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Hundreds of allergy and cold medicines on retail shelves contain oral phenylephrine, with brands including Sudafed PE and Suphedrine PE totaling over a billion dollars in sales each year. However, that oral decongestant -- the only one available outside the pharmacy -- doesn't work, an FDA advisory panel said.

All 16 voting members of the Nonprescription Drugs Advisory Committee at a meeting held on September 11 and 12 voted against the drug being effective for nasal congestion when used as labeled.

Moreover, no member favored additional studies into phenylephrine pharmacokinetics or higher doses to try to rescue its over-the-counter (OTC) use.

Further studies would be "kind of beating a dead horse," said panelist Paul Pisarik, MD, MPH, a geriatric physician at ArchWell Health in Tulsa, Oklahoma. "This is a done deal. As far as I'm concerned, it doesn't work."

Phenylephrine and pseudoephedrine are the only two oral nasal decongestants available without a prescription, but most brands switched their OTC products to contain phenylephrine when pseudoephedrine moved "behind-the-counter" due to a 2005 federal regulation aimed at stemming its use in making methamphetamine.

If FDA follows the advice of the panel -- which it usually does, but not always -- oral phenylephrine would lose its "Generally Regarded as Safe and Effective" status based on lack of efficacy and would have to leave the market.

The scale of the potential impact is staggering.

Representing the many companies with phenylephrine products on the market, the Consumer Healthcare Products Association (CHPA) pointed to nationally representative data suggesting that roughly half of U.S. households had purchased a phenylephrine product over the course of a year. Even based on sales databases that capture an incomplete picture, the retail sales of OTC phenylephrine products totaled approximately $1.8 billion in 2022, according to Tracy Pham, PharmD, the FDA's drug utilization analyst. In comparison, pseudoephedrine products tallied up to only about half a billion in sales in 2022.

While the 2020 CARES Act made changes that should speed along the administrative process of changing OTC monographs, it didn't change the standards for efficacy.

FDA started looking at the efficacy of oral phenylephrine in response to a 2007 citizen's petition and held an advisory committee meeting on the issue that same year. Notably, that panel had come to remarkably similar conclusions on efficacy and called for more data.

After that point, four studies were completed -- all negative:

• Two , both finding that 10- or 12-mg phenylephrine compared with placebo
• A of adults with seasonal allergic rhinitis, in which none of the groups randomized to fixed phenylephrine hydrochloride doses of 10 to 40 mg showed a statistically significant change from baseline in instantaneous or reflective nasal congestion scores compared with placebo
• A in which 30-mg modified-release tablets of phenylephrine hydrochloride didn't improve nasal congestion scores over baseline compared with placebo among adults with seasonal allergic rhinitis

FDA reviewers pointed to a litany of problems with the earlier studies upon which approval had been based, ranging from use of an unvalidated and non-standardized surrogate endpoint (nasal airway resistance measure instead of symptom scoring) to potentially fraudulent data.

"We see anomalies and huge variability in the results that cannot be easily explained," said Peter Starke, MD, the FDA's lead clinical reviewer. Further, "all were single-center studies and all had extremely small N's with no sample size calculations, no statistical analysis plans, and no controls for multiplicity ... The bottom line is that none of the original studies stand up to modern standards of study design or content."

But there appeared to be a deeper problem with the drug itself -- bioavailability.

Only phenylephrine itself is active as an alpha-1 adrenergic receptor agonist that can tackle the dilation of nasal blood vessels that is a major feature of nasal congestion; its metabolites are not. "Due to the extensive first pass metabolism, only a fraction of the orally administered dose is present as parent phenylephrine in the systemic circulation," Theresa Michele, MD, director of the FDA Office of Nonprescription Drugs, told the panel. "Because the blood vessel is the target organ and the site of action for phenylephrine, the plasma concentration of parent phenylephrine is clinically relevant. This peak plasma concentration is unlikely to achieve the pharmacologic effect in the nasal mucosa needed for nasal decongestion."

According to panelist Jennifer Le, PharmD, MAS, of the University of California San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences, "most clinicians and pharmacists would actually cite about 38% bioavailability."

