Practice Point: Oral phenylephrine, found in Sudafed PE, is not effective for nasal congestion.
EBM Pearl: Open-label trials lack blinding by definition and are at risk of bias towards the intervention. An otherwise well-done open-label trial that fails to find benefit is strong evidence that additional trials are not likely to demonstrate benefit either.
If you haven’t heard the news yet, oral formulations of phenylephrine are likely to be pulled from drugstore shelves in the U.S. soon. As of September, an FDA advisory committee concluded that oral formulations of phenylephrine are no longer GRASE (Generally Recognized As Safe and Effective) for the treatment of nasal congestion due to a growing body of evidence that the drug is no more effective than placebo. While the FDA has not yet made a final decision to order removal of the drug from their OTC monographs (which would affect labeling), the recommendation itself is making headlines and is likely already affecting sales. However, the lack of efficacy is not actually news from an evidence standpoint.
For starters, the body of evidence is small with very few trials of oral phenylephrine. This is likely because trials are usually designed (and funded) based on a hypothesis that something should work, often based on pathophysiology or pharmacokinetics. Well, we already knew that phenylephrine is inactivated in the gut and usually does not reach threshold bioavailability levels in the serum. It shouldn’t work in theory, and data show it doesn’t work in real life. The same is not true for intranasal or IV administration.
The best evidence we have is a 2015 open-label trial requested by the FDA that compared doses of oral phenylephrine ranging from 10 - 40 mg q4h for 7 days against placebo in 539 adults with seasonal allergic rhinitis, which failed to find a significant difference on a 4-point subjective improvement scale. And by no significant difference, we mean nearly identical results comparing all 4 doses to placebo, including nearly identical confidence intervals. Not even a hint of a trend towards significance in this open-label trial, and no suggestion that the study bears repeating. There are also several systematic reviews that have concluded that oral phenylephrine doesn’t work better than placebo, but many of the studies analyzed combined nasal and oral formulations of the drug which make it hard to separate out the magnitude of benefit (or lack thereof) from either alone.
From a logistical standpoint, it’s important to note that the FDA order theoretically may only apply to formulations where oral phenylephrine is the single active ingredient (such as Sudafed PE), but many OTC cold remedies are combination products (like Theraflu and NyQuil Severe Cold and Flu, which all contain phenylephrine). It is possible that oral phenylephrine has a synergistic or additive benefit for treating nasal congestion, even if monotherapy is ineffective. But we predict that a removal of the FDA’s OTC monograph will trigger widespread reformulations of OTC products within the industry. Oral phenylephrine saw an uptick in use since 2006 when the more effective pseudoephedrine was put behind drugstore counters due to safety concerns because it was being used to manufacture the street drug methamphetamine.
To be clear, safety concerns played no role in the recommendation to remove the FDA monograph for oral formulations of phenylephrine. It’s worth mentioning, however, that there can be safety issues when people don’t realize what they are taking. Drug companies rely on brand awareness but similarly named products, particularly combination products, can confuse the savviest consumer. Are you able to name each ingredient found in combination products such as Tylenol PM, Nyquil/Dayquil, or the many subtypes of Robitussin? Did you know that Sudafed contains pseudoephedrine, whereas Sudafed PE is phenylephrine?
So as we stand nose-to-nose with cold and flu season, what do you tell your patients with nasal congestion now? Well, intranasal formulations of phenylephrine still have some proven efficacy (provided they are used for no more than 3 consecutive days to avoid rebound rhinitis). Besides that, there is always the good ol’ neti pot, which is both the most effective and most unpleasant way to clear your nasal passages.
For more information, see the topic Viral Upper Respiratory Infection (URI) in Adults and Adolescents in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Katharine DeGeorge, MD, MS, Senior Deputy Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia. Edited by Alan Ehrlich, MD, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; Dan Randall, MD, Deputy Editor at DynaMed; Nicole Jensen, MD, Family Physician at WholeHealth Medical; Vincent Lemaitre, PhD, Medical Editor at DynaMed; Elham Razmpoosh, PhD, Postdoctoral fellow at McMaster University; and Sarah Hill, MSc, Medical Writer at DynaMed.