Oct. 19, 2000 (Washington) -- An ingredient found in a number of over-the-counter cold medications andappetite suppressants can not be classified as "safe" because it mayincrease stroke risk, even in relatively young, healthy people, FDA advisorsconcluded Thursday. A "safe" classification is critical to a drugs' abilityto be sold over-the-counter.
The FDA has suspected since the early 1990s that phenylpropanolamine, or PPA, increases the riskof stroke, but after reviewing all the available datain 1992, the agency concluded that the data did not warrant removing PPAfrom the over-the-counter market.
The panel's conclusion Thursday was based in part on a recently completedstudy designed to address the FDA's suspicions. The five-year study wasconducted by researchers at Yale University and was sponsored by theConsumer Healthcare Products Association (CHPA), the nation's largestrepresentative of over-the-counter drug makers.
A stroke occurs when the blood supply to the brain is interrupted or shut off. This usually occurs when an artery is clogged or when it bursts open and bleeds. The researchers suspected that PPA increases the risk of the latter, bleeding kind of stroke called a hemorrhagic stroke. The study, including more than 2,000 people aged 18-49, compared the risk of hemorrhagic strokes in the general population with the risk incurred by those using PPA-containing products.
Once the study population was distilled to people that had used the products, the researchers were left with a total of eight patients that had used PPA products immediately prior to their stroke, and five people that had used PPA products without suffering a stroke. After adjusting for other risk factors, such as smoking, the comparison was further reduced to six people that had suffered a stroke compared with one person that did not.
An independent panel of experts commissioned by CHPA to review the conclusions found that the study was a failure. Although the study was thoughtfully designed, there simply was an insufficient number of participants to draw any conclusions, the experts said.
As a consequence, the FDA panel's decision already is mired in controversy.
"Even if the association is real, the risk appears to be exceeding small," said Noel Weiss, MD, DrPH, the independent panel's chair and a professor of epidemiology at the University of Washington in Seattle.
"We are back where we were when we started the study," added William Soller, PhD, senior vice president and director of science at CHPA.
Still, the results suggest that PPA is an independent risk factor for hemorrhagic stroke, said the study's lead researcher, Walter Kerman, MD, associate professor of medicine at Yale. This association is proven by the total number of people using PPA products that suffered a stroke compared with the expected incidence of hemorrhagic stroke in this age group, he told committee members.
The FDA reviewers supported this analysis, noting that previous studies also have suggested that PPA causes hemorrhagic stroke. The FDA database of adverse events associated with PPA products includes 22 cases of hemorrhagic stroke reported between February 1991 and July 2000, including four deaths, the reviewers said.
"The burden of proof now falls upon the industry to show us that it's safe," said Lois La Gernade, MD, MPH, the lead FDA reviewer. "At a minimum, consumers should be adequately informed."
"This is the best data we are going to see. It is time to proceed with rulemaking," added Charles Ganley, MD, director of the agency's over-the-counterdivision, while observing that conducting a new study to address theproblems could take more than a decade.
What kind of rule making will come from this committee decision is unclear.On one hand, the FDA had proposed a stronger warning label for allover-the-counter products containing PPA in 1996, to which the industry hasnow agreed. Yet the new conclusions of the FDA's expert panel could providethe agency with the ammunition to simply withdraw the products from themarket by declaring PPA unsafe.
Certain consumer groups are now petitioning the FDA to ban allPPA-containing products sold over-the-counter. Among them is Public Citizen,a group that has in the past played a large role in influencing the FDA'spolicies.
Further complicating the issue is that certain consumer groups are now petitioning the FDA to ban all over-the-counter PPA-containing products. Among them is Public Citizen, a group that has in the past played a large role in influencing the FDA's policies.
And finally, while the FDA usually follows its committee's recommendations,this committee was not asked to determine whether these products should bewithdrawn. Even then, the FDA is not bound by this conclusion, which is sureto be protested by CHPA as well as drugmakers.