Wellbutrin XL® NDA 21-515 Cover Letter - Approval Package August 28, 2003
Wellbutrin XL® NDA 21-515 Approval Package - Contents August 28, 2003
Approval Letter
Labeling *
Drug Product Expiry *
Dissolution Specifications *
Risk Managment Plan and Post-Marketing Commitment *
Patient Education *
Methods Validation *
Promotional Materials *
MedWatch-to-Manufacturer Program *
Approvable Letter 1
Proposed Trademark Wellbutrin XL *
Chemistry, Manufacturing, and Controls (CMC) *
CMC: Methods Validation *
CMC: Categorical Exclusion *
Clinical Pharmacology and Biopharmaceutics *
Clinical/Clinical Safety *
Request for Safety Update *
Labeling (Package Insert and Container Labeling) *
Promotional Materials *
Options Under 21 CFR 314.110 *
Opportunity for Informal Meeting Under 21 CFR 314-102(d) *
Content Page - Pages Withheld
Approved Labeling
Description *
Clinical Pharmacology *
Pharmacodynamics *
Pharmacokinetics *
Absorption *
Distribution *
Metabolism *
Elimination *
Population Subgroups *
Hepatic *
Renal *
Left Ventricular Dysfunction *
Age *
Gender *
Smokers *
Clinical Trials *
Indications and Usage *
Contraindications *
Warnings *
Seizures *
Dose *
Patient Factors *
Recommendations for Reducing the Risk of Seizure *
Precautions *
General: Agitiation and Insomnia *
Table 1. Incidence of Agitation, Anxiety and Insomnia in Placebo-Controlled Trials *
Psychosis, Confusion, and Other Neuropsychiatric Phenomena *
Activation of Psychosis and/or Mania *
Altered Appetite and Weight *
Table 2. Incidence of Weight Gain and Weight Loss in Placebo-Controlled Trials *
Suicide *
Allergic Reactions *
Cardiovascular Effects *
Hepatic Impairment *
Renal Impairment *
Information for Patients *
Laboratory Tests *
Drug Interactions *
Drugs Metabolized By Cytochrome P460IID6 (CYP2D6) *
MAO Inhibitors *
Levodopa and Amantadine *
Drugs That Lower Seizure Threshold *
Nicotine Transdermal System *
Carcinogenesis, Mutagenesis, Impairment of Fertility *
Pregnancy: Teratogenic Effects *
Labor and Delivery *
Nursing Mothers *
Pediatric Use *
Geriatric Use *
Adverse Reactions *
Incidence in Controlled Trials With Bupropion: Adverse Events Associatd With Discontinuation of Treatment Among Patients Treated With Bupropion *
Table 3. Treatment Discontinuation Due to Adverse Events in Placebo-Controlled Trials *
Adverse Events Occurring at an Incidence of 1% of More Among Patients Treated With Bupropion *
Table 4. Treatment-Emergent Adverse Events in Placebo-Controlled Trials *
Incidence of Commonly Observed Adverse Events in Controlled Clinical Trials *
300 mg/day of the Sustained-Release Formulation *
400 mg/day of the Sustained-Release Formulation *
Other Events Observed During the Clinical Development and Postmarketing Experience of Bupropion *
Body (General) *
Cardiovascular *
Digestive *
Endocrine *
Hemic and Lymphatic *
Metabolic and Nutritional *
Musculoskeletal *
Nervous System *
Respiratory *
Skin *
Special Senses *
Urogenital *
Drug Abuse and Dependence *
Controlled Substance Class *
Humans *
Animals *
Overdosage *
Dosage and Administration
General Dosing Considerations *
Initial Treatment *
Increasing the Dosage Above 300 mg/day *
Switching Patients From Wellbutrin Tablets or From Wellbutrin SR *
Sustained-Release Tablets *
Maintenance Treatment *
Dosage Adjustment For Patients With Impaired Hepatic Function *
Dosage Adjustment For Patients With Impaired Renal Function *
How Supplied *
Patient Information - Detachable Leaflet *
Medical Review
Clinical Review of Safety
I. Overview & Summary of Safety Conclusions *
II. Introduction and Background *
A. Drug Established and Proposed Trade Name, Drug Class, Sponsor's Proposed Indication, Dose, Regimens, Age Group *
B. Discussions with the Division about the NDA Submission *
C. Foreign Marketing History *
III. Clinical Relevant Findings from Chemistry, Biopharmaceutics *
IV. Safety Analysis of WELLBUTRIN XL *
A. Description of Clinical Data and Sources *
B. Exposures, Deaths, SAE, Discontinuation due to AE, and Common AE in the Bioavailablity Studies*
Table 1. Safety Parameters for the 5 Bioavailability Studies with WELLBUTRIN XL *
Table. 2. Common Adverse Events in WellBURIN XL Bioavailablity Studies
C. Safety Data from 3 Ongoing Clinical Trials Using WellBUTRIN XL *
(Table 3.) Discontinuations due to Adverse Events in Ongoing Trials
