With the Decongestant SNAFU, the FDA Tries Something New

It’s easy to understand how a medicine like phenylephrine got onto pharmacy shelves in the first place. The common decongestant, used most often as an ingredient in multidrug cold medications like DayQuil and Sudafed PE, was initially designated as “safe and effective” by the Food and Drug Administration (FDA) in 1976, when the agency was newly—and less stringently than today—greenlighting drugs that had been on the market for years before the agency had established any efficacy standards. After a full review of 14 studies (12 unpublished and two published) from pharmaceutical companies—a fair body of evidence for the time—the panel of experts assigned to evaluate over-the-counter allergy medications ruled that phenylephrine was effective.

Except phenylephrine has never worked. What’s puzzling, then, is how it stayed on those shelves for 50 years without a challenge. That changed on Sep. 12, when a different FDA advisory committee looking in part at that same early research voted 16-0 that the common oral form of phenylephrine is ineffective, opening the door for products claiming it works as a decongestant to be pulled from stores altogether. Though a final decision by agency authorities could take months and face legal challenges, the panel vote alone could be a death blow to the medication, which appears in products that together account for nearly $1.8 billion in U.S. spending each year.

Experts agree that an over-the-counter medication shouldn’t easily be able to go half a century without being reevaluated against new scientific standards. The FDA has since the late 1960s required that over-the-counter medications meet formal standards for both safety and efficacy, but since its initial market purge of medications that didn’t meet those criteria in the early 1970s, such approvals have really only been called into question over safety concerns. “In 50 years, I don’t ever remember a drug being removed from the market because it wasn’t effective,” says Leslie Hendeles, a professor emeritus at the University of Florida’s College of Pharmacy and an FDA consultant. In other words, if it isn’t broken, the FDA usually doesn’t have the bandwidth to fix it. The story of phenylephrine, then, isn’t just an example of the agency’s past oversights, but could be what Hendeles calls the “poster child” of a new effort to clean them up in every aisle.

Though it’s popular now, phenylephrine became the main over-the-counter decongestant through a sort of process of elimination. The 1976 panel that allowed it to stay on the market after the FDA updated its standards also approved two other decongestants: pseudoephedrine and phenylpropanolamine. The studies that formed the basis for phenylephrine’s approval were shaky by today’s standards; Hendeles says that the results are riddled with statistical anomalies, and that “some even had fraudulent data.”

At the time, phenylephrine was the least common of the three. Around the turn of the century, however, large studies began to demonstrate an association between phenylpropanolamine and deadly brain bleeds, and so the market for phenylephrine and pseudoephedrine increased.

Most manufacturers who used phenylpropanolamine switched to pseudoephedrine around 2000, Hendeles says—the most popular allergy medications at the time, including Claritin D, which led the market, all contained pseudoephedrine along with the standard antihistamines, which fight allergy symptoms triggered by the immune system, like itchiness and swelling. But pseudoephedrine at the time was also the easiest-to-acquire form of one potential key ingredient in the production of crystal meth, and with the passage of the Combat Methamphetamine Epidemic Act of 2005, any medication containing it could no longer be sold on shelves; you didn’t need a prescription, but it was only accessible by pharmacists and all sales were tracked. “Companies didn’t want to lose the income from sales in front of the counter,” Hendeles says, “and phenylephrine could be purchased in grocery stores, convenience stores, airports, cruise ships—everywhere.” Reformulations and new options with phenylephrine proliferated. Today, there are 261 over-the-counter products containing the drug.

But not all manufacturers made the switch. Schering-Plough (since bought out by Merck), the maker of Claritin D, was hesitant, says Hendeles. “They were effective, and they didn’t want to make the switch unless it was going to give them the same efficacy,” he says. Internally, the company ran some of the first studies of phenylephrine since the 1970s, and sure enough, they showed that the last over-the-counter option was ineffective. So they chose to keep making Claritin D with pseudoephedrine, even though it meant the drug would have to go behind the counter. The makers of Zyrtec and Allegra followed suit with their pseudoephedrine products.

Around the same time, in 2007, Hendeles’s University of Florida colleague Randy Hatton filed a public records request that granted him access to the dozen original studies on phenylephrine that the FDA had initially looked at decades earlier. Together, the two researchers concluded that the evidence showed oral phenylephrine at the allowed dose was no better than a placebo, and immediately filed a citizen’s petition asking the FDA to require pharmaceutical companies to test doses higher than the maximum allowed 10 mg of phenylephrine. In response, the agency assembled the Non-Prescription Drug Advisory Committee (NDAC) to address Schering-Plough’s findings and the concerns raised by Hendeles and Hatton.

Amid conflicting presentations and interpretations of research given by the petitioners, manufacturers, and the Consumer Healthcare Products Association, which represents the industry, the NDAC ultimately voted “yes” on a resolution that the evidence on phenylephrine was “suggestive of efficacy.”

Hendeles didn’t agree then, and today claims that the meeting was far from thorough and fair. “The head of the [NDAC] said that the ideal outcome of this meeting would be for the committee to say that it’s effective and didn’t need additional studies,” he says. “He said, ‘that way, we won’t have to change the monograph’”—referencing, Hendeles says, the established rule sheet for a family of drugs. According to Hendeles, a chronically understaffed and underfunded FDA may have simply not been able to give the issue the attention it deserved at the time.

In the FDA’s own recounting of the 2007 meetings, the agency suggests that some consultants present were likely swayed by the fact that studies have actually shown that phenylephrine can be an effective nasal decongestant. Of course, what the NDAC was supposed to be assessing in this case was its efficacy as an oral decongestant, processed in the gut. That the body metabolizes a drug differently based on method of administration isn’t unusual, but can certainly make specifying its usage more confusing.

Following those meetings, the FDA also asked companies manufacturing oral phenylephrine test higher-dosage versions of their drugs, as Hendeles had requested. But two extensive studies by Merck found that even 40 mg of phenylephrine—a whopping four times the largest dosage being sold in Claritin pills in stores—was no more effective than a placebo. In 2015, “when we saw the results of this dose ranging study, Dr. Hatton and I went and submitted another petition” to the FDA, Hendeles says. “This time that petition was actually to remove the drug from the marketplace.”

Though it took another half decade, that second petition, and its support from groups including the American Pharmacy Association, is a big part of what finally got the FDA to take its most recent look at phenylephrine. Another reason for the FDA’s recent move was the Coronavirus Aid, Relief, and Economic Security Act, passed in 2020, which enabled the agency to more easily revise over-the-counter approvals and recommendations.

If the FDA does decide to take phenylephrine off the market, it may signal to the market that more medications might be subject to new regulatory scrutiny. In the allergy aisle alone, Hendeles has a few other products in his crosshairs, including the cough suppressant dextromethorphan, found in Robitussin, and the mucus thinner guaifenesin, found in Mucinex. “The data that’s in the literature suggests that neither of those two are effective,” he says.

For now, with no given timeline for a final decision from the FDA, phenylephrine is still on the market. Still, with flu season coming, a word to the wise and congested: It’s time to get comfortable with nasal spray.

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