November 12, 2000-Drugs's Ill Effects Often Discovered Years Later
Despite widespread testing of over-the- counter drugs, some problems can be detected only when used by the public at large. Ann Seifried grabbed the Dimetapp she had long given her son for his allergies, the Alka-Seltzer cold medicine her husband favored. She rummaged through her medicine cabinet and found some others, then headed for the trash. "I did take my stuff and throw it away," Mrs. Seifried of South Pasadena said last week. "You panic." The U.S. Food and Drug Administration last week warned millions of consumers to stop using scores of over-the-counter cold medicines and diet pills containing phenylpropanolamine, or PPA, because the ingredient has been linked to strokes in young people, especially women.
The news shocked many, even though reports of stroke date to the early 1980s, and experts say the FDA's warning underscores an.phpect of drug testing many don't understand: The American people serve as one huge clinical trial.
Although a drug must prove safe in studies of several hundred or even a few thousand people before it is approved, side effects often don't surface until thousands have taken it for a considerable length of time. At least six times in the past three years, the FDA has banned or all-but-banned common drugs after life-threatening side effects were reported years after the drugs hit the market. "Once it's post-market, that's when you're going to find the problem," FDA spokeswoman Laura Bradbard said. "In a small clinical trial, a rare event isn't even going to appear."
The FDA is trying to improve the way it keeps track of such side effects, but a strong contingent of researchers says the delay in banning PPA shows the system is too weak and takes too long. The agency's MedWatch program relies on doctors, pharmacists and patients to report so-called adverse incidents from prescription and non-prescription drugs, and even the FDA acknowledges that unpredicted side effects can go underreported for years. To researchers who have long questioned the safety of PPA, the delay in FDA action is glaring.
"It does point out the problem that we need a better, more systematic approach to reporting and quantifying drugs that are used by hundreds of thousands or millions of people," said Dr. Paul E. Leaverton, a professor of epidemiology and biostatistics at the University of South Florida in Tampa, who studies clinical trials. "Right now, it's these anecdotal kind of things that come to light. It takes a hell of a lot for FDA to withdraw a drug. It's amazing, if you look at it." In March, the FDA banned the diabetes drug Rezulin, which had been approved in 1997, after it was linked to more than 30 deaths from sudden liver failure. The FDA also recently ended the marketing of Propulsid, a popular prescription heartburn drug for sale since 1993, after it was linked to at least 70 deaths.
The action taken Monday against PPA is similar to what happened three years ago to fen-phen, a combination of two prescription weight-loss pills, fenfluramine and phentermine, that had been taken separately since the 1960s. Use of the combination became widespread after 1992. About 6-million Americans were taking fen-phen when the FDA pulled fenfluramine from the market in 1997 after the combinationwas linked to leaky heart valves and an often fatal lung disease, pulmonary hypertension. Monday's warning about PPA hit the giants of the $ 3.5-billion cough and cold remedy market, including Contac, Triaminic and Robitussin, as well as popular appetite suppressants such as Dexatrim and Acutrim. Customers said they were surprised to find products they had used for two decades suddenly had been deemed too risky.
"You would think that the pharmaceutical manufacturers would have it pretty down pat," said Gulfport resident Doug Burkholder, 54, who uses Alka-Seltzer Plus, which contains PPA. But Dr. Tim Covington, professor of pharmacy at Sanford University in Birmingham, Ala., and a national expert on over-the-counter drugs, said people didn't realize the risks of taking PPA because the dangers have been drowned out by advertising. "Look at the brand names of drugs that contain phenylpropanolamine. They're standard names. They're household words," Covington said. "When you market a drug, you de-emphasize the dark side of the drug and you emphasize the positives.
"The whole story has not been appreciated by the consumers, and in a lot of cases not by the professionals." Phenylpropanolamine was never deemed safe by the FDA in the first place. It went on the market in the 1970s, before modern regulations were in place, and the government began looking into problems in the 1980s. The New England Journal of Medicine published the first look at strokes linked to PPA - especially in high doses in diet drugs - in 1983. "FDA was noticing these odd adverse incidents popping up in young people . . . who should never be having strokes," Bradbard said. "What in essence (the agency) said was, "We need more information before we determine how safe this is.' "
The agency has added money and staff to its reporting system and has asked for more resources, but Congress has been reluctant to provide them. "They need epidemiologists and statisticians and doctors interested in developing a system that reports these things in a sensible, scientific way earlier," said Leaverton, the USF professor. "Society doesn't do a good job of picking up things until there are disastrous incidents." Bradbard said the agency had trouble getting research about PPA from the drug industry, which maintains it is safe if used properly. Because strokes and deaths are rare, gathering enough data to study it properly took years.
Even now, FDA figures lag: The agency has received reports of just 44 strokes and four deaths related to PPA, even though physicians, 15-year-old medical reports and a recent study by Yale University have chronicled dozens more. The first successful lawsuits against the makers of products containing phenylpropanolamine (pronounced fee-nil-pro-pan-ol-ameen) date to 1987 in California, the Times found. Five years ago, the FDA and the Consumer Healthcare Products Association, which represents drugmakers, agreed to a study of PPA-related strokes by researchers at Yale University. The study ended earlier this year and results were to be published in the Dec. 21 issue of the New England Journal of Medicine, but the findings were so compelling they were released seven weeks early: 18- to 49-year-old victims of hemorrhagic strokes were two to 15 times more likely to have taken PPA within three days of the stroke.
The study excluded stroke victims who had died or lost their ability to communicate, so the risk is probably much greater, researchers said. PPA is a central nervous system stimulant that can increase the heart rate and blood pressure. Caffeine makes it worse. In the most extreme cases, the spike in blood pressure ruptures an artery in the brain, causing a hemorrhagic stroke. The FDA said the danger to most people is very small, but the benefits of taking the drug don't outweigh the risk. Although no other similar weight-loss aids are available, consumers can find suitable nasal decongestants, particularly those with pseudoephedrine, such as Sudafed, or nasal sprays. The FDA estimates that ending its use will prevent 200 to 500 strokes a year in people ages 18 to 49.
Dr. Gary Zaloga, a critical care doctor in Maryland who treated patients with strokes related to PPA as early as 1982, and other researchers say the FDA's action against the drug should remind consumers of a fundamental truth about medicine: For every benefit, there is also a potential risk. And non-prescription drugs don't have to meet the same standards as prescription drugs. "A lot of people think if it's over-the-counter, it must be safer than a prescription drug. That's not true at all," Zaloga said. "There's no such thing as a really safe medicine. If you're clearly taking medicine chronically, you probably ought to find out more about them."
The FDA plans to ban PPA, but that process can take months. In the meantime, it has asked drug manufacturers to quit marketing products with PPA or to reformulate them. Most major drug store chains, including Walgreens and Eckerd, pulled products with PPA from their shelves last week. People who want to avoid buying them at other stores or who want to check for the ingredient in medicine they already have should look at the ingredients on the package for phenylpropanolamine hydrochloride.
Laura and Carl Fisher, a fit-looking couple from Treasure Island who are tearing through their 70s, said the news made them head for the medicine cabinet to check, and they have to look for a replacement for the Robitussin they have long used. Mr. Fisher is a diabetic, so his alternatives are limited, but they do plan to find one. "It came as a complete surprise to me," Mrs. Fisher said. "We always relied on the . . . pharmacist, and Walgreens." Added her husband, "Even if you get the magnifying glass out and read all the fine print on the bottle, you can never be sure."
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