D. Post-Marketing Experience *
IV. (s/b V.) Conclusions *
Review of Complete Response to Approvable Letter
1. Overview and Summary Conclusions *
II. Review of Safety Updae for WELLBUTRIN XL *
A. Description of Clinical Data and Sources *
A. Deaths, SAE, Discontinuations due to AE, and Common AE *
Serious Adverse Events *
Discontinuations due to Adverse Events *
Pregnancy *
Most Commonly Reported Adverse Events *
IV. Conclusions *
Chemistry Review(s) 8/29/03
Table of Contents*
Chemistry Review Data Sheet - Review #4 - 8/28/03*
Chemisty Review Template *
The Chemistry Review for NDA 21-515 *
The Executive Summary *
I. Recommendations *
A. Recommendation and Conclusion on Approvability *
B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk Management Steps, if Approvable *
II. Summary of Chemistry Assessments *
A. Description of the Durg Product(s) and Drug Substance(s) *
B. Description of How the Drug Product is Intended to be Used *
C. Basis of Approvability or Not Approval-Recommendation *
III. Administrative *
A. Reviewer's Signature *
B. Endorsement Block *
C. CC Block *
Chemistry Assessment (These two [2] pages were not included in package.)
Establishment Evaluation Request
Chemistry Review(s) 8/15/03
Table of Contents *
Chemistry Review Data Sheet - Review #3 - 8/15/03*
The Executive Summary *
I. Recommendations *
A. Recommendation and Conclusion on Approvability *
B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk Management Steps, if Approvable *
II. Summary of Chemistry Assessments *
A. Description of the Drug Product(s) and Drug Substance(s) *
B. Description of How the Drug Product is Intended to be Used *
C. Basis for Approvability or Not-Approval Recommendation *
III. Administrative *
A. Reviewer's Signature *
B. Endorsement Block *
C. CC Block *
Chemistry Assessment (Page not included in packet)
I. Drug Substance (Page not included in packet)
1. Description & Characterization (Page not included in packet)
a. Description (Page not included in packet)
b. Characterization / Proof of Structure (Page not included in packet)
2. Manufacturer (Page not included in packet)
3. Synthesis / Method of Manufacture (Page not included in packet)
a. Starting Materials - Specs & Tests (Page not included in packet)
b. Solvents, Reagents, etc. (Page not included in packet)
c. Flow Chart (Page not included in packet)
d. Detailed Description (Page not included in packet)
4. Process Controls (Page not included in packet)
a. Reaction Completion / Other In-Process Tests (Page not included in packet)
b. Intermediate Specs & Tests (Page not included in packet)
5. Reference Standard (Page not included in packet)
a. Preparation (Page not included in packet)
b. Specifications (Page not included in packet)
6. Regulatory Specifications / Analytical Methods (Page not included in packet)
a. Drug Substance Specifications & Tests (Page not included in packet)
b. Purity Profile (Page not included in packet)
c. Microbiology (Page not included in packet)
7. Containter / Closure System For drug Substance Storage (Page not included in packet)
8. Drug Substance Stability (Page not included in packet)
II. Drug Product (Page not included in packet)
1. Components / Composition (Page not included in packet)
2. Specifications & Methods For Drug Product Ingredients (Page not included in packet)
a. Active Ingredient(s) (Page not included in packet)
Inactive Ingredients (Page not included in packet)
3. Manufacturer (Page not included in packet)
4. Methods of Manufacturing and Packaging (Page not included in packet)
a. Production Operations (Page not included in packet)
b. In-Process Controls & Tests (Page not included in packet)
c. Reprocessing Operations (Page not included in packet)
5. Regulatory Specifications and Methods For Drug Product (Page not included in packet)
a. Sampling Procedures (Page not included in packet)
b. Regulatory Specifications and Methods (Page not included in packet)
6. Container / Closure System (Page not included in packet)
7. Microbiology (Page not included in packet)
8. Drug Product Stability (Page not included in packet)
III. Investigational Formulations (Page not included in packet)
IV. Environmental Assessment (Page not included in packet)
V. Methods Validation (Page not included in packet)
