Clinical trial NCT04311463
Conditions: Anxiety Disorders
Keywords: Anxiety Disorders Bioequivalence study Paroxetine hydrochloride PAXIL Fasting condition
Sponsor: GlaxoSmithKline
Start date: 2020-12-09; Completion date: 2021-01-02
Enrollment: 38 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study will be conducted to evaluate and compare the single oral dose bioavailability of Paroxetine manufactured by GlaxoSmithKline (GSK) Pharmaceuticals S.A. for GlaxoSmithKline México, S.A. de C.V. with that of PAXIL® (Paroxetine) of GlaxoSmithKline, México, S.A. de C.V. in healthy, adult, male and female participants under fasting conditions. Maximum 38 participants will be randomized and dosed. The expected duration of this study will be 12 days including 7 days of washout period in-between each dosing. PAXIL is a registered trademark of GSK group of companies.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Paroxetine hydrochloride intervention 2: PAXIL (Paroxetine hydrochloride )
Intervention descriptions: intervention 1: Paroxetine hydrochloride will be administered. intervention 2: PAXIL will be administered.

Protocol documents:
Prot_000.pdf: 
 
  
Format No.: CPF127-03E                                                                                                     No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
Page1 of 94 
CONFIDENTIAL 
Avant Santé Research Center S.A. de C.V 
PROJECT NO. / PROTOCOL NO.: AS/BK/OCT-19/0055 
Sponsor Code: 212969  
 
TITLE 
 
An oral single-dose, randomized, balanced, open-label, two-sequence, two-treatment, two-period, 
crossover bioequivalence study of Paroxetine tablets 20 mg of GlaxoSmithKline Pharmaceuticals S.A, 
with that of PAXIL (Paroxetine) tablets 20 mg of GlaxoSmithKline México S.A. de C.V., in healthy 
adult male and female subjects under fasting conditions. 
 
Version No.: 02  
Date: 12/Oct/2020 
CONTRACT RESEARCH ORGANIZATION 
SPONSOR 
 
Avant Santé Research Center S.A. de C.V. 
Av. Lázaro Cárdenas No. 500 
Col. Residencial San Agustín 
San Pedro Garza García, Nuevo León 
México, C.P. 66260 
Tel.: 
 
www.avantsante.com 
 
GlaxoSmithKline México, S.A. de C.V. 
Calzada México Xochimilco No. 4900 Col. 
San Lorenzo Huipulco 14370 Ciudad de 
México. 
 
 
 
CONFIDENTIALITY STATEMENT 
The information contained and/or attached to this document controlled by the quality system, as well as its formats and/or 
related registries, is confidential information property of Avant Santé Research Center S.A. de C.V and GlaxoSmithKline 
México, S.A. de C.V. Any unauthorized use or violation to this notice is prohibited and may be subject to sanctions under 
applicable law. 
 
PPD


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
Project No./Protocol No.: AS/BK/OCT-19/0055 
Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
Page 2 of  94 
 
                             CONFIDENTIAL 
      Avant Santé Research Center S.A. de C.V 
 
 
CONTACT INFORMATION OF SPONSOR / INVESTIGATOR 
 
Sponsor: 
GlaxoSmithKline México, S.A. de C.V. 
Calzada México Xochimilco No. 4900 Col. 
San Lorenzo Huipulco 14370 Ciudad de México 
 
 
Primary Study Manager: 
 
 
GlaxoSmithKline México, S.A. de C.V. 
Calzada México Xochimilco No. 4900 Col. 
San Lorenzo Huipulco 14370 Ciudad de México 
Phone number: 
 
Email: 
 
 
 
Sponsor’s Authorized Signatory: 
Sigfrido Manuel Rangel Frausto 
GlaxoSmithKline México, S.A. de C.V. 
 
 
 
Calzada México Xochimilco No. 4900 Col. 
San Lorenzo Huipulco 14370 Ciudad de México 
Phone number: 
 
Email: 
 
 
 
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Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
Project No./Protocol No.: AS/BK/OCT-19/0055 
Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
Page 3 of  94 
 
                             CONFIDENTIAL 
      Avant Santé Research Center S.A. de C.V 
 
Name and address of Principal Investigator: 
Dr. Javier Jesús Osorio Escobar 
Avant Santé Research Center S.A. de C.V. 
Avenida Lázaro Cárdenas No. 500, Col Residencial San Agustín, San Pedro Garza García, Nuevo 
León., México, C.P 66260. Tel.: 
extension -
. 
E-mail: 
 
 
Name and address of Clinical Investigator: 
Dr. José Guillermo Sander Padilla 
Avant Santé Research Center S.A. de C.V. 
Avenida Lázaro Cárdenas No. 500, Col Residencial San Agustín, San Pedro Garza García, Nuevo 
León., México, C.P 66260 Tel.: 
 extension 
. 
E-mail: 
 
 
 
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Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
Project No./Protocol No.: AS/BK/OCT-19/0055 
Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
Page 4 of  94 
 
                             CONFIDENTIAL 
      Avant Santé Research Center S.A. de C.V 
Author: This protocol is prepared based on the available literature and applicable regulatory 
requirements to the best of my knowledge, as well as of previous experience from the sponsor  
GlaxoSmithKline México, S.A. de C.V. 
 
Name: ___________________________________ Signature and Date: ___________________ 
 
STATEMENT OF COMPLIANCE 
We, the undersigned have read and understood this protocol and hereby agree to conduct the study in 
accordance with the same and to comply with all the requirements regarding the obligations of 
investigators and all other pertinent requirements of the NOM 177-SSA1-2013 (COFEPRIS), the 
Declaration of Helsinki, the ICH Guidelines on Good Clinical and Laboratory Practices (WHO) of 
COFEPRIS and all internal relevant SOPs. We further agree to ensure that all the personnel involved 
in the conduct of this study are duly informed regarding their obligations. 
 
 
Signature: _______________________________ 
  
Date: _______________ 
Dr. Javier Jesús Osorio Escobar 
Principal Investigator 
 
 
Signature: _______________________________  
 
 
Date: _______________ 
Dr. José Guillermo Sander Padilla 
Clinical Investigator 
 
 
 
 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
Project No./Protocol No.: AS/BK/OCT-19/0055 
Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
Page 5 of  94 
 
                             CONFIDENTIAL 
      Avant Santé Research Center S.A. de C.V 
Signature: _______________________________ 
  
Date: _______________ 
Biol. 
 
 
 
 
Signature: _______________________________  
 
        Date: _______________ 
, PhD. 
 
 
 
Signature: _______________________________ 
  
Date: _______________ 
, PhD. 
 
 
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Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
Project No./Protocol No.: AS/BK/OCT-19/0055 
Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
Page 6 of  94 
 
                             CONFIDENTIAL 
      Avant Santé Research Center S.A. de C.V 
SANITARY RESPONSIBLE AND QUALITY ASSURANCE 
 
 
Signature: _______________________________ 
  
Date: _______________ 
Q.F.B 
 
 
 
 
Signature: _______________________________ 
  
Date: _______________ 
M. Sc. 
 
 
 
 
Signature: _______________________________ 
  
Date: _______________ 
M.B.A. 
 
 (Clinical and Bioanalytical Unit) 
 
 
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Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
Project No./Protocol No.: AS/BK/OCT-19/0055 
Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
Page 7 of  94 
 
                             CONFIDENTIAL 
      Avant Santé Research Center S.A. de C.V 
SPONSOR'S APPROVAL 
 
I, the undersigned, have read and understood this protocol and agree hereby to have the study 
conducted in accordance with the same and to comply with all the requirements regarding the 
obligations of Sponsor and all other pertinent requirements of the current NOM-177-SSA1-2013 
(COFEPRIS), of the Declaration of Helsinki, ICH Guidelines on Good Clinical and Laboratory 
Practices (WHO) and of COFEPRIS. 
 
__________________________________________ 
 
Date: _______________ 
 
Authorization Signature 
 
 
Sigfrido Manuel Rangel Frausto 
GlaxoSmithKline México, S.A. de C.V. 
Calzada México Xochimilco No. 4900 Col. 
San Lorenzo Huipulco 14370 Ciudad de México 
Ph. No.: 
   
Email: 
 
 
 
 
 
 
 
 
PPD
PPD


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
Project No./Protocol No.: AS/BK/OCT-19/0055 
Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
Page 8 of  94 
 
                             CONFIDENTIAL 
      Avant Santé Research Center S.A. de C.V 
TABLE OF CONTENTS 
TITLE 1 
CONTACT INFORMATION OF SPONSOR / INVESTIGATOR .............................................................................. 2 
STATEMENT OF COMPLIANCE ............................................................................................................................... 4 
SANITARY RESPONSIBLE AND QUALITY ASSURANCE ................................................................................... 6 
SPONSOR'S APPROVAL ............................................................................................................................................ 7 
TABLE OF CONTENTS ............................................................................................................................................... 8 
LIST OF FIGURES ..................................................................................................................................................... 11 
LIST OF TABLES ....................................................................................................................................................... 11 
1.0 
PROTOCOL SUMMARY .......................................................................................................................... 15 
2.0 
STUDY RELATED SERVICES ................................................................................................................ 25 
3.0 
BACKGROUND INFORMATION ........................................................................................................... 26 
3.1 
Mechanism of Action ................................................................................................................................... 27 
3.2 
Therapeutic Indications .............................................................................................................................. 28 
3.3 
Pharmacokinetics ........................................................................................................................................ 28 
3.3.1 
Absorption .................................................................................................................................................... 28 
3.3.2 
Distribution .................................................................................................................................................. 29 
3.3.3 
Metabolism ................................................................................................................................................... 29 
3.3.4 
Excretion ...................................................................................................................................................... 29 
3.4 
Dosage and Administration: ....................................................................................................................... 30 
3.5 
Interactions .................................................................................................................................................. 30 
4.0 
STUDY OBJECTIVES ............................................................................................................................... 36 
4.1 
Primary Objective ....................................................................................................................................... 36 
4.2 
Secondary Objective .................................................................................................................................... 36 
5.0 
HYPOTHESIS OF THE STUDY ............................................................................................................... 36 
6.0 
STUDY RATIONALE ................................................................................................................................ 37 
6.1 
Dose Rationale ............................................................................................................................................. 38 
7.0 
STUDY DESIGN ......................................................................................................................................... 38 
7.1 
Study Design ................................................................................................................................................ 38 
7.2 
Rationale for Study Design and Blood Sampling Points .......................................................................... 39 
7.3 
Sample Size .................................................................................................................................................. 40 
7.4 
Justification of the Sample Size .................................................................................................................. 40 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
Project No./Protocol No.: AS/BK/OCT-19/0055 
Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
Page 9 of  94 
 
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      Avant Santé Research Center S.A. de C.V 
7.5 
Washout Period ........................................................................................................................................... 41 
7.6 
Duration of the Study .................................................................................................................................. 42 
7.7 
Randomization ............................................................................................................................................. 42 
7.8 
Blinding ........................................................................................................................................................ 42 
7.9 
Test and Reference Products ...................................................................................................................... 42 
7.10 
Reception and Storage of Investigational Products .................................................................................. 43 
7.11 
Accounting of Investigational Products ..................................................................................................... 45 
7.12 
Dispensing .................................................................................................................................................... 45 
8.0 
SELECTION AND WITHDRAWL OF SUBJECTS ............................................................................... 46 
8.1 
Screening (selection and enrollment) ......................................................................................................... 46 
8.2 
Clinical Laboratory Tests ........................................................................................................................... 47 
8.3 
Inclusion Criteria......................................................................................................................................... 48 
8.4 
Exclusion Criteria ........................................................................................................................................ 49 
8.5 
Criteria for Subject Withdrawal from the Study ..................................................................................... 51 
9.0 
TREATMENT OF SUBJECTS .................................................................................................................. 53 
9.1 
Drug Administration ................................................................................................................................... 53 
9.2 
Dietary Plan ................................................................................................................................................. 53 
9.3 
Restrictions ................................................................................................................................................... 54 
9.4 
Housing ......................................................................................................................................................... 56 
9.5 
Sampling Schedule ....................................................................................................................................... 57 
9.6 
Sample Processing and Storage .................................................................................................................. 59 
9.7 
Sample transfer ............................................................................................................................................ 59 
10.0 
ASSESSMENT OF EFFICACY ................................................................................................................. 60 
11.0 
ASSESSMENT OF SAFETY (CLINICAL SAFETY MEASURES) ...................................................... 60 
11.1 
Recording of Vital Signs and Medical Examination ................................................................................. 60 
11.2 
Identification, Handling and Reporting of AE and SAE .......................................................................... 61 
12.0 
BIOANALYSIS............................................................................................................................................ 70 
12.1 
Sample analysis ............................................................................................................................................ 70 
12.2 
Reporting of drug concentration data ....................................................................................................... 70 
13.0 
PHARMACOKINETIC PARAMETERS ................................................................................................. 71 
14.0 
STATISTICAL ANALYSIS ....................................................................................................................... 72 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
Project No./Protocol No.: AS/BK/OCT-19/0055 
Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
Page 10 of  94 
 
