems. Patients who need pain therapy should start with naproxen, the medicine found in Naprosyn and Aleve, he said. If their stomach hurts, they could take an over-the-counter heartburn pill like Prilosec, he said. They should try several other painkillers before considering Celebrex, he said.

Dr. Steven Nissen, a cardiologist at the Cleveland Clinic who served on the panel, also recommended that patients start with naproxen and, if their stomach hurts, take Prilosec. Few should take Celebrex, he said.

The F.D.A.'s announcement was yet another blow to Pfizer, which as recently as Tuesday assured Wall Street that sales of Celebrex and Bextra would soon rebound. It was the latest in a string of announcements by the company regarding the two drugs that quickly proved untrue.

Last fall, Pfizer repeatedly insisted that it knew of no studies of either Celebrex and Bextra that showed that the drugs hurt the heart. It later admitted that it had sponsored studies on both drugs that showed worrisome heart effects. Coping with slumping sales and earnings, Pfizer is entering a period during which many of its biggest selling drugs will face generic competition.

Pfizer suspended its enormous advertising campaign for Celebrex last fall when worries about the drug first surfaced. The February advisory panel voted overwhelmingly that the company should never again advertise the drug. But F.D.A. officials said that they could not ban the advertising of any drug.

Dr. Galson said that any new ads for Celebrex would have to "acknowledge the new risks." Indeed, being forced to alert consumers about serious health risks often dissuades drug companies from any advertising. Still, Dr. Galson said that banning ads for one drug made little sense when similar pain pills have similar risks.

Longtime critics of the agency said Thursday that they were still unhappy. Dr. Sidney Wolfe, a director of Public Citizen, said that the F.D.A. should have forced Celebrex's withdrawal as well. And its contention that it sought the withdrawal of Bextra because of its rare effects on the skin "is ludicrous."

Doug Bandow, a senior fellow at the Cato Institute, said that the agency should have left Bextra on the market with appropriate warnings about its risks. "For patients, it's always better to have more choice than less," he said.

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