Halcion : an independent assessment of safety and efficacy data / Committee on Halcion: An Assessment of Data Adequacy and Confidence, Division of Health Sciences Policy, Division of Neuroscience and Behavioral Health, Institute of Medicine.

Format:

Book

Author/Creator:

Institute of Medicine (U.S.). Committee on Halcion: An Assessment of Data Adequacy and Confidence.

Language:

English

Subjects (All):

Triazolam.

Tranquilizing drugs.

Physical Description:

1 online resource (176 p.)

Edition:

1st ed.

Place of Publication:

Washington, D.C. : National Academy Press, 1997.

Language Note:

English

Summary:

Regulatory agencies within the United States and the United Kingdom, among several other countries, have reviewed extensively the safety and efficacy of Halcion (triazolam)--a once commonly used hypnotic drug. Concerns began to emerge about the safety of Halcion when a Dutch physician reported a possible link between it and a syndrome that included such effects as depression, amnesia, hallucinations, and increased anxiety. In addition, in 1991 its manufacturer, Upjohn, noted that "errors had been identified in a report of one of the clinical studies included in the original" application for approval. Since then, the drug has been removed from the market in several countries, whereas in the United States and Canada, the drug's labeling has been modified to reduce the recommended dose and duration of treatment and to heighten awareness of possible side effects. Yet different data and analyses have resulted in conflicting messages that are difficult to reconcile and interpret. In response to a request from the Food and Drug Administration to resolve these controversial issues related to the safety and efficacy of Halcion, this IOM book assesses the adequacy of the drug's clinical trials; the quality and quantity of data on adverse reactions; overall confidence in the data on effectiveness, adverse events, and side effects at different doses; and whether additional studies are needed.

Contents:

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

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

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

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

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

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

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

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

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

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.

Notes:

Bibliographic Level Mode of Issuance: Monograph

Includes bibliographical references.

ISBN:

9786610187201

9780309174442

0309174449

9781280187209

1280187204

9780309591454

0309591457

9780585156323

0585156328

OCLC:

43477344