Was It Really Necessary to Take PPA Off the Market?

Alex Otto

Pharmacy Today. 2001;7(3) 

Introduction

More than 4 months have passed since phenylpropanolamine (PPA) began disappearing from pharmacy shelves. OTC cough and cold medications reformulated with pseudoephedrine have taken their place, and diet drug makers -- perhaps the hardest hit by the withdrawal -- have reformulated at least some of their products with ephedrine alkaloids.

FDA's sudden recommendation in November to stop using PPA -- and the industry's prompt recall of nearly all products containing the stimulant at the agency's request -- caught many in the pharmacy community by surprise. Although the media's attention has shifted elsewhere, many pharmacists still have questions. Was FDA too hasty in its recommendation? Was the withdrawal really necessary? Do study data really justify making such a widely used medication unavailable to 284 million Americans?

FDA's actions were based on the strength of one study, the Yale Hemorrhagic Stroke Project (HSP). "The study was well designed, but it showed that only women had an increased risk of stroke," noted Miles Doane, PharmD, community pharmacy practice resident at Family PharmaCare in West Lafayette, Indiana. "The findings definitely warrant looking at the drug and maybe putting restrictions on it, but an all-out removal seems drastic." This sentiment is shared by many of the pharmacists Pharmacy Today interviewed for this story.

Looking for Answers

Americans were taking 6 billion doses of PPA-containing products annually before November. About 80% of those products were cough and cold medications, while the rest were appetite suppressants such as Acutrim and Dexatrim. PPA has been on the market for approximately 50 years.

To be sure, there was reason for concern before last fall. It has long been known that PPA, a sympathomimetic agent, causes a slight, transient rise in blood pressure after it is taken and that the rise might cause problems in patients who are hypertensive or who have other risk factors for stroke. The tendency was particularly worrisome among diet aid users, many of whom have preexisting stroke risk factors.

These concerns were not just theoretical. Several dozen cases of stroke and other hypertension-related adverse events with PPA use were reported over the past decades. However, a causal link was far from certain. As researchers noted in the Annals of Allergy in May 1986, "The evidence to support the widespread belief that sympathomimetic decongestants are unsafe in hypertensive patients is weak and circumstantial." Even FDA epidemiologists who looked at the data in the late 1980s could not reach a conclusion.

That uncertainty prompted the agency to ask industry to initiate the HSP in 1992. During the study, Yale researchers interviewed 702 patients between the ages of 18 and 49 within 30 days of having a hemorrhagic stroke. The goal was to see if patients had used PPA products within 3 days of the onset of symptoms. Age-, sex-, and race-matched controls where then polled to see if they had used a product that contained PPA within those same 3 days.

Only the link between hemorrhagic stroke and appetite suppressant use in women proved statistically significant in the study, which was released on the day of FDA's November announcement and published in the New England Journal of Medicine's December 21 issue. Women who used PPA-containing diet aids were 16 times more likely to have a stroke than those who did not. The link between cough and cold product use in women, though suggestive, was not significant. No association was found between the use of cough and cold remedies and increased stroke risk in men, and no men in the study reported using PPA-containing diet aids. Overall, just 27 (3.8%) of the stroke patients interviewed had used a PPA product in the days before their stroke.

OTC industry representatives attacked the study when it was first presented at an October FDA hearing. Most of the patients who had used PPA, they pointed out, had other risk factors for stroke such as hypertension and cigarette smoking, and, despite researchers' efforts to control for them statistically, these concomitant factors could have affected results. In addition, the strong association between stroke and the use of diet aids was based on only six patients, some of whom had risk factors. In an article on the Fox News Web site in November, a biostatistician called this conclusion "statistical absurdity" and accused FDA of alarmism.

Despite the concerns, the FDA committee that reviewed the study in October voted unanimously that the drug should no longer be recognized as safe. The committee also voted that the results supported link between PPA and stroke. One PhD statistician dissented from this conclusion, saying the evidence was inconclusive.

"An alternative would have been to limit PPA use in women with risk factors," said Loyd Allen, PhD, professor emeritus of pharmaceutics at the University of Oklahoma Health Sciences Center. "The precedent FDA is setting is worrisome; that they are making decisions based on one or two studies, decisions that are far ranging."

Defending the Call

Asking for the withdrawal was simply a matter of protecting public health, said Robert Sherman, a regulatory review biologist in FDA's division of OTC drugs who was involved in the PPA review. The modest benefits offered by the substance do not justify the possibility of a catastrophic adverse event no matter how remote, he asserted. Sherman stands by the agency's actions, including its seemingly contradictory conclusion that PPA was not dangerous enough to warrant an immediate recall even though the substance was, by committee estimates, responsible for 200 to 500 strokes in the United States each year.

"There is no reason to believe that there is something different about women," Sherman said when asked why the agency did not just limit use to men. "All of the stroke cases happen to be women, but we can't say from that that men are not at risk. There is no way to predict who is at risk."

Removing diet aids from the market but allowing cold products to remain was never really an option, either. "Cough/cold products are used in much greater volume," Sherman explained. "Even if there is greater risk with weight control products, there is so much more use of the cough/cold preparations that the actual problem might be greater there."

