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Executive Summary

LOREX' AMBIEN (ZOLPIDEM) SHOULD BE SCHEDULE V HYPNOTIC DRUG, FDA's Drug Abuse Advisory Committee voted five to four on Feb. 27. The recommendation to classify the company's non-benzodiazepine hypnotic zolpidem in the least stringently regulated of the five drug schedules would put it in a different category than the benzodiazepine hypnotics, which are in Schedule IV. Lorex is a joint venture between Searle and the French firm Synthelabo. The close vote followed the four to five defeat of a proposal to designate Ambien as Schedule IV. FDA Pilot Drug Evaluation Staff Director John Harter, MD, said that he interpreted the two close votes to mean "that either answer is acceptable" and "I don't think anyone should leave the room today feeling that you know what the decision is." He said the agency "will probably pick one" of the two schedules for Ambien. The committee first voted, however, on whether to put off the scheduling decision entirely due to what Committee Chairman Theodore Cicero, PhD, Washington University, St. Louis, called a lack of "hard data." The group voted four to five against delaying a decision on zolpidem's abuse potential. Before the vote, Lorex General Manager Frank Sternberg told the committee that zolpidem "should at least be allowed to be marketed" and that "we are willing to do Phase IV studies." The NDA for Ambien has been pending at FDA since January 1989. FDA interdisciplinary scientist Michael Klein, PhD, reviewed two placebo-controlled crossover studies in patients with a history of drug abuse. One study compared the abuse potential of zolpidem (10 mg, 20 mg and 40 mg) with diazepam (10 mg, 20 mg) in 12 patients and the other compared zolpidem (15 mg, 30 mg, 45 mg) to triazolam (.25 mg, .5 mg, .75 mg) in 15 patients. Patients with a history of drug abuse were observed and filled out questionaires to evaluate the effects of the drugs. Klein said that "most of the responses" on scales of drug effects, drug identification, and next-day effects "showed equivalence between diazepam and zolpidem." Klein also reported "similar responses" for both triazolam and zolpidem. Klein reported that, on a scale on which study participants tried to identify the kind of medication they had taken, "both triazolam and zolpidem showed its major responses in being identified as barbituates, benzodiazepines or the alcohol category." Klein concluded by saying, "overall the drug [zolpidem] shows a profile like the...benzodiazepines so our position for Schedule IV relates to how the drug would be received by the medical community." He said "it is a fairness issue: the drug is so much like the benzodiazepines that are marketed that we feel it should be marketed similarly." Lorex Director of Clinical Research Rachel Ochs-Campbell, MD, said that zolpidem "has a unique structure" and binds to a different subgroup of receptors than benzodiazepines. She pointed out that the efficacy of zolpidem "plateaus" at a certain dosage level. Because of these differences, she stated that zolpidem should "be Schedule V to tell physicians that it may be safer." She stated that zolpidem has "less potential to produce public health and social problems than the benzodiazepines and other sedatives used as hypnotics." NIDA staff pharmacologist Yng-shiuh Sheu, PhD, presented an analysis of two clinical studies. Zolpidem and diazepam produced a "similar, but not identical, profile of effects," he said, and zolpidem may exhibit "some abuse potential of the diazepam type." The comparative study with triazolam was summarized by Sheu as showing that "zolpidem and triazolam produced dose-related increases in several subjective effects that are often considered to reflect likelihood of abuse; however, this study showed that high doses of zolpidem produce negative subjective effects and vomiting which could decrease the likelihood that zolpidem would be abused." Donald Jasinsky, MD, Johns Hopkins University, a paid consultant for Lorex and lead investigator of the diazepam/zolpidem trial, agreed with Sheu's conclusion that zolpidem's adverse effects at higher doses would deter abuse. He said, "when you push the tend to get the nausea and vomiting, people start seeing double...and they really don't want to take much more of it." The company's adverse event data from the seven European countries in which zolpidem is marketed showed that out of 494 documented adverse events reports on zolpidem, collected between February 1988 and December 1990, "we identified seven with potential abuse," including either withdrawal or outright abuse, said Ochs-Campbell. Of 75 ADRs collected between January 1991 and September 1991 there were two cases of suspected abuse.

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