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FELDENE PROPOSED FDA LABELING WOULD LIMIT DOSING TO 20 MG/DAY, ENCOURAGE LOWER DOSES IN ELDERLY; FOR ALL NSAIDs, FDA FEELS "LOWER IS PROBABLY BETTER"

Executive Summary

FDA is considering a lbeling statement for Feldene (piroxicam) that would limit dosing to 20 mg/day and suggest to physicians that for certain patients a lower dose might be appropriate. The agency presented a draft paragraph on the risk of gastrointestinal ulcerations, bleeding and perforation from NSAID therapy to its Arthritis Drugs Advisory Committee Dec. 2. The labeling statement is intended for all perscription nonsteroidal anti-inflammatory drugs. An additional statement specifically pertaining to piroxicam states: "Pooled data from controlled clinical trials of piroxicam suggest that above 20 mg/day piroxicam carries a sufficiently greater risk of these more serious reactions so doses higher than 20 mg/day are not recommended." The proposed piroxicam labeling adds: "In patients who require chronic therapy and who have risk factors for peptic ulcer disease or who might tolerate peptic ulceration and/or bleeding less well, such as elderly or debilitated patients, physicians may wish to try decreasing the dose of piroxicam to see whether or not sufficient benefit is maintained at a lower dose which may carry less risk of these serious reactions." FDA's proposed statement follows recent petitions by the Health Research Group to restrict use of Feldene. The group initially sought to ban use of the drug in the elderly. When FDA denied this request, HRG filed a petition calling for a not-for-initial use boxed warning in the labeling until results from low-dose Feldene studies become available ("The Pink Sheet" Oct. 27, T&G-3). FDAers have been indicating an interest in lower dosing for Feldene for several months ("The Pink Sheet" Sept. 15, p. 5). The proposed label statement expressed that position. The advisory committee did not make any suggestions on the proposed statement for piroxicam, but several members voiced concern about the agency's general dosing statement for NSAIDs as a class. The general statement concludes with the recommendation that patients "be maintained on the lowest dose of [drug name] possible, and, if higher doses are necessary, sufficient benefit should be observed to offset a potential increased risk." Committee consultant Michael Weissman, MD, University of California/San Diego, stated that the "pretty unanimous feeling" of the committee is that such a statement would be inappropriate and incorrect. Members pointed out that a lower effective dose may not provide the best anti-inflammatory action. The lowest dose possible recommendation follows FDA's statement: "Studies to date have not permitted precise determination of the relative risk of various NSAIDs in causing such reactions. It seems reasonably probable that high doses of any NSAID carry a greater risk of these reactions than lower doses, although few controlled clinical trials have actually demonstrated this." Alternatively, FDA proposed the statement: "Pooled data from controlled clinical trials suggest that higher doses of any NSAID carry a greater risk of these more serious reactions than lower doses." Explaining the agency's reasoning in the proposed labeling statement, FDA Office of Drug Research & Review Robert Temple, MD, said it seems resonably probable that "high doses are more likely to cause bleeding than low doses, but there are not alot of studies that show that, and it's not easy to show, and there are reasons why it may turn out not to be true." He stated that "it certainly must be so that bleeding has a dose response curve, the question is where that curve is." Therefore, he said, the agency "collectively thought lower is probably better." FDA also proposed a draft paragraph for the patient information section of NSAID labeling that notes that "[drug name], like other drugs of its class, is not an innocuous agent particularly when used for more than a few days." The statement observes that the drugs "are often essential agents in the management of arthritis and have major roles in the treatment of pain, but they are also commonly prescribed for conditions that are not so serious." It concludes that "patients may wish to discuss with their physician the potential risks and likely benefits of [drug name] . . . particularly when the drugs are for mild or self-limited conditions where treatment without drugs may represent an acceptable alternative to both them and the physician." Temple said he has "somewhat mixed emotions" about the paragraph. Temple commented: "The perception is that apart from their uses to treat rheumatoid arthritis, troublesome osteoarthritis or even bad musculoskeletal problems, these drugs may be used when a patient, who is reminded of the possibility [that drug treatment may not be necessary] will say -- oh, what the heck, I think I'll just wait until it goes away." He added that "if the drugs were quite innocuous you wouldn't worry too much, but they're not innocuous and they have some rather nasty risks [that] while very rare will actually occur when you're talking about various exposures."
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