Comments on the FDA’s Proposed Order Regarding Removal of Oral Phenylephrine
Comments Regarding the Food and Drug Administration’s Notice of Proposed Administrative Order To Remove Oral Phenylephrine Products As Nasal Decongestants Due to Their Ineffectiveness
(FDA-2024-N-4734-0001)
Submitted electronically
Public Citizen submits the below comments in strong support of the Food and Drug Administration’s (FDA’s) notice of proposed administrative order (proposed order) OTC000036, “Amending Over-the-Counter [OTC] Monograph M012: Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug Products for Over-the-Counter Human Use.”[1] Published in the Federal Register on November 8, 2024, this proposed order, if finalized, would remove orally administered phenylephrine hydrochloride and effervescent phenylephrine bitartrate as nasal-decongestant active ingredients from the OTC monograph M012 because they are ineffective.
Public Citizen is a research-based nonprofit consumer advocacy organization with more than 500,000 members and supporters nationwide. We have advocated for the removal of ineffective and unsafe drugs from the U.S. market since 1971. We do not have any financial conflicts of interest and do not accept government or industry funding.
We are deeply concerned that, for almost fifty years, the FDA has maintained the “generally recognized as safe and effective” (GRASE) status of oral phenylephrine for nasal congestion in the OTC monograph for cold, cough, allergy, bronchodilator, and antiasthmatic drugs despite compelling research evidence against its effectiveness. Although there are no safety concerns for oral phenylephrine products, U.S. consumers would not be served by leaving such placebo-like products on the market.[2]
With more than 700 unique oral phenylephrine-containing products (such as DayQuil, Sudafed PE, other brands, and generics) on shelves as of 2021, the drug has become the most common oral decongestant in the United States.[3] Prior to 2006, the drug was not commonly used.
The surge in phenylephrine products occurred after the FDA revoked the GRASE status of phenylpropanolamine in 2000 due to its risk of hemorrhagic strokes and moved pseudoephedrine (Sudafed and generics) behind the counter in 2006 to decrease its illicit use to produce methamphetamine. These FDA actions left OTC manufacturers with no GRASE-designated oral nasal-congestion drugs other than phenylephrine, an option that they have pursued fully.
Even before oral phenylephrine became the only available oral OTC decongestant, there was consistent evidence challenging its efficacy. For example, a well-conducted 1971 study at Columbia University demonstrated that oral phenylephrine (at doses of 10, 20, or 40 milligrams [mg]) is no better than placebo on nasal airway resistance (NAR) over a four-hour period.[4] In contrast, the study found that oral pseudoephedrine and phenylpropanolamine were effective in decreasing NAR.
In 2006 Dr. Ronald Eccles, a Cardiff University professor, wrote in an article published in the British Journal of Clinical Pharmacology that “[t]here is support in the literature for the efficacy of [pseudoephedrine] as an orally administered nasal decongestant [sic]… but no support [exists] for the efficacy of oral [phenylephrine].”[5]
In 2007 a meta-analysis was conducted by researchers at the University of Florida (UF) who evaluated eight unpublished efficacy studies for the 10-mg dose (the monographed dose) of oral phenylephrine in reducing NAR in participants with nasal congestion.[6] These studies were conducted between 1959 and 1975, cited in the Federal Register and obtained by the researchers through a Freedom of Information Act request to the FDA. Contrary to common assumptions, the meta-analysis did not find oral phenylephrine to be efficacious. Therefore, in 2015 two of the UF researchers petitioned the FDA to remove oral phenylephrine from the OTC monograph.[7]
In September 2023 an FDA Nonprescription Drugs Advisory Committee unanimously voted (16-0) that the current dosage of orally administered phenylephrine is not effective for nasal congestion relief.[8] The committee’s decision was based on consistent and compelling scientific evidence presented by FDA scientists that oral phenylephrine does not work.
The FDA scientists conducted a new analysis of the original efficacy studies supporting the GRASE status of oral phenylephrine. The scientists uncovered many methodological and statistical problems that make these studies equivalent to phase 1 studies by current standards.[9] Notably, two of these original studies generated unbelievable “near textbook perfect results” that were not duplicated in other similar studies by the same sponsor, according to the agency’s scientists.