VI. Labeling (Page not included in packet)
VII. Establishment Inspection (Page not included in packet)
VIII. Draft Deficiency Letter (Page not included in packet)
Chemistry Review(s) 5/23/03
Table of Contents *
Chemistry Review Data Sheet - Review #1 - 5/23/03*
The Executive Summary *
I. Recommendations *
A. Recommendation and Conclusion on Approvability *
B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk Management Steps, if Approvable *
II. Summary of Chemistry Assessments *
A. Description of the Drug Product(s) and Drug Substance(s) *
B. Description of How the Drug Product is Intended to be Used *
C. Basis for Approvability or Not-Approval Recommendation *
III. Administrative *
A. Reviewer's Signature *
B. Endorsement Block *
C. CC Block *
Chemistry Assessment (Page not included in packet)
I. Drug Substance (Page not included in packet)
1. Description & Characterization (Page not included in packet)
a. Description (Page not included in packet)
b. Characterization / Proof of Structure (Page not included in packet)
2. Manufacturer (Page not included in packet)
3. Synthesis / Method of Manufacture (Page not included in packet)
a. Starting Materials - Specs & Tests (Page not included in packet)
b. Solvents, Reagents, etc. (Page not included in packet)
c. Flow Chart (Page not included in packet)
d. Detailed Description (Page not included in packet)
4. Process Controls (Page not included in packet)
a. Reaction Completion / Other In-Process Tests (Page not included in packet)
b. Intermediate Specs & Tests (Page not included in packet)
5. Reference Standard (Page not included in packet)
a. Preparation (Page not included in packet)
b. Specifications (Page not included in packet)
6. Regulatory Specifications / Analytical Methods (Page not included in packet)
a. Drug Substance Specifications & Tests (Page not included in packet)
b. Purity Profile (Page not included in packet)
c. Microbiology (Page not included in packet)
7. Containter / Closure System For drug Substance Storage (Page not included in packet)
8. Drug Substance Stability (Page not included in packet)
II. Drug Product (Page not included in packet)
1. Components / Composition (Page not included in packet)
2. Specifications & Methods For Drug Product Ingredients (Page not included in packet)
a. Active Ingredient(s) (Page not included in packet)
Inactive Ingredients (Page not included in packet)
3. Manufacturer (Page not included in packet)
4. Methods of Manufacturing and Packaging (Page not included in packet)
a. Production Operations (Page not included in packet)
b. In-Process Controls & Tests (Page not included in packet)
c. Reprocessing Operations (Page not included in packet)
5. Regulatory Specifications and Methods For Drug Product (Page not included in packet)
a. Sampling Procedures (Page not included in packet)
b. Regulatory Specifications and Methods (Page not included in packet)
6. Container / Closure System (Page not included in packet)
7. Microbiology (Page not included in packet)
8. Drug Product Stability (Page not included in packet)
III. Investigational Formulations (Page not included in packet)
IV. Environmental Assessment (Page not included in packet)
V. Methods Validation (Page not included in packet)
VI. Labeling (Page not included in packet)
VII. Establishment Inspection (Page not included in packet)
VIII. Draft Deficiency Letter (Page not included in packet)
Clinical Pharmacology And Biopharmaceutics Review(s)
Executive Summary *
Recommendations and Comments to Sponsor *
Possible Drug Interactions *
Table of Contents *
Summary of Clinical Pharmacology and Biopharmaceutics Findings *
4.1 Background *
4.2 Current Submission *
3.2.1 Dissolution Specifications *
3.2.2. Evaluation of the Potential for Drug Interactions *
3.2.3. Recommended Labeling Changes *
4.3 Recommendations *
5. References *
Clinical Pharmacology and Biopharmaceutics Review 5/12/03
1 Executive Summary *
- Bioequivalence
1.1 Recommendations and Comments to Sponsor *
2 Table of Contents *
3 Summary of Clinical Pharmacology and Biopharmaceutics Findings *
3.1 Background *
3.2 Current Submission *
4 Question-Based Review *
4.1 General Attributes *
4.1.1 What are the highlights of the chemistry and physical=chemical properties of Wellbutrin XL, and the formulation of the drug product?
