Researchers suggest FDA remove phenylephrine from the OTC drug monograph after their study found the ingredient, in doses up to 40mg every four hours, is no more effective than a placebo in alleviating nasal congestion from seasonal allergic rhinitis.

The study authors, led by Eli Meltzer, of the Allergy and Asthma Medical Group and Research Center in San Diego, say their research shows “an optimal dose of PE that is safe and produces clinically significant decongestion is still unknown.”

In 2007, FDA’s Nonprescription Drugs Advisory Committee said available evidence was “suggestive of efficacy” but committee members voted to recommend and FDA requested new studies on responses to higher doses of PE Also see "Data Support Phenylephrine Efficacy, But More Studies Needed – NDAC" - Pink Sheet, 17 December, 2007..

In an accompanying editorial also published in the September/October edition of the Journal of Allergy & Clinical Immunology: In Practice, authors of a 2006 citizen petition to FDA questioning PE’s efficacy point to the study as the evidence the agency said it wanted on PE at doses higher than the approved level of 10mg every four hours for temporary nasal congestion relief.

The editorial authors – Randy Hatton, a clinical professor of pharmacotherapy and translational research, and Leslie Hendeles, a professor of pharmacotherapy and translational research and professor of pediatrics at the University of Florida’s College of Pharmacy – say Meltzer and his colleagues “have responded to the FDA request for a dose-response study of the treatment of nasal congestion. The results of this study clearly indicate that PE is no more effective than placebo.”

They urge FDA to remove PE rom the OTC decongestant monograph. They note that consumers have other “safe, effective and available OTC” options, including nonprescription oral pseudoephedrine sold behind the counter, as well as nasal steroids for allergic rhinitis and topical decongestants for viral-induced nasal stuffiness.

Hatton and Hendeles say FDA should heed the study because its large sample size overcomes its few limitations, including not being completely double-blinded

Their petition asked FDA to withdraw OTC approval for PSE use by children under 12 and to raise the maximum dose to 25mg. They will submit another petition to FDA noting the latest study Also see "Citizen Petition On Phenylephrine Requests Pulling OTC Status For Children" - Pink Sheet, 12 February, 2007..

539 Subjects, 4 Dosages

The research team sought to answer FDA’s call for information on PE, which has widespread use as symptoms of seasonal or perennial allergic rhinitis are “highly prevalent” in the US at 11.9% to 30.2% of the adolescent and adult population, according to the study.

The multi-center, parallel, open-label trial randomized 539 adults with seasonal allergic rhinitis, through seven-day treatment of either PE or a placebo. Subjects received the drug in doses of 10, 20, 30 or 40mg every four hours.

The primary efficacy endpoint was the mean change from baseline over the treatment period in daily reflective nasal congestion score, notes the study. For the endpoint, “none of the active treatment groups had a statistically significant change from baseline in reflective nasal congestion scores compared with placebo,” the researchers say.

The mean changes from baseline in reflective nasal congestion, based on the subjects’ ratings, were: -0.460 for the 10mg group; -0.499 for 20mg; -0.508 for 30mg; and -0.428 for 40mg.

The figures were calculated from daily ratings recorded in the subjects’ diaries as the average of the morning and evening reflective nasal congestion score for the entire treatment period. The subjects rated the severity of congestion symptoms on a 4-point scale, from 0 for none to 3 for severe.

The researchers said doses up to 30mg were well-tolerated; dose-related increases in systolic blood pressure and decreases in heart rate on the first day of treatment were recorded but resolved during the trial.

The lack of efficacy of oral PE most likely is a result of poor bioavailability of the ingredient in oral form, say the researchers. Oral doses of 10mg to 40mg PE “would theoretically result in very low plasma concentrations and a short-lived time course of PE [active moiety] and therefore have minimal clinical and pressor effects,” they say.

Monograph Process Also Questioned

Hatton and Hendeles also suggest FDA to validate the entire OTC monograph process.

“The OTC monograph process served its usefulness in accomplishing a monumental task of reviewing thousands of OTC drugs for safety and efficacy,” they note, but add, “it should be recognized that the methods used had limitations and the science reviewed would often not meet today’s standards for good evidence.”

The use of PE increased dramatically after the final OTC nasal decongestant monograph was published in 1994, partly because the drug was the only “in front of the counter” OTC option at the time.

“The FDA appears to be motivated more by safety concerns than by ineffectiveness. Patients who seek an OTC remedy should get what they pay for: an effective and relatively safe alternative to a prescription drug,” the pharmacy professors say.

“At this point, we essentially have a system in which evidence must show that an OTC product is unsafe and/or does not work for it to be removed from the market.

FDA’s Center for Drug Evaluation and Research has acknowledged the current monograph system is “not workable” and looks to overhaul it with potential changes including a streamlined process to allow prompt resolution of existing tentative final monographs and issuing monographs by administrative order ([A#05140224012]).

The researchers suggest that “some of the transient efficacy observed with [PE] in the studies that supported the inclusion of PE” in the nasal decongestant monograph could be because the ingredient’s active moiety “peaks within 30 minutes and decays rapidly compared with total PE, which has a much broader profile.”

Meltzer noted that none of the studies FDA used in deciding to include PE in the monograph included more than 25 patients per group and each one used nasal airway resistance as the efficacy outcome, examined only to a maximum of 240 minutes after dosing.

On the other hand, most studies included in a separate meta-analysis also conducted for FDA’s review concluded that insufficient evidence supports oral PE as effective for OTC use as a decongestant at the 10mg dose.

And the latest study, the researchers said, “examined subjective nasal congestion responses over seven days of treatment and is thus likely to represent a more externally and ecologically valid measure of PE’s effectiveness.”

Study Stirs Doubts On Phenylephrine, Questions On Monograph Process

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