                             CONFIDENTIAL 
      Avant Santé Research Center S.A. de C.V 
14.1 
Descriptive Statistics ................................................................................................................................... 73 
14.2 
Analysis of Variance .................................................................................................................................... 74 
14.3 
Statistical Model .......................................................................................................................................... 74 
14.4 
Two One-Sided Test for Bioequivalence .................................................................................................... 74 
14.5 
Statistical Power .......................................................................................................................................... 75 
14.6 
Ratio Analysis .............................................................................................................................................. 75 
14.7 
Intra-Subject Variability ............................................................................................................................ 75 
14.8 
Analysis of Outliers ..................................................................................................................................... 75 
14.9 
Criteria for elimination of subject data from the statistical analysis. ..................................................... 76 
14.10 
Bioequivalence Criteria ............................................................................................................................... 77 
15.0 
AMENDMENTS AND PROTOCOL DEVIATIONS .............................................................................. 77 
16.0 
TERMINATION OF A STUDY ................................................................................................................. 79 
17.0 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ....................................................................... 79 
18.0 
QUALITY CONTROL AND QUALITY ASSURANCE ......................................................................... 81 
19.0 
INVESTIGATOR AND DELEGATION OF DUTIES ............................................................................ 81 
20.0 
ETHICAL CONSIDERATIONS ............................................................................................................... 81 
20.1 
Ethical Standards ........................................................................................................................................ 81 
20.2 
Research Ethics Committee and Research Committee ............................................................................ 82 
20.3 
Informed Consent Process .......................................................................................................................... 82 
20.4 
Subject Participation Compensation ......................................................................................................... 83 
20.5 
Subject’s Insurance ..................................................................................................................................... 83 
21.0 
DATA HANDLING AND RECORD KEEPING ...................................................................................... 83 
21.1 
Clinical Study Report .................................................................................................................................. 84 
21.2 
Confidentiality of Data ................................................................................................................................ 84 
21.3 
Archiving ...................................................................................................................................................... 84 
21.4 
Publication Policy ........................................................................................................................................ 85 
22.0 
LIST OF ATTACHMENTS ....................................................................................................................... 85 
23.0 
REFERENCES ............................................................................................................................................ 86 
 
 
 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
Project No./Protocol No.: AS/BK/OCT-19/0055 
Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
Page 11 of  94 
 
                             CONFIDENTIAL 
      Avant Santé Research Center S.A. de C.V 
 
LIST OF FIGURES 
 
Figure 1 Paroxetine structural formula ............................................................................................... 27 
Figure 2 Study Design Diagram.......................................................................................................... 39 
 
 
 
LIST OF TABLES 
 
Table 1 Pharmacokinetic Parameters of Paroxetine ........................................................................... 30 
Table 2 Adverse reactions of Paroxetine ............................................................................................ 34 
Table 3 Investigational Product Details .............................................................................................. 42 
Table 4 Laboratory Tests .................................................................................................................... 47 
Table 5 Nutritional value of diet on study day 1 ................................................................................. 54 
Table 6 Blood volume of samples to be collected during the study ................................................... 57 
Table 7 Adverse Reaction Classification ............................................................................................ 65 
Table 8 Pregnancy follow up .............................................................................................................. 69 
 
 
 
 
 
 
 
 
 
 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
Project No./Protocol No.: AS/BK/OCT-19/0055 
Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
Page 12 of  94 
 
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ABBREVIATIONS 
 
ADR(s) 
: 
Adverse Drug Reaction(s) 
AE(s) 
: 
Adverse Event(s) 
ANOVA 
: 
Analysis of Variance 
AUC0-inf 
: 
Area Under Plasma Concentration-Time Curve from Time 0 to Infinite 
AUC0-t 
: 
Area Under Plasma Concentration-Time Curve from Time Zero to the Last Measurable 
Concentration 
BLOQ 
: 
Below the Limit of Quantification 
BMI 
: 
Body Mass Index 
Cmax 
: 
Maximum Concentration Observed in Plasma 
COFEPRIS 
: 
Federal Commission for the Protection against Sanitary Risk (Comisión Federal para la 
Prevención contra Riesgos Sanitarios) 
CNFV 
: 
Pharmacovigilance National Center (Centro Nacional de Farmacovigilancia) 
CNS 
: 
Central Nervous System 
CoA 
: 
Certificate of Analysis 
COVID-19 
: 
The coronavirus disease  
COX-2 
: 
Cyclooxygenase-2 
CRF(s) 
: 
Case Report Form(s) 
CV 
: 
Coefficient of Variation 
CYP 
: 
Cytochrome P 
ECG 
: 
Electrocardiogram 
GCP 
: 
Good Clinical Practices 
GLP 
: 
Good Laboratory Practices 
H 
: 
Hour 
HIV 
: 
Human Immune Deficiency Virus 
ICF 
: 
Informed Consent Form 
ICH 
: 
International Council for Harmonization 
ICU 
: 
Intensive Care Unit 
IP(s) 
: 
Investigational Product(s) 
Kg 
: 
Kilogram 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
Project No./Protocol No.: AS/BK/OCT-19/0055 
Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
Page 13 of  94 
 
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L 
: 
Liter 
LOQ 
: 
Limit of quantification 
M 
: 
Missing Sample 
m2 
: 
Square Meter 
MAOIs 
: 
Monoamine Oxidase Inhibitors 
mg 
: 
Milligram 
mL 
: 
Milliliter 
mmHg 
: 
Millimeter of Mercury 
Ng 
: 
Nanogram 
NOM 
: 
Mexican Official Norm 
NSAIDs 
: 
Nonsteroidal Anti-Inflammatory Drugs 
OCD 
: 
Obsessive Compulsive Disorder 
OTC 
: 
Over-the-counter 
pH 
: 
Potential hydrogen 
PI 
: 
Principal Investigator 
QA 
: 
Quality Assurance 
QC 
: 
Quality Control 
QT 
: 
Q-wave and T-wave 
REC/RC 
: 
Research Ethics Committee / Research Committee 
RLS 
: 
Restless Legs Syndrome 
RMF 
: 
Research Master File 
Rpm 
: 
Revolutions Per Minute 
RT-PCR 
: 
Real time–Polymerase Chain Reaction 
SADR(s) 
: 
Serious Adverse Drug Reaction(s) 
SAE(s) 
: 
Serious Adverse Event(s) 
SARS-CoV-2 
: 
Severe Acute Respiratory Syndrome Coronavirus 2 
SAS 
: 
Statistical Analysis System 
SGPT/ALT 
: 
Serum Glutamate Pyruvate Transaminase / Alanine Transferase 
SGOT/AST 
: 
Serum Glutamate Oxaloacetate Transaminase / Aspartate Transferase 
SIADH 
: 
Syndrome of Inappropriate Anti-Diuretic Hormone Secretion 
SOP(s) 
: 
Standard Operating Procedure 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
Project No./Protocol No.: AS/BK/OCT-19/0055 
Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
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SSRIs 
: 
 Selective Serotonin Reuptake Inhibitors 
t½ 
: 
Half-Life 
TCAs 
: 
Tricyclic Antidepressants 
THC 
: 
Tetra Hydro Cannabinoids 
TMF  
: 
Trial Master File 
Tmax 
: 
Time of the Maximum measured plasma concentration 
UADR(s) 
: 
Unexpected Adverse Drug Reaction(s) 
UPLC 
: 
Ultra Performance Liquid Chromatography 
USFDA 
: 
United States Food and Drug Administration 
VDRL 
: 
Venereal Disease Research Laboratory 
% 
: 
Percent 
0C 
: 
Degree Celsius 
µg 
: 
Microgram 
5-HT 
: 
5-hydroxytryptamine 
 
 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
Project No./Protocol No.: AS/BK/OCT-19/0055 
Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
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1.0 
PROTOCOL SUMMARY 
Study Title 
An oral single-dose, randomized, balanced, open-label, two-sequence, two-
treatment, two-period, crossover bioequivalence study of Paroxetine tablets 20 mg 
of GlaxoSmithKline Pharmaceuticals S.A, with that of PAXIL (Paroxetine) 
tablets 20 mg of GlaxoSmithKline México S.A. de C.V., in healthy adult male 
and female subjects under fasting conditions. 
Regulatory 
Agency and 
Country of 
Submission  
COFEPRIS-México. 
Study 
Objective 
Primary Objective: 
To evaluate and compare the single oral dose bioavailability of Paroxetine tablets 
20 mg manufactured by GlaxoSmithKline Pharmaceuticals S.A. for 
GlaxoSmithKline México, S.A. de C.V. with that of PAXIL (Paroxetine) tablets 
20 mg of GlaxoSmithKline México, S.A. de C.V. in healthy, adult, male and 
female subjects under fasting conditions. 
Secondary Objective: 
To evaluate safety and tolerability of single oral dose of Paroxetine 20 mg tablets 
in healthy adult male and female subjects under fasting conditions. 
Study Design 
An oral single-dose, randomized, balanced, open-label, two-sequence, two-
treatment, two-period, crossover bioequivalence study under fasting conditions. 
Sample Size 
At least 34 healthy adult male and female subjects will be randomized and dosed 
in this study. 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
Project No./Protocol No.: AS/BK/OCT-19/0055 
Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
Page 16 of  94 
 
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      Avant Santé Research Center S.A. de C.V 
Study 
Treatments 
Test product (A): Paroxetine tablets 20 mg.  
[Paroxetine as Paroxetine hydrochloride]. 
Manufactured by: GlaxoSmithKline Pharmaceuticals S.A. 
Manufactured for: GlaxoSmithKline México, S.A. de C.V. 
Reference product (B): PAXIL (Paroxetine as Paroxetine hydrochloride) tablets 
20 mg. 
Manufactured by: GlaxoSmithKline México, S.A. de C.V. 
Sanitary Registration Number: 008M93SSA IV.  
Introduction 
Paroxetine is an antidepressants drug. It is the hydrochloride salt of a 
phenylpiperidine 
compound 
identified 
chemically 
as 
(-)-trans-4R-
(4'fluorophenyl)-3S-[(3',4'-methylenedioxyphenoxy) 
methyl] 
piperidine 
hydrochloride 
hemihydrate 
and 
has 
the 
empirical 
formula 
of 
C19H20FNO3•HCl•1/2H2O. 
Paroxetine is indicated for the treatment of: 
• Major depressive disorder. 
• Obsessive Compulsive Disorder (OCD). 
• Panic disorder with and without agoraphobia. 
• Social anxiety disorders/social phobia. 
• Generalised anxiety disorder. 
• Post-traumatic stress disorder. 
Screening 
(selection and 
enrollment) 
Healthy adult male & female volunteers, light or non or ex-smokers, aged between 
18 and 55 years (both inclusive), with a weight ≥ 50.00 kg, with a BMI between 
≥ 18.0 and ≤ 27.0 kg/m2 will be selected according to the inclusion and exclusion 
criteria. 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
Project No./Protocol No.: AS/BK/OCT-19/0055 
Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
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      Avant Santé Research Center S.A. de C.V 
All the subjects will have a medical history during the selection and enrollment 
process. 
Volunteers shall be found healthy according to the physical examination 
(including vital signs assessment), normal laboratory test results and 12-lead 
ECG. 
The physical examination findings, ECG and laboratory tests will be considered 
valid for a maximum period of 90 days prior to the dosing on the first period of 
the study. 
Pregnancy test in urine will be carried out during the screening period and at the 
time of each period check-in for all female subjects. 
Real-time (RT-PCR) test for the detection and diagnosis of SARS-COV-2 will be 
carried out within the 72 hours prior to the first period check-in for all the subjects. 
Avant Santé Research Center S.A. de C.V. will ensure the volunteer participation 
history by verifying the COFEPRIS database for bioequivalence studies. 
 
