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Phenylephrine: The story of  an ineffective nasal decongestant
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Phenylephrine: The story of an ineffective nasal decongestant

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Image of phenylephrine molecule.

Mary Warner

On September 12, 2023, the FDA Nonprescription Drugs Advisory Committee unanimously agreed that oral phenylephrine is ineffective, setting the stage for FDA to require its removal from hundreds of nonprescription products. But why did it take so long for a decongestant that patients claimed didn’t work to be brought to the committee for evaluation?

Leslie Hendeles, PharmD, and Randy Hatton, PharmD, faculty members at the University of Florida College of Pharmacy, have been advocating for the removal of oral phenylephrine from the market for many years. In a 1993 article in Pharmacotherapy, Hendeles wrote that “phenylephrine is subject to first-pass metabolism and therefore is not bioavailable in currently recommended doses.” Ten years later, Hatton noticed an increase in calls to the University of Florida Drug Information and Pharmacy Resource Center hotline asking about the efficacy of phenylephrine. Pharmacists were asking why patients consistently claimed that phenylephrine didn’t work.

Those calls led him to Hendeles and the two began a collaboration that eventually included two Citizen Petitions (endorsed by APhA), based upon research to determine if phenylephrine was effective at the dosage available over the counter, and a Freedom of Information Act request for unpublished data, as well as multiple studies that confirmed their skepticism about phenylephrine’s effectiveness.

Market forces

Until early 2006, when the Combat Methamphetamine Epidemic Act (CMEA) forced pseudoephedrine behind the pharmacy counter, phenylephrine was in very few products, as pseudoephedrine dominated the market. But pseudoephedrine is a primary ingredient used by illegal methamphetamine synthesis labs, and when the CMEA forced restriction of pseudoephedrine sales, requiring identification and maximum purchase amounts, pharmaceutical manufacturers turned to their only other option to not lose OTC  sales: phenylephrine.

Hendeles and Hatton convinced U.S. Representative Henry Waxman of California to support their efforts to remove phenylephrine from OTC medications and Waxman wrote four letters during late 2006 to FDA’s acting commissioner asking for “a thorough scientific review of phenylephrine’s effectiveness at the monograph dose of 10 mg.” FDA replied by restating the findings of its 1976 decision that both pseudoephedrine and phenylephrine are generally recognized as safe and effective (GRASE). Phenylephrine is now in hundreds of nonprescription medications, from Sudafed PE, to Nyquil, to Benadryl Cold, to Tylenol Cough and Cold.

The two professors then filed a Citizen Petition requesting the agency to determine if doses higher than 10 mg were effective and to remove approval for children <12 years since there were no data on safety or efficacy in this age group.  Congressman Waxman’s persistence led to an FDA advisory hearing in 2007 where both Hatton and Hendeles made presentations. The Consumer Healthcare Products Association, the group representing the manufacturers of nonprescription medication, maintained that phenylephrine worked, likely because they had no alternative decongestants to use in their formulations. However, representatives for Schering Plough—the maker of Claritin-D at the time, which contained pseudoephedrine—told the advisory group that they had studied phenylephrine and found it ineffective. The advisory committee voted 11 to 1 that “evidence is supportive” that phenylephrine “may be effective,” and called for more research on higher doses, as the petition requested.

Proving the point

According to Hatton, the systematic review and meta-analysis that he and his colleagues published in Annals of Pharmacotherapy in 2007 revealed the limitations of the data that FDA used decades ago to designate phenylephrine as effective. The study included unpublished data from the 1960s and 1970s that had not undergone peer review. “The FDA review did not apply meta-analytic methods and focused primarily on expert opinion in the interpretation of conflicting data. Thus, phenylephrine lacks adequate data to support its efficacy at the FDA-approved dose,” noted Hatton and Hendeles in the article.

“My resident and I reviewed every study on phenylephrine, revealing much about the data quality and phenylephrine’s effectiveness,” said Hatton. “The study also led to a forensic analysis of one laboratory with the most dominant positive data [Elizabeth Biochemical], which suggested a methodologic problem at that lab—or worse, possible fraud. Without that suspect data, the data used by FDA in 1976 to approve phenylephrine would have definitely shown it to be ineffective.”

Finally, after pandemic legislation expanded FDA staffing and changed the process for approving nonprescription drugs to align more closely with those for prescription drugs, FDA produced an 89-page review of phenylephrine that not only confirmed Hendeles and Hatton’s earlier conclusions, but also noted the apparent bias in some of the original data that led to the initial approval.

