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The Phenylephrine Puzzle

AACP Article

Two University of Florida College of Pharmacy faculty members finally convinced the FDA that a widely used nasal decongestant does not work.

By Matt Splett

Phenylephrine is a popular ingredient found in more than 260 over-the-counter cold and allergy medicines. Drug makers have long contended that it helps clear nasal decongestion—but two professors from the University of Florida College of Pharmacy spent two decades refuting that claim. Backed by science, they finally convinced the FDA that the common nasal decongestant does not work.

In 2005, Dr. Randy Hatton was co-directing the Drug Information Center at UF Health Shands Hospital when questions about oral phenylephrine began flooding the phone lines. Pharmacists and physicians from around Florida were calling the center asking if oral phenylephrine worked and what dose to take.

A federal law enacted that year mandated retailers move pseudoephedrine products behind the counter to combat illicit methamphetamine production. Pharmaceutical manufacturers reformulated common cold and allergy medicines using phenylephrine instead of pseudoephedrine. Yet, skepticism emerged within the healthcare community regarding the effectiveness of oral phenylephrine. “The Drug Information Center fielded many similar calls questioning whether oral phenylephrine worked as a decongestant,” said Hatton, a clinical professor in the college. “The UF College of Pharmacy students and residents staffing the center would examine the literature to provide informed responses to the healthcare professionals. In the case of phenylephrine, they did not have to look far for an answer.”

In 1993, Dr. Leslie Hendeles, a professor of pharmacy in the UF College of Pharmacy, published a review paper in the journal Pharmacotherapy addressing the choice of decongestants and mentioned the ineffectiveness of oral phenylephrine. While the drug posed no safety risks, he referenced earlier unpublished studies suggesting phenylephrine’s resemblance to a placebo, with it being inactivated in the gut during the first pass through the liver resulting in little of the drug reaching the bloodstream.

image of Timeline of Oral Phenylephrine in the U.S.

Hendeles and Hatton met one day to discuss their suspicions about phenylephrine. As academic pharmacists, they prioritized evidence-based approaches to ensure the safety and efficacy of drug therapies for patients. They left the meeting with a mutual determination to investigate the inefficacy of oral phenylephrine and share the evidence with the FDA.

Dr. Hendeles and Dr. Hatton, pictured in 2006.

The 20-Year Journey

For almost 20 years, the endeavor to persuade the FDA of the inefficacy of oral phenylephrine encompassed extensive research, editorials, citizen petitions and advocacy efforts aimed at influencing policymakers and public sentiment. Hendeles and Hatton acknowledge they may have been a bit naïve at the beginning, believing the task would be straightforward. Nevertheless, as the journey unfolded, their commitment to the cause never wavered. “Every time new evidence emerged that supported our assumptions, it would reignite us,” said Hendeles, now a professor emeritus in the college. “We were committed to the issue and viewed our efforts as a public service.”

In 2006, Hendeles and Hatton published their first editorial in the Journal of Allergy and Clinical Immunology. They contested the FDA’s endorsement of the 10-milligram oral dosage approved in 1976, citing inconclusive evidence to support phenylephrine’s effectiveness in alleviating nasal congestion. A few months later, Hatton submitted a Freedom of Information Act request to the FDA. They sought all the available data employed by the agency in evaluating the safety and efficacy of oral phenylephrine.

“We were able to use all that information and do a systematic review and meta-analysis to support what Leslie had published in 1993 and what pharmacists were calling the Drug Information Center and reporting that oral phenylephrine did not work,” Hatton said.

Dr. Russell McKelvey, a pharmacy resident at the UF Drug Information Center, contributed to the systematic review and meta-analysis that was published in 2007. The same year, Hendeles and Hatton filed their first of two citizen petitions asking the FDA to reevaluate the dose of phenylephrine. They thought a higher dose might compensate for the poor absorption. The move spurred the FDA to form a Drug Advisory Committee to review phenylephrine’s effectiveness, but the panel ultimately decided more data was needed before a decision could be reached.

“Every student who went through this college during our tenure was taught that oral phenylephrine was ineffective. It was gratifying to hear from former students expressing their excitement that tangible progress had finally been made with the FDA.”

—Dr. Leslie Hendeles

As the years passed, new studies contributed to the mounting evidence against oral phenylephrine. Despite persistent advocacy efforts from Hendeles and Hatton urging action from the FDA, progress seemed elusive. However, a significant turn of events occurred in 2023, when the FDA appointed a second drug advisory committee to review the issue. The 16-member committee evaluated the existing data and heard testimony from drug makers advocating for the efficacy of oral phenylephrine alongside experts like Hendeles and Hatton who advocated against its ongoing use—setting the stage for a momentous decision.

Making Headlines

On Sept. 12, 2023, the FDA’s Nonprescription Drugs Advisory Committee voted unanimously that oral phenylephrine is ineffective. The decision came as no surprise to Hendeles and Hatton, who had dedicated a considerable part of their professional lives advocating against its use in cold remedies. “For the vote to be unanimous, that was a significant achievement,” Hatton said. “I was delighted when it happened, feeling vindicated for what we had been saying for a long time.”

The committee’s decision made immediate headlines across the country. Americans spend about $1.8 billion on cold medicines annually, so the idea that one of the key ingredients was deemed ineffective carried considerable implications. Hendeles and Hatton found themselves inundated with interview requests from many major media outlets ranging from the New York Times and Wall Street Journal to National Public Radio and CBS News. It seemed everyone wanted to hear from the two University of Florida pharmacists who had figured out that a key ingredient in cold and allergy remedies does not work. “The media attention was more than I expected,” Hendeles said. “If it wasn’t for the two of us and recent studies with modern study designs, the FDA would have never addressed the oral phenylephrine issue.”

Headlines such as “The Two Scientists Taking Down Cold Medicines That Don’t Work” and “Florida Pharmacists Bring National Attention to Ineffective Drug” put the spotlight on the two decades of research and advocacy led by Hendeles and Hatton. They accepted as many media interview requests as their schedules allowed, as they aimed to inform the public about oral phenylephrine’s ineffectiveness.

Following the ruling, Hendeles and Hatton received messages from numerous colleagues and former students, including those who had been affiliated with the UF Drug Information Center or studied in the college’s Pharm.D. program. “Every student who went through this college during our tenure was taught that oral phenylephrine was ineffective,” Hendeles said. “It was gratifying to hear from former students expressing their excitement that tangible progress had finally been made with the FDA.”

Although the committee’s decision cleared a significant hurdle toward eliminating decongestants containing phenylephrine from shelves, the actual removal process is expected to take some time. The FDA must finalize its decision and allow for public commentary. Hatton anticipates that it may be another year before oral phenylephrine is completely phased out from cold medications. In the interim, he hopes that heightened public awareness about phenylephrine will encourage consumers to be more discerning in their cold and allergy medicine purchases.

“We are just two pharmacists looking out for the best interests of patients to ensure their cold medicines are safe and effective,” Hatton said. “Leslie and I have always been focused on helping the public get the most out of their drug therapy.”

This article is reprinted with permission from the University of Florida College of Pharmacy. It appears in the latest issue of the college’s alumni magazine.

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