Approval Letter And Related Correspondence

Summary Basis of Approval Cover Form

Letter of Approval to James E. Murray Dated Oct 4, 1996 (Robert Temple, M.D.)
    Clinical (Blank)*
    Biopharmaceutics *
    Manufacturing and Controls *
      Expiration Date *
Memorandum Approval Action: NDA 20-358 (September 30, 1996) (Paul Leber, M.D.)

Memorandum Recommendation for Approval Action For Wellbutrin (bupropion) SR (September 16, 1996) (Thomas P. Laughren, M.D.)
    1.0 Background *
    2.0 Safety Update *
    3.0 Foreign Regulatory Status *
    4.0 Final Labeling *
    5.0 Expiration Date *
    6.0 Dissolution Specifications *
    Conclusions and Recommendations *
Approval Letter with Label and Safety Revision Requests (March 12, 1996) (Robert Temple, M.D.)
    Labeling *
    Safety Update *
    Regulatory Status Update *
    Manufacturing and Controls *
      Expiration Date *
      Container Labels *
    Biopharmaceutics *
      Dissolution Specification *
Memorandum Approval Action: NDA 20-358 (February 26, 1996) (Paul Leber, M.D.)
    Efficacy *
    Safety and Labeling *
    Discussion *
    Recommendation *
Memorandum Proposed Changes to Approvable Letter and Draft Labeling (March 6, 1996) (Thomas P. Laughren, M.D.)
    Responses to questions:
    Bupropion/Metabolites Pharmacokinetics (p. 3) *
    Left Ventricular Dysfunction Population Subgroup (p. 4) *
    Drug Interactions (p. 14) *
    Carcinogenesis, etc and Pregnancy (pp. 14-15) *
Memorandum Recommendation for Approval Action For Wellbutrin (bupropion) SR (February 8, 1996) (Thomas P. Laughren, M.D.)
    1.0 Background *
    2.0 Labeling Revision *
      Clinical Pharmacology *
        Pharmacodynamics *
        Pharmacokinetics *
        Clinical Trials *
      Indications and Usage *
      Warnings *
      Precautions *
      Adverse Reactions *
      Dosage and Administration *
    3.0 Conclusions and Recommendations *
Final Printed Label


