A citizen petition asks FDA to withdraw OTC approval for phenylephrine use by children under 12 years old and to raise the maximum dose to 25 mg, but also recommends more research to determine the most effective dosage level.

In a petition submitted Feb. 1, University of Florida pharmacy professors Leslie Hendeles, Pharm.D., and Randy C. Hatton, Pharm.D., say, "Additional studies should be required to validate that a 25 mg dose would be more efficacious than a 10 mg dose of phenylephrine given every four hours, and as safe."

Hendeles, who also is a pediatrics professor, and Hatton submitted the petition following the Jan. 30 publication of a meta-analysis they led.

Their meta-analysis included eight studies with 138 patients examining PE efficacy at the 10 mg dose; the document references other studies considering different dosage levels, including the 25 mg dose.

"There is insufficient evidence to justify the use of oral phenylephrine at the [10 mg] dose suggested in the FDA's nonprescription labeling," the researchers conclude in their study published online in the Annals of Pharmacotherapy.

However, in their petition Hatton and Hendeles say differences between the methodologies used in the studies they reviewed support their request for more research on the most effective PE dosage level.

"The heterogeneity across studies included in this meta-analysis suggests possible measurement bias," they say. "This limits the conclusion about which is the most efficacious dose."

However, they found "no data on either the safety or the efficacy" of PE on children under 12, they add.

"We believe that this drug should only be used in children [12 and under] under the advice of a licensed prescriber and FDA should withdraw OTC approval for this age group."

Hatton said he and Hendeles are asking for better science and additional data regarding the decongestant because scientific debate is ongoing about PE's efficacy.

However, the Consumer Healthcare Products Association says a meta-analysis it conducted contradicts the results of the pharmacists' study. CHPA says a 10 mg dose of PE is effective as a decongestant.

"We strongly disagree with both recommendations" in the citizen petition, said Heinz Schneider, M.D., CHPA's vice president for regulatory and scientific affairs.

PE "use in the U.S. is very, very similar to its use in many other regions of the world" and is "based on a sound scientific review judgment by the FDA, both in children and adults," Schneider said.

CHPA's research follows "current best scientific recommendations" and its "outcome is very relevant," he said.

In their study, the pharmacists also recommend changing oral PE from nonprescription Category I status - generally recognized as safe and effective - to Category III, requiring further testing.

In an e-mail, Hendeles says this recommendation isn't part of the citizen petition because there is sufficient data to support a discussion about the 25 mg dose.

The meta-analysis included only randomized, placebo-controlled clinical trials that compared PE efficacy as a single agent. Studies that involved combination products or compared PE with another oral decongestant were excluded.

Hatton et al. found "effect estimates ranged from a mean difference in [nasal airway resistance] decrease between phenylephrine and placebo from 41.0% to -12.1%."

CHPA's meta-analysis found the average change from baseline NAR for PE was "approximately two-thirds to two times greater than that for placebo" between 15 and 90 minutes post-dose.

The trade group says its meta-analysis is more relevant because "it measures when the medicine starts working and for how long."

CHPA also says Hatton's meta-analysis "did not employ FDA's preferred method of analyzing the medicine's efficacy profile over time, but rather looked at peak effects."

In an e-mail to "The Tan Sheet," Hatton says FDA should set the study standards. He says FDA should decide what should be measured, what instruments to use, what "assurance of precision must be documented," and what duration of time should be studied among other things.

"If several independent labs using these standards do these studies ... then a meta-analysis is done, then we have the definitive answer," he says. "Why wouldn't we want the science to make the decision?"

"Whether it is our meta-analysis or the one done by CHPA, one should not make a definitive conclusion based on any combination of these results, including a meta-analysis," says Hatton, who is co-director of the Drug Information and Pharmacy Resource Center in the Shands research hospital at the University of Florida. "That is why we are suggesting that additional study is needed."

CHPA does not share that view. "I disagree with that comment by 50 percent," said Schneider, adding the CHPA study, not the Hatton meta-analysis, is sufficient to show an effective PE dosage level.

CHPA's meta-analysis included 163 patients in seven efficacy studies - with some overlap with the Hatton analysis - and found PE was "statistically significantly superior to placebo at the primary time points" of 30, 60 and 90 minutes post-dose.

Based on concerns raised about PE efficacy, Rep. Henry Waxman, D-Calif., has called for FDA to convene the Nonprescription Drugs Advisory Committee to re-evaluate the ingredient (¹ Also see "Phenylephrine “Not Significantly Different From” Placebo – Schering Study" - Pink Sheet, 13 November, 2006., p. 6).

Waxman could hold a hearing on the topic himself - as well as other OTC issues - considering he chairs the committee on Oversight and Government Reform.

Waxman contacted FDA near the Sept. 30, 2006 deadline for retailers to move pseudoephedrine products behind the counter in compliance with Combat Meth provisions of the Patriot Act.

Restrictions imposed by state laws as well as Combat Meth on sales of pseudoephedrine-containing products led some firms to reformulate cough/cold products with PE (² Also see "Pseudoephedrine Will Be Behind The Counter Across The Country By October" - Pink Sheet, 6 March, 2006., p. 5).

CHPA formed a task group to study PE efficacy as a result of communications between Waxman and FDA.

- Rebekah Moan (r.moan@elsevier.com)

Citizen Petition On Phenylephrine Requests Pulling OTC Status For Children

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