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SMITHKLINE BEECHAM’s RELAFEN LABELING CONTAINS DATA ON LOW INCIDENCE OF PEPTIC ULCER, BUT FIRM MUST DO STUDY TO PROMOTE CLAIMS; NSAID APPROVED DEC. 24

Executive Summary

SmithKline Beecham's Relafen (nabumetone) labeling cites data showing that the new nonsteroidal anti-inflammatory drug has a lower incidence of peptic ulcers than other NSAIDs. Relafen was approved by FDA on Dec. 24. Relafen's labeling states that "in controlled clinical trials involving 1,677 patients treated with Relafen (1,140 followed for one year and 927 for two years), the cumulative incidence of peptic ulcers was 0.3% at three to six months, 0.5% at one year and 0.8% at two years." In comparison, the warning section of labeling for other NSAIDs, such as Syntex' Naprosyn (naproxen) notes: "In patients observed in clinical trials of several months to two years duration, symptomatic upper GI ulcers, gross bleeding or perforation appear to occur in approximately 1% of patients treated for three to six months, and in about 2%-4% of patients treated for one year." In its approval letter, FDA states that if SmithKline Beecham wants to claim that Relafen use results in a lower incidence of peptic ulcers and bleeding than other NSAIDs, "then a study of peptic ulcer, perforation and bleed is needed." SmithKline Beecham said it plans to conduct such a study. Another likely selling point for Relafen is that, unlike most other NSAIDs, nabumetone is administered once a day. Pfizer's Feldene (piroxicam) is the only other one-a-day NSAID. Relafen will be a launched "early in 1992" and will be priced competitively, SmithKline Beecham said. FDA's review of the Relafen NDA (19-583) took almost six years since the original submission on Feb. 6, 1986. The agency's approval letter says that the NDA was "resubmitted in the NDA Day format on May 10, 1991." Relafen was classified by FDA as a "1C" drug, denoting a new chemical entity with little or no therapeutic gain over existing therapies. "Relafen is a member of a new class of NSAID known as naphthylalkanones," SmithKline Beecham said in a Dec. 31 press release. "What distinguishes Relafen from other NSAIDs is that it is nonacidic and is a prodrug -- that is it does not become active until after it passes through the stomach and is biotransformed by the liver," SmithKline Beecham pointed out. Labeling for Relafen notes that in clinical trials, patients taking Relafen had fewer gastrointestinal lesions than patients treated with other NSAIDs. "In five clinical trials that compared a total of 194 patients on Relafen 1,000 mg daily or naproxen 250 mg or 500 mg twice daily for three to 12 weeks, Relafen treatment resulted in fewer patients with endoscopically detected lesions (>3 mm)," labeling says. "In two trials, a total of 101 patients on Relafen 1,000 mg or 2,000 mg daily or piroxicam 10 mg to 20 mg for seven to 10 days, there were fewer Relafen patients with endoscopically detected lesions." Labeling notes that in comparative trials with indomethacin and ibuprofen, Relafen showed a lower incidence of G-I lesions. Another NSAID, Wyeth-Ayerst's Lodine (etodolac), was also approved in 1991. Although Lodine's labeling carries the same statement on the incidence of ulcers and bleeding as other marketed NSAIDs, it also contains data demonstrating that Lodine results in fewer GI lesions than other NSAIDs. Relafen's approval letter outlines 10 postmarketing commitments that the company has agreed to meet, including "a healthy elderly study (70 years old) with expected decreases in both renal and hepatic function." Another pharmacokinetic trial requested by FDA is "a hepatic insufficiency study which evaluates metabolite conversion and protein binding effects on both the bound and unbound drug." The recommended starting dose for Relafen is "1,000 mg taken as a single dose with or without food," labeling says. "Some patients may obtain more symptomatic relief from 1,500 mg to 2,000 mg per day." Relafen will be supplied in 500 mg and 750 mg tablets.

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