Painkillers Fall Under Sharp Review
Health Officials to Focus On Side Effects,
With Eye Toward Regulatory Action
By THOMAS M. BURTON in Chicago,
ANNA WILDE MATHEWS in Washington and
ANTONIO REGALADO in New York
Staff Reporters of THE WALL STREET JOURNAL
December 24, 2004; Page A3
Federal authorities say they will broaden their scrutiny of painkiller side effects to include dozens of known clinical studies of at least 18 anti-inflammatory pain medications, several of them household names.
The list of studies is potentially so broad that neither the National Institutes of Health nor the Food and Drug Administration, which are heading the initiative, could specify yesterday exactly how many such clinical trials will be intensely reviewed.
There are at least 40 known clinical studies alone involving Pfizer Inc.'s Celebrex, the popular painkiller put under a recent cloud by a study that suggested possibly elevated heart-attack risk when used at high doses.
Officials at the NIH said they will study side effects in all NIH-sponsored research involving all so-called nonsteroidal anti-inflammatory drugs, commonly called NSAIDs. These drugs include such familiar products as aspirin and ibuprofen (sold under brand names including Advil and Motrin), as well as a dozen or more other medicines with names including Aleve, Voltaren, Mobic and Toradol.
Meanwhile, the FDA said it will look at side effects in all "prevention studies" of Celebrex and Pfizer's Bextra. These studies are designed to see if the drugs can prevent certain diseases, including cancers, and could lead to the FDA's approving them for prevention or treatment of those conditions. The safety agency said it also will analyze data on the 18 or more painkillers as well. The FDA said it is conducting its overall review with an eye toward possible regulatory action. The federal review, undertaken in response to recently released trial results adding to evidence of side effects from some of the drugs, promises to be very broad, and the FDA's findings will surface in February, when an advisory panel will evaluate the issue.
Earlier this week, the NIH said it was halting an Alzheimer's-prevention study, citing signs of heart risk from naproxen, an over-the-counter painkiller sold by Bayer AG as Aleve. But people close to the study say the risk involved was small and the reaction overblown. Regardless, the news added to confusion over the safety of a range of painkillers.
"I suspect that the FDA is under such pressure from Congress that they'll do anything right now," said rheumatologist Michael H. Ellman of the University of Chicago, who uses these drugs for arthritis patients. "It may be that it will take them so long to do the study that by the time it comes out, we won't be worrying about it."
The most meaningful studies to be scrutinized for side effects likely will be newer ones involving drugs such as Celebrex.
"From a cardiovascular risk perspective, we're casting a very wide net," said John Jenkins, director of the FDA's office of new drugs. "Aspirin is not the main focus," he said, but added: "We're definitely reviewing all the NSAIDs."
The FDA also specifically urged doctors and patients to be cautious in using all of the painkillers, and to limit their use of the Cox-2 inhibitor class that includes Celebrex and Bextra. (Cox-2 drugs are a subset of NSAIDs, and are supposed to be easier on the stomach than the others.) The new statement from the agency is its most specific since the broader safety questions emerged about some of the most widely used drugs in the U.S., but still leaves a number of questions for physicians and people who take the anti-inflammatory medicines for arthritis pain and other problems.
The agency recommended that doctors weigh the growing signs of risk with all Cox-2 drugs, but still consider them in cases where they might provide a unique benefit, such as a patient at high risk for gastrointestinal problems. That would lead to "more limited prescribing than would currently" be practiced under the drugs' labeling, said Dr. Jenkins.
The current national anxiety over painkillers began in September, when Merck & Co. withdrew its Cox-2 drug Vioxx from the market because of heart-attack risk. In subsequent weeks, the FDA came under fire on Capitol Hill and from prominent cardiologists because earlier epidemiological studies previously suggested such a risk with Vioxx. Since then, the NIH has disclosed possible increased heart risk with Celebrex and then with naproxen. Manufacturers have defended these products, and doctors' views about their meaning are varied.
The FDA also explicitly raised concerns about the entire range of anti-inflammatory painkillers, recommending that "individual patient risk for cardiovascular events and other risks commonly associated with" anti-inflammatory painkillers should be taken into account. The FDA is examining older studies, but it isn't clear how much evidence ties the older painkillers, except naproxen, to cardiovascular risk. The agency also told consumers to limit their use of the over-the-counter versions of the painkillers to 10 days, unless under the advice of a physician.
The FDA said it will require a new examination of all studies currently under way that evaluate Celebrex and Bextra for preventing the onset of disease, in light of concerns about cardiovascular risk.
The FDA said its advisory was an interim measure until it could review all of the data about the drugs.
Its decision to issue early, cautious advice, pending more information, isn't unusual for the agency in a situation when there are emerging signals of risk about a medicine or class of drugs -- for instance, last year the FDA released several different notices as more information came to light about the possible tie between antidepressant drugs and suicidal tendencies in young people. It took over a year, between when the concern initially emerged with one of the drugs and the agency's decision this fall to call for a strong "black box" warning for all antidepressants.
The FDA already had urged doctors to be careful in using Celebrex, and use the lowest effective dose. The label of Bextra also recently got warning language about the drug's possible cardiovascular risks. But the new caution flags come after years of rising concerns about the possible heart risks of the Cox-2 drugs.
Bextra was approved in November 2001 for treating osteoarthritis and rheumatoid arthritis at a low dose of 10 milligrams, or 20 milligrams twice a day for menstrual pain. But an FDA reviewer had recommended against approving high doses of the drug for treating acute pain, because of an "excess of serious adverse events," including deaths, when the drug in oral and intravenous form was compared with a placebo in a study of patients who underwent coronary-artery bypass surgery. The reviewer specifically raised concerns about the risk of cardiovascular problems because of blood clots.
In a statement yesterday, Pfizer said, "The U.S. FDA advisory committee hearing in February is the appropriate forum for a thorough review of all available data evaluating the benefits and risks of medicines used by millions of Americans to treat arthritis and joint pain. Pfizer is continuing to provide the FDA as well as regulatory authorities around the world with extensive safety and efficacy data for its Cox-2 medicines, Celebrex and Bextra."
Makers of some widely sold NSAIDs generally reiterated the safety of their drugs when used as directed.
Whether the most popular over-the-counter medicines such as aspirin will undergo scrutiny isn't clear. An NIH spokesman said it "does not appear immediately that aspirin and ibuprofen are included" in the studies it will review. An FDA official said aspirin technically is part of the review, but probably won't be a major focus.
Aspirin has been around so long -- since the 19th century -- that it never underwent the sort of stringent FDA approval process that new drugs have faced since the 1970s. Dr. Ellman says aspirin has enough known dangerous side effects, such as gastrointestinal bleeding, that it probably couldn't gain FDA approval today.
Even so, aspirin bears cardio-protective effects and is arguably the world's most trusted painkiller.
"What if they reviewed aspirin?" Dr. Ellman asked. "It would be taken off the market with all its side effects."
--Heather Won Tesoriero contributed to this article.
Write to Thomas M. Burton at tom.burton@wsj.com11, Anna Wilde Mathews at anna.mathews@wsj.com12 and Antonio Regalado at antonio.regalado@wsj.com13
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