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Executive Summary

OTC naproxen sodium at 220 mg would raise the potential of frequent self-medication use of the ingredient at the prescription dosage, Arthritis Advisory Committee Chair David Trentham, MD, Beth Israel, contended shortly before the June 2 vote to reject the Syntex/P&G switch application. Summarizing the reservations of the Arthritis and OTC Drugs Advisory Committees about the OTC marketing of 220 mg tablets of naproxen sodium as a general analgesic, 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. The 220 mg dosage represents 80% of each of the two ingredients of the prescription product Anaprox: 250 mg of naproxen and 25 mg of sodium. "I'm a little taken aback by a singular tablet being the panacea proposed at 200 mg [of naproxen per] tablet," 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." Ironically, the naproxen sodium 220 mg dosage was suggested by FDA as an appropriate OTC dosage based on an analysis of pharmacokinetic/pharmacodynamic data submitted by Syntex. FDAer Dennis Bashaw explained how the dosage was selected during a June 1 presentation to the advisory committees. "Looking at the data, we felt the best dosage form pursued for development would be the 220 mg sodium tablet in that it had release characteristics and that its rate of absorption seemed to be fast enough," Bashaw told the committee. He reported that "from this information, we asked the sponsor to go back and do a new pharmacokinetic trial with a larger number of studies and a larger number of subjects." A second concern of the advisory committee was the 12-hour half-life of the drug. Accepting the proposed dosing schedule of one tablet every six to 12 hours, Trentham said the compressed "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 to speed 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 dysmenorhea, the very excitable ones...[take] medications until they get to the point where they get constant relief." Among the side effects the committee pointed out as hurdles to the Rx-to-OTC switch was pseudoporphyria, or 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 occurred relatively rarely and 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 often under-reported. "Pseudoporphyria is not a rare condition. We don't report it; we just take those [patients] off," she said adding, "I am concerned about safety, not only because of the skin manifestations, but because I think [naproxen] is a more dangerous...drug for the GI tract." Some advisory committee members maintained that permitting the switch dose to contain 200 mg active ingredient naproxen might invite chronic use of the product as an anti-inflammatory. Arthritis committee liaison representative Sanford Roth, MD, Arthritis Center, Ltd., said that he was concerned "primarily because of what that says to abuse and chronic use of the drug that wasn't 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 its presentation to the committee, Syntex had reported six fatal and 24 non-fatal over doses of 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 the drug is "also mentioned and 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 the naproxen sodium is a "more rapid a dose formulation," Juhl commented: "Unfortunately, most of the studies were [using] the slower formulation." Arthritis advisory committee member George Ehrlich, MD, University of Pennsylvania, asked Syntex about the dosage choice. "You seem pretty confident from the data that the minimum effective dose is [220 mg]...but you've also shown us a considerable body of data that suggests that the 100 mg dose as a second dose is effective." Syntex responded: "The [200 mg] dose is the best single dose [because it is] the lowest consistently effective dose. Harter indicated that the Syntex dosing recommendation reflected marketing realities. "Two hundred is going to be very competitive with ibuprofen, and with acetaminophen. If they were to go into the marketplace with 100 mg, yes, some people would get relief but [Syntex would] get killed...with a drug that was not as effective as their main competitors," Harter observed. However, he noted the flip side: "I would have liked to have seen 165 mg with the sodium...but they elected to go with the dose they did and I think you have to come on the other side of that equation and say, 'how dangerous is that drug for OTC use?'" Initially, Syntex had planned to pursue the single ingredient naproxen as their switch candidate. The company felt that the drug was better known and that consumers might be concerned with the levels of sodium in Anaprox. However, FDA's pilot drug review staff, which analyzed the Syntex submission, urged the company to pursue a reduced dosage of Anaprox: naproxen plus sodium. FDA's pilot drug review staff examined the Syntex submission and the 187.5 mg naproxen dosage formula that the company had originally intended to pursue as their switch candidate. This was the dosage that the company used in most of its clinical trials. Analyzing the data, FDA determined that the 187.5 mg naproxen tablet "was the bottom line. It had a very slow and prolonged rate of onset in terms of plasma concentration compared to the... equivalent sodium dosage form," Bashaw said. To determine a recommended dosage, FDA selected 40 minutes as a target for onset of action, the FDAer explained. "That seemed to be a reasonable time for most people to expect analgesia...40 minutes after taking the dosage form." With that target in mind, FDA went back to an 80-patient dental extraction study to correlate plasma concentrations to pain relief. FDA concluded that the 220 mg dosage form would satisfy the requirements for OTC use. 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 of the transitional drug class was outside of its scope in the application review.

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