Composition of Wellbutrin Tablets Table *
4.1.2 What is the proposed mechanism of drug action and what is the proposed therapeutic indication? *
4.1.3 What is the proposed dosage and route of administration *
4.1.4 What efficacy and safety information contributes to the assessment of clinical pharmacology and biopharmaceutics study data (e.g., can disparate efficacy measurements or adverse events reports to be attributed to intrinsic or extrinsic factors that alter drug exposure/response relationships in patients)?
4.2 General Clinical Pharmacology *
4.2.1 What is the basis for selecting the response endpoints, i.e., clinical or surrogate endpoints, or biomarkers (also called pharmacodynamics, PD) and how are they measured in clinical pharmacology and clinical studies. *
4.2.2 Are the active moieties in the plasma (or other biological fluid) appropriately indentified and measured to assess pharmacokinetic parameters and exposure response relationships? *
4.2.3 What are the characteristics of the exposure-response relationships (dose-response, concentration-response) for efficacy and safety? *
- Based on PK parameters, what is the degree of linearity or nonlinearity in the dose-concentration relationship for WELLBUTRIN XL? *
- Do PK Parameters change with time following chronic dosing? *
- How long is the time to onset and offset of the pharmacological response or clinical endpoint?
*
- Are the dose and dosing regimen consistent with the known relationship between dose-concentration-response, and are there any unresolved dosing or administration issues?
*
4.2.4 What are the basic pharmacokinetic parameters after administration of WELLBUTRIN XL and how does the PK of the drug and its major active metabolites in healthy volunteers compare to that in patients?
A HREF="WellXLNDAPg119.htm">*
4.2.5 What is the inter-subject variability of PK parameters in volunteers and patients, and what are the major causes of variability? *
4.3 Intrinsic Factors *
4.3.1 What intrinsic factors (age, gender, race, weight, height, disease, genetic polymorphism, pregnancy, and organ dysfunction) influence exposure and/or response and what is the impact of any differences in exposure on the pharmacodynamics? *
4.3.2 Based upon what is known about exposure-response relationships and their variability, and the groups studied, what dosage regimen adjustments, if any, are recommended for each of these groups? *
4.4 Extrinsic Factors *
4.4.1 What extrinsic factors (drugs, herbal products, diet, smoking, and alcohol use) influence exposure and/or response and what is the impact of any differences in exposure on pharmacodynamics? *
4.4.2 Based upon what is known about exposure-response relationships and their variability, what dosage regimen adjustments, if any, do you recommend for each of these factors: If dosage regimen adjustments across factors are not based on the exposure-response relationships, describe the basis for the recommendation. *
4.4.3 Drug-Drug Interactions *
4.4.3.1 Is there an in vitro basis to suspect in vivo drug-drug-interactions with bupropion that are mediated by CYP450? *
4.4.3.2 Is bupropion an inducer of CYP enzymes? *
4.4.3.3 Is the drug a substrate and/or an inhibitor of P-glycoprotein transport processes? *
4.4.3.4 Are there other metabolic/transporter pathways that may be important in the pharmacokinetics of bupropion? *
4.4.3.5 Does the label specify co-administration of another drug (e.g., combination therapy in oncology) and, if so, has the interaction potential between these drugs been evaluated? *
4.4.3.6 What other co-medications are likely to be administered to the target patient population? *
