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This article was originally published in The Tan Sheet

Executive Summary

NAPROXEN SODIUM PROPOSED OTC DOSE COULD COME TOO CLOSE TO Rx LEVELS under self-medication conditions, Arthritis Committee Chairman David Trentham, MD, Beth Israel, contended shortly before the June 2 vote on the Syntex/P&G switch application. Summarizing the reservations of the Arthritis and OTC Drugs Advisory Committees about the OTC marketing of naproxen sodium 220 mg (200 mg of naproxen and 20 mg sodium), Trentham said that "the first concern relates to the fact that the recommended doses of naproxen are really pretty close to [prescription] pharmacological doses." Stating that the OTC dosage for the 1984 ibuprofen switch at 200 mg "is clearly at sub-prescription level," Trentham maintained that in contrast, OTC dosing for naproxen could easily climb into the prescription range between 250 mg and 500 mg. "I'm a little taken aback by a [200 mg] singular tablet being the panacea," he said, adding that if patients "load" the initial dose or "'use with experience' two tablets, [they consume] 400 mg. That is well into reasonable prescription drug range [and] that has clear cut biologic consequences, including prostaglandin inhibition, that may not be obtainable with other analgesic preparations." A second concern was the 12-hour half-life of the drug. Accepting the proposed dosing schedule of one tablet every six to 12 hours, Trentham said "compressing dosage intervals to every six hours should be on our minds." Arthritis Committee member Graciela Alarcon, MD, University of Alabama, asked the committee: "If you have a drug that has a 12- hour half-life, why is the label indication going to be to use every six hours as needed? I also see [on] this label: take two [tablets] and then one every six hours; don't take more than four in a 24-hour period. That's very confusing to the lay person. I'm saying that the patient will end up taking actually five tablets in one day." The potential for overdose as a result of attempts by consumers to speed up the onset of action was also cited as a concern. OTC Drugs Committee member Joseph Veltri, Intermountain Regional Control Center, questioned "whether the drug really gets there quick enough, so that individuals won't be taking [more than] sufficient doses, whatever their starting dose. My experience is that in younger patients who are women taking this for dysmenorrhea, the very excitable ones . . . [take] medications until they get to the point where they get constant relief." Among the side effects of concern to the committee was pseudoporphyria, heightened sensitivity to sunlight. OTC Drugs Committee member Maria Chanco Turner, MD, National Institutes of Health, explained that because "what you see in pseudoporphyria is a photosensitivity reaction . . . it could be a matter of dose or how much sun you get; there will be a whole lot of variables." Syntex maintained that pseudoporphyria is a relatively rare side effect of naproxen use that occurs mostly in children below the recommended age for use listed on the label. Arthritis Committee member Deborah Kredick, MD, Duke University, responded that the condition was not limited to children, and is often under-reported. "Pseudoporphyria is not a rare condition. We don't report it; we just take those [patients] off [the drug(BRACKET)" she said, adding: "I am concerned about safety, not only because of the skin manifestations, but because I think [naproxen] is a more dangerous, if you will, drug for the GI tract." Some committee members pointed to the proposed 200 mg switch dose as an anti-inflammatory drug that would invite chronic use. Arthritis Committee Liaison Sanford Roth, MD, Arthritis Center, Ltd., said he was concerned "primarily because of what that says to abuse and chronic use of the drug that was not intended for that purpose. That brings in issues of ulcers and renal safety and a particular focal population: the elderly. We need to concentrate on that [because] issues of safety are involved there." In the company's presentation to the committee, Syntex reported overdoses involving six fatal and 24 non-fatal adverse reactions to naproxen in the 17-year history of the drug. Trentham asked FDA Pilot Drug Evaluation Staff Director John Harter, MD, to contrast FDA reports with the company's records. Harter reported that FDA files contain "about twice as many cases reported of non- fatal adverse reactions to naproxen" and "about four times the number of deaths that are associated" with the drug. He cautioned, however, that the agency tabulates all "cases where it's also mentioned [even though it] may not be the suspect drug." OTC Drugs Advisory Committee Chair Randy Juhl, PhD, University of Pittsburgh, noted that the review of the switch application was "confounded by two different formulations" -- naproxen and naproxen sodium. Noting that naproxen sodium is a "more rapid dose formulation," Juhl commented: "Unfortunately, most of the studies were [using] the slower formulation." Following the committee's nonrecommendation for OTC marketing, the American Society of Clinical Pharmacology and Therapeutics Liaison (Analgesics) to the Arthritis Committee, Saul Bloomfield, MD, University of Cincinnati, recommended a motion to consider allowing naproxen onto the OTC market if it were dispensed by a pharmacist in a transitional drug class. The committee decided that a discussion on a "third class of drugs" was outside the scope of the panel's application review.

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