Table of Contents
Edwin Hemwall, Ph.D. Regulatory Affairs
Back Problems Are a Common Medical Condition in the U.S.
Nonprescription FLEXERIL® 5 mg NDA 21-070
OTC Availability of Muscle Relaxants
OTC Availability of Muscle Relaxants
Flexeril OTC Development Program
Flexeril OTC Development Program
Flexeril OTC Development Program
Proposed Labeling for FLEXERIL 5 mg Tablets
Flexeril OTC Development Program
Consultants
Consultants
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Program Objectives
Outline of Presentation
Efficacy
Efficacy Questions for Pivotal Trials Studies 006 and 008
Design of Efficacy Studies
Efficacy Ratings Timeline
Efficacy Ratings by Patients Primary Endpoints
Criteria for a Successful Trial
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Primary Efficacy Results Study 006
Primary Efficacy Results Study 008
Mean Relief from Starting Backache
Time to “A Lot of” or “Complete” Relief Protocol 006 (Secondary Endpoint)
Time to “A Lot of” or “Complete” Relief Protocol 008 (Secondary Endpoint)
Magnitude of Effect % Responders - Difference vs. Placebo
Magnitude of Effect % Responders - Difference vs. Placebo
Effect Size
Efficacy Without Sedation Protocols 006 and 008 Combined Clinical Global Impression of Change - Visit 2
Spasm Rating by Physicians
Physician Rating of Muscle Spasm Mean Scores
Muscle Spasm by M.D. vs. Patient Ratings Protocols 006 and 008
Self-Diagnosis of Muscle Spasm
Efficacy Conclusions
Safety
Pharmacologic Effects of Cyclobenzaprine at Therapeutic Plasma Concentrations
Safety
Cyclobenzaprine Pharmacokinetics
Cyclobenzaprine Plasma Concentration by Age
Cyclobenzaprine Metabolism and Excretion Radiolabeled Oral Dose-10 mg
Pharmacokinetic Drug-Drug Interactions
Adverse Experiences
Clinical Adverse Experiences Protocols 006 and 008 Incidence ?2% on CYC 5
Discontinuations for Clinical Adverse Experiences Phase III Studies-Incidence ?0.5% on CYC 5
Adverse Experience Intensity Rating
Maximum Severity of Somnolence Protocols 006 and 008-Cyclobenzaprine 5 mg
First Report of Somnolence by Study Day Cyclobenzaprine 5 mg - Protocols 006 and 008
Adverse Experiences by Age Phase III-Cyclobenzaprine All Doses Reported by 2 or More Patients ?65 Years
Safety Conclusions Phase III Studies
Overview of Psychomotor Studies
Early Psychomotor Studies (001, 002, 003, 012)
Elderly Driving Related Skills Study (014) Design
Rationale for Test Battery
Elderly Driving Related Skills Study (014) Psychomotor Tests
Elderly Driving Related Skills Study (014) Critical Tracking Task: Lambda Score (N=32) Geometric Mean (95% CI)
Elderly Driving Related Skills Study (014) Psychomotor Tests
Elderly Driving Related Skills Study (014) Divided Attention Task: Overall Performance Score (N=32) Geometric Mean (95% CI)
Elderly Driving Related Skills Study (014) Psychomotor Tests
Elderly Driving Related Skills Study (014) Vigilance Task: Response Time (N=32) Geometric Mean (95% CI)
Elderly Driving Related Skills Study (014) Vigilance Task: Number of Errors (N=32) Geometric Mean (95% CI)
Psychomotor Study Conclusions Cyclobenzaprine 5 mg
Postmarketing Surveillance Study
Worldwide Adverse Experience System (WAES)
Spontaneous Reports to Merck - 10 mg
Spontaneous Reports - Fatal Outcomes WAES
Spontaneous Reports - Fatal Outcomes FDA Database
Life-Threatening Dysrhythmias WAES
Life-Threatening Dysrhythmias FDA Database
Spontaneous Reports - Seizures WAES
Spontaneous Reports - Seizures FDA Database
AAPCC Data Other OTC Drugs
Overdose American Association of Poison Control Centers (AAPCC)
AAPCC Summary of Outcomes
Weighted Emergency Department Estimates 1993
Abuse Potential
Safety Conclusions from Marketed Use
Label Development
Proposed Sedation Warnings
Proposed Warnings Ask a Doctor Before Use
Label Development
Concepts Well Understood Label Alone
Comprehension Results Ask a Doctor Before Use
Comprehension Results When Using this Product
Concepts Not Well Understood Label Alone
Label Comprehension Study Works Differently than Pain Relievers
Label Comprehension Study Efficacy on First Day
Revisions After Comprehension Study
Pattern-of-Use Study (009) Design
Pattern-of-Use Study (009) Compliance Data
Concomitant Analgesic Use (Study 009)
Summary Efficacy Results
Summary Safety Results
Summary Label Development
Overall Conclusions
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Pattern-of-Use Study (009) Global Responders by Prior Cyclobenzaprine Use
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Cyclobenzaprine Prescribed Dosing
Muscle Spasm by M.D. vs. Patient Ratings Protocols 006 and 008
Muscle Spasm by M.D. vs. Patient Global Protocol 006 - Visit 3 - CYC 5 mg
Patient-Rated Clinical Global Impression of Change Visit 2 Study 008 (All-Patients-Treated Approach)
Pattern-of-Use Study (009) Concomitant Analgesic Use
Spontaneous Reports - Hallucinations WAES
Spontaneous Reports - Hallucinations FDA Database
Label Comprehension Study Self-Selection: Reasons for Not Being Appropriate
Primary Efficacy Parameters - 006 and 008 Odds Ratios (95% CI) CYC 5 vs. Placebo All Patients Treated
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Reported Congenital Anomalies WAES
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