In 2005, federal law compelled retailers nationwide to move pseudoephedrine, sold as Sudafed, from over-the-counter (OTC) to behind it, so as to combat its use in making illicit methamphetamine. This move changed the formulas of cough and cold medicines in the U.S.. It also led me and my colleague Leslie Hendeles to prove that pseudoephedrine’s replacement, oral phenylephrine, was ineffective as a decongestant.
We petitioned the Food and Drug Administration (FDA) twice, yet it took the agency more than a decade and a half to act. on our findings In September, an agency advisory panel finally agreed with our conclusion that this compound did little to quell congestion and recommended that products containing it be pulled from shelves. If FDA acts on this recommendation, oral phenylephrine could be the first OTC drug approved under the agency’s “monograph” process to be discontinued. But in the meantime, millions of people have been trusting the FDA’s OTC regulatory process to ensure that medications work but instead, have been wasting money for nearly two decades on ones that don’t.
FDA regulation of OTC medications with older ingredients needs to change. In the process of figuring out that oral phenylephrine doesn’t work, we’ve also spotlighted a loophole in FDA’s regulatory process that must be fixed so that people can trust not just recent over-the-counter approvals, but historic ones as well.
Once pseudoephedrine was moved behind the counter in the 2000s, that left phenylephrine as the only remaining oral decongestant sold on the shelves of pharmacies, grocery stores, convenience stores and other retail outlets. Makers of oral decongestants and cold remedies reformulated their products to contain phenylephrine, sold as Sudafed PE, among others, instead of pseudoephedrine.
Phenylephrine products went from few to many.
I learned that customers did not recognize that these products had been reformulated. Consumers complained to their pharmacists when Sudafed PE did not work like the “old” Sudafed. Those pharmacists contacted me at the University of Florida (UF) drug information service, a laboratory for doctor of pharmacy students that teaches them how to receive, research and answer drug-related questions. They asked us: Does oral phenylephrine work? If so, what is the correct dose?
My students and I searched the literature. We located an article by Hendeles, published in 1993. He was reporting on well-done but unpublished studies from before 1971 by Hylan Bickerman of Columbia University that showed phenylpropanolamine, a common oral decongestant at the time, worked, as did another compound called pseudoephedrine, but oral phenylephrine did not. Hendeles’ paper did not get much attention since phenylephrine wasn’t widely used in the 1990s. However, roughly 10 years later, it was suddenly important.
I contacted Hendeles and he and I decided to get to the bottom of whether oral phenylephrine worked. Before the FDA required that drugs had to be proven effective, it determined whether OTC drugs were effective through expert panels that reviewed existing data. These OTC monographs establish what older OTC ingredients can be marketed without FDA approval.
The oral decongestant monograph panel reviewed a few published studies and multiple unpublished studies for phenylephrine. Of the unpublished studies, only four studies showed oral phenylephrine was effective, while seven showed it was no better than placebo. We requested copies of all evidence used by the nasal decongestant review panel via a Freedom of Information Act request and performed a systematic review and meta-analysis ourselves.
Our findings validated the concerns from the Bickerman study and the pharmacists’ calls to UF. Interestingly, we found that one commercial laboratory gave strikingly positive results for oral phenylephrine’s efficacy. The low variability of the data, a lack of increasing effect with an increased dose and the lack of a placebo response prompted us to look at the data more closely. A statistical analysis of this laboratory’s data suggested integrity issues; normal variation of measurements should have a typical distribution from zero to nine for the last digit, but here nearly a quarter of all observations ended with a five. Such anomalies occur when data are falsified. We were confident then that oral phenylephrine did not work.
We then naively contacted the FDA to inform them of what we had found. They were not interested. Oral phenylephrine was not harming anyone, so they saw no need to limit sales. FDA uses a risk-based approach to regulatory actions because they have limited resources, so the relative safety of oral phenylephrine relegated it to the back burner despite its ineffectiveness. So, we took the political route, contacting then-congressman Henry Waxman, whose committee at the time had FDA oversight. Waxman’s office wrote four letters imploring the agency to reconsider oral phenylephrine’s effectiveness. We also submitted a citizen’s petition to the FDA in early 2007.
Finally, in December 2007, more than a year after we first discovered oral phenylephrine didn’t work, the FDA somewhat begrudgingly formed a Nonprescription Drug Advisory Committee meeting to review the compound’s effectiveness.
The FDA has multiple regulatory processes for different types of medicinal compounds. People are perhaps most familiar with the New Drug Application process, which leads to clinical trials for prescription drug approvals. However, many OTC or nonprescription drugs are regulated differently. In fact, a law passed in 1951, the Durham-Humphrey Amendment to the 1938 Food, Drug, and Cosmetic Act, created the categories of prescription and nonprescription drugs. In 1962, the act was amended again so that drugs had to be shown to be effective, hence the requirement for well-done clinical trials.