Medical Officers Review

Addendum to Review and Evaluation of Clinical Data (May 14-15, 1996)
    I. Background *
    II. Safety Update *
      A. Database *
      B. Review of Safety Data *
        Methodology *
        Serious Adverse Events *
        Adverse Events Leading to Premature Discontinuation *
      C. Conclusions *
    III. Foreign Regulatory Actions *
    IV. Introductory Promotional Materials *
    V. Labeling *
Review and Evaluation of Clinical Data (March 7, 1994; Completed November 14, 1994)
    Table of Contents *
      1.0 Material Utilized in Review *
        1.1 Material from NDA *
        1.2 Related Reviews *
      2.0 Background *
        2.1 Indication *
        2.2 Related INDs and NDAs *
        2.3 Administrative History *
        2.4 Proposed Directions for Use *
        2.5 Foreign Marketing *
      3.0 Chemistry *
      4.0 Animal Pharmacology
      5.0 Description of Clinical Data Sources *
        5.1 Primary Development Program *
          5.1.1 Study Type and Design/Patient Enumeration *
          Table 5.1.1 Summary of All Studies *
          5.1.2 Demographics *
            Table 5.1.2.1 Demographic Profile of Bupropion sustained-release for Phase 1 Studies *
            Table 5.1.2.2 Demographic Profile for Phase 2 and 3 Clinical Efficacy Studies *
            Table 5.1.2.3 Demographic Profile for Phase 3 Seizure Incidence Study *
          5.1.3 Extent of Exposure (dose/duration) *
            Table 5.1.3.1 Number and Percentage of All Volunteers Receiving Bupropion Sustained-Release According to Mean Daily Dose and Duration in Phase 1 Clinical Pharmacology Studies *
            Table 5.1.3.2 Number and Percentage of All Patients Receiving Bupropion Sustained-Release According to Mean Daily Dose and Duration in all Phase 2 and 3 Studies *
        5.2 Secondary Sources *
          5.2.1 Post-Marketing Experience *
          5.2.2 Literature *
      6.0 Summary of Human Pharmacokinetics *
      7.0 Efficacy Findings *
        7.1 Overview of Studies Pertinent to Efficacy *
        7.2 Overview of Studies Pertinent to Efficacy *
          7.2.1 Study 203 *
            7.2.1.1 Investigators and Location *
            7.2.1.2 Study Plan *
              7.2.1.2.1 Objective/Rationale *
              7.2.1.2.2 Population *
              7.2.1.2.3 Planned Study Conduct/Dosing Plan *
              7.2.1.2.4 Efficacy Assessments *
              7.2.1.2.5 Safety Assessment *
              7.2.1.2.6 Analysis/Plan *
            7.2.1.3 Study Conduct and Outcome *
              7.2.1.3.1 Patient Disposition *
              Table 7.2.1.3.1 Reason for Premature Study Discontinuation from Protocol 203 *
              7.2.1.3.2 Demographic Characteristics *
              7.2.1.3.3 Baseline Illness Severity *
              7.2.1.3.4 Dosing Information *
              7.2.1.3.5 Concomitant Medications *
              7.2.1.3.6 Efficacy Results *
              Table 7.2.1.3.6 Summary of Efficacy Variables in Study 203 *
                7.2.1.3.6.1 17-Item HAMD *
                7.2.1.3.6.2 28-Item HAMD *
                7.2.1.3.6.4 CGI-S *
                7.2.1.3.6.5 CGI-I *
            7.2.1.4 Conclusions *
          7.2.2 Study 205 *
            7.2.2.1 Investigators and Location *
            7.2.2.2 Study Plan *
              7.2.2.2.1 Objectives/Rationale *
              7.2.2.2.2 Population *
              7.2.2.2.3 Planned Study Conduct/Dosing Plan *
              7.2.2.2.4 Efficacy Assessments *
              7.2.2.2.5 Safety Assessments *
              7.2.2.2.6 Analysis/Plan *
            7.2.2.3 Study Conduct and Outcome *
              7.2.2.3.1 Patient Disposition *
              Table 7.2.2.3.1 Reasons for Premature Study Discontinuation from Protocol 205 *
              7.2.2.3.2 Demographic Characteristics *
              7.2.2.3.3 Baseline Illness Severity *
              7.2.2.3.4 Dosing Information *
              7.2.2.3.5 Concomitant Medications *
              7.2.2.3.6 Efficacy Results *
              Table 7.2.2.3.6 Summary of Efficacy Variables in Study 205 *
                7.2.2.3.6.1 17-Item HAMD *
                7.2.2.3.6.2 28-Item HAMD *
                7.2.2.3.6.3 HAMD-Item #1 *
                7.2.2.3.6.4 CGI-S *
                7.2.2.3.6.5 CGI-I *
            7.2.2.4 Conclusions *
          7.2.3 Other Studies *
