Rethinking Over-the-Counter Drugs
Finding on Aleve Underscores Dearth of Overall Research;
Little Incentive for Trials
By SCOTT HENSLEY
Staff Reporter of THE WALL STREET JOURNAL
December 22, 2004; Page D1
A government finding that Aleve, the widely used pain reliever, appears to increase the risk for heart problems underscores how little is known about possible side effects of some common older medicines.
Although much attention has been paid recently to drug-safety problems that have emerged in newer prescription drugs, such as Vioxx, the same scrutiny hasn't been applied to older over-the-counter medicines and prescription drugs that long ago went generic. The reasons have to do with changing regulatory standards and economic incentives.
These older pills came to market decades ago as prescription drugs when standards for approval were more relaxed -- Aleve, generically known naproxen, was a medicine available by prescription only for nearly 20 years before the over-the-counter version was approved a decade ago. Prescription-strength naproxin still is sold. In the past, studies were smaller and less comprehensive, sometimes lasting weeks or months. Today, studies can run for years.
One reason safety problems such as these are coming to light now is that larger, longer drug trials -- such as the government's Alzheimer's disease-prevention study that raised alarm bells about Aleve -- are putting some of these older drugs to more rigorous tests. A careful clinical trial can tease out safety signals that may have been lurking undetected or underappreciated.
Aleve marks the fourth major pain killer in recent months to show signs of raising the odds of heart attack and stroke. The others were Pfizer's Bextra and Celebrex and Merck & Co.'s Vioxx. Those three are so-called Cox-2 inhibitors, a new category in the broader class of painkillers known as nonsteroidal anti-inflammatory drugs, or NSAIDs, including Aleve.
For years, Aleve was thought to be protective of the heart, like aspirin. Indeed, Merck has cited that to explain why patients taking Vioxx had more heart problems than patients taking naproxen in a clinical trial.
But the heart-protection assumption about Aleve hadn't been proven in rigorous clinical trials. When it was put to a careful test, the Alzheimer's study sponsored by the National Institutes of Health, a safety check turned up the indication that Aleve appeared to increase by about 50% the risk of cardiovascular problems, such as strokes and heart attack, in elderly patients taking the drug daily for several years.
A spokesman for Aleve's maker, Bayer AG, says the company is "obviously concerned" by reports on the Alzheimer's trial but hasn't seen the data yet, since the full analysis hasn't been completed or released by the study's independent safety committee. The company said the findings contradict nearly 30 years' experience of safe use of the drug. Bayer agrees with the FDA that consumers should carefully follow the instructions of the Aleve label, which limits treatment of pain to 10 days or less, unless otherwise directed by a doctor.
The findings from studies like the Alzheimer's research can be jarring because of prevailing perceptions among consumers that drugs approved by the Food and Drug Administration are free of risk. The image of safety is particularly true of medicines that don't require a prescription and are heavily advertised.
But that isn't always the case, drug experts say. "People are misunderstanding that a drug is safe because it's over-the-counter," says Brian L. Strom, chair of the Department of Epidemiology & Biostatistics at the University of Pennsylvania School of Medicine. "Drugs are inherently poison that are given to interfere with the body's normal system," he says. Society allows medicine to be sold "because we think the benefits are greater than the side effects."
Some doctors make the point that the odds of cardiovascular trouble arising from short-term use of common painkillers is slight. In the Alzheimer's study, for instance, patients received Aleve for as long as three years -- well beyond the 10-day period indicated for over-the-counter use. "Yes, there's a risk with any drug of something untoward happening," says Evelyn Hermes DeSantis, clinical associate professor of pharmacy at Rutgers University in New Brunswick, N.J. She says the cardiovascular risk from over-the-counter products is minimal with limited use.
For drugs to move from prescription to over the counter, the FDA must determine they are safe and effective for people to use without the help of a doctor. Drug makers typically submit clinical data and results from real-world tests of how consumers use the medicine. The FDA must weigh whether people will be able to self-diagnose the problem, figure out the appropriate treatment and how to use it.
Painkillers are commonplace in medicine chests everywhere, especially the category of the nonsteroidal anti-inflammatory drugs, NSAIDs, that include ibuprofen and naproxen. Besides being perceived as safe, these drugs are old and unlikely to generate blockbuster sales growth. Therefore the companies have little incentive to run clinical trials that would look for side effects.
Older NSAIDs present a challenge for the FDA because many haven't been part of big trials, an agency spokesman said. The FDA is examining the data that are available, including trials that compare newer COX-2 inhibitors to older NSAIDs, he said.
NSAIDs have long been known to raise the risk of gastrointentinal bleeding with long-term use. In fact, that shortcoming is what fueled the development of drugs such as Vioxx and Celebrex to relieve pain and inflammation while reducing the risk of bleeding.
Vioxx was pulled from the market by Merck in September after a study found it doubled the risk for heart attacks and strokes in patients taking the drug for 18 months and longer. Celebrex was believed to have a lower risk of cardiac problems than Vioxx. That view was shaken when a safety review announced last week found an increased rate of heart attack and strokes in patients taking the drug as part of a study in colon cancer prevention.
Yesterday, British authorities advised doctors by letter to switch from Celebrex to drugs other than Cox-2 inhibitors, especially for patients with cardiovascular risk. The regulators cited the emerging evidence on the drug class, including the new data on Celebrex.
--Sarah Lueck and Leila Abboud contributed to this article.
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