That popular figure stems from a 1982 study with many problems. Not only did it analyze total phenylephrine rather than the active metabolite alone, but it also compared oral and IV formulations in different patients at different time points in a way that would have been expected to skew the numbers, said Yunzhao Ren, MD, PhD, an FDA presenter on the clinical pharmacology.

Cathy K. Gelotte, PhD, who conducted studies as a Johnson & Johnson employee on the pharmacokinetics of phenylephrine following the 2007 advisory committee meeting and has since retired, argued on behalf of CHPA against taking the 1% bioavailability emphasized by the FDA as too solid a number. "There are no reliable data to estimate the bioavailability," she said.

Even so, she added, "it is noteworthy that even when a drug has low bioavailability, it does not mean a lack of efficacy or minimal efficacy. We know that other factors have a role in determining efficacy, such as drug concentrations at the site of action. Like phenylephrine, many FDA-approved medicines have low to moderate bioavailability ... Some drugs, such as bisphosphonates that treat osteoporosis, are less than 1% bioavailable."

"Well, I disagree," countered Leslie Hendeles, PharmD, professor emeritus at the University of Florida in Gainesville, who was one of the petitioners who prompted the FDA to look at phenylephrine's monograph. "CHPA mentioned in their briefing that low oral bioavailability does not mean lack of efficacy ... I think at least for phenylephrine, it sure does."

The proof was the contemporary studies on efficacy, argued panelist Stephen C. Clement, MD, a pulmonologist at the University of Virginia School of Medicine and Inova Fairfax Hospital in Falls Church, Virginia. "The older data is completely not credible," he said, whereas the more recent trials with up to four times the labeled dose were "compelling" in that there was "no signal, none, zero" for reduction in nasal congestion.

Another point of contention by the CHPA was the study population of the newer trials in looking at allergic rhinitis rather than the older studies looking largely at people with the common cold, suggesting that those with more durable symptoms wouldn't have fit the temporary use called for in the monograph.

However, Michele of the FDA reaffirmed that the indication is for temporary relief of nasal congestion regardless of etiology, covering allergic rhinitis and the common cold alike, and noted that the contemporary studies are viewed by FDA as relevant.

While the panelists acknowledged the sentiment of CHPA's impassioned plea for an oral nasal decongestant to remain available to consumers when pharmacies are closed or inaccessible, they argued that it's better to inform patients of the many options for addressing cold and allergy symptoms that actually work.

"I think we clearly have better options in the over-the-counter space to help our patients," said panel chair Maria C. Coyle, PharmD, of Ohio State University College of Pharmacy in Columbus.

For the common cold, Hendeles pointed to nasal sprays -- including oxymetazoline and the nasal formulation of phenylephrine -- and oral pseudoephedrine as highly effective. For allergic rhinitis, nasal steroids are the most effective OTC agents, he noted, while the topical spray antihistamine azelastine (Astelin, Astepro) is effective against stuffiness because of the mast cell stabilizing effect, and pseudoephedrine works too, alone or in combination.

Regardless of the ease of obtaining alternatives, many panelists argued that having essentially a placebo available to patients is not doing them a service.

"When the drug doesn't work, it is a patient safety issue," said Le.

The medical toxicologist on the panel, Maryann Amirshahi, PharmD, MD, MPH, PhD, of Georgetown University and the National Capital Poison Center in Washington, D.C., also pointed to the additional unrecognized cost of unnecessary or delayed doctor or urgent care visits and risks associated with patients upping their dose beyond the labeled amount or adding on products or combination products in an attempt to get symptom relief.

Not to mention the "financial toxicity associated with an ineffective drug," added panelist William D. Figg, PharmD, MBA, of the National Cancer Institute in Bethesda, Maryland. "It's really amazing the amount of money being spent on an ineffective drug."

What's needed next after the FDA acts is education, the panel agreed.

Along with communicating with the public about what are safe and effective alternatives for symptom relief, pharmacists and physicians should likely be targeted, noted Le.

"This is going to change how the cold and cough aisle looks in the pharmacy," agreed panelist Susan J. Blalock, PhD, professor emeritus at the University of North Carolina at Chapel Hill School of Pharmacy. "FDA really shouldn't underestimate the communication challenges that are going to be associated with this, but that does not suggest in any way that they should not stay the course."

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