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WYETH-AYERST'S LODINE APPROVED FOR TREATMENT OF OSTEOARTHRITIS AND PAIN RELIEF; TWICE-DAILY ANTIARTHRITIC WILL ENTER CROWDED NSAID MARKET THIS SPRING

Executive Summary

Wyeth-Ayerst's nonsteroidal anti-inflammatory drug Lodine (etodolac) will be launched this spring following FDA approval on Jan. 31. FDA's review of the drug took just over eight years. The NDA for etodolac was first filed at FDA in December 1982 for use of the drug as an analgesic. At that time, Wyeth planned to call the drug Ultradol. In October 1983, Wyeth submitted additional data to the agency in support of an anti-inflammatory indication. Besides an osteoarthritis claim, Wyeth also pursued a claim for rheumatoid arthritis. The company also indicated early on in the review process that it was considering whether to seek a claim for remission of rheumatoid arthritis. Lodine is indicated for the treatment of osteoarthritis and for relief of pain. However, the NSAID is not labeled for the treatment of rheumatoid arthritis. The drug will be available in 200 mg and 300 mg capsules, at a price "comparable" to other NSAIDs, Wyeth-Ayerst said. Lodine is entering a crowded NSAID market that includes two relatively recent entries: Ciba-Geigy's Voltaren, launched in 1988, and Upjohn's Ansaid, introduced in early 1989. However, because many regular NSAID users are dissatisfied with their current medication, there is usually a reservoir of patients ready to try new treatments. The test facing Wyeth-Ayerst will be to successfully launch Lodine while Voltaren and Ansaid are still in a strong growth phase. Lodine's twice-daily recommended regimen for osteoarthritis and its relatively mild gastrointestinal side effects profile will likely be the chief selling-points for the drug. Syntex' Naprosyn can be taken twice-daily, Pfizer's Feldene is the only one-a-day NSAID, and Voltaren is taken two or three times a day. According to Lodine draft labeling, the recommended dose for osteoarthritis is "initially 800-1,200 mg/day in divided doses, followed by dosage adjustment within the range of 600 to 1,200 mg/day given in divided doses: 400 mg t.i.d. or b.i.d.; 300 mg q.i.d., t.i.d., or b.i.d.; 200 mg q.i.d. or t.i.d." For analgesia, the recommended dose is "200 to 400 mg every 6-8 hours, as needed." However, Lodine labeling specifically makes clear that the drug is not to be used for the treatment of rheumatoid arthritis. The draft labeling says that the drug "is not recommended for the treatment of patients with rheumatoid arthritis because in controlled clinical trials, although Lodine treatment was sometimes better than placebo treatment, it was generally not as effective as treatment with other marketed NSAIDs." In annual reports to shareholders, American Home Products has claimed that etodolac is "10 times more potent than aspirin" and has touted the drug's "gastrointestinal and pharmacologic advantages." FDA classified Lodine as a "1C," a new chemical entity with little or no therapeutic gain over existing therapies. In clinical trials in analgesia, onset of pain relief began about 30 minutes after administration and "was comparable for Lodine (200-400 mg), aspirin (650 mg), acetaminophen with codeine (600 mg/60 mg), and zomepirac (100 mg)," Lodine's draft labeling states. In a trial of patients with osteoarthritis of the knee Lodine (600 to 1,000 mg/day) "was comparable to naproxen 1,000 mg/day." Lodine's labeling carries the warning common to all NSAIDs: "Risk of gastrointestinal ulceration, bleeding, and perforation with NSAID therapy: serious G-I toxicity, such as bleeding, ulceration, and perforation, can occur at any time, with or without warning symptoms, in patients treated chronically with NSAIDs." The labeling also notes that in "special studies," Lodine was compared with other NSAIDs in inducing gastrointestinal bleeding. "Lodine 1,200 mg/day caused less GI blood loss than ibuprofen 2,400 mg/day, indomethacin 200 mg/day or naproxen 750 mg/day." Lodine was also compared with piroxicam 20 mg/day in two studies. "Piroxicam caused more blood loss than Lodine in one of these studies but not the other," the labeling states. The labeling's pharmacokinetics section says that "no dosage adjustment of Lodine is generally required in patients with mild to moderate renal impairment, however, etodolac should be used with caution in such patients because, as with other NSAIDs, it may further decrease renal function in some patients with impaired renal function." Labeling cautions that "as with other NSAIDs, long-term administration of etodolac to rats has resulted in renal papillary necrosis and other renal medullary changes." Like other NSAIDs "borderline elevations of one or more liver function tests may occur in up to 15% of patients," the labeling says. "Meaningful elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients" in Lodine trials. FDA is asking Wyeth-Ayerst to perform eight Phase IV studies with Lodine. Lodine is Wyeth-Ayerst's second NSAID in the U.S. Orudis (ketoprofen) was approved in early 1986 for osteoarthritis, analgesia, rheumatoid arthritis, and primary dysmenorrhea in a twice-daily or three-times-a-day dosing regimen. An NDA for a once-daily dosage form of ketoprofen is pending at FDA. The company has another NSAID under FDA review, oxaprozin (Durapro), for which an NDA has been pending since 1982. The NDA covers once-daily use of the drug for the treatment of osteoarthritis and rheumatoid arthritis. However, Searle currently holds U.S. and Canadian marketing rights to oxaprozin under a December 1988 agreement.
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