Psychopharmacological Drugs Advisory Committee Meeting

3/29/01


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Table of Contents

Psychopharmacological Drugs Advisory Committee Meeting

Agenda

The Agitated Patient

Agitation

Agitation: Definition

Agitation: Clinical Implications

Agitation: A Major Clinical Challenge Psychiatric Emergency

Agitation: A Major Clinical Challenge Mechanical Restraint

Agitation: A Major Clinical Challenge Assaults

Parenteral Pharmacotherapy

Limitations of Parenteral Pharmacotherapy for Agitation

Acute Treatments for Agitation vs. Sustained Therapies for Specific Diseases

Clinical Development of IM Olanzapine

Optimal Features of IM Pharmacotherapy

History of Regulatory Interactions

Proposed Label Indication

Clinical Trial Challenges

Efficacy and Safety of IM Olanzapine

Mean Values of Olanzapine PK Variables: One 10 mg Oral Dose vs. Two 5 mg IM Doses

Mean Olanzapine Plasma Concentrations: One 10 mg Oral Dose vs. Two 5 mg IM Doses

Mean Olanzapine Plasma Concentrations: Three 10 mg IM Doses

Comparison of Cmax after IM Doses vs. Oral Olanzapine Steady-State Concentrations

Pharmacokinetic Profile of IM Olanzapine

Efficacy and Safety of IM Olanzapine

Selection of Efficacy Measures for the Assessment of Agitation

Core Battery of Agitation Scales

Selection of Primary Efficacy Measure: PANSS Excited Component

PANSS Excited Component: Items and Anchor Descriptions

Secondary Efficacy Measure: Agitation-Calmness Evaluation Scale (ACES)

Secondary Efficacy Measure: Corrigan Agitated Behavior Scale (CABS)

Secondary Efficacy Measure: Cohen-Mansfield Agitation Inventory (CMAI)

Criteria for Selected Patient Populations

Patient Populations Selected: Diverse Clinical Characteristics

Study Designs

Agitation: 4 Pivotal Studies

Comparator Dose Selection

Study Design: 4 Pivotal Studies 24 Hour IM Dosing Period

Criteria for Inclusion in Agitation Study

Other Entry Criteria

Patient Characteristics: Demographics

Clinical Characteristics at Baseline: Four Pivotal Studies

Baseline Level of Agitation: Mean PANSS EC Scores of 4 Pivotal Studies

PANSS Excited Component: Distribution of Total Scores at Baseline

Baseline Agitation Across Disease States* PANSS EC: Mean Scores of the 5 Items

Efficacy and Safety of IM Olanzapine

Primary Analysis: Efficacy at 2 Hours PANSS Excited Component Mean change from baseline to 2 hrs post first IM inj (LOCF)

Response Rates PANSS Excited Component - 2 Hours After First Injection

Efficacy at 24 Hours: PANSS Excited Component Mean change from baseline to 24 hrs (LOCF)

PANSS EC By-Item Analysis: 2 Hours (LOCF) Significant Contribution of All 5 Items: 5-10 mg Olz vs. Placebo

Efficacy at 2 Hours: Agitation-Calmness Evaluation Scale Mean Value at Endpoint - 2 hours (LOCF)

Efficacy in Agitation at 2 Hours: Corrigan / Cohen-Mansfield Mean change from baseline to 2 hours post first IM inj (LOCF)

Onset of Efficacy: PANSS EC Schizophrenia Study Timepoint-wise change from baseline to 2 hrs post first IM inj (LOCF)

Efficacy at 2 Hrs by Baseline Severity: Schizophrenia Study

Number of IM Injections During 24 Hours: Schizophrenia Dose Ranging Study

Efficacy Assessed by Presence of Psychosis Comparison at 2 Hours: Bipolar Study PANSS EC: Mean change from baseline (LOCF)

Efficacy Assessed by Presence of Psychosis Comparison at 2 Hrs: Dementia Study

Efficacy and Safety of IM Olanzapine

Summary of Safety Databases

Adverse Events

Adverse Events: Overall Patient Database Discontinuations and Serious Adverse Events

Adverse Events: 24 Hour IM Period Placebo-Controlled Database

Adverse Events: 24 Hour IM Period Geriatric Placebo-Controlled Database

Adverse Events: Summary Olanzapine vs. Haloperidol and Lorazepam

Sedation

Sedation Assessed Using: Agitation-Calmness Evaluation Scale

Sedation Assessed Using: Treatment-Emergent Adverse Events

Laboratory Analyses

Laboratory Results: Schizophrenia, Bipolar, and Dementia Studies

Vital Signs

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Bradycardia

Sinus Pauses

Bradycardia Proposed Mechanism: Vasovagal Response (i.e., Neurally Mediated Reflex Bradycardia)

Vital Signs: Change to Value Outside Reference Range - Any Time During 24 Hrs Placebo-Controlled Database

Vital Signs: Change to Value Outside Reference Range - Any Time During 24 Hrs Haloperidol-Controlled Database

Vital Signs: Change to Value Outside Reference Range Any Time During 24 Hrs Geriatric Placebo-Controlled Database

Incidence of Treatment-Emergent Dizziness and Syncope: Data from IM and Oral Studies

Electrocardiograms

QTc Intervals: 2 Hours Post-Injection Placebo-Controlled Database

QTc Intervals: 2 Hours Post-Injection Haloperidol-Controlled Database

Dementia Study: Age and Co-Morbid Conditions

Original QTc Data*: Dementia Study Mean Change from Baseline to 2 Hours

ECG Data from Dementia Study: Decision for Re-Read

Re-Read QTc Data*: Dementia Study Mean Change from Baseline to 2 Hours

QTc Intervals: 2 Hours Post-Injection Geriatric Placebo-Controlled Database

Comparison of Cmax after IM Doses vs. Oral Olanzapine Steady-State Concentrations

QTc Intervals: Normal to Prolonged 6-week Oral Study in Schizophrenia

Summary of ECG Data: Interval Data and Descriptive Findings

Extrapyramidal Symptoms

Extrapyramidal Symptoms: Schizophrenia Dose Ranging Study Mean change from baseline to 24 hrs post first IM inj (LOCF)

Extrapyramidal Symptoms: Schizophrenia Study Mean change from baseline to 24 hrs post first IM inj (LOCF)

Extrapyramidal Symptoms: Bipolar Mania Study Mean change from baseline to 24 hrs post first IM inj (LOCF)

Extrapyramidal Symptoms: Dementia Study Mean change from baseline to 24 hrs post first inj (LOCF)

Conclusions: Efficacy of IM Olanzapine

Conclusions: Safety of IM Olanzapine

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Author: rz90099