 
 
Drug 
Administration 
(Dosing) 
In each study period, all subjects will be required to fast overnight for at least 
10.00 hours prior to dosing until at least 04.00 hours post-dose. 
In each study period, a single-dose of either the test product (A) or reference 
product (B) will be orally administered to the subjects in sitting posture along with 
250 mL of water at room temperature under fasting conditions. 
The administration of the test or reference products to each subject will be 
performed as per a randomization schedule. 
The subjects will be instructed to swallow the tablet as a whole as mentioned in 
the prescribing information and not to touch the tablet with their hands, chew or 
crush the tablet since this can affect the drug release. 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
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Hands and mouth will be checked after dosing to ensure compliance and also the 
subject does not touch the IP with hands. 
Immediately after dosing in each period trained study personnel will evaluate the 
compliance by supervising the complete administration procedure SOP CP020 
(Administration of the Investigational Product). 
Drug administration will be registered in the respective source documents. 
 
 
 
Dietary Plan 
 
 
 
 
 
 
Subjects will be provided with standard meals throughout their stay in the 
facilities. 
On the check-in day (day -1) they will receive dinner, which will be finished at 
the latest 10.00 hours prior to dosing at the following day in each study period. 
Subjects will be required to fast overnight for at least 10.00 hours prior to dosing 
and until at least 04.00 hours post-dose in each study period. 
After the dose administration of test or reference product (day 1), lunch, snack 
and dinner will be provided at 04.00, 08.00 and 12.00 (with a grace period of + 45 
minutes) hours post-dose respectively, in each study period. 
The meal plan will be uniform for all the subjects and same between the study 
periods. 
Information on the amount of meal consumed and the time of consumption by 
each subject will be registered in the respective source documents. 
Study 
Restrictions 
All subjects will be instructed to follow the below mentioned restrictions for at 
least 72.00 hours prior to dosing and till last blood sample collection in each study 
period: 
• 
Smoking of cigarettes or nicotine containing products. 
• 
Any food or beverages containing xanthine- (tea, coffee, theobromine, 
theophylline, chocolates, cola drinks, etc.). 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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Sponsor Code: 212969 
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• 
Alcohol or related products. 
• 
Smoked or carbon cooked food. 
• 
Beverages with pomelos or grapefruit juice or products containing 
grapefruit extract (e.g. soda). 
Medications 
All subjects will be asked about their medication history. They will be instructed 
not to take any medication until the study is completed; particularly during the 
last 14 days preceding the first dosing for any prescribed medication, the last 7 
days before for OTC medicinal or herbal products used for therapeutic purposes, 
and the last 30 days before for any enzyme inhibiting / inducing drugs preceding 
the first dosing. 
Subjects will be specifically reminded that the restriction mentioned above 
includes analgesics, cold & anti-allergic preparations, vitamins and natural 
products used for therapeutic benefits and antacid preparations. 
Vitamins used as nutritional supplements in non-therapeutic doses (as judged by 
the principal investigator or designee) may be accepted, but their consumption 
must be stopped from at least 7 days prior to the dosing and until the study is 
completed. 
Fluid (water) restriction 
The subjects will not be allowed to drink water 1 hour before and until 2 hours 
post-dose except for the 250 mL of water provided for the dosing, unless it is 
clinically indicated; at all other times water will be provided ad libitum. 
Postural (activity) Restriction 
The dose will be administered to all subjects at the scheduled time and subjects 
will be instructed to remain in comfortable sitting position for the first 02.00 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
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Sponsor Code: 212969 
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hours following the drug administration except when clinically indicated or 
protocol specified activity (blood sample collection) or due to natural exigencies. 
After 02.00 hours post-dose, subjects will be allowed to wander and will be 
advised to avoid any severe physical exertion. 
In case of an adverse event (AE), subjects will be maintained in the proper position 
as per physician’s assessment in each study period. 
Housing 
Subjects will be in the clinical facility from at least 10.50 hours prior to the dosing 
until the last in-house blood sample collection i.e. 24 hours in each study period. 
Subjects will visit clinical facility at 36.00, 48.00 and 72.00 hours for the 
collection of the ambulatory samples in each study period. 
Subjects will be instructed to self-quarantine during the outpatient period of the 
study i.e. until 72 h blood sample collection in period-2 or until withdrawal, 
whichever is earlier, and to monitor at home their daily body temperature. 
Washout 
Period 
There will be a washout period of at least 7 days between successive dosing.  
Sampling 
Schedule 
In each study period, a total of 24 blood samples (4 mL each) will be collected 
from each subject as per the following schedule: 
• The first blood sample will be collected within 1.50 hours prior to the 
dosing (00.00 hours / pre-dose). 
• The remaining samples will be collected after the dosing of the test or 
reference drug at 00.50, 01.00, 01.50, 02.00, 02.50, 03.00, 03.50, 04.00, 
04.50, 05.00, 05.50, 06.00, 06.50, 07.00, 08.00, 09.00, 10.00, 12.00, 16.00, 
24.00, 36.00, 48.00 and 72.00 hours. 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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Sponsor Code: 212969 
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• The samples corresponding to 36.00, 48.00 and 72.00 hours post dose will 
be collected on separate visits as ambulatory sample in each period of the 
study. 
The total blood volume collected from each subject will not exceed 223 mL, 
which includes about 10 mL for the selection process (selection and enrollment), 
21 mL for the discarded heparinized blood and 192 mL for the pharmacokinetic 
evaluation. 
If circumstances arise, where more than 223 + 10 mL of blood from each subject 
needs to be withdrawn the subject will be asked for additional consent and REC / 
RC will be informed. 
Blood Sample 
Collection, 
Processing and 
Storage 
Once collected, the blood samples will be placed in an ice-filled container or 
another cooling device until the centrifugation process is started. 
Centrifugation process will be started within 45 minutes from the time of blood 
sample collection and will be performed at 3000 rpm for 10 minutes at 4 ± 2 ºC. 
The plasma obtained from blood samples will be transferred as soon as possible 
into two different cryo-tubes (aliquot 1 and aliquot 2), pre-labeled with project 
number, period number, subject number, sample number and aliquot number. 
The plasma volume obtained from blood sample will be allocated as follows: 
Aliquot 1: 1.0 mL of plasma (approximately). 
Aliquot 2: rest of the plasma. 
All plasma samples (aliquot 1 for sample analysis and aliquot 2 as back-up) will 
be stored at a temperature of -50 °C or below. 
Safety 
Assessment 
Medical examination will be performed before check-in, prior to the dosing and 
before the check-out in each study period. 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
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Nevertheless, it may also be performed at any time during the study conduction if 
judged necessary by the physician. 
Physical examination will be performed before check-in of each study period and 
may also be performed at any time during the study conduction if judged 
necessary by the physician. 
Vital signs (sitting blood pressure, pulse rate, respiratory rate and axillary-body 
temperature) will be measured and registered at the time of check-in,  
prior to dosing, at 03.00, 05.00 and 12.00 hours (within ±45 minutes) after the 
dosing, before the check-out and at the time of each ambulatory sample collection 
in each study period. 
The subjects’ well-being will be asked at the time of the medical examination, 
during the vital signs recording and at the time of each ambulatory sample 
collection in each study period; this will be registered in the respective source 
document. 
Seven (7) to 9 days after the collection of 72-h blood sample in second period or 
after the withdrawal, a telephone call will be made to each subject by the personnel 
designated by the PI to monitor any serious adverse event, specifically, subjects 
will be questioned about any symptoms related to COVID-19. 
Bioanalysis 
The concentration of Paroxetine in plasma samples collected during the study 
will be quantified using a validated bioanalytical UPLC/MS-MS method (LOQ - 
0.106 ng/mL) according to COFEPRIS guidelines, GLP and in-house SOPs. 
Method validation and subject sample analysis will be performed using same 
anticoagulant (K2-EDTA) that will be used for blood sample collection in clinical 
phase. 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
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Pharmacokinetic 
Parameters 
Employing the observed concentration vs. time profiles of Paroxetine and using 
WinNonlin® software (version 6.4 or higher), the following pharmacokinetic 
parameters will be calculated: 
• Primary Variables: Cmax and AUC0-t., 
• Secondary Variables: AUC0-inf, AUC_% Extrap, Tmax, Kel, t½. 
Statistical 
Analysis 
Descriptive statistics will be calculated. Statistical analysis will be performed by 
using ANOVA on ln-transformed pharmacokinetic parameters Cmax and AUC0-t. 
The statistical model used in this research is a general linear model and the same 
is covered in protocol section 14.3 
 
BE Criteria 
Based on the statistical results of classic 90% confidence interval for the ratio of 
the geometric least squares means for ln-transformed pharmacokinetic 
parameters Cmax and AUC0-t for Paroxetine conclusion will be drawn for test 
product (A) vs. the reference product (B) under fasting conditions. 
The bioequivalence of the test product (A) with that of the reference product (B) 
under fasting conditions will be concluded, if the 90% Confidence Intervals of the 
ratio of the test and reference product (test/reference) falls within the acceptance 
range of 80.00 – 125.00% for the ln-transformed parameters Cmax and AUC0-t for 
Paroxetine. 
Ethical 
Considerations 
This study will be conducted carried as per NOM-177-SSA1-2013, COFEPRIS 
guidelines, ICH-GCP and principles of Declaration of Helsinki (Fortaleza, Brazil, 
October 2013). 
Protocol, Case Report Form (CRF) and the informed consent form (ICF) approval 
will be taken from the REC / RC, and COFEPRIS before initiation of the study. 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
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Clinical Study 
Report 
The clinical study report will be prepared as per NOM-177-SSA1-2013 
(COFEPRIS) and sponsor requirements, having all the clinical, bioanalytical, 
pharmacokinetic and statistical data subjected to Quality Assurance audits. 
Archiving 
The raw data and reports will be filed at Avant Santé Research Center S.A. de 
C.V, with controlled access for 30 years. 
Avant Santé Research Center S.A. de C.V. will not destroy/discard any document 
related to the study without written confirmation from the sponsor. 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
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Sponsor Code: 212969 
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2.0 
STUDY RELATED SERVICES 
2.1 Research Ethics Committee 
Research Ethics Committee of Avant Santé Research Center S.A. de C.V., 
Av. Lázaro Cárdenas # 500, Col. Residencial San Agustín, 
San Pedro Garza García, N. L., 
México, C. P. 66260.Tel: 
 to 
 
2.2 Research Committee 
Research Committee of Avant Santé Research Center S.A. de C.V., 
Av. Lázaro Cárdenas # 500, Col. Residencial San Agustín, 
San Pedro Garza García, N. L., 
México, C. P. 66260.Tel: 
 to 
. 
2.3 Clinical Diagnostic Laboratory 
• Swiss Lab (SwissLab S.A. de C.V.)  
Río San Juan 200, Miravalle, CP 64660. 
Monterrey, N.L. México, Tel. 
 
and / or 
• Grupo Diagnóstico Médico Proa S.A. de C.V. (This lab is considered as a back-up) 
Alfonso Herrera 75, Col. San Rafael, Delegación Cuauhtémoc. Ciudad de México. 
México. CP 06470. Tel: 
 
