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
PPT Slide
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
PPT Slide
|