FDA Advisory Committee: Over-the-Counter Oral Phenylephrine Is Not Effective for Relief of Nasal Congestion

Phenylephrine is an old drug that temporarily constricts blood vessels. It is generally safe when taken in recommended doses, regardless of the route of administration (including nasally, orally or by injection into the vein). There is strong evidence that all non-oral forms of phenylephrine — including the nasal form for relief of nasal congestion — are effective. The effectiveness of the oral form of this drug has, however, been disputed for many years.[1],[2]

Oral phenylephrine is a component of several generic prescription drugs. It is more commonly available as part of many over-the-counter (OTC) products, often as a component of allergy, cold, flu or sinus medications (such as ADVIL ALLERGY AND CONGESTION RELIEF, DAYQUIL, SUDAFED PE, TYLENOL COLD + FLU SEVERE).

Despite uncertainty about its effectiveness, the Food and Drug Administration (FDA) has maintained the status of OTC oral phenylephrine as “Generally Recognized as Safe and Effectiveness” for temporary relief of nasal congestion (stuffiness).[3]

In Sept. 2023, an independent FDA nonprescription drugs advisory committee unanimously voted (16-0) that the current dosage of orally administered phenylephrine (10 milligrams [mg] every four hours) is not effective for relief of nasal congestion. The committee’s decision was based on consistent and compelling scientific evidence, presented by FDA scientists, demonstrating that oral phenylephrine does not work.

Testifying in the open public hearing during the advisory committee meeting, Public Citizen’s Health Research Group urged the committee to vote against the effectiveness of oral phenylephrine.[4] Subsequently, we issued a statement urging the FDA to prioritize prompt removal of all oral phenylephrine products from the U.S. market.[5]

Low bioavailability of oral phenylephrine

For many years, proponents of oral phenylephrine have claimed that the bioavailability of oral phenylephrine (the percentage of the drug that is completely available at its intended site of action, in this case the nasal tissues) is 38%.[6] This estimate, however, was based on erroneous outdated procedures, as clarified by the FDA’s pharmacological reviewer in a presentation to the advisory committee. This reviewer emphasized that the actual bioavailability of phenylephrine, when taken orally, is less than 1%, because the drug is largely destroyed in the gastrointestinal system. The reviewer also showed that the duration of action for oral phenylephrine is far shorter than its standard dosing interval (every four hours).

Faulty original effectiveness studies

Phenylephrine was first marketed at a time when the FDA required drug manufacturers to demonstrate only the safety of their products. In 1976, the agency first evaluated the effectiveness of oral phenylephrine. The FDA panel that evaluated 14 effectiveness studies of oral phenylephrine (hereafter referred to as the original studies) noted that these studies were “not strongly indicative of effectiveness.” The panel, however, recommended that the drug be categorized as safe and effective.

After analyzing the original studies using modern drug review methods, the FDA’s medical reviewer uncovered numerous methodological and statistical problems with them. Modern standards show that the original studies are equivalent to phase 1 studies. For example, these studies used an unreliable and indirect congestion endpoint called nasal airway resistance (which was measured based on airflow and air pressure in the nasal passages). The agency no longer accepts this endpoint. Additionally, almost all of the studies evaluated oral phenylephrine in subjects with the common cold (a highly variable nasal congestion condition) instead of allergic rhinitis (also known as hay fever), a condition with less variable congestion symptoms over time. Most of the original studies were small and were single-center crossover studies with significant problems. None of these studies adequately controlled for potential biases and most were neither peer reviewed nor published. Notably, two of the studies generated unbelievable “near textbook perfect results” that were not duplicated in other similar studies by the same sponsor, according to FDA scientists.

Recent well-designed effectiveness trials

FDA clinical reviewers analyzed publicly available data from three recent large clinical trials evaluating the effectiveness of oral phenylephrine for nasal congestion. Merck (formerly Schering Plough) conducted two of these trials in subjects with allergic rhinitis,[7],[8] and Johnson & Johnson conducted the third trial in subjects with the common cold.[9] All of these trials used clinically acceptable designs and reliable congestion symptom scores as endpoints (these scores are currently accepted endpoints).

These trials highlighted a lack of effectiveness of oral immediate-release phenylephrine at doses of up to 40 mg and extended-release doses of 30 mg. The FDA scientists therefore concluded that orally administered phenylephrine is ineffective at any dose that can be administered within a reasonable margin of safety. Notably, high doses of phenylephrine can cause high blood pressure.

Benefits of changing the status of oral phenylephrine

In 2022, people in the U.S. purchased at least 242 million products that contain oral phenylephrine, at a cost of at least $1.8 billion. Therefore, revoking the “Generally Recognized as Safe and Effective” status of oral phenylephrine and removing this ineffective drug from the U.S. market would save many people money.

Additional benefits would include a greater likelihood of using effective treatments for nasal congestion, when needed, avoiding potential allergic reactions or other adverse events caused by taking multiple products containing oral phenylephrine and decreasing the risk of accidentally exposing children to the drug.

What You Can Do

If you have nasal congestion, regardless of the cause, do not take drugs containing oral phenylephrine. Read the Drug Facts section of the product label to determine if an OTC drug contains phenylephrine.

If you need drug treatment for nasal congestion, talk to your clinician about other treatment options including nasal phenylephrine (AFRIN and other brand name products, as well as generics), nasal corticosteroids or intranasal saline products. Your doctor may also recommend short-term treatment with the behind-the-counter oral nasal decongestant drug pseudoephedrine (SUDOGEST and other brand name products, as well as generics), whose effectiveness has been established. However, do not use pseudoephedrine if you have heart or thyroid diseases, diabetes, high blood pressure or difficulty in urination due to an enlarged prostate.[10]
 

References

[1] 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.

[2] Eccles R. Substitution of phenylephrine for pseudoephedrine as a nasal decongestant. An illogical way to control methamphetamine abuse. Br J Clin Pharmacol. 2007;63(1):10-14.

[3] 21 C.F.R. § 341.20.

[4] Public Citizen. Testimony before the FDA’s nonprescription drugs advisory committee regarding the efficacy of oral phenylephrine as a nasal congestion. 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 September 29, 2023.

[5] Public Citizen. Press statement: FDA must prioritize removal of oral phenylephrine from shelves. September 15, 2023. https://www.citizen.org/news/fda-must-prioritize-removal-of-oral-phenylephrine-from-shelves/. Accessed September 29, 2023.

[6] 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 September 29, 2023.

[7] Meltzer EO, Ratner PH, McGraw T. Phenylephrine hydrochloride modified-release tablets for nasal congestion: a randomized, placebo-controlled trial in allergic rhinitis patients. Ann Allergy Asthma Immunol. 2016;116(1):66-71.

[8] Meltzer EO, Ratner PH, McGraw T. Oral phenylephrine HCl for nasal congestion in seasonal allergic rhinitis: A randomized, open-label, placebo-controlled study. J Allergy Clin Immunol Pr. 2015;3(5):702-708.

[9] Johnson & Johnson Consumer Inc. Randomized, double-blind, placebo-controlled, efficacy study of a new formulation of phenylephrine HCL in the common cold (PIER). Last updated June 2019. https://classic.clinicaltrials.gov/ct2/show/results/NCT03339726. Accessed September 29, 2023.

[10] Major Pharmaceuticals. Label: pseudoephedrine (SUDOGEST). March 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d46577aa-7fd7-2130-6ed6-4b3f7562491f. Accessed September 29, 2023.