"We needed to come to some conclusion on this and not let it sit around," he added. "Even though the Yale study was small, FDA felt it was done appropriately. HSP took 5 years. To do a bigger or better study would take two or three times that length of time."

Other dynamics may have influenced the agency's actions, as well. The request to pull PPA came at a time when FDA was under fire for approving drugs too quickly. Although the agency denies it, there are some indications that drug approval rates have slowed in recent months, perhaps signaling the adoption of a more cautious approach to regulation. The recent withdrawal of alosetron (Lotronex) -- a drug used by men even though it was approved by FDA only for women -- also told the agency that it has little control over who uses drugs that are left on the market.

Walter Kernan, MD, lead HSP investigator and associate professor of internal medicine at Yale, thinks FDA acted appropriately, but told Pharmacy Today that "the study was not designed to determine or understand genetic differences in susceptibility which may explain our findings."

Preemptive Strike

Despite FDA's request, the decision to remove PPA products from the market was made in the boardrooms of OTC manufacturers, not at FDA headquarters. FDA simply asked manufacturers to voluntarily stop using the substance shortly after the committee vote. FDA is moving to categorize PPA as "not generally recognized as safe" (non-GRAS), but the agency has not yet banned its use in the United States.

Even before last fall, OTC companies had started to reformulate cough and cold medications with pseudoephedrine. Novartis Consumer Health introduced PPA-free Triaminic in early October, and Whitehall-Robins announced plans to reformulate Robitussin-CF, the only Robitussin product with PPA, over a year ago. The decisions to reformulate were made with the impending Yale results in mind.

It's widely believed PPA was pulled to avoid litigation. In the wake of FDA's request, company lawyers would have had a hard time explaining to jurors deciding a stroke-injury case why the substance was left on the market.

The concerns seem justified. In early November, a new industry mushroomed on the Internet: recruiting patients for class action lawsuits that accuse manufacturers of hiding the risks of PPA from the public. The first was announced in California days after the committee vote, and law firms continue to look for plaintiffs. On one Web site, Kahn, Smith & Collins, a Baltimore, Md., law firm, poses a rhetorical question: "Why do you think users of PPA should sue?" and adds, "Under the law of most states, a consumer can receive compensation for the injuries suffered as the result of an unreasonably dangerous product. The FDA recently issued a public health advisory warning Americans to seek alternatives to PPA because of the risk of stroke." Radio stations are running similar ads.

Industry Reacts

FDA will propose non-GRAS status for PPA in the next few weeks. Although there will be a short comment period after the proposal is printed in the Federal Register, Sherman said he "can't see what industry could submit to change" FDA's mind. The categorization will effectively ban use of PPA in OTC products in the United States. Smith acknowledged, however, that PPA might be able to be used safely with physician and pharmacist counseling and that, as a result, it could stay available as a prescription drug.

In the meantime, the reformulation of cough and cold products seems to be going smoothly. Whitehall-Robins has reintroduced its Dimetapp line with pseudoephedrine replacing PPA. Bristol-Myers Squibb plans to make the same substitution in its Comtrex Flu Therapy and Deep Chest products and reintroduce the products shortly. Novartis Consumer Health expects to start shipping reformulated Triaminicin and Tavist by April, and Bayer's reformulated Alka-Seltzer Plus effervescent line is expected to debut next fall.

The diet industry is finding making the adjustment a bit more difficult, however. Chattem pulled PPA-containing Dexatrim in November, but has left Dexatrim Natural -- introduced a year ago -- on the market in two formulations, one with ephedrine and the other with bitter orange peel. Chattem plans to introduce additional products for weight control and "fat burning," a company representative said, but with different active ingredients and not under the Dexatrim brandname. Like several other companies, Chattem is also promoting chromium for weight loss.

Veterinarians Looking for PPA Replacement

Veterinarians are also coping with the loss of PPA, one of the most effective medications to treat urinary incontinence in cats and dogs. "We weren't aware of the magnitude of that until we began to get calls form very upset consumers," Sherman said. "Most of the use in the veterinary world is the human drug being used off label." There are a few animal formulations, he said, "but I am not sure they can meet demand if we take the human drug off the market."

"It works particularly well in cats," Family PharmaCare's Doane said. "The tablets are small, cheap, and easy to use. Luckily, we had a bottle of 1,000 tablets on hand for that. But once that bottle goes, that's it." Alternatives such as imipramine (e.g., Tofranil) do not work as well and carry greater risk.

Doane can no longer order PPA tablets or even compounding powder from wholesalers. Only one PPA product appears to remain on the market: DuraPharm's extended-release formulation, Entex LA. The company has no immediate plans to withdraw it, according to a spokesperson.

Although there were reports last November of patients stocking up on cough and cold remedies, they seem to have adjusted well to the withdrawal. "I think a lot of people were upset when there were no products on the shelves, but now that there are products on the shelves again, people are pretty accepting," said Winnie Landis, pharmacy manager and diabetes care specialist at Osco Drug in Lafayette, Ind. "Every time you turn around, something is being pulled or changed or regulated. People get to the point where they just accept it."

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