        7.3 Summary of Data Pertinent to Important Clinical Issues *
          7.3.1 Predictors of Response *
          7.3.2 Size of Treatment Effect *
          7.3.3 Choice of Dose *
          7.3.4 Duration of Treatment *
        7.4 Conclusions Regarding Efficacy Data *
      8.0 Safety Findings *
        8.1 Methods *
        8.2 Deaths *
        8.3 Assessment of Dropouts *
          8.3.1 Overall Pattern of Dropouts *
            Table 8.3.1.1 Incidence of Dropout by Treatment Group and Reason in Protocols 203 and 205 *
            Table 8.3.2.1 Incidence of Dropout by Treatment Group and Reason in Protocol 208 *
          8.3.2 Adverse Events Associated with Dropout *
        8.4 Safety Findings Discovered with Other Specific Search Strategies *
        8.5 Other Safety Findings *
          8.5.1 ADE Incidence Tables *
            Table 8.5.1.1 Treatment Emergent Adverse Experiences in Placebo-Controlled Phase 2-3 Trials (Reported by at least 1% of Patients Treated with Bupropion Sustained-Release) *
            Common Drug-Related Adverse Events *
            Drug Response for Common, Drug-Related Adverse Events *
            Table 8.5.1.2 Treatment Emergent Adverse Experiences in Placebo-Controlled Phase 2-3 Trials (Reported by at least 1% of Patients Treated with Bupropion Sustained-Release with Dose Dependency Apparent) *
          8.5.2 Laboratory Findings *
            8.5.2.1 Serum Chemistry *
              Table 8.5.2.1.1 Proportions of Patients Having Potentially Clinically Significant Changes in Serum Chemistry Variables in Protocols 203 and 205) *
              Table 8.5.2.1.2 Wilcoxon Rank Sum Analysis of Clinical Chemistry Changes Scores in Protocols 203 and 205 *
            8.5.2.2 Hematology *
              Table 8.5.2.2.1 Proportions of Patients Having Potentially Clinically Significant Changes in Hematology Variables in Protocols 203 and 205 *
              Table 8.5.2.2.2 Wilcoxon Rank Sum Analysis of Hematology Change Scores in Protocols 203 and 205 *
            8.5.2.3 Urinalysis *
            Table 8.5.2.3 Proportions of Patients Having Potentially Clinically Significant Changes in Urinalysis Variables in Placebo-Controlled Studies 203 and 205 *
          8.5.3 Vital Signs and Weight *
          Table 8.5.3 Differences in Effect of Bupropion Sustained-Release vs. Placebo on Vital Signs *
          8.5.4 Electrocardiograms *
          8.5.5 Special Studies *
          Table 8.5.5 Number of Patients in Cohort by Treatment Day of Protocol 208 *
          8.5.6 Withdrawal Phenomena/Abuse Potential *
          8.5.7 Human Reproduction Data *
          8.5.8 Overdose Experience *
        8.6 Summary of Important Adverse Events Considered Drug Related *
          8.6.1 Seizures *
          8.6.2 Allergic Phenomena *
          8.6.3 Anxious States *
          8.6.4 Theoretical Risk of Treatment-Emergent Mania *
        8.7 Summary of Other Important Adverse Events Considered Not Drug Related *
        8.8 Summary of Drug Interactions *
          8.8.1 Drug-Demographic Interactions *
          8.8.2 Drug-Disease Interactions *
          8.8.3 Drug-Drug Interactions *
      9.0 Labeling Review *
      10.0 Conclusions *
      11.0 Recommendations *
Appendix Statistical Review Chemist Review ( Date Reviewed: 28-Aug-96) Letter of Non-Approval (Robert Temple, M.D. May 25, 1995)
    Letter of Non-Approval
      Overview of Basis for Non-Approval Decision*
      Deficiencies in the Efficacy Data *
      Study Results *
      Comments on Efficacy Data for Individual Studies
        Study 203
          Unadjusted Results *
          Adjusted Results *
          Impression *
        Study 205
          Unadjusted Results *
          Adjusted Results *
          Impression *
        Study 212
          Unadjusted Results *
          Adjusted Results *
          Impression *
        Overall Conclusions Regarding Efficacy Data for Bupropion SR *
        Deficiencies in the Chemistry and Manufacturing *
        Deficiencies in the Environmental Assessment *
          Item 4. Description of the Proposed Action *
            Requested Approval *
            Need for Action *
            Production Locations *
          Item 7. Fate of Emitted Substances in the Environment *
          Item 8. Environmental Effects of Released Substances *