Furthermore, FDA clinical scientists examined publicly available data from three adequately controlled, industry-sponsored clinical trials conducted since a 2007 Nonprescription Drugs Advisory Committee meeting that discussed the efficacy and safety of oral phenylephrine. These trials represent the largest and most well-designed available studies evaluating the efficacy of oral phenylephrine for nasal congestion. The trials illustrated the lack of efficacy of oral immediate-release phenylephrine at doses up to 40 mg and extended-release doses of 30 mg.
In addition, FDA clinical pharmacologists have confirmed that based on updated technological methods, the bioavailability of phenylephrine when taken orally is less than 1% because the drug is broken down during absorption. These scientists also have concluded that the half-life of oral phenylephrine is significantly shorter than the current four-hour dosing interval.
Therefore, Public Citizen urges the FDA to promptly move forward with finalizing its proposed order to revoke the GRASE designation of oral phenylephrine for relief of nasal congestion and remove it from the OTC monograph.
The decades-long availability of oral phenylephrine products on shelves has been a huge disservice to the American people because it had misled countless patients and delayed their access to effective relief of nasal congestion while wastefully enabling drug companies to profiteer from these placebo drugs.
In the meantime, to allay concerns from the public, the FDA should inform consumers about the merits of removing oral phenylephrine from the market through a public messaging campaign. Until multi-ingredient allergy and cold OTC products that contain phenylephrine are reformulated, patients can utilize prescription oral pseudoephedrine as an effective alternative. Those with contraindications for pseudoephedrine can use intranasal phenylephrine (Neo-Synephrine, other brands, and generics) or oxymetazoline (Afrin, other bands, and generics).
The oral-phenylephrine saga is unacceptably reminiscent of the snake oil era. Therefore, the FDA should seek to uphold the statutory standards of efficacy and safety by expanding its nonprescription drug review process to include evidence supporting other potentially ineffective or unsafe products that have been grandfathered into OTC monographs.
Thank you for your consideration of our comments regarding this important issue.
Sincerely,
Azza AbuDagga, M.H.A., Ph.D.
Health Services Researcher
Public Citizen’s Health Research Group
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[1] Food and Drug Administration. Proposed administrative order (OTC000036). Amending over-the-counter monograph M012: Cold, cough, allergy, bronchodilator, and antiasthmatic drug products for over-the-Counter human use. November 8, 2024. https://www.regulations.gov/document/FDA-2024-N-4734-0001. Accessed May 6, 2025.
[2] Public Citizen. Testimony before the FDA’s nonprescription drugs advisory committee regarding the efficacy of oral phenylephrine as a nasal congesant. September 11, 2023. https://www.citizen.org/article/testimony-before-the-fdas-nonprescription-drugs-advisory-committee-regarding-the-efficacy-of-oral-phenylephrine-as-a-nasal-congestion/. Accessed May 6, 2025.
[3] Anderson TS, Suda KJ, et al. Trends in phenylephrine and pseudoephedrine sales in the US. JAMA. 2024;331(9):796-798.
[4] Bickerman HA. Current research methodology in the evaluation of proprietary medicines. Physiologic and pharmacologic studies on nasal airway resistance (RN). 1971. As cited in the 2023 FDA briefing document (see ref. # 9 below).
[5] Eccles R. Substitution of phenylephrine for pseudoephedrine as a nasal decongeststant. An illogical way to control methamphetamine abuse. Br J Clin Pharmacol. 2006;63(1):10-14.
[6] Hatton RC, Winterstein AG, McKelvey RP, et al. Efficacy and safety of oral phenylephrine: Systematic review and meta-analysis. Ann Pharmacother. 2007;41(3):381-390.
[7] Hendeles L, Hatton RC. Citizen’s petition 2015-P-4131-0001 requesting a final rule removing oral phenylephrine from the final monograph for OTC nasal decongestant products. November 13, 2015. https://www.regulations.gov/document/FDA-2015-P-4131-0001. Accessed May 6, 2025.
[8] FDA advisory committee: Over-the-counter oral phenylephrine is not effective for relief of nasal congestion. Worst Pills, Best Pills News. December 2023. https://www.worstpills.org/newsletters/view/1571. Accessed May 6, 2025.
[9] Food and Drug Administration. FDA briefing document, efficacy of oral phenylephrine as a nasal congestion; Nonprescription Drug Advisory Committee Meeting. September 11 and 12, 2023. https://www.fda.gov/media/171915/download. Accessed May 6, 2025.