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.