4.4.3.7 Are there an in vivo drug-drug interaction studies that indicate the exposure alond and/or exposure-response relationships are diffferent when drugs are co-administered? *
4.4.3.8 Is there a known mechanistic basis for pharmacodynamic drug-drug interactions, if any? *
4.4.3.9 Are there any unresolved questions related to metabolism, active metabolites, metabolic drug interactions or protein binding? *
4.4.4 What issues related to dose, dosing regimen, or administration are unresolved, and represent significant omissions? *
4.5 General Biopharmaceutics *
4.5.1 If the NDA is for a modified release formulation of an approved immediate product without supportive safety/efficacy studies, what dosing regimen changes are necessary, if any, in the presence or absence of PK-PD relationship? *
- What is the bioavailability of WELLBUTRIN XL 300 mg relative to immediate release WELLBUTRIN tablets (100 mg three times daily)? *
Figures: Mean Steady State Plasma Concentration Time Course for Bupropion and Its Metabolites After Administration of Test or Reference Formulations in Study 2543 *
Table: Steady State Pharmacokinetic Parameters (Arithmetic Mean) for Bupropion and Metabolites *
- What dosing regimen changes are necessary, if any, in the presence or absence of PK-PD relationship? *
4.5.2 Based on BCS principles, in what class is this drug and formulation? What solubility, permeability and dissolution data support this classification? *
4.5.3 What is the in vivo relationship of the proposed to be-marketed formulation to the pivotal clinical trial formulation in terms of comparative exposure? *
4.5.4 What is the effect of food on the bioavailability (BA) of the drug from the dosage form? *
Figures: Mean Plasma Concentration Time Course for Bupropion and its Metabolites and the PAWC after Administration of Bupropion XL During the Test (open squares) and References (solid circles) Periods in Study AK1BIOVAIL2548 (as provided by Sponsor) *
Table: Pharmacokinetic parameters (arithmetic mean) for bupropion and metabolites (Study 2548) *
- What dosing recommendations should be made, if any, regarding administration of the product in relation to meals or meal types? *
4.5.5 When would a fed BE study be appropriate and was one conducted? *
4.5.6 How do the dissolution conditions and specifications assure in vivo performance and quality of the product? *
4.5.7 Are different-strength formulations bioequivalent based on standard criteria? What clinical safety and efficacy data support the approval of the various strengths of the to-be-marketed product? *
4.5.8 If unapproved products or altered approved products were used as active controls, how is BE to the approved product demonstrated? What is the basis for using either in vitro or in vivo data to evaluate BE? *
4.5.9 What other significant, unresolved issues related to in vitro dissolution or in vivo BA and BE need to be addressed? *
4.5.10 If replicate design studies were conducted and individual BE was analyzed, what were the outcomes with respect to variability and subject-by-formulation interactions? *
4.6 Bioanalytical Method *
4.6.1 How are the active moieties identified and measured in the plasma in the clinical pharmacology and biopharmaceutics studies? *
4.6.2 Which metabolites have been selected for analysis and why?*
4.6.3 For all moieties measured, is free, bound or total measured? What is the basis for that decision, if any, and is it appropriate? *
4.6.4 What bioanalytical methods are used to assess concentrations? *
- What is the range of the standard curve and how does it relate to the requirements for the clinical studies?