The briefing document

FDA noted in the introduction to the review (i.e., the briefing document for the committee) that the study includes all available clinical pharmacology and clinical data. This includes significant new data that were not available at the time the original decision was made to include oral phenylephrine in the OTC monograph, as well as a detailed evaluation of each of the original studies that supported that decision. The briefing document further stated that “we have now come to the initial conclusion that orally administered phenylephrine is not effective as a nasal decongestant at the monographed dosage (10 mg of PE hydrochloride every 4 hours) as well as at doses up to 40 mg (dosed every 4 hours).”

Finally, FDA stated that there were a number of potential benefits to changing the GRASE status of oral phenylephrine, including avoiding the unnecessary costs and delay in care of taking a drug that has no benefit, avoiding the risks of potential allergic reactions or other adverse effects related to use of phenylephrine in combination products, avoiding the inherent risks (especially for combination therapies) of taking more medication in order to seek some benefit, avoiding the risks of medication use in children, lowering overall health care costs, and avoiding missed opportunities for use of more effective treatments (including seeing a doctor if needed). However, a significant impact on industry would be inevitable, FDA noted, and could lead to significant supply chain issues.

Vote dissent

Although the committee’s vote was unanimous, there have been some vocal disagreements with the outcome. Notably, former FDA commissioner Scott Gottlieb said of the vote, “This is a shame. At FDA we looked closely at this question in 2005 when pseudoephedrine was forced behind the counter, concluding phenylephrine was active. Now cold sufferers may have even fewer accessible options, driving up health care costs.” Gottlieb has close ties to industry, which may have played a role in his comments. And, said Hatton, “it appears his perspective is that it is okay to have ineffective drugs on the market because the market will sort it out. This contradicts the 1962 Kefauver-Harris Amendments to the Food, Drug and Cosmetic Act, which requires all drugs, prescription and nonprescription, to be safe and effective.” Gottlieb may also have been unaware of the comprehensive investigation conducted by the FDA team, added Hendeles.

Pharmaceutical manufacturers are also pushing back on any action that would remove phenylephrine from the market, saying that it’s safe, even if it isn’t as effective as previously claimed. The Consumer Healthcare Products Association issued a statement defending the use of phenylephrine and stating that “it is important to integrate new data within the broader framework of existing evidence rather than viewing it as a complete substitute for the previous body of evidence,” clearly taking issue with FDA’s recent evaluation of earlier data.

But it’s unlikely that anything will happen anytime soon. FDA must still review the panel’s recommendation and will almost certainly solicit public comments and give manufacturers time to adjust their formulas to remove phenylephrine. Oral phenylephrine is safe, though one of the Advisory Committee members expressed concern that patients taking products containing multiple ingredients may increase the dose or repeat the dose and get toxicity from one of the other ingredients, such as acetaminophen that can cause liver failure. Patients should be aware that they should not expect relief from these drugs.

Future developments

The decision by FDA (and confirmed by the Nonprescription Drugs Advisory Committee) that oral phenylephrine is ineffective as a decongestant has been a long time coming (close to 40 years), but it’s not the end of the discussion. FDA has not yet directed that oral products containing phenylephrine be removed from store shelves, but on October 20, 2023, CVS Health said it would remove all oral products that contain phenylephrine as the only ingredient from its stores. Over the coming months, or even years, there will likely be much debate about how to move forward.

However, what is clear is that Hendeles and Hatton will remain a part of the discussion. “The FDA Briefing Document was a joy to read,” said Hendeles, who added “Nothing was as exciting and exhilarating as the vote.” Hatton added, “We feel vindicated for something that we worked on for a long time. But it’s not over.” ■

Alternatives to phenylephrine

Oral phenylephrine is ineffective because 99% of each dose is inactivated by first-pass metabolism, allowing insufficient concentrations to reach systemic circulation. However, phenylephrine delivered via a nasal spray is effective. Other alternatives for nasal stuffiness include

  • Oxymetazoline nasal spray
  • Oral pseudoephedrine
  • Nasal steroids (fluticasone, mometasone, triamcinolone)
  • Nasal antihistamine/mast cell stabilizer (azelastine)

Patients should understand that phenylephrine and oxymetazoline should only be used for stuffiness caused by a cold and not for allergic rhinitis. In contrast, neither nasal steroids nor azelastine are effective for virus-induced stuffiness but are very effective for nasal stuffiness associated with allergies.



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