But what about the drugs that were approved before 1962? This is the loophole that some OTC drugs fall through. For prescription drugs, FDA tried to address pre-1962 approvals through a review of over 3,000 prescription drugs. Most of those drugs have now been reviewed and addressed, but there are still unapproved prescription drugs on the market today, such as an extended-release form of oral nitroglycerin.
For nonprescription drugs, FDA established the OTC monograph process 10 years after the 1962 amendment to the Food, Drug, and Cosmetic Act, which required products not proven effective to be reconsidered. FDA formed advisory panels grouping hundreds of ingredients into 26 categories based on the products’ uses. After gathering all available information, both published and unpublished, from manufacturers, the advisory panels issued final reports to FDA about whether these ingredients were GRASE (generally recognized as safe and effective), not GRASE, or inconclusive. GRASE ingredients can be used in nonprescription drugs without FDA approval if the use matches the monograph.
The monograph for OTC nasal decongestants started in 1976 and listed three effective oral decongestants: phenylephrine, phenylpropanolamine, and pseudoephedrine. The review took 18 years, and the final monograph was released in 1994. Phenylpropanolamine was removed from the market in the 2000s, because it was associated with strokes. It was effective—just not safe.
At the time, most OTC nasal decongestants contained either phenylpropanolamine or pseudoephedrine—few contained oral phenylephrine, perhaps because manufacturers privately questioned its effectiveness. FDA’s charge for the 2007 Nonprescription Drug Advisory Committee was to determine whether phenylephrine in a 10-mg immediate release formulation may be effective when dosed every [four] hours for symptomatic relief of nasal congestion. Although most of the committee voted that there was some evidence that oral phenylephrine may be effective, they recognized the limitations of the available evidence. They asked for new data on the absorption and efficacy of oral phenylephrine using more modern standards.
Schering-Plough, the maker of Claritin D (loratadine and pseudoephedrine), was already studying phenylephrine as an alternative oral decongestant. In addition to funding two studies that found phenylephrine was no better than placebo when patients with seasonal allergies were exposed to allergens (grass and ragweed) in a controlled chamber, they funded additional research.
The oral absorption of phenylephrine is erratic. Perhaps that is why it was not used as an oral decongestant until it was the only choice. It had long been known that enzymes in the gut lining metabolized oral phenylephrine to inactive metabolites, reducing the amount of the active compound that could enter the bloodstream. The most cited study found that an oral dose of phenylephrine had an absorption rate of 38 percent of an oral dose of phenylephrine, but this study measured more than just the compound’s active form. Later studies with more sensitive tests found that less than 1 percent of oral phenylephrine enters the bloodstream in an active form. Phenylephrine causes blood vessels to constrict, so if there isn’t enough of the active compound in the bloodstream, it won’t reduce the swelling of nasal blood vessels to aid in reducing nasal congestion.
After the 2007 FDA advisory committee suggested better data on phenylephrine’s efficacy were needed, Schering-Plough funded Eli Meltzer to do two studies showing oral phenylephrine was no better than placebo—even when using up to four times the approved dosage.
Based on Meltzer’s research, we filed a second citizen’s petition in 2015. The science was clear: oral phenylephrine does not work. Then, we waited. Nothing seemed to happen at FDA. We wrote an academic commentary in 2022 asking, “Why is Oral Phenylephrine on the Market After Compelling Evidence of Its Ineffectiveness as a Decongestant?” We did not know that with a new administration and new FDA Commissioner, the agency had already started a thorough review of all the available data.
In 2023, 16 external experts on the second Nonprescription Drug Advisory Committee looked at all the evidence compiled by FDA staff, heard manufacturers’ arguments that oral phenylephrine was effective, and heard from experts like me who argued that oral phenylephrine was ineffective. In the end, they concluded that oral phenylephrine is not GRASE. A final ruling on whether these decongestants can be sold will take time. Hopefully, science will prevail.
We’ve learned from this experience that the monograph process for OTC drugs approved before 1962 needs to be reexamined. Other nonprescription drugs like guaifenesin (sold in Mucinex and Robitussin), dextromethorphan (sold in Robitussin DM), and antihistamines for a cold like chlorpheniramine likely don’t help with coughs and colds. They are usually not dangerous, but their effects are likely to be a placebo response; more modern research is needed.
The oral phenylephrine example shows that FDA needs more funding to look at these old drugs. We need public funds to support independent researchers who want to examine these products objectively. The government should be able to spend millions to save consumers billions on ineffective products. Companies that market these products have no incentive to prove they don’t work. Nonprescription drugs must be effective—not just safe.
Considering all the confusion around these drugs, remember pharmacists receive considerable education on OTC drugs—more than any other health care profession. Ask your pharmacist when you have questions about which OTC products to choose. And then ask your local congressional representatives to support modern scientific reviews of these old OTC products. Your pocketbook, if not your respiratory health, will see the rewards.
This is an opinion and analysis article, and the views expressed by the author or authors are not necessarily those of Scientific American.