- Is the bioanalytical method adequately documented and validated? *
5 Detailed labeling recommendations (only the changed sections are included here) (31 pages not included in packet)
6 Appendice
6.1 Sponsor Proposed Package Insert (Annotated) With OCPB Comments Highlighted (Pages not included in packet)
6.2 Clinical Pharmacology and Biopharmaceutics Individual Study Reviews *
6.2.1 PET STUDY OF DOPAMINE TRANSPORTER OCCUPANCY (OHB10001)*
Study Investigators and Site *
Protocol Number *
Objectives *
Formulations *
Study Design *
Assay *
Results *
Demographics *
Pharmacokinetics *
Table 2: Pharmacokinetic parameters for bupropion and metabolites at steady state *
Figures: Indivual Plasma concentrations for buproion and composite concentration value (CCV) reflection a combination of bupropion, blacked out and erytho/threohydrobupropion *
Pharmacodynamics *
Figures: The dopamine transporter occupancy (RO, %) in the striatum at T=3, 12 and 24 hours after the last dosing of WELLBUTRIN SR for subjects 1-6. [Figures blacked out]
Pharmacogenetics *
Safety *
Conclusions *
6.2.2 FOOD-EFFECT STUDY (AK1BIOVAIL2548) *
Study Investigators and Site *
Protocol Number *
Objectives *
Formulations *
Table 1. Product used in AK1BIOVAIL2548 *
Study Design *
Table 2. Treatment Sequence in AK1BIOVAIL2548 *
Inclusion/Exclusion Criteria *
Assay *
Table 3. Performance of Analytical Method for AK1BIOVAIL2548 * [Most blacked out]
Results *
Demographics *
Table 4. Demographics of Subjects Included in the Pharmacokinetic Analysis Population *
Pharmacokinetics *
Safety *
Conclusion *
6.2.3 DOSAGE STRENGTH EQUIVALENCE (AK1BIOVAIL2571)*
Study Investigators and Site *
Protocol Number *
Objectives *
Formulations *
Table 1: Product used in AK1BIOVAIL2571 Study *
Study Design *
Table 2: Treatment Sequence in AK1BIOVAIL2571 *
Inclusion/Exclusion Criteria *
Assay *
Table 3. Performance of Analytical Method for AK1BIOVAIL2571 *
Results *
Demographics *
Table 4. Demographics of Subjects Included in the Pharmacokinetic Analysis Population *
Pharmacokinetics *
Safety *
Conclusions *
6.2.4 BIOEQUIVALENCE STUDY (AK1BIOVAIL2543)*
Study Investigators and Site *
Protocol Number *
Objectives *
Formulations *
Table 1. Products used in AK1BIOVAIL2543
Study Design *
Table 2. Treatment Sequence in AK1BIOVAIL2543 *
Inclusion/Exclusion Criteria *
Assay *
Table 3. Performance of Analytical Mthod for AK1BIOVAIL2543 *
Results *
Demographics *
Table 4. Demographics of Subjects Completing the Study *
Pharmacokinetics *
Safety *
Conclusions *
6.2.5 BIOANALYTICAL METHOD *
6.2.6 DISSOLUTION METHOD DEVELOPMENT (Page not included in packet)
6.3 Consult Reviews (Including Pharmacometric Reviews) (Page not included in packet)
6.4 Cover Sheet and OCPB Filing/Review Form (Page not included in packet)
Clinical Pharmacology/Biopharmaceutics Review June/20/03
Background *
Current Review *
Conclusions and Recommendations *
Administrative and Correspondence Documents
Patent Information (Confidential) *
Applicable Patent Numbers and Expiration Dates *
Exclusivity Summary *
Part I: Is An Exclusivity Determination needed? *
Part II: Five-Year Exclusivity for New Chemical Entities *
Part III. Three-Year Exclusivity For NDA's and Supplements *
Marketing Exclusivity *
Pediatric Page *
A. Table of Contents
B. Action Package Checklist (for AP action) * (10 pages not included in packet)
C. Action Letter with Labeling 8/21/2003* (7 pages not included in packet)
Approval letter [Letter] and Labeling (Pages not included in packet)
Approvable Letter and Labeling (Pages not included in packet)
D. Labeling (Pages not included in packet)
Agreed-upon labeling for AP action (see Tab C) (Pages not included in packet)
Comparison of Agreed-upon AP labeling to FDA�s AE labeling (Pages not included in packet)
Most recent version of Applicant�s Proposed Wellbutrin XL insert, marked up and clean (Pages not included in packet)
Applicant�s proposed 7/3/03 version, marked up and clean (Pages not included in packet)
Container / Carton Labeling (Pages not included in packet)
Current Wellbutrin insert (Pages not included in packet)
Current Wellbutrin SR insert (Pages not included in packet)
E. Patent Information (certification, exclusivity request from applicant) (Pages not included in packet)