Enclosures Review and Evaluation of Clinical Data (September 22, 1995)
    I. Description of Compound *
    II. Background *
    III. Data Reviewed Proposed Labeling for Wellbutrin SR *
      Clinical Pharmacology Section *
      Absorption, Distribution, Pharmacokinetics, and Elimination Section *
      Indications and Usage Section *
      Contraindications Section *
      Warning Section *
        Seizures *
        Hepatotoxicity *
      Precautions Section *
      Information to Patients Section *
      Drug Interactions, Carcinogenesis-Mutagenesis-Impairment-of-Fertility, Pregnancy, and Pediatric Use Sections *
      Adverse Events Section *
    III. Conclusions and Recommendations *
Review of Chemistry, Manufacturing, and Controls

Review of Environmental Assessment for NDA 20-358 (October 26, 1995) Environmental Assessment and Finding of No Significant Impact
    Finding of No Significant Impact

    Environmental Assessment Information
      4. Description of Proposed Action *
        4.a Describe the requested approval *
        4.b Describe the need for action *
        4.c Describe Location(s) Where the Product(s) are to be
          1. Produced *
          2. Used *
          3. Disposed *
        4.d Describe the Type of Environment Present at and Adjacent to Production and Disposal Sites *
      5. Identification of Chemical Substances That are Subject to the Proposed Action *
      6. Introduction of Substances into the Environment * 7. Fate of Emitted Substances in the Environment *
        7.a Aquatic Compartment *
          Water Solubility *
          Hydrolysis Rate *
          Dissociation Constant *
          Aerobic Biodegradation *
          Photodegradation *
          Summary *
        7.b Air Compartment *
          Vapor Pressure Estimate *
          UV Spectra *
          Summary *
        7.c Terrestrial Compartment *
          n-Octonal/Water Partition Coefficient (Log P) *
          Summary *
        7.d Bioavailability and Metabolites *
      8. Environmental Effects of Release Substances *
        Microbial Growth Inhibition *
        Additional Toxicity Information *
      9. Use of Resources and Energy *
        9.a Use of Water and Energy *
          Drug Substance *
          Drug Product *
          Waste Disposal *
          Transportation of Drug Product *
        9.b Effects on Endangered or Threatened Species and Upon Property Listed in or Eligible for Listing in the National Register of Historic Places *
      10. Mitigation Measures *
        10.a Primary Manufacturing Division (PMD) *
          Procedure for Off-Site Chemical Waste Disposal *
          Training Documentation for PMD Facility Personnel in the Handling of Chemical Waste *
          Determination of the Composition of PMD Waste Streams *
          Reporting of PMD Incidents or Accidents *
          PMD Emergency Plan *
          PMD Spill Containment Plan * Vent Spill Containment System for PMD Module Building *
          Transfer Lines Between PMD and Environmental Services *
          Draining Containment Dikes and Trenches in PMD *
          Emission Control for Reactors, Crystallizers, and Centrifuges *
          Fugitive Emissions Monitoring *
          Recycling of Fiber Level-Paks *
        10.b Product Formulation Areas (SDFMD) *
          Dress Code and Safety Precautions for SDFMD *
          Procedure to Ensure CGMP Compliance in SDFMD *
          Response to Audible Alarms in the Solid Dose Formulations Manufacturing Department *
          Removal of Product Waste from SDFMD *
          Volatile Organic Compound (VOC) Emission reporting for SDFMD Coating *
        10.c Environmental Services Department *
          Spill Control Contingency Plan (SCCP) *
          Procedure for Monitoring Cooling Water Discharged to Parkers Creek in Compliance with NPDES (National Pollutant Discharge Elimination System) Permit NC001058 *
          Astro Unit Operating Procedures *
          Responsibilities of Burroughs Wellcome Co. Hazardous Materials Response Team (HAZMAT) *
          Wastewater Pre-treatment Plant (WWPP) and Wastewater Monitoring Operations Inspection/Corrective Actions *
          Labeling Disposition, and On-Site Destruction of Product-Related Waste *
          Operation of the Solid Waste Incinerator *
        10.d Corporate Policies *
          Corporate Policy #306, Waste Minimization and Disposal *
          Corporate Policy #307, Solid Waste Recycling *
      11. Alternatives to the Proposed Action *
      12. List Preparers of the Assessment *
      13. Certification *
      14. References *

    Misc Physical Chemical Data/Environmental Data
          Hydrolysis Rate *
          Dissociation Constant *
          n-Octanol/Water Partition Coefficient *
          Vapor Pressure Estimate *
          Aqueous Biodegradation Half Life *
          Photodegradation in Water *
          LC50s (Microbial Inhibition) *
          LD50s*
Attachment I
    Material Safety Data Sheet for Bupropion Hydrochloride
      Material Safety Data Sheet
        Section I: Identification *
        Section II: Hazardous Ingredients of Mixtures *
        Section III: Physical Data *
        Section IV: Fire and Explosion Data *
        Section V: Health Hazard Data *
        Section IV: Reactivity Data *
        Section VII: Spill or Leak Procedures *
        Section VIII: Special Protection Information *
        Section IX: Special Precautions *
        Section X: References *

    Review of Chemistry, Manufacturing, and Controls (August 15, 1994) (Unapproval) *
    Review of Chemistry, Manufacturing, and Controls (March 7, 1995) (Unapproval) *