2.4 Contract Hospital 
Swiss Hospital S.A.P.I. de C.V., 
Río San Juan # 200, Colonia Miravalle, Monterrey, Nuevo León, México, 
C.P. 64650, Tel: 
, Emergencies: 
 
 
2.5 Ambulance 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
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      Avant Santé Research Center S.A. de C.V 
Emergencia Médica Profesional, S. C. 
Calzada San Pedro No. 504-A, Colonia Fuentes del Valle, San Pedro Garza García, Nuevo 
León. C.P. 66220 
Tel: 
, Emergency: 
 
2.6 Clinical Unit 
Avant Santé Research Center S.A. de C.V. 
Ave. Lázaro Cárdenas No. 500, Col. Residencial San Agustín, San Pedro Garza García,  
Nuevo León, México, C.P. 66260 
Tel.: 
 to 
 
2.7 Bioanalytical Unit 
Avant Santé Research Center S.A. de C.V. 
Ave. Lázaro Cárdenas No. 500,  
Col. Residencial San Agustín, San Pedro Garza García, Nuevo León, México, C.P. 66260 
Tel.: 
 to 
 
2.8 Biostatistics Service 
Avant Santé Research Center S.A. de C.V. 
Ave. Lázaro Cárdenas No. 500, Col. Residencial San Agustín,  
San Pedro Garza García, Nuevo León, México, C.P. 66260 
Tel.: 
 to 
 
2.9 Biological Waste Management 
Veolia Soluciones Industriales México, S.A de C.V 
Av. Lázaro Cárdenas No. 435, PISO 10, Col. Zona Loma Larga Oriente  
San Pedro Garza García, Nuevo León C.P 66266  
Tel.: 
 Fax 
 
e-mail: 
           www.veolia.com.mx 
3.0 
BACKGROUND INFORMATION 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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Paroxetine is an antidepressant drug [1]. It is the hydrochloride salt of a phenylpiperidine 
compound identified chemically as (-)-trans-4R-(4'fluorophenyl)-3S- [(3',4' methylene di oxy 
phenoxy) methyl] piperidine hydrochloride hemihydrate and has the empirical formula of 
C19H20FNO3•HCl•1/2H2O. Its molecular weight is 374.8 g/mol. and its structural formula is: 
[2] 
 
Figure 1 Paroxetine hydrochloride structural formula 
 
3.1 Mechanism of Action 
Paroxetine is a potent and selective inhibitor of 5-hydroxytryptamine (5-HT, serotonin) 
reuptake and is thought to be related to its specific inhibition of 5-HT reuptake in brain 
neurons. 
Paroxetine is chemically unrelated to the tricyclic, tetracyclic and other available 
antidepressants. 
Paroxetine has low affinity for muscarinic cholinergic receptors and animal studies have 
indicated only weak anticholinergic properties. 
In accordance with this selective action, in vitro studies have indicated that, in contrast to 
tricyclic antidepressants, paroxetine has little affinity for alpha1, alpha2 and beta-
adrenoceptors, dopamine (D2), 5-HT1 like, 5-HT2 and histamine (H1) receptors. This lack 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
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of interaction with post-synaptic receptors in vitro is substantiated by in vivo studies which 
demonstrate lack of CNS depressant and hypotensive properties. [1] 
3.2 Therapeutic Indications 
Paroxetine is indicated for the treatment of: 
• Major depressive disorder. 
• Obsessive Compulsive Disorder (OCD). 
• Panic disorder with and without agoraphobia. 
• Social anxiety disorders/social phobia. 
• Generalised anxiety disorder. 
• Post-traumatic stress disorder. [1] 
3.3 Pharmacokinetics 
3.3.1 Absorption 
Paroxetine is well absorbed after oral dosing and undergoes first-pass metabolism. Due to 
first-pass metabolism, the amount of paroxetine available to the systemic circulation is less 
than that absorbed from the gastrointestinal tract. Partial saturation of the first-pass effect and 
reduced plasma clearance occur as the body burden increases with higher single doses or on 
multiple dosing. This results in disproportionate increases in plasma concentrations of 
paroxetine and hence pharmacokinetic parameters are not constant, resulting in non-linear 
kinetics. However, the non-linearity is generally small and is confined to those subjects who 
achieve low plasma levels at low doses. 
Steady state systemic levels are attained by 7 to 14 days after starting treatment with 
immediate or controlled release formulations and pharmacokinetics do not appear to change 
during long-term therapy. [1] 
 
 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
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3.3.2 Distribution 
Paroxetine is extensively distributed into tissues and pharmacokinetic calculations indicate 
that only 1% of the paroxetine in the body resides in the plasma. Approximately 95% of the 
paroxetine present is protein bound at therapeutic concentrations. 
No correlation has been found between paroxetine plasma concentrations and clinical effect 
(adverse experiences and efficacy). [1] 
3.3.3 Metabolism 
The principal metabolites of paroxetine are polar and conjugated products of oxidation and 
methylation which are readily cleared. In view of their relative lack of pharmacological 
activity, it is most unlikely that they contribute to paroxetine's therapeutic effects. 
Metabolism does not compromise paroxetine's selective action on neuronal 5-HT uptake. [1] 
3.3.4 Excretion 
Urinary excretion of unchanged paroxetine is generally less than 2% of dose whilst that of 
metabolites is about 64% of dose. About 36% of the dose is excreted in faeces, probably via 
the bile, of which unchanged paroxetine represents less than 1% of the dose. Thus, paroxetine 
is eliminated almost entirely by metabolism. 
Metabolite excretion is biphasic, being initially a result of first-pass metabolism and 
subsequently controlled by systemic elimination of paroxetine. 
 [1] 
 
 
 
 
 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
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Table 1 Pharmacokinetic Parameters of Paroxetine  
Reference 
Drug  
Dose 
Cmax 
Tmax 
T1/2 
(mg) 
(ng/mL) 
(h) 
(h) 
3 (In-house 
data 
(Avant Santé) 
AS/AO/ABR-
17/0012 
Paroxetine tablets 
20 mg 
6.884 
4.806 
11.4 
4 
Paroxetine tablets 
20 mg 
5.396 
(µg/L) 
5.35 
11.98 
 
Special Populations: 
Elderly: Increased plasma concentrations of paroxetine occur in elderly subjects. [1] 
3.4 Dosage and Administration:  
The recommended initial dose is 20 mg daily. 
Administration: Paroxetine tablets can be administered with or without food. [2] 
3.5 Interactions 
Interaction with other medicinal products and other forms of interaction: 
Serotonergic drugs: 
As with other SSRIs, co-administration with serotonergic drugs may lead to an incidence of 
5-HT associated effects. Caution should be advised and a closer clinical monitoring is 
required when serotonergic drugs (such as L-tryptophan, triptans, tramadol, linezolid, methyl 
thioninium chloride (methylene blue)), SSRIs, lithium, pethidine and St. John's Wort 
– Hypericum perforatum – preparations) are combined with paroxetine. Caution is also 
advised with fentanyl used in general anesthesia or in the treatment of chronic pain. 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
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Concomitant use of paroxetine and MAOIs is contraindicated because of the risk of serotonin 
syndrome. 
Pimozide 
Increased pimozide levels of on average 2.5 times have been demonstrated in a study of a 
single low dose pimozide (2 mg) when co-administered with 60 mg paroxetine. This may be 
explained by the known CYP2D6 inhibitory properties of paroxetine. Due to the narrow 
therapeutic index of pimozide and its known ability to prolong QT interval, concomitant use 
of pimozide and paroxetine is contraindicated. 
Drug metabolizing enzymes 
The metabolism and pharmacokinetics of paroxetine may be affected by the induction or 
inhibition of drug metabolizing enzymes. 
When paroxetine is to be co-administered with a known drug metabolizing enzyme inhibitor, 
consideration should be given to using paroxetine doses at the lower end of the range. 
No initial dosage adjustment is considered necessary when the drug is to be co-administered 
with known drug metabolizing enzyme inducers (e.g. carbamazepine, rifampicin, 
phenobarbital, phenytoin) or with fosamprenavir/ritonavir. Any paroxetine dosage 
adjustment (either after initiation or following discontinuation of an enzyme inducer) should 
be guided by clinical effect (tolerability and efficacy). 
Neuromuscular Blockers: 
SSRIs may reduce plasma cholinesterase activity resulting in a prolongation of the 
neuromuscular blocking action of mivacurium and suxamethonium. 
Fosamprenavir/ritonavir:  
Co-administration of fosamprenavir/ritonavir 700/100 mg twice daily with paroxetine 20 mg 
daily in healthy volunteers for 10 days significantly decreased plasma levels of paroxetine by 
approximately 55%. The plasma levels of fosamprenavir/ritonavir during co-administration 
of paroxetine were similar to reference values of other studies, indicating that paroxetine had 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
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no significant effect on metabolism of fosamprenavir/ritonavir. There are no data available 
about the effects of long-term co-administration of paroxetine and fosamprenavir/ritonavir 
exceeding 10 days. 
Procyclidine: Daily administration of paroxetine increases significantly the plasma levels of 
procyclidine. If anti-cholinergic effects are seen, the dose of procyclidine should be reduced. 
Anticonvulsants: carbamazepine, phenytoin, sodium valproate. Concomitant administration 
does not seem to show any effect on pharmacokinetic/dynamic profile in epileptic patients. 
CYP2D6 inhibitory potency of paroxetine: 
As with other antidepressants, including other SSRIs, paroxetine inhibits the hepatic 
cytochrome P450 enzyme CYP2D6. Inhibition of CYP2D6 may lead to increased plasma 
concentrations of co-administered drugs metabolised by this enzyme. These include certain 
tricyclic antidepressants (e.g. clomipramine, nortriptyline, and desipramine), phenothiazine 
neuroleptics (e.g. perphenazine and thioridazine), risperidone, atomoxetine, certain Type 1c 
antiarrhythmics (e.g. propafenone and flecainide) and metoprolol. It is not recommended to 
use paroxetine in combination with metoprolol when given in cardiac insufficiency, because 
of the narrow therapeutic index of metoprolol in this indication. 
Pharmacokinetic interaction between CYP2D6 inhibitors and tamoxifen, showing a 65-75% 
reduction in plasma levels of one of the more active forms of tamoxifen, i.e. endoxifen, has 
been reported in the literature. Reduced efficacy of tamoxifen has been reported with 
concomitant usage of some SSRI antidepressants in some studies. As a reduced effect of 
tamoxifen cannot be excluded, co-administration with potent CYP2D6 inhibitors (including 
paroxetine) should whenever possible be avoided. 
Alcohol: 
As with other psychotropic drugs patients should be advised to avoid alcohol use while taking 
paroxetine. 
 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
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Oral anticoagulants: 
A pharmacodynamic interaction between paroxetine and oral anticoagulants may occur. 
Concomitant use of paroxetine and oral anticoagulants can lead to an increased anticoagulant 
activity and haemorrhagic risk. Therefore, paroxetine should be used with caution in patients 
who are treated with oral anticoagulants. 
NSAIDs and acetylsalicylic acid, and other antiplatelet agents: 
A pharmacodynamic interaction between paroxetine and NSAIDs/acetylsalicylic acid may 
occur. Concomitant use of paroxetine and NSAIDs/acetylsalicylic acid can lead to an 
increased haemorrhagic risk. 
Caution is advised in patients taking SSRIs, concomitantly with oral anticoagulants, drugs 
known to affect platelet function or increase risk of bleeding (e.g. atypical antipsychotics such 
as clozapine, phenothiazines, most TCAs, acetylsalicylic acid, NSAIDs, COX-2 inhibitors) 
as well as in patients with a history of bleeding disorders or conditions that may predispose 
to bleeding. 
Pravastatin: 
An interaction between paroxetine and pravastatin has been observed in studies suggesting 
that co-administration of paroxetine and pravastatin may lead to an increase in blood glucose 
levels. Patients with diabetes mellitus receiving both paroxetine and pravastatin may require 
dosage adjustment of oral hypoglycaemic agents and/or insulin. 
 
