FDA’s Proposal to Remove Oral Phenylephrine from the OTC Monograph Isn’t a Surprise but What is Left “Over-the-Counter”?

On November 8, 2024, FDA issued a proposed order to remove the oral decongestant ingredient phenylephrine (including both phenylephrine hydrochloride and phenylephrine bitartrate) (collectively, PE) from the OTC monograph on the basis of a lack of effectiveness.  FDA also noted that it has concluded that no safety signal was identified for oral PE at doses permitted under the monograph. The action follows the September 2023 meeting of the Nonprescription Drug Advisory Committee (NDAC) at which the NDAC voted unanimously that the current scientific data do not support that the monograph dosage or oral PE is effective as a nasal decongestant and reached a consensus that the data presented did not support that a higher dose would be safe and effective.  As dictated by the process provided for in the 2020 CARES Act,  FDA announced issuance of the proposed order in a Federal Register notice and published the proposed order itself on FDA’s website.

Comments on the proposed order are due May 7, 2025.  Notably, the proposed order provides that the order, if finalized, will become effective one year after the final rule is published.  That means almost certainly no sooner than the second half of 2026.

Along with the proposed order, FDA issued as a supporting document the “Scientific Review Supporting Proposed Administrative Order” in which it describes the scientific data on the efficacy, pharmacology, and safety of oral PE underlying its determination to issue the proposed order. The review included the studies that supported the inclusion of PE in the original tentative final monograph and final monograph, as well as studies that became available after the monograph was finalized.  PE was proposed as Category I in the 1985 tentative final monograph and determined to be generally recognized as safe and effective as an oral decongestant when the final rule (monograph) was adopted in 1994.

Missing from FDA’s POA, generally, or the Background, Regulatory History for Oral Phenylephrine, is any discussion of why PE is so widely used.  As those of us of a certain age remember, prior to 2005/2006, pseudoephedrine was the decongestant of choice for OTC multi-symptom cold medicine. Along with phenylephrine hydrochloride and phenylephrine bitartrate, pseudoephedrine hydrochloride and pseudoephedrine sulfate (collectively, pseudoephedrine) were and are the only GRASE oral nasal decongestants active ingredients.  21 C.F.R. § 341.20(a); OTC Monograph M012: § M012.20.  Then, Congress passed, and the President signed the Combat Methamphetamine Epidemic Act of 2005. As FDA explained, “The act bans over-the-counter sales of cold medicines that contain the ingredient pseudoephedrine, which is commonly used to make methamphetamine.”  Going forward, “The sale of cold medicine containing pseudoephedrine is limited to behind the counter.”  In its response to FAQs, FDA further explained that the law affected combination products and touted that “In response to the issue of misuse of pseudoephedrine-containing products, many companies are voluntarily re-formulating their products . . ..”  That historical context does not change the question of whether PE is effective, but comparisons of the efficacy of PE to pseudoephedrine, see pp. 8, 10, and 14, without noting  the concerns about the misuse of pseudoephedrine that led to the behind the counter requirement does not present the full regulatory history.

Nor does it allow for full consideration of the implications of removing PE from the monograph and leaving pseudoephedrine as the only oral decongestant active ingredient that can be used in an OTC drug marketed under the monograph.  As reflected by the numerous combinations of antihistamine, antitussive, bronchodilator, expectorant, nasal decongestant, and internal analgesic-antipyretic ingredients permitted under the monograph, consumers seeking relief from the symptoms of the common cold are often looking for an OTC drug that can address multiple symptoms.  Although after finalization of the proposed monograph in its current form, these various permissible combinations would remain intact (the proposed order does not propose changes to these sections), the reality is that with the only remaining decongestant ingredients required to be kept behind-the-counter, no products containing an oral decongestant will be available on the shelf available for consideration and purchase by consumers.  Whether those products will be reformulated to include pseudoephedrine and then held behind-the-counter is unknown but seems unlikely as well as unwelcome from the standpoint of pharmacy management. While that may not be a reason to keep PE available, it does bear consideration in decision-making.

Most of the permissible combinations that include an oral decongestant can also be permissibly marketed as a combination without the oral decongestant ingredient. There is at least one permissible combination of four ingredients, however, that is not covered by the monograph except with an oral decongestant. Section M012.40 (n) provides for a permissible combination consisting of an antitussive, an expectorant, an oral nasal decongestant, and an analgesic-antipyretic. There is no permissible combination listed that covers the same product if the oral decongestant is removed.  This may simply be an oversight, but it highlights the unusual potential consequences of this particular proposed change to the monograph.