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Executive Summary

Searle's Ambien (zolpidem tartrate) will test the depth of the market niche for a new, non-benzodiazepine sedative/hypnotic beginning early in 1993. FDA approved the company's NDA (19-908) on Dec. 16 after a 47-month review and a busy autumn of back-and- forth negotiations. Ambien, an imidazopyridine derivative, is entering the hypnotic market during a period of unrest. Upjohn's Halcion has been losing sales at a steep rate following suspension of sales in the U.K. in October 1991 and the subsequent repackaging and relabeling in the U.S. In the third quarter of 1992, Halcion sales were off 47% worldwide. Prescription data provided by FDA at a May 1992 review of Halcion and the hypnotic sedative class indicated that doctors were shifting away from the benzodiazepines to other forms of non-benzodiazepines. IMS data for the twelve-month period through September 1992 indicate a 22% drop in Rxs (to 14 mil. Rxs) in the sleep aid category and a 16% drop in dollars to $167 mil. Searle is ready to try to take advantage of the market disruption from the negative publicity affecting currently marketed benzodiazepines. Calling zolpidem the "first in a new class of chemical compounds," an introductory fact sheet on the drug highlights that Ambien is "structurally unrelated to the benzodiazepines." The approved indication for the new sleep aid, however, mirrors FDA's recently required emphasis on short-term use. "Ambien is indicated," labeling states, "for the short-term treatment of insomnia. Hypnotics should generally be limited to 7- 10 days of use, and re-evaluation of the patient is recommended if they are to be taken for more than 2-3 weeks." A caution against prescribing in quantities exceeding a 1-month supply is also contained in the indications section. Searle apparently had pressed FDA in final negotiations to give the product a different indication from existing therapies. The Dec. 16 FDA approval letter from Office of Drug Evaluation I Director Robert Temple, MD, notes that Searle "prefer[s] an Indications and Usage section that does not include a recommendation to re-evaluate patients needing therapy between 2-3 weeks and does not limit prescriptions to 1 month." The agency pointed out to Searle, however, that "since we are in the process of trying to implement such changes for all hypnotics, we feel it is both fair and essential to obtain this language for Ambien at this stage." FDA also advised Searle not to contraindicate the drug in pregnancy. The approval letter observes that the company has appeared to favor the contraindication "for liability reasons." Temple said FDA does not believe "there is a sufficient basis for such a contraindication." The agency deferred to the company on at least one of the final issues of disagreement. FDA backed off from a requirement for unit-of-use packaging for Ambien similar to the Halcion repackaged product. FDA said: "While we acknowledge your arguments against the implementation of unit-of-packaging for Ambien, we still intend to pursue such packaging since we consider it to be in the public interest. Nevertheless, we do not feel that the approval of this NDA should be held up on this basis." The product will be supplied as 5 mg and 10 mg capsule-shaped tablets in bottles of 100 and 500 tablets, and in blister packs containing 100 unit-of-use doses. Searle has not disclosed a launch date for the product. The extent of the likely marketing effort is reflected in introductory materials on general educational programs about insomnia. The company says it "is supporting organizations dedicated to educating physicians and consumers on insomnia and the proper use of the various treatment alternatives." The firm specifically mentions a grant to the National Sleep Foundation to sponsor a "series of insomnia workshops for primary-care physicians to be held in 20 cities in early 1993." The approved FDA labeling notes the extent of the chemical difference between the imidazopyridine derivative and benzodiazepines. "In contrast to the benzodiapines, which nonselectively bind to and activate all three omega [benzodiazepine] receptor subtypes," the clinical pharmacology section says, "zolpidem in vitro binds with the omega-one receptor preferentially." The selective binding, labeling observes, "is not absolute, but it may explain the relative absence of myorelaxant and anticonvulsant effects in animal studies as well as the preservation of deep sleep (stage 3-4) in human studies of zolpidem at hypnotic doses." The labeling summary of clinical effects similarly refers to the effects of the drug on different levels of sleep. "In studies that measured the percentage of sleep time spent in each sleep stage," labeling states, "Ambien has generally been shown to preserve sleep stages. Sleep time spent in stage 3-4 (deep sleep) was found comparable to placebo with only inconsistent, minor changes in REM (paradoxical) sleep." Searle emphasizes the experience record of the product overseas. Ambien is a product of the Lorex joint venture between Searle (51%) and Synthelabo (49%). The product has been marketed by Synthelabo in Europe since 1988 (first approval in France). The company estimates that "approximately 340 mil. patient nights of use have been monitored in Europe." In pooled clinical trials data on 3,021 patients, the side effects occurring at a frequency of greater than 1 in 100 were ataxia, confusion, euphoria, insomnia, vertigo, diplopia, and vision abnormalities. Under the warnings section of labeling, Ambien carries the general caution about "a variety of abnormal thinking and behavioral changes." The labeling points out that "it can rarely be determined with certainty whether a particular instance of the abnormal behaviors...are drug induced." Even before the Halcion problems began to surface, Searle execs were predicting a major impact for Ambien in the sedative/hypnotic class. In May 1991, Searle Chairman Sheldon Gilgore said that the product would "more than supplant Halcion as the leader in its class." The approval comes at a good time for Searle and could bouy the company morale after the announcement of a 23% cutback on Nov. 23. The company notes that it has had four drugs approved this year, including the antibiotic Maxaquin and the NSAID Daypro. One of those four approvals, another Lorex product, the beta blocker/diuretic combo Kerledex (betaxolol/chlorthalidone), quietly cleared FDA on Oct. 30. The antihypertensive was recommended for approval by the Cardio-Renal Drugs Advisory Committee on Dec. 13, 1990, and was deemed "approvable" by FDA on June 4 ("The Pink Sheet" Aug. 24, p. 7). Searle, which has not publicly announced the approval, has not yet decided on its plans for the product. Searle has marketed single agent betaxolol as (Kerlone) since May 1990. FDA's approval of the Ambien with several final dictums on labeling indicates a creative use of the end-of-year deadline in protracted negotiations with a drug company. In its Dec. 16 letter, FDA was, in essence, telling Searle that negotiations on the specific label were over. In a method similar to the approval of Warner-Lambert's Penetrex at the end of last year, FDA is softly asserting its right to decide when a drug's indication is acceptable and when the product should be approved. The approval came after at least 11 back-and-forth communications between the company and the agency in a three-month period.

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