Drugs affecting gastric pH: 
In vitro data have shown that dissociation of paroxetine from the oral suspension is pH-
dependant. Therefore, drugs that alter gastric pH (such as antacid drugs, proton pump 
inhibitors or histamine H2-receptor antagonists) may affect plasma paroxetine concentrations 
in patients taking the oral suspension. [1] 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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3.6 Adverse Drug Reactions 
Some of the adverse drug reactions listed below may decrease in intensity and frequency with 
continued treatment and do not generally lead to cessation of therapy. Adverse drug reactions 
are listed below by system organ class and frequency. Frequencies are defined as: very 
common (≥ 1/10), common (≥ 1/100, <1/10), uncommon (≥ 1/1,000, <1/100), rare (≥ 
1/10,000, <1/1,000), very rare (<1/10,000), including isolated reports. [1] 
Table 2 Adverse reactions of Paroxetine 
 
 
System organ class 
Frequency 
Adverse Reaction 
Blood and lymphatic 
disorders 
Uncommon 
Abnormal bleeding, predominantly of the skin and mucous membranes 
(including ecchymosis and gynecological bleeding). 
Very rare 
Thrombocytopenia. 
Immune system disorders 
Very rare 
Severe and potentially fatal allergic reactions (including anaphylactoid 
reactions and angioedema). 
Endocrine disorders 
Very rare 
Syndrome of inappropriate anti-diuretic hormone secretion (SIADH). 
Metabolism and nutrition 
disorders 
Common 
Increases in cholesterol levels, decreased appetite. 
Uncommon 
Altered glycaemic control has been reported in diabetic patients. 
Rare 
Hyponatraemia. 
Psychiatric disorders 
Common 
Somnolence, insomnia, agitation, abnormal dreams (including 
nightmares). 
Uncommon 
Confusion, hallucinations. 
Rare 
Manic reactions, anxiety, depersonalization, panic attacks, akathisia. 
Nervous system disorders 
Common 
Dizziness, tremor, headache, concentration impaired. 
Uncommon 
Extrapiramidal disorders. 
Rare 
Convulsions, restless legs syndrome (RLS). 
Very rare 
Serotonin syndrome (symptoms may include agitation, confusion, 
diaphoresis, hallucinations, hyperreflexia, myoclonus, shivering, 
tachycardia and tremor). 
Eye disorders 
Common 
Blurred vision. 
Uncommon 
Mydriasis. 
Very rare 
Acute glaucoma. 
Cardiac disorders 
Uncommon 
Sinus tachycardia. 
Rare 
Bradycardia. 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
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3.7 Contraindications 
Paroxetine is contraindicated with following: 
• Hypersensitivity to the active substance or to any of the excipients. 
• In combination with monoamine oxidase inhibitors (MAOIs including linezolid and 
methylene blue). 
System organ class 
Frequency 
Adverse Reaction 
Vascular disorders 
Uncommon 
Transient increases or decreases in blood pressure, postural 
hypotension. 
Respiratory, thoracic and 
mediastinal disorders 
Common 
Yawning. 
Gastrointestinal disorders 
Very 
common 
Nausea. 
Common 
Constipation, diarrhoea, vomiting and dry mouth. 
Very rare 
Gastrointestinal bleeding. 
Hepatobiliary disorders 
Rare 
Elevation of hepatic enzymes. 
Very rare 
Hepatic events (such as hepatitis, sometimes associated with jaundice 
and/or liver failure). 
Skin and subcutaneous 
tissue disorders 
Common 
Sweating. 
Uncommon 
Skin rashes, pruritus. 
Very rare 
Severe cutaneous adverse reactions (including erythema multiforme, 
Stevens-Johnson syndrome and toxic epidermal necrolysis), urticaria, 
photosensitivity reactions. 
Renal and urinary 
disorders 
Uncommon 
Urinary retention, urinary incontinence. 
Reproductive system and 
breast disorders 
Very 
common 
Sexual dysfunction. 
Rare 
Hyperprolactinaemia/galactorrhoea, menstrual disorders (including 
menorrhagia, metrorrhagia, amenorrhoea, menstruation delayed and 
menstruation irregular). 
Very rare 
Priapism. 
Musculoskeletal and 
connective tissue disorders 
Rare 
Arthralgia, myalgia. 
General disorders and 
administration site 
conditions 
Common 
Asthenia, body weight gain. 
Very rare 
Peripheral oedema. 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
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• Paroxetine should not be used in combination with thioridazine, because, as with other 
drugs which inhibit the hepatic enzyme CYP450 2D6, paroxetine can elevate plasma 
levels of thioridazine. Administration of thioridazine alone can lead to QTc interval 
prolongation with associated serious ventricular arrhythmia such as torsade’s de 
pointes, and sudden death. 
• Paroxetine should not be used in combination with pimozide. [1] 
 
4.0 
STUDY OBJECTIVES 
4.1 Primary Objective 
To evaluate and compare the single oral dose bioavailability of Paroxetine tablets 20 mg 
manufactured by GlaxoSmithKline Pharmaceuticals S.A. for GlaxoSmithKline México, S.A. 
de C.V. with that of PAXIL (Paroxetine) tablets 20 mg of GlaxoSmithKline México, S.A. de 
C.V. in healthy, adult, male and female subjects under fasting conditions. 
4.2 Secondary Objective 
To evaluate the safety and tolerability of single oral dose of Paroxetine 20 mg tablets in 
healthy adult male and female subjects under fasting conditions. 
5.0 
HYPOTHESIS OF THE STUDY 
Null hypothesis: H0: mean test / mean reference < L or mean test / mean reference > U   
Paroxetine tablets 20 mg manufactured by GlaxoSmithKline Pharmaceuticals S.A. and 
PAXIL (Paroxetine) tablets 20 mg of GlaxoSmithKline México, S.A de C.V. are not 
bioequivalent. 
Alternative hypothesis: H1: L ≤ mean test / mean reference ≤ U 
Paroxetine tablets 20 mg manufactured by GlaxoSmithKline Pharmaceuticals S.A. and 
PAXIL (Paroxetine) tablets 20 mg of GlaxoSmithKline México, S.A. de C.V. are 
bioequivalent. 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
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Two one-sided t-tests will be carried out on each PK parameter of Paroxetine using least 
squares means (LSM) values for geometric LSMs of the primary PK parameters (mean test 
or mean reference = LSM value of the corresponding PK parameter for test or reference 
product). The type I error will be set to α = 5% and therefore 90% (two-tailed) confidence 
intervals will be provided together with the indication whether the null hypothesis of 
nonequivalence for the appropriate parameter can be rejected. 
Probabilities p(t) of Schuirmann, left tail (tl) and right tail (tr) values will be calculated for the 
lower limit L = 0.80 and upper limit +U = 1 / 0.80 = 1.25 for geometric LSM of 
pharmacokinetic parameters Cmax and AUC0-t.  
 
6.0 
STUDY RATIONALE 
Paxil (Paroxetine) tablets 20 mg of GlaxoSmithKline México, S.A. de C.V. is listed as a 
reference product by COFEPRIS. Currently, the drug product is manufactured at Xochimilco, 
México site using wet granulation process and Xochimilco, México site will exit GSK 
network in 2021.  
Considering the same, Paroxetine tablets 20 mg manufactured using direct compression 
process at GlaxoSmithKline Pharmaceuticals S.A. site was selected as new supplier. 
Additionally, formulation composition is modified with respect to in-active ingredients.  
To register the above mentioned changes [change in the drug product manufacturing site, 
differences in the formulations and process] in the marketing registration application for 
México, a bioequivalence study is required as per Oficio Circular CAS/OR/01/868/2013 [5] to 
establish similarity between the test product (new) manufactured at GlaxoSmithKline 
Pharmaceuticals S.A. and reference product manufactured at Xochimilco, México site.  
México.  


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
Project No./Protocol No.: AS/BK/OCT-19/0055 
Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
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This product is an immediate release product and can be administered with or without food; 
hence, the test product (to be marketed) should be bioequivalent to the reference product 
under fasting conditions determined by Cmax and AUC0-t values of Paroxetine 
Hence, the test product PAXIL (Paroxetine) tablets 20 mg manufactured by GlaxoSmithKline 
Pharmaceuticals S.A. manufactured for GlaxoSmithKline México S.A. de C.V. will be 
compared with that of Paxil (Paroxetine) tablets 20 mg GlaxoSmithKline México, S.A. de 
C.V.  to evaluate bioequivalence. 
6.1 Dose Rationale 
The recommended initial dose of Paroxetine is 20 mg/ day. Hence, 20 mg dose of Paroxetine 
is within the dose range, which is expected to be tolerable in healthy adult volunteers. [2] 
7.0 
STUDY DESIGN 
Each period will have identical procedures. For a detailed schedule of events, see Attachment-
II. 
7.1 Study Design 
An oral single-dose, randomized, balanced, open-label, two-sequence, two-treatment, two-
period, crossover bioequivalence study under fasting conditions. 
The study design is presented in Figure 2 below. 
 
 
 
 
 
 
 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
Project No./Protocol No.: AS/BK/OCT-19/0055 
Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
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Figure 2 Study Design Diagram 
 
7.2 Rationale for Study Design and Blood Sampling Points 
Generally, bioequivalence studies are conducted in healthy adult volunteers. As this product 
is indicated for men and women, this bioequivalence study is planned in healthy adult human 
male and female volunteers. These products are an immediate release formulation and it can 
be administered with or without food, fasting bioequivalence study is required.  
In this study two formulations are being compared, a randomised, two-period, two-sequence 
single dose crossover fasting study design is planned in healthy subjects to assess 
bioequivalence. 
Sampling points have been placed with sufficient frequency to characterize Cmax and AUC 
parameters adequately, considering the Tmax and half-life of Paroxetine. The Tmax occurs 
approximately 5.00 hours after the drug administration and the mean elimination half-life is 
approximately 12 hours [3].  
A minimum of seven times the mean half-life will be considered as wash-out period between 
consecutive treatments to avoid carry-over effects, hence a wash-out period of at least 7 days 
Subjects 
RANDOMIZATION 
Sequence 2 
Sequence 1 
Reference 
Test 
Reference 
Test 
WASHOUT 
II 
Period 
I 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
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is considered. The duration of blood sampling is planned till 72.00 hours to cover at-least four 
half-lives for Paroxetine. 
7.3 Sample Size 
At least 34 healthy adult male and female subjects are required to meet at least a statistical 
power of 90% at 5% level of significance to achieve the bioequivalence results within 80.00-
125.00% in this study. In addition, a maximum of 4 subjects will be dosed in account for 
withdrawal and dropouts.  
Hence, a maximum of 38 subjects will be randomized and dosed. No subjects should be 
replaced after administered with the study treatment. 
If possible, a maximum of two additional standby subjects (Stand by-I, Stand by-II) will be 
enrolled to replace any subject, who is withdrawn or dropped due to any reason prior to 
administration of study medication in period-1. 
7.4 Justification of the Sample Size 
Based on the in-house study data [3], a maximum intra subject variability of coefficient of 
variation (ISCV %) of 23.1 was observed for Cmax of Paroxetine. According to NOM-177-
SSA1-2013, section 8.5.1.1, the statistical power must not be less than 80%. Based on the 
observed maximum ISCV% of 23.1% and assuming the test/reference ratio of 95%, the 
inclusion of 34 subjects in the study is required to meet at least a statistical power of 80% at 
5% level of significance to achieve the results within 80.00-125.00% for 2-way crossover 
study. 
Using the intra-subject variability and the expected test/reference ratio from above paragraph, 
the sample size is estimated from the following equation: 
ni≥2 [t1-α, n-2+t1-, n-2]2[CV/(-ln(L)- (-ln ())]2 where   ≤ 1 
 
