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.