Sensitive - Review of Environmental Assessment #1 (January 10, 1995)
    Environmental Assessment (Adequate/Deficient) *
      4. Description of the Proposed Action *
        a. Requested Approval *
        b. Need for Action *
        c. Production Locations *
          i. Proprietary Intermediate(s) *
          ii. Drug Substance *
          iii. Finished Dosage Form *
        d. Expected Locations of Use (Drug Product) *
        e. Disposal Locations *
        f. Description of type of environments present at or adjacent to production and disposal sites *
      5. Identification of Chemical Substances That are the Subject of the Proposed Action *
        Drug Substance *
        Impurities *
      6. Introduction of substances into the environment: For the site(s) of production *
        a. Potential Emitted Substances *
        b. Controls (Air, Liquid Effluent, Solid) *
        c. Compliance with Federal, State, and Local Emission Requirements *
        d. Effect of Approval on Compliance with Current Emissions Requirements *
        e. Estimated Expected Emitted Concentration/Quantities *
      7. Fate of Emitted Substances in the Environment *
      8. Environmental Effects of Released Substances *
      9. Use of Resources and Energy *
        a. Use of Water and Energy *
        b. Effect on endangered or threatened species and property listed in or eligible for listing in the National Register of Historic Places *
      10. Mitigation measures *
      11. Alternativs to the Proposed Action *
      12. List of Preparers and Their Qualifications *
      13. Cerification *
      14. References *
      15. Appendices *

      Draft Deficiency Letter *
Attachments Pharmacologist Review
    Pharmacologist Review of NDA 20-358
      New Preclinical Studies Submitted *
      Table of Contents *
      90 day p.o. toxivity in rats *
        A) Dosage *
        B) Results *
          1) Observed signs *
          2) Mortality *
          3) Bodyweight *
          4) Food consumption *
          5) Ophthalmoscopic exam *
          6) Hemaology *
          7) Blood Chemistry *
          8) Urinalysis *
          9) Organ Weights *
            a) Liver *
            b) Thyroid *
            c) Adrenal *
            d) Kidney *
          10. Gross pathology *
          11. Microscopic pathology *
            a) Liver *
            b) Kidney *
          12. PK data *
            Table 8. Pharmacoidentic Parameters for Bupropion and 306U73 in Rats on Day 10 Following and Oral Administration of Bupropion(TOX 648) *
            Table 9. Pharmacoidentic Parameters for Bupropion and 306U73 in Rats on Day 82 Following and Oral Administration of Bupropion (TOX 648) *
      Segment II reproduction in rats *
        Dosage *
        Results *
          1) Observed signs *
          2) Mortality *
          3) Bodyweight *
          4) Food Consumption *
          5) Reproductive data *
          6) Fetal exam *
          7) PK data * Genotoxicity Studies
            Ames tests *
              Plate incorporation method *
              Preincubation Method *
            In vivo cytogenetic study in rats *
              Dosage *
              Results *
                a) Observed signs *
                b) Mortality *
                  Table 2. Mutagenicity Assay Results - Summary - Plate Incorporation *
                  Table 3. Mutagenicity Assay Results - Individual Plate Counts and Summary - Plate Incorporation *
                  Table 2. Mutagenicity Assay Results Summary Preincubation
                c) Bodyweight *
                d) Cytogenetic data *
                e) PK Data *
                  Table 11. Summary of Structural Aberrations *
                  Table 12. Percentage of Cells with Non-Diploid Chromosome Nos *
                  Table 2. Individual Plasma Concentrations of Bupropion and 306U73 in Rats on Day 5 Following and Oral Adminstration of Bupropion (MUT 223) *
            Summary *

          Labelling *
            Table 2. Comparison of the Seizures Produced in Mice by Oral Doses of a 2 hr Controlled Release Formulation of Bupropion to Those Produced by Oral Doses of Bupropion HCl in Water *
            Figure 1. Bupropion Control Release vs Buporpion HCl - Mouse PO 60 mg/kg *
            Figure 1. Controlled Release - Bupropion in Plasma - 2 hr release beads 60 mg/kg *
            Figure 2. Instant Release - Bupropion in Plasma - Dist. Water Soln., 60 mg/kg *
            Figure 3. Controlled Release - 306U73 in Plasma - 2 hr release beads 60 mg/kg *
            Figure 4. Instant Release - 306U73 in Plasma - Dist. Water Soln., 60 mg/kg *
            Figure 5. Controlled Release - 494U73 in Plasma - 2 hr release beads 60 mg/kg *
            Figure 6. Instant Release - 494U73 in Plasma - Dist. Water Soln., 60 mg/kg *
          Labeling Continued *
            Table 1. The Effects of Bupropion and Three of its Major Metabolites in the Antitertrabenazine (Anti-TBZ) and Lethal Effects (LD50) in the Mouse After Intraperitoneal Administration *
            Chemical Structures: 17U67, 494U73, 287U73, 306U73 *
          Evaluation *
          Recommendations *
Biopharmaceutics Review March 21, 1995 Review of Original NDA (June 22, 1994)
Misc Letter

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