 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
Project No./Protocol No.: AS/BK/OCT-19/0055 
Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
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α: 
Probability of Type I error (0.05) 
:  
Probability of Type II error (0.1) 
CV: Intra Subject Variability (0.231) 
:  
Expected T/R ratio (0.95) 
L:  Lower bioequivalence limit (0.80) 
Assuming the minimum sample size required (n) as 12, the sample size is estimated as 
follows: 
ni≥2 [t1-0.05, 12-2+t1-0.1, 12-2]2 [0.231/ (-ln (0.8) - (-ln (0.95))]2  
ni≥37 
Using the estimated sample size form previous iteration (n=37) from the above estimation, 
the sample size is again estimated as follows: 
ni≥2 [t1-0.05, 37-2+t1-0.1, 37-2]2 [0.231/ (-ln (0.8) – (-ln (0.95))]2 
ni≥32 
Using the estimated sample size form previous iteration (n=32) from the above estimation, 
the sample size is again estimated as follows: 
ni≥2 [t1-0.05, 32-2+t1-0.1, 32-2]2 [0.231/ (-ln (0.8) – (-ln (0.95))]2 
ni≥33 
Using the estimated sample size form previous iteration (n=33) from the above estimation, 
the sample size is again estimated as follows: 
ni≥2 [t1-0.05, 33-2+t1-0.1, 33-2]2 [0.231/ (-ln (0.8) – (-ln (0.95))]2 
ni≥33 
Convergence has reached and the estimated sample size is at least 34 (round to equal number) 
subjects to meet at least a statistical power of 80% at 5% level of significance to achieve the 
results within 80.00-125.00% for 2-way crossover study. 
7.5 Washout Period 
There will be a washout period of at least 7 days between successive dosing. 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
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7.6 Duration of the Study 
The expected duration of the subjects’ participation in the study will be at-least 12 days, 
including a wash-out period of 7 days between each dosing. 
7.7 Randomization 
The order of receiving the test and reference products for each subject during each period of 
the study will be determined according to a randomization, generated by using SAS® software 
(version 9.4 or higher). This randomization will be balanced for the test product (A) and 
reference product (B). All the subjects should be divided into blocks of equal size and two-
sequence “AB” and “BA” will be used for assignment of treatment in the respective study 
period (refer Figure-2). Analysts will not have access to the period randomization schedule. 
Randomization will be performed according to the procedure PB009 (Procedure for 
Randomization Schedule Generation).  
7.8 Blinding 
This study is an open label study; the subjects and the investigators will not be blinded 
towards the identity of the study treatments. Analysts (bioanalytical personnel) will be 
blinded with regard to the sequence of administration of test and reference products. 
7.9 Test and Reference Products 
Table 3 Investigational Product Details 
IP Details 
Reference Product (B) 
Test Product (A) 
Distinctive Name 
PAXIL 
N/A 
Generic name  
Paroxetine hydrochloride  
Paroxetine hydrochloride 
Pharmaceutical 
form 
Tablets 
Tablets 
Formulation 
Immediate release 
Immediate release 
Strength 
20 mg 
20 mg 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
Project No./Protocol No.: AS/BK/OCT-19/0055 
Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
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IP Details 
Reference Product (B) 
Test Product (A) 
Dose 
20 mg 
20 mg 
Lot / Batch No. (1) 
To be designated 
To be designated 
Expiry date / Re-
test date (1) 
To be designated 
To be designated 
Storage 
Conditions 
Store at 25°C (77°F): excursions 
permitted to 15–30°C (59–
86°F). 
Store at 25°C (77°F): excursions 
permitted to 15–30°C (59–86°F). 
Name of the 
manufacturer 
GlaxoSmithKline México, S.A. 
de C.V. 
Manufactured by: 
GlaxoSmithKline 
Pharmaceuticals S.A. 
Manufactured for: 
GlaxoSmithKline México, S.A. 
de C.V. 
Sanitary 
Registration 
Number 
008M93SSA  
Not applicable (2) 
1: Research Ethics Committee and Research Committee shall be notified on the lot / batch number and the 
expiry/retest date of the study drugs before conducting the clinical stage. The same information shall be 
notified to COFEPRIS in the final report of the study. 
2: The Test drug will be evaluated for obtaining COFEPRIS registration.  
7.10 Reception and Storage of Investigational Products 
In accordance to the NOM-177-SSA1-2013, a sufficient quantity of the investigational 
products (test and reference) will be supplied to the research center by the sponsor in its 
original marketing package (applicable for reference product) or in a sealed package along 
with its Certificate of Analysis (CoA) for the conduct of the study as well as for retention 
(once the study is completed). Therefore, at least 80 tablets of reference product and 80 tablets 
of test product will be supplied and stored at Avant Santé facilities, in order to guarantee the 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
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necessary resources for dosing the product of investigation at least once and also for its 
retention (once the study is concluded to be able to repeat the study). 
The study drug reception, handling and storage of investigational products will be performed 
according to SOP CP017 (Study Drug Reception and Storage). 
The test and reference products will be supplied in sealed packages. 
Once received, both investigational products (test and reference) will be kept in separate 
boxes (labeled with project number, IP name, IP type, batch number, manufacturing date and 
/ or expiration date, and storage conditions along with “For clinical research use only” 
statement) and stored in pharmacy as per the storage conditions mentioned on the label. 
If the aforementioned conditions are not specified, the IPs will be stored as per the conditions 
specified by the sponsor or the available literature. 
Upon completion or termination of the study, the investigational products will be stored in 
Avant Santé Research Center, S.A. de C.V. for at least 1 year after completion of the study or 
until test product / reference product expiry date is due, whichever occurs first. Test and 
reference products return or disposal will be followed according to respective in-house 
procedures. [6,7] 
• The test and reference products shall be in the valid expiry date at the time of the study 
conduction. 
• The percentage of assay content of the test product must be within the limits established 
in the relevant pharmacopeias and it should not differ by more than 5% with that of the 
reference product. 
• Criteria for acceptance or rejection of drugs are followed according to SOP CP017 (Study 
Drug Reception and Storage). 
 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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Sponsor Code: 212969 
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7.11 Accounting of Investigational Products 
The recording of the total quantity of investigational products received, dispensed, used, 
retained, disposed or returned to the sponsor, will be performed in the respective forms and 
kept in the pharmacy of Avant Santé Research Center, S.A. de C.V. The investigational 
products balance will be included in the clinical study report. This activity will be performed 
according to SOPs CP018 (Study Drug Dispensing and Retention) and CP019 
(Investigational Products Return or Disposal). 
7.12 Dispensing 
The pharmacist will dispense required units of the test and reference products at least a day 
prior the dosing in each period of the study under the supervision of a person from Clinical 
Pharmacology department and a person from Quality Assurance. The doses will be transferred 
to the dispensing containers as per the randomization schedule and properly labeled with the 
project number, period number, subject number, IP type (test/reference) and storage 
conditions, along with the following statement: “For clinical research use only”. 
At least one dose of each test and reference product will be dispensed as “standby” in order 
to handle any unexpected loss or damage of the medications during their administration. This 
activity will be performed according to CP018 (Study Drug Dispensing and Retention) 
The test and reference product tablet will be removed from blister pack / package only at the 
time of dosing. 
 
 
 
 
 
 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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Sponsor Code: 212969 
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8.0 
SELECTION AND WITHDRAWL OF SUBJECTS 
8.1 Screening (selection and enrollment) 
Healthy adult male & female volunteers, light or non or ex-smokers, aged between 18 and 55 
years (both inclusive), with a weight ≥ 50.00 kg, with a BMI between ≥ 18.0 and ≤ 27.0 kg/m2 
will be selected according to the inclusion and exclusion criteria. 
All the subjects will have a medical history during the selection and enrollment process. 
Volunteers shall be found healthy according to the physical examination (including vital signs 
assessment), normal laboratory test results and 12-lead ECG. 
The physical examination findings, ECG and laboratory tests will be considered valid for a 
maximum period of 90 days prior to the dosing on the first period of the study. 
Pregnancy test in urine will be carried out during the screening period and at the time of each 
period check-in for all female subjects. 
The process of selection and enrollment or withdrawal of subjects who will participate will 
be done according to the present protocol and as per the procedures CP002 (Volunteer 
Registration and Screening) and CP003 (Screening-Failing volunteers). 
Real-time (RT-PCR) test for the detection and diagnosis of SARS-COV-2 will be carried out 
within the 72 hours prior to the first period check-in for all the subjects. 
Avant Santé Research Center S.A. de C.V. will ensure the volunteer participation history by 
verifying the COFEPRIS database for bioequivalence studies. 
 
 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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Sponsor Code: 212969 
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8.2 Clinical Laboratory Tests 
As part of the selection process the following laboratory tests will be performed to each 
subject. 
Table 4 Laboratory Tests 
 
 
 
 
 
Blood tests 
Urine analysis 
Hematology 
Biochemistry 
Red blood cell count 
White blood cell count 
Differential white blood cell 
count 
Hemoglobin estimation 
Hematocrit  
Platelet count  
MCH, 
MCV, 
Mean Platelet Volume 
Blood glucose (Random) 
Blood urea, Blood urea nitrogen 
(BUN) 
Serum creatinine 
Serum sodium, potassium and 
Chloride 
Serum uric acid 
Liver Function Tests: 
Total bilirubin 
Direct bilirubin 
Indirect bilirubin 
SGOT (AST)  
SGPT (ALT) 
Serum alkaline phosphatase 
Total protein 
Serum albumin 
Serum Globulin 
Lipid profile  
 
pH 
Specific gravity 
Protein 
Glucose 
Ketones 
Bilirubin 
Urobilinogen 
Blood / Red blood cells 
Nitrites 
Microscopic examination 
Pregnancy 
test 
(female 
subjects) 
Serology 
Urine drug screen 
HIV (1 & 2) antibodies 
HBsAg (Hepatitis B surface 
antigen) 
HCV 
(Hepatitis 
C 
virus) 
antibodies) and VDRL 
Cannabinoids 
(Marijuana 
/ 
Tetrahydrocannabinol-
THC), Cocaine, Opiates, 
Amphetamine, 
Methamphetamine 
and 
Benzodiazepines 
Alcohol breath analysis test for all the subjects will be performed before check-in of each study period. 
Urine drug screen for all the subjects and pregnancy test in urine for female subjects will be performed before check-in 
of each period. 
Real-time (RT-PCR) test for the detection and diagnosis of SARS-COV-2 will be carried out within the 72 hours prior 
to the first period check-in for all the subjects. 
 
 
 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
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8.3 Inclusion Criteria 
Subjects must fulfill all of the following criteria to be considered for their inclusion in this 
study: 
1. Healthy adult male or female subjects aged between 18 and 55 years (both inclusive). 
2. Subjects is a light or non- or ex-smoker (A light* smoker is defined as someone who smoke 
9 or less cigarettes per day and an ex-smoker being defined as someone who completely 
stopped smoking for at least 6 months before day 1 of this study). 
*: If any subjects stop smoking during last 6 months before day 1 of the study and smoke 
9 or less cigarettes per day, the subject will also be considered as a light-smoker. 
3. With a weight  50.00 kg. 
4. With a body mass index (BMI) ≥ 18.0 kg/m2 and ≤ 27.0 kg/m2. 
5. Found healthy according to the clinical laboratory results and physical examination 
(performed within 90 days prior to the dosing on period-1). 
6. Have a normal 12 lead ECG and vital signs. 
7. Have laboratory test results within the laboratory's stated normal range; if not within this 
range, they must lack of no clinical significance as judged by the PI or responsible 
physician. 
8. Willing to avoid sexual contact or use an acceptable contraceptive method during the study 
including the washout period (for females). In case of male subjects, they should avoid 
sexual contact or use a latex or synthetic condom each time they have sex with a woman 
while taking Paroxetine and during 7 days after the end of the study. 
9. If study subject is a female and is of child bearing potential, she shall practice a method of 
birth control for the duration of the study as judged by the investigator (s), like combined 
short acting (estrogen and progestogen containing) hormonal contraception e.g. oral, 
intravaginal, and progestogen-only hormonal contraception e.g. oral, intrauterine device 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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Sponsor Code: 212969 
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(IUD), intrauterine hormone-releasing system (IUS), condoms, foams, jellies and 
diaphragm 
Or 
Abstinence  
Or 
If study subject is a female and is postmenopausal for at-least 1 year 
Or 
Is surgically sterile (bilateral tubal ligation, bilateral oophorectomy or hysterectomy has 
been performed on the study subject). 
10. Have a negative test for active COVID-19, within 72 hours prior to the first period check-
in. The testing should be done using a molecular (RT-PCR) approved by the country 
regulatory authorities.  
11. Subject is able to communicate effectively and voluntarily agreed to participate in this 
study by signing written informed consent after being informed sufficiently about study 
aspects like objectives, study procedures, characteristics of the investigational drug, 
expected adverse events. 
12. Subject willing to adhere to protocol requirements as described in informed consent 
(written) approved by REC / RC. 
 