F. Exclusivity Checklist (Pages not included in packet)
G. Pediatric Information (Pages not included in packet)
Partial deferral and partial waiver request from firm (Pediatric Rule has been suspended) (Pages not included in packet)
Pediatric Page (Pages not included in packet)
Pediatric WR for bupropion, with reports due February, 2004, covers exclusivity for all bupropion dosage forms under the Pediatric Exclusivity provisions (WR copy attached) (Pages not included in packet)
H. User Fee Information and Debarment Certification (see AE package) (Pages not included in packet)
I. DSI (completed in first review cycle; see AE package) (Pages not included in packet)
J Division Director Memo (Pages not included in packet)
K. Clinical Team leader Memo (Pages not included in packet)
L. Clinical Review (Pages not included in packet)
M. Safety Review (see clinical review) (Pages not included in packet)
Mc. Consult Reviews
Request for Consultation 7/14/03 (trademark review) *
Request for Consultation 7/8/03 (trademark review) *
Request for Consultation 2/27/03 (trademark review) *
Resubmission review of proposed trademark (Pages not included in packet)
Reviews of patient labeling, container labeling, patient education proposals (J. Best, D. Toyer) (Pages not included in packet)
Proprietary Name Review 7/29/03 *
I. Introduction *
II. Risk Assessment *
A. Expert Panel Discussion *
B. Safety Evaluator Risk Assessment *
III. Labeling, Packaging, and Safety Issues *
IV. Risk Management Plan *
V. Recommendations *
N. Statistical Review (not needed for this submission)
O. Biopharmaceutics / Clinical Pharmacology Review (Pages not included in packet)
P. Pharmacology Review (not needed for this submission: cross-reference provided)
Q. Chemistry Review (Pages not included in packet)
Chemistry Reivew of Resubmission (Pages not included in packet)
Establisment Inspection Report (EES) (Pages not included in packet)
Environmental Assessment (Categorical Exclusion) Granted in First Review Cycle. (Pages not included in packet)
R. Correspondence
Applicant to FDA (Pages not included in packet)
Appendix I. Summary of Sponsor's Risk Communication Plan
Activities Directed To Physicians (Pages not included in packet)
Activities Directed to Pharmacists (Pages not included in packet)
Activities Directed to Patients (Pages not included in packet)
Other Activities (Pages not included in packet)
Consultant Response 7/11/03 (Proprietary name, labeling) *
Request for Consultation 7/8/2002 (NDA Resubmission) *
Letter From GlaxoSmithKline 8/28/03 Response to FDA Request: Updated Educational Communication Plan For Wellbutrin XL *
Application to Market a New Drug, Biologic or An Antibiotic Drug For Human Use 8/28/03 *
Letter From GlaxoSmithKline 8/21/03 Response to FDA Comment: Labeling *
Guide to FDA Reviewers *
Application to Market a New Drug, Biologic or An Antibiotic Drug For Human Use 8/21/03 *
Letter From GlaxoSmithKline 7/3/03 Response to Approvable Letter: Clinical Pharmacology, CMC, Labeling, Safety *
Proposed Trademark *
Chemistry, Manufacturing and Controls (CMC) *
Bulk Packaging Process *
Sampling Plan *
Impurity/Degradant Factors *
Secondary Packaging Systems *
Drug Product Stability Information *
Methods Validation *
Categorical Exclusion *
Clinical Pharmacology and Biopharmaceutics *
Dissolution Method *
CYP2B6. Possible Drug Interactions *
Literature Search Request *
Clinical/Clinical Safety *
Request for Safety Update *
Additional Pertinent Information *
Labeling (Package Insert and Container Labeling *
Promotional Materials *
NDA Amendment Organization *
Review Aids/Copies *
Field Copy *
Closing Information *
Application to Market a New Drug, Biologic or An Antibiotic Drug For Human Use 7/3/03 *
FDA to Applicant
Letter to GlaxoSmithKline - User Fee Goal Date *
S. Minutes of Meetings
Resubmission Filing Meeting Minutes 7/15/2003 *
T. ISE (See EDR submission) (Pages not included in packet)
U. ISS (See EDR submission) (Pages not included in packet)
V. Submission History (Pages not included in packet)
Log of Documents Submitted to NDA (DSS and EDR versions) (Pages not included in packet)
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