On November 7, 2024, the FDA introduced that it’s proposing to take away oral phenylephrine as a drug that’s permitted to be used in over-the-counter (OTC) drug merchandise. This can be a good choice for shoppers, as a result of phenylephrine is ineffective as an ingredient, and will by no means have been approved as a chilly treatment.
In in the present day’s submit I need to evaluation the lengthy path to rethink the FDA’s approval phenylephrine, and I’ll quote extensively from a few of my previous posts.
Colds are ubiquitous. Surprisingly, whereas there are actually dozens of cough and chilly cures on pharmacy cabinets, all of them use combos of the identical core handful of components. And the proof supporting a few of these merchandise could be very, very weak.
In 1976, the FDA concluded that three medicines had been protected and efficient for the therapy of nasal congestion attributable to colds, allergy symptoms, and sinusitis: phenylpropanolamine, pseudoephedrine, and phenylephrine. Nearly 25 years later, phenylpropanolamine was withdrawn from the market after use was related to strokes. Pseudoephedrine is an efficient decongestant that’s chemically similar to methamphetamine, a addictive and managed drug that’s topic to abuse. Pseudoephedrine doesn’t share the identical stimulant properties as methamphetamine, although it may possibly trigger jitteriness, gentle tremors, and insomnia. Nonetheless, as a result of pseudoephedrine can be utilized to manufacture methamphetamine, the over-the-counter sale of cough and chilly merchandise that include this ingredient aren’t permitted. Gross sales had been moved “behind the counter” within the US (it’s extra broadly out there in different international locations), with the requirement for the client to supply photograph identification and the requirement for the pharmacy to take care of a log of all gross sales, tracked by buyer identify and deal with. Not surprisingly, this put a damper on gross sales.
When pseudoephedrine was moved behind the counter, producers of cough and chilly merchandise both needed to settle for a a lot smaller marketplace for their pseudoephedrine-containing product, or reformulate.
Some firms reformulated their merchandise to include phenylephrine as an alternative, which was the final remaining non-prescription ingredient that the FDA permitted to be used to deal with congestion. Phenylephrine is from a class of medication referred to as alpha-1 agonists: they stimulate alpha-1 receptors which might be current all through the physique, together with the nasal passages. It’s used as a nasal spray, however extra generally in america as a oral product taken to deal with nasal congestion. There was an issue with FDA’s historic approval, nevertheless. There was little convincing proof phenylephrine, when taken orally, was truly efficient at decreasing congestion.
The case towards phenylephrine
Phenylephrine is a poorly-absorbed drug (i.e., it has low bioavailability). A lot of the drug is damaged down throughout the absorption course of, after passing via the liver. So there have been persistent questions if the drug was truly efficient.
In scientific trials, oral phenylephrine was in comparison with different decongestants in a randomized managed trial of 20 sufferers (method again in 1971) and located to be no more practical than placebo in decreasing lung airway resistance. One other trial in contrast single doses of 4 totally different decongestants towards placebo in 88 sufferers with congestion. It additionally discovered that phenylephrine was no more practical than placebo. In a evaluation of the info that the FDA had thought-about, that evaluation famous that for the 10mg dose, 4 research confirmed efficacy and 7 confirmed no distinction from placebo. The authors concluded {that a} systematic evaluation didn’t help the FDA’s choice. Different trials carried out since that point (like this one in 2009) are supportive of the conclusion that the 10mg dose is ineffective.
The truth that we’re counting on trials carried out within the 1970’s just about tells us what we have to learn about phenylephrine. Given how poorly it’s absorbed, there may be the query of whether or not merely giving larger doses will work – and it seems it might. Nonetheless, the 10mg dose is what’s out there in US cough and chilly merchandise – and one of the best proof exhibits that this drug is successfully a placebo at that dose. I’ll level out that the producers of the patron merchandise that include this ingredient proceed to write their very own papers suggesting that there’s proof of efficacy. Nonetheless, regardless of the massive gross sales of those merchandise, they haven’t produced any new randomized managed trials to indicate that they’re efficient.
The FDA’s re-review of the proof
In March 2023 I blogged about how the FDA had dedicated to re-review the proof for phenylephrine. The Non-Prescription Drug Advisory Committee met in September 2023. The committee concluded that the proof doesn’t help that phenylephrine is efficient as a nasal decongestant. Listed here are a number of of the important thing slides and conclusions from that evaluation:
Phenylephrine has motion towards alpha receptors – not its metabolites. Lower than 1% of the drug is definitely absorbed because the “energetic” drug. The utmost efficient blood focus (Cmax) is decrease than the EC50, which is half maximal efficient focus. Lastly, the drug is shortly eradicated from the physique. All of this implies that the drug won’t be clinically efficient. And right here is their backside line on the scientific knowledge, which received’t be shocking primarily based on the pharmacology of the drug within the physique:
The company commented that the info out there in the present day refutes a number of the assumptions made again within the 1970’s (pg. 55):
Lastly, the science has modified within the interim, and a full understanding of the scientific pharmacology of PE [phenylephrine] when administered orally was not appreciated on the time that the Panel issued its suggestions. We now know that along with PE having lower than 1% systemic bioavailability, the half-life can be considerably shorter than the unique 4-hour dosing interval. These knowledge weren’t out there to the Panel, nor was the know-how to completely assess oral bioavailability out there till across the flip of this century. Due to this fact, is it not shocking that the Panel thought-about the equivocal findings within the authentic research as ample to help a discovering of efficacy (and security) of PE 10 mg administered orally each 4 hours.
and, curiously (pg. 60),
After cautious evaluation, we be aware that there have been many methodological and statistical points with these research. We imagine that these points considerably restrict any judgement of a statistical “win”, and extra importantly a scientific “win”, for any of those research. Actually, if these research had been submitted to the Company in the present day all would at most be thought-about Part 1 research at finest. In consequence, we imagine that these research don’t stand as much as the brand new knowledge that at the moment are out there with regard to the efficacy of orally administered PE as a nasal decongestant.
In the end, the committee unanimously concluded that the proof doesn’t help that the advisable dosage of orally administered phenylephrine is efficient as a nasal decongestant. Importantly, no issues of safety with use of oral phenylephrine on the advisable dose had been recognized.
Your likelihood to remark
The FDA is at the moment inviting feedback on this proposed order. Choices out there to the FDA embrace a ultimate order eradicating oral phenylephrine from the “OTC monograph” which implies that cough and chilly merchandise would now not be permitted to include oral phenylephrine. The FDA says it might present producers with time to give you new formulations, or take away these merchandise from.
Does this restricts shopper alternative? Sure, however solely from being marketed merchandise that don’t work as labelled. Having oral phenylephrine out there with the FDA’s obvious approval, when it’s ineffective, presents a false alternative that preys on shopper ignorance. And a regulatory customary that ensures accredited product are each protected and efficient is in the end a win for shoppers. Whereas overdue, it’s to the FDA’s credit score that it’s keen to scrutinize, mirror, and act on the proof, even for a choice with a big, however constructive, shopper affect.