8.4 Exclusion Criteria 
Subjects will be excluded if they meet any of the following criteria: 
a. If subject’s age is less than 18 or older than 55 years. 
b. Have any history of allergy or hypersensitivity to Paroxetine or to any of its 
metabolites/derivatives or related drugs or excipients. 
c. Have a positive test result for hepatitis B surface antigen (HBs Ag) or hepatitis C virus 
antibody (HCV Ab) or HIV antibodies (types 1 and 2) or VDRL. 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
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d. Subjects with symptoms suggestive of active COVID-19 infection (i.e. fever, cough, 
respiratory difficulties) within 14 days of inpatient admission. 
e. Subjects with known COVID-19 positive contacts* within the past 14 days prior to the first 
period check-in. 
*Positive Contact; this means, if the subject has been living, providing, care, being within  
1.5 m for at least 15 min or having exposure to respiratory secretions with/to a person who 
has COVID-19. 
f. Study drug is contraindicated for medical reasons to the subject as per protocol section 3.7. 
g. Have any history or presence of significant cardiovascular, pulmonary, hepatic, renal, 
gastrointestinal, seizures, endocrine, dermatological, neurological or psychiatric disease or 
disorder (e.g. Subjects with uncontrolled hypertension, phaeochromocytoma, carcinoid, 
thyrotoxicosis, bipolar depression, schizoaffective disorder and acute confusional states). 
h. Presence of significant gastrointestinal, hepatic or kidney disease, or surgery or any other 
conditions known to interfere with the absorption, distribution, metabolism or excretion of 
drugs or known to potentiate or predispose to undesired effects. 
Or 
Subjects with a history of gastrointestinal disorder or surgery which may affect the 
absorption of investigational drug. 
i. Have a history of alcohol abuse or drug abuse during the last 1 year prior to period-1 
dosing. 
j. Have a history of smoking ≥ 10 cigarettes per day during the last 6 months prior to period-
1 dosing. 
k. Have history or presence of cancer. 
l. Have any history of gastrointestinal ulcers / intestinal bleeding. 
m. Have difficulty in swallowing solid medications such as tablet. 
n. Have history of difficulty for donating blood. 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
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o. Have clinically significant abnormal laboratory tests results. 
p. Have a systolic blood pressure < 90 or > 140 mmHg or diastolic blood pressure is < 60 or 
> 90 mmHg. 
q. Have a pulse rate < 60 beats/minute or > 100 beats/minute (Lower range of pulse range 
will be accepted up to 45 beats/minute in case of athlete). 
r. Have used any prescribed medication during the last 14 days preceding the first dosing, or 
use OTC, medicinal or herbal products during the last 7 days or use medicinal enzyme 
inhibitors / inducers during last 30 days preceding the first dosing. 
s. Have participated in a drug research study or donated blood within the last 3 months. 
t. Have 
a 
positive 
result 
for 
drugs 
of 
abuse 
test 
[Cannabinoids 
(Marijuana/Tetrahydrocannabinol-THC), Cocaine, Opiates/Morphine, Amphetamine, 
Methamphetamine and Benzodiazepines] performed during screening. 
u. Female subject, who is currently breast feeding or a who is pregnant or who is likely to 
become pregnant during the study. 
v. Female subject has a positive pregnancy test results. 
w. Unwillingness or inability to comply with the instructions on the lifestyle described in this 
Protocol. 
x. If the PI considers, for any reason, that the volunteer is not a suitable candidate to receive 
the study drug. 
8.5 Criteria for Subject Withdrawal from the Study 
Subjects have the right to withdraw their consent from the study at any time and for any reason 
without facing any related prejudice. The Principal Investigator may withdraw a subject from 
the study if: 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
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a. The subject wishes to withdraw consent (In case the subject request to disposal of the 
collected samples, the same shall be documented and will be informed to sponsor and 
REC/RC). 
b. The subject suffers from significant inter-current illness or undergoes surgery during the 
study. In case a subject is positive for COVID-19 or has a related symptom (i.e. fever, 
cough, respiratory difficulties), they shall be isolated for 14 days and they shall be 
discontinued In case any other subject was exposed to a COVID-19 patient, they must 
report this to Avant Santé, GSK and/or their primary care provider. 
c. Subject fails to comply with the requirements of the protocol section 9.3 Restrictions. 
d. Subject experiences an adverse event and it is not in the subject’s best interest to continue 
in the study (as judged by the PI). 
e. Subject has a positive result for the breath alcohol test or urine drugs of abuse test 
[Cannabinoids (Marijuana/Tetrahydrocannabinol-THC), Cocaine, Opiates/Morphine, 
Amphetamine, Methamphetamine and Benzodiazepines] prior to check-in of each study 
period. 
f. The subject vomits at the time of the drug administration or vomiting / diarrhea occurs 
within 10 hours of drug administration (representing twice the median Tmax of  5 hours). 
g. In case of a female subject a positive result for the pregnancy test. 
h. Subjects who miss 4 or more consecutive blood draws in any of the study periods. 
According to NOM-177-SSA1-2013, section 8.9.5, frequent sampling points are needed 
around the Tmax and also at least four samples during the log-terminal phase to obtain the 
extraction rate constant. If any subject misses 4 or more consecutive sampling points during 
the absorption phase or the extraction phase, it will have an impact on the precise accuracy 
of the Cmax and AUC curve. 
i. The study is suspended or terminated by the sponsor or PI or EC/REC.  


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
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It should be noted that any subject that is not discontinued or withdrawn from the study will 
be considered as a subject who finishes the study. 
9.0 
TREATMENT OF SUBJECTS 
9.1 Drug Administration 
In each study period, all subjects will be required to fast overnight for at least 10.00 hours 
prior to dosing until at least 04.00 hours post-dose. 
In each study period, a single-dose of either the test product (A) or reference product (B) will 
be orally administered to the subjects in sitting posture along with 250 mL of water at room 
temperature under fasting conditions. 
The administration of the test or reference products to each subject will be performed as per 
a randomization schedule. 
The subjects will be instructed to swallow the tablet as a whole as mentioned in the prescribing 
information and not to touch the tablet with their hands, chew or crush the tablet since this 
can affect the drug release. 
Subject’s hands and mouth will be checked after dosing to ensure compliance with dosing. 
Immediately after dosing in each period trained study personnel will evaluate the compliance 
by supervising the complete administration procedure (SOP CP020, Administration of the 
Investigational Product). 
Drug administration will be registered in the respective source documents. 
9.2 Dietary Plan 
Subjects will be provided with standard meals throughout their stay in the facilities.  
On the check-in day (day -1) they will receive dinner, which will be finished at the latest 
10.00 hours prior to dosing at the following day in each study period. 
Subjects will be required to fast overnight for at least 10.00 hours prior to dosing and until at 
least 04.00 hours post-dose in each study period. 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
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After the dose administration of test or reference product (day 1), lunch, snack and dinner will 
be provided at 04.00, 08.00 and 12.00 (with a grace period of + 45 minutes) hours post-dose 
respectively, in each study period. 
The meal plan will be uniform for all the subjects and same between the study periods. 
Information on the amount of meal consumed and the time of consumption by each subject 
will be registered in the respective source documents. The nutritional value of the meals is 
presented in the following table. 
 
Table 5 Nutritional value of diet on study day 1 
 
 
Nutritional Value of meals 
2000 kcal ± 10% 
Calories (%) 
Proteins 
15-20% 
Lipids 
25-30% 
Carbohydrates 
50-60% 
Total 
*100% 
*% of kilocalories is within its adequate distribution of 90–110%. 
9.3 Restrictions 
•   Smoking 
All subjects will be instructed to refrain from smoking of cigarettes / nicotine containing 
products for at least 72.00 hours prior to the dosing and until the last sample collection in each 
period and will be prohibited from smoking during their in-house stay. 
• Medications 
All subjects will be asked about their medication history. They will be instructed not to take 
any medication until the study is completed; particularly during the last 14 days preceding the 
first dosing for any prescribed medication, the last 7 days before for OTC medicinal or herbal 
products used for therapeutic purposes, and the last 30 days before for any enzyme inhibiting 
/ inducing drugs preceding the first dosing. 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
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Subjects will be specifically reminded that the restriction mentioned above includes 
analgesics, cold & anti-allergic preparations, vitamins and natural products used for 
therapeutic benefits and antacid preparations. 
Vitamins used as nutritional supplements in non-therapeutic doses (as judged by the principal 
investigator or designee) may be accepted, but their consumption must be stopped from at 
least 7 days prior to the dosing and until the study is completed. 
If a drug therapy other than that specified in the protocol is required prior to, during the study 
or in the washout period, the Principal Investigator shall decide whether to continue or 
discontinue the subject’s participation based on the following: 
➢ The pharmacology and pharmacokinetics of the non-study medication. 
➢ The likelihood of a drug–drug interaction, which may affect the pharmacokinetic 
comparison of the study drugs. 
➢ The time and duration of administration of the non-study medication. 
• Diet 
All subjects will be instructed to avoid the consumption of any xanthine-containing food or 
beverages (tea, coffee, theobromine, theophylline, chocolates, cola drinks, etc.) at least 72.00 
hours prior to the dosing and until the last blood sample collection in each study period. 
Subjects will be instructed to avoid the consumption of alcohol (or related products) as well 
as smoked or carbon cooked food from at least 72.00 hours prior to the dosing, until the last 
blood sample collection in each study period. 
Subjects will be instructed to avoid the consumption of pomelos or grapefruit juice or products 
containing grapefruit extract (e.g. soda) from at least 72.00 hours prior to the dosing, and till 
the last blood sample collection in each study period. 
The consumption of above-mentioned products will also be prohibited during their in-house 
stay. 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
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Fluid (water) restriction 
The subjects will not be allowed to drink water 1 hour before and until 2 hours post-dose 
except for the 250 mL of water provided for the dosing, unless it is clinically indicated; at all 
other times water will be provided ad libitum. 
Postural (activity) Restriction  
The dose will be administered to all subjects at the scheduled time and subjects will be 
instructed to remain in comfortable sitting position for the first 02.00 hours following the drug 
administration except when clinically indicated or protocol specified activity (blood sample 
collection) or due to natural exigencies. 
After 02.00 hours post-dose, subjects will be allowed to wander and will be advised to avoid 
any severe physical exertion. 
In case of an adverse event (AE), subjects will be maintained in the proper position as per 
physician’s assessment in each study period. 
• 
Recommendations during washout period and visits to the center (ambulatory samples) 
In case a subject has symptoms of COVID-19, the following recommendations will be 
provided (the same as dictated by the WHO): 
• Isolation for 14 days at home: Staying at home except to get medical care immediately 
if having an emergency warning sign (i.e., trouble breathing). 
• Monitoring temperature: average human body temperature is 36-37°C. 
• Any related-COVID-19 symptom, worsening or recovery, must be reported to their 
primary care provider and to Avant Santé Principal Investigator. 
9.4 Housing 
Subjects will be in the clinical facility from at least 10.50 hours prior to the dosing until the 
last in-house blood sample collection i.e. 24 hours in each study period. 
Subjects will visit clinical facility at 36.00, 48.00 and 72.00 hours for the collection of the 
ambulatory samples in each study period. 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
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Subjects will be instructed to self-quarantine during the outpatient period of the study i.e. until 
72 h blood sample collection in period-2 or until withdrawal, whichever is earlier, and to 
monitor at home their daily body temperature. 
9.5 Sampling Schedule 
In each study period, a total of 24 blood samples (4 mL each) will be collected from each 
subject as per the following schedule: 
• 
The first blood sample will be collected within 1.50 hours prior to the dosing (00.00 
hours / pre-dose). 
• 
The remaining samples will be collected after the dosing of the test or reference drug at 
00.50, 01.00, 01.50, 02.00, 02.50, 03.00, 03.50, 04.00, 04.50, 05.00, 05.50, 06.00, 06.50, 
07.00, 08.00, 09.00, 10.00, 12.00, 16.00, 24.00, 36.00, 48.00 and 72.00 hours. 
• 
The samples corresponding to 36.00, 48.00 and 72.00 hours post dose will be collected 
on separate visits as ambulatory sample in each period of the study.  
The total blood volume collected from each subject will not exceed 223 mL, which includes 
about 10 mL for the selection process (selection and enrollment), 21 mL for the discarded 
heparinized blood and 192 mL for the pharmacokinetic evaluation. 
If circumstances arise, where more than 223 + 10 mL (may be collected for safety evaluation 
purpose) of blood from each subject needs to be withdrawn the subject will be asked for 
additional consent and the REC / RC will be informed. 
Table 6 Blood volume of samples to be collected during the study 
Sample Type 
Sample 
Volume (mL) 
Number of Sampling Times 
Total Volume 
(mL) 
Screening 
Study Period 
Follow-Up 
Screening 
10 mL 
1 
------- 
------- 
10 
PK Blood 
Samples 
4 mL 
------- 
48 samples 
(Period 1,2) 
------- 
192 
Heparinized blood 
0.5 mL 
------- 
42 samples 
(Period 1,2) 
------- 
21 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
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At the time of each blood sample collection, 4 mL will be collected through an indwelling 
cannula placed temporarily (for at least 24.00 hours post-dose) in a forearm vein or as per 
subject’s convenience for practical reasons and the remaining sample(s) will be collected 
through direct venipuncture. 
Blood samples will be obtained in K2-EDTA vacuum tubes (pre-labeled with project number, 
period number, subject number and sample number). 
If the times of sample collection vital signs or medical examination and food consumption 
overlap during the housing period, the order will be as follows. 
Sample collection → vital signs or medical examination → food consumption. 
Blood samples shall be collected not earlier or later than (±) 2 minutes of the specified 
sampling time for all the in-house samples and not earlier or later than (±) 60 minutes of the 
specified sampling time for ambulatory samples. Blood sampling will be registered in the 
respective source documents. 
If blood samples are collected earlier or later than this period from the scheduled time, this 
shall be reported as a deviation from this protocol. 
Heparin-lock technique (with 0.5 mL) will be used to prevent coagulation of the blood in the 
cannula. Prior to the blood collection through the cannula, 0.5 mL of heparinized blood will 
be withdrawn and discarded in order to prevent the heparin interfering with the sample 
analysis. If for any reason the indwelling cannula is blocked or removed, direct venipuncture 
will be performed to collect the samples. 
All this process is described in detail in the procedure CP021 (Phlebotomy Performance). 
If any subject misses any blood sampling point, it will be considered as missing sample. 
The same will be denoted as (M), it will be considered as protocol deviation and mentioned 
in the clinical study report. 
 
