Halcion -- Copyright -- Acknowledgments -- Preface -- Contents -- Executive Summary -- THE DATA -- ASSESSMENT OF EFFICACY DATA -- Conclusions and Recommendations -- Data Adequacy -- Clinical Trial Design -- Tolerance -- ASSESSMENT OF SAFETY DATA -- Conclusions and Recommendations -- Clinical Trials and Surveillance -- BROADER IMPLICATIONS -- 1 Introduction -- HISTORICAL OVERVIEW OF HALCION -- Overseas Events -- FDA Activity -- Spontaneous Reports -- FDA Reassessment -- FDA Task Force -- CHARGE TO THE IOM COMMITTEE -- ORGANIZATION OF THE REPORT -- 2 Assessment of Efficacy Data -- PURPOSE AND EVALUATION OF HYPNOTIC DRUGS -- Evaluating Efficacy -- FDA Efficacy Requirements -- Available Efficacy Data on Halcion -- QUALITY OF PROTOCOLS AND STUDY DESIGN -- Study Design -- Endpoints -- Polysomnographic Studies -- REVIEW OF STATISTICAL METHODS USED BY UPJOHN AND FDA TO EVALUATE EFFICACY DATA -- Statistical Reanalysis and Evaluation of Clinical Trial Efficacy Data -- Random-Effect Regression Models -- Results of Reanalysis -- Dose Response -- LITERATURE REVIEW -- Polysomnographic Studies of Halcion in the Published Literature -- CONCLUSIONS AND RECOMMENDATIONS -- Data Adequacy -- Clinical Trial Design -- Tolerance -- 3 Assessment of Safety Data -- WELL-CONTROLLED PREMARKETING CLINICAL TRIALS -- Adverse Events -- Integrated Summary of Safety -- Observation 1: Comparable Safety Profile -- Observation 2: Comparable Rates of CNS-Related Events -- Observation 3: Increased Sensitivity in Geriatric Subjects -- Summary -- IOM Analysis of Upjohn's Integrated Summary of Safety -- Nervousness -- Memory Impairment -- Impaired Coordination -- Confusion -- Summary -- Analysis of Dropouts -- FDA Analysis -- IOM Analysis -- Statistical Analysis -- Halcion (0.5 mg) Versus Placebo in Non-geriatric Subjects.

Halcion (0.5 mg) Versus Flurazepam (30 mg) in Non-geriatric Subjects -- Halcion (0.25 mg) Versus Placebo in Geriatric Subjects -- Halcion (0.25 mg) Versus Flurazepam (15 mg) in Geriatric Subjects -- Summary -- DATA SETS FOR POSTMARKETING STUDIES -- Randomized Study: Protocol M/2100/0235 -- Randomized Polysomnographic Studies -- A Nonrandomized Controlled Study: EMIC -- VAMP: A COHORT STUDY -- SPONTANEOUS REPORTING OF ADVERSE EVENTS: THE FDA SYSTEM -- Statistical Evaluation of the SRS Data -- LITERATURE REVIEW -- Pharmacokinetic and Pharmacodynamic Issues Regarding the Comparability of Triazolam to Other Benzodiazepines -- Pharmacokinetic Issues -- Affinity for Benzodiazepine Receptors -- Lipophilicity -- Agonist Status -- Levels in Plasma -- Pharmacodynamic Interactions -- Unique Effects of Triazolobenzodiazepines on Locus Coeruleus Neurons -- Summary -- Consideration of Amnestic Effects of Halcion -- Performance of Memory Tasks After Single and Multiple Doses -- Spontaneous Reports of Memory Impairment -- Halcion and State-Dependent Learning -- Summary -- Review of Data Regarding Possible Anxiogenic or Insomniac Effects Associated with Halcion Administration or Withdrawal -- Halcion Effects on Daytime Anxiety -- Withdrawal-Related Anxiety or Insomnia Following Short- and Long-Term Halcion Use -- Rebound Anxiety -- Rebound Insomnia -- Summary -- Ataxia, Disinhibition, and Psychotogenic, Confusional, or Dissociative Effects of Halcion -- Consideration of Other Potential Adverse Effects -- Early Termination of Use -- Adverse Effects Defined Generally -- Other Adverse Effects -- Summaries and Meta-Analyses -- Closing Comments -- CONCLUSIONS AND RECOMMENDATIONS -- Clinical Trials and Surveillance -- 4 Additional Comments on Broader Implications -- References -- A FDA Safety Tables -- B Summary Tables of Literature Reviewed for Safety of Halcion.

C Glossary -- D Acronyms -- E Resources Reviewed by the Committee -- F Consent to Disclosure -- CONSENT TO DISCLOSURE -- G Committee and Staff Biographies -- COMMITTEE -- IOM STAFF.