In September, a surprising publication by the U.S. Food and Drug Administration regarding the efficacy of oral phenylephrine as a nasal decongestant, caused a ruckus.¹ This publication would not come as a surprise to those following the past 15 years of efforts by the research teams examining phenylephrine. While they conclude that phenylephrine lacks efficacy, there remain important limitations to the scope of this action.

The GRASE Pathway

Phenylephrine has been available for oral administration within the FDA scope of non-prescription drugs under the designation Generally Recognized as Safe and Effective (GRASE). The GRASE pathway traces its origins back to the Kefauver-Harris Amendment signed into law by President Kennedy in 1962, which charged the FDA with establishing a process for reviewing the evidence surrounding classes of non-prescription pharmaceuticals.

Phenylephine, along with its cousin pseudoephedrine, was approved for use in a Tentative Final monograph in 1985, ultimately finalized in 1994. These included oral and nasal spray formulations of these two decongestants, but a third, phenylpropanolamine, was excluded due to safety concerns relating to hemorrhagic strokes.

Recently, the 2020 Coronavirus Aid, Relief, and Economic Security Act provided resources and processes to relieve some of the burden for review of these monographs. Changes to the administrative order process, reaffirming specific FDA authority to amend the prior monographs, ultimately paved the way for this most recent announcement. These changes are of note because data regarding limited efficacy were presented to the FDA in 2007 and 2015. Despite the cumulative weight of evidence, until now the feasibility of action was limited.

The original FDA review relied upon 14 studies, conducted primarily between 1959 and 1975. Most of these comprised a handful of participants and 10 of the 14 conducted by the original pharmaceutical manufacturer, the Sterling-Winthrop Research Institute. The outcomes measured in these studies usually entailed subjective nasal symptoms, but also “change in nasal airway resistance,” following single or repeated administration of oral phenylephrine. The studies demonstrated mixed positive and negative results while remaining difficult to assess due to sparse reporting of study methods. Phenylephrine was, however, clearly safe, and the original review leaned toward its inclusion in the monograph based on the class effect seen with pseudoephedrine and phenylpropanolamine.

Much has since changed, however, since these virtually prehistoric data. Primarily, and the most obviously damning concern, pertains to oral bioavailability for phenylephrine. An internal Schering-Plough study, first presented in 2007, described the metabolism and pharmacokinetics of a single oral dose of phenylephrine in 14 healthy volunteers. Compared to the previously estimated oral bioavailability of about 38 percent, this study found an oral bioavailability of less than one percent, with virtually all of the phenylephrine parent drug converted to three metabolites on hepatic first-pass metabolism. With respect to five alpha-adrenergic receptors upon which phenylephrine is biologically active, each of the three primary metabolites demonstrates no activity.

This is, effectively, where the story ends for phenylephrine. How could a medication be effective if converted to inactive metabolites immediately upon ingestion? The flaws in the original evidence base, the problematic nature of the methodology used, and these pharmacokinetic data were all presented over a decade ago. Incredulously, the FDA panel reviewing the data at the time voted, with 11 of 12 members voting “yes,” that the evidence for phenylephrine was still “suggestive of efficacy.” The panel noted further clinical data would be required to reverse the prevailing opinion.

Since the 2007 meeting, several clinical trials were performed. These studies, performed by the same Schering-Plough group, now in partnership with Merck, had two-fold intent. First, given the precarious pharmacokinetic data supporting the efficacy of phenylephrine in oral formulation, these studies tested the hypothesis clinically meaningful effects might be obtained from higher doses of the oral formulation. Second, as a much higher dose of phenylephrine is associated with iatrogenic hypertension, the trials aimed to confirm the safety of a higher dosage.

The first study, published in 2015, was a simple placebo-controlled trial of a 30mg modified-release phenylephrine tablet taken every 12 hours for seven days.² With a primary outcome of “daily reflective nasal congestion score,” there was no difference in the primary outcome.

Each group improved a small amount across the length of the trial, consistent with a placebo effect. The second trial, published in 2016, was a placebo-controlled dose-ranging trial, with immediate-release phenylephrine doses ranging from 10 to 40mg.³ In this latter trial, again, improvements in the primary outcome directly mirrored placebo, with no differences between any of the doses.

Clearly, now, both pharmacokinetic and clinical data confirm phenylephrine-containing oral preparations are of no value. The question remains: what obstacle prevents the removal of phenylephrine from the FDA decongestant monograph? The simple answer is economic. In 2022, at least 250 million individual packages of over-the-counter phenylephrine-containing products were sold in the United States alone. These sales easily exceed two billion dollars (USD) in annual value, a non-trivial dent in the direct-to-consumer pharmaceutical industry. The ramifications go beyond simply sales, as these findings affect the entire manufacturing and supply chain. There remains stock of these medicines on the shelf, in warehouses, and presently undergoing manufacture. The authors of the review report note these findings ought to be disseminated with some delicacy, and phenylephrine transitioned off the monograph.

An important note is that these findings only pertain to the oral preparation of phenylephrine. The intranasal spray bypasses first-pass hepatic metabolism by virtue of the route of delivery, and ought still be considered efficacious. Pseudoephedrine does not possess the same hepatic metabolism as phenylephrine and retains demonstrable beneficial clinical effects. However, access to pseudoephedrine has been restricted since the Combat Methamphetamine Epidemic Act of 2005, the enactment of which resulted in phenylephrine’s rapid rise in consumption.

The means of widespread notification of the lack of efficacy of oral phenylephrine, primarily through lay media coverage, was likely not the intended effect of the FDA advisory report. However, the recommendations for its removal from the monograph are now widely known. Despite the barriers to access, pseudoephedrine is presently the only efficacious oral over-the-counter decongestant available, physicians should educate patients to this effect.

Dr. Radecki (@emlitofnote) i s an emergency physician and informatician with Christchurch Hospital in Christchurch, New Zealand. He is the Annals of Emergency Medicine podcast co-host and Journal Club editor.

References

1. U.S. Food and Drug Administration. NDAC briefing document: oral phenylephrine in the CCABA monograph. Efficacy of oral phenylephrine as a nasal decongestant: Nonprescription drug advisory committee meeting September 11 and 12, 2023. FDA website. Accessed November 29, 2023.
2. Meltzer EO, Ratner PH, McGraw T. Phenylephrine hydrochloride modified-release tablets for nasal congestion: a randomized, placebo-controlled trial in allergic rhinitis patients. Ann Allergy Asthma Immunol. 2016;116(1):66-71.
3. Meltzer EO, Ratner PH, McGraw T. Oral phenylephrine HCl for nasal congestion in seasonal allergic rhinitis: a randomized, open-label, placebo-controlled study. J Allergy Clin Immunol Pract. 2015;3(5):702-708.