TOTAL 
223 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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Sponsor Code: 212969 
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9.6 Sample Processing and Storage 
Once collected, the blood samples will be placed in an ice-filled container or another cooling 
device until the centrifugation process is started. 
Centrifugation process will be started within 45 minutes from the time of blood sample 
collection and will be performed at 3000 rpm for 10 minutes at 4 ± 2 ºC. 
The plasma obtained from blood samples will be transferred as soon as possible into two 
different cryo-tubes (aliquot 1 and aliquot 2), pre-labeled with project number, period number, 
subject number, sample number and aliquot number. 
The plasma volume obtained from blood sample will be allocated as follows: 
Aliquot 1: 1.0 mL of plasma (approximately). 
Aliquot 2: rest of the plasma. 
All plasma samples (aliquot 1 for sample analysis and aliquot 2 as back-up) will be stored in 
the Clinical facility at a temperature of -50 °C or below until transferred in dry ice to the 
Bioanalytical facility, where they will be stored at a temperature of -50 C or below until their 
analysis. 
9.7 Sample transfer 
At the end of each period or clinical phase, samples will be separated and sorted by subject, 
period and aliquot as per the procedure CP031 (Biological Samples Processing, Storage, 
Shipment and Spillage Handling). Once the samples of each subject are sorted, they will be 
placed in propylene storage containers or in an auto-sealed bag, previously labeled with the 
project number, period number, subject number, aliquot number and number of samples. 
Process of separation, sorting and sample verification will be done with sufficient dry ice. 
Temperature will be monitored during the separation sorting and verification process with a 
calibrated data-logger and under supervision of quality assurance department personnel. 
At the end of the clinical phase of the study or each study period, aliquot 1 (used for the 
quantification and re-analysis) samples will be shipped for analysis to the Bioanalytical 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
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facility in a container with dry ice while transfer and temperature will be monitored. The 
aliquot 2 (for back-up) samples will be shipped using the same procedure and only after 
confirming the reception or loss of the aliquot 1 samples. If required, Aliquot 2 will be used. 
Aliquots will be stored in different deep freezers under the same condition in bioanalytical 
area. 
The process of reception, handling, storage and disposal of biological samples in the 
Bioanalytical unit, will be carried out according to procedure BL021 (Reception, 
Management, Storage, Transfer and Disposition of Biological Samples). 
CP personnel shall send the information "subjects samples to be analyzed" (including the 
reason or justification for not analyzing other samples of subjects) to the Bioanalytical 
department with the approval of the Principal Investigator and authorized by QA. 
10.0 
ASSESSMENT OF EFFICACY 
As this is a bioequivalence study, no efficacy assessment will be performed. The 
pharmacokinetic parameters of the test and reference formulations will be assessed. 
11.0 
ASSESSMENT OF SAFETY (CLINICAL SAFETY MEASURES) 
11.1 Recording of Vital Signs and Medical Examination 
Medical examination, which consists on subject’s anamnesis, inquiry for possible AEs, 
evaluation of vital sings and overall health status to determine if further physical examination 
is required will be performed before check-in, prior to the dosing and before the check-out in 
each study period. 
Nevertheless, it may also be performed at any time during the study conduction if judged 
necessary by the physician. 
Physical examination, which consists on subject’s anamnesis, examination of the head, neck, 
thorax, abdomen, and extremities (but not limited), inquiry for possible AEs and evaluation 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
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of vital sings will be performed before check-in of each study period and may also be 
performed at any time during the study conduction if judged necessary by the physician. 
Vital signs (sitting blood pressure, pulse rate, respiratory rate and axillary body temperature) 
will be measured and registered before check-in, prior to dosing, at 03.00, 05.00 and 12.00 
hours (within ±45 minutes) hours after the dosing, before the check-out and at the time of 
each ambulatory sample collection in each study period. 
The subjects’ well-being (assessed by verbal questionnaire to gather information about AEs)    
will be asked at the time of the medical examination, during the vital signs recording and at 
the time of each ambulatory sample collection in each study period; this will be registered in 
the respective source document. 
Seven (7) to 9 days after the collection of 72-h blood sample in second period or after the 
withdrawal, a telephone call will be made to each subject by the personnel designated by the 
PI to monitor any serious adverse event, specifically, subjects will be questioned about any 
symptoms related to COVID-19. 
11.2 Identification, Handling and Reporting of AE and SAE 
• 
Definitions 
Adverse Event (AE): Any untoward medical occurrence that may occur in a research subject 
during the clinical research phase of a drug or vaccines but which does not necessarily has a 
causal relationship with this. 
An adverse event can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
drug (research product), whether or not considered related to the research product. 
Abnormal laboratory results will be reported as adverse events under the following 
circumstances: 
• When the abnormal lab report is accompanied with associated symptoms. 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
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• When a medical or surgical intervention is required. 
• When an additional diagnostic test is required. 
• When it precedes and is associated with any of the outcomes included in the definition of 
serious adverse event. 
• When it is so considered by the PI. 
• Abnormal laboratory value as well as a significant shift from baseline within normal range 
which the qualified investigator or medically qualified delegate considers to be clinically 
significant (CS). If the Principal Investigator or the qualified medical delegate considers 
the abnormalities to be not Clinically Significant (NCS), the abnormalities do not need to 
be reported as AE. 
Therefore, a clinically significant laboratory value is one that indicates a new disease process, 
exacerbation or worsening of an existing condition or that requires additional measures. 
Adverse Drug Reaction (ADR): Any undesirable effect, associated with the use of a drug that 
may occur as part of the drug's pharmacological action or may be unpredictable in its 
occurrence. 
Suspected Adverse Drug Reaction (SADR): Any unwanted clinical manifestation that gives 
an indication or appearance of having a causal relationship with one or more drugs. 
Unexpected Adverse Drug Reaction (UADR): an adverse reaction which nature or severity 
is not described in scientific literature, neither in the label nor in the applicable product 
information, nor in the documentation presented for its registration, additionally, that it is not 
possible to infer it from its pharmacological activity and that it may be more serious that 
indicated on the label.  
Serious Adverse Event (SAE): any medical occurrence that at any dose: 
• Put patient’s life in risk or results in death. 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
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• Requires in-patient hospitalization or prolongation of existing hospitalization. 
• Results in persistent or significant disability/incapacity. 
• Is a congenital anomaly/birth defect. 
• Other important medical events: events that may not be immediately life-threatening or 
result in death or hospitalization, but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition. 
• 
Identification of Adverse Events 
The subjects will be monitored throughout the study for any adverse event manifestation. 
They will be encouraged to report any sign, symptom, and any health change to the clinical 
staff. The severity of each AE and its relationship to the study treatments will be determined 
by the PI based on observation and questioning of the subjects and in accordance to the 
following classification: non-assessable or unclassifiable, conditional or unclassifiable, 
unlikely, possible, probable or certain. 
The following measures will be employed to ensure that the adverse event is detected at the 
earliest: 
• The physical examination and vital signs recording will be performed at regular intervals 
after the study drug administration. 
• The subjects’ well-being will be enquired at regular intervals (see section 11.1). 
• All subjects who have received at least a single dose of the study drug will undergo a 
complete medical evaluation after the completion of the last sample collection for safety 
reasons. 
 
 
 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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• 
Management of Adverse Events 
A medically qualified designee will be available round-the-clock during the period of housing 
at the clinical facility. If any subject develops an AE the following measures will be adopted: 
• Subject will be evaluated by the physician or designated personnel, treated and/or 
followed-up until the symptoms disappear or laboratory values return to normal levels, as 
judged by the PI. 
• In case of a SAE, subject will be treated by a physician in the ICU, fully equipped with all 
the emergency handling material like defibrillator, ventilation mask, ECG machine, 
suction apparatus, etc., or may be referred to the contract hospital. 
• 
Recording of Adverse Events 
Any symptom, sign or significant abnormal laboratory finding (after repeat test confirms the 
abnormality) whether observed or reported during the course of the study (i.e., within 7 to 9 
days after the last sample collection or after the withdrawal) will be recorded as an adverse 
event whether it has a causal relationship with the drug or not. 
The following information has to be individually recorded for each AE in an Adverse Event 
reporting form: 
• Description of the AE. 
• Subject number, period, date and time of last dosing. 
• Type of adverse event. 
• Seriousness of adverse event. 
• Date and time of onset/reporting. 
• Date and time of resolution. 
• Intensity (mild, moderate or severe). 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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• Relatedness to the study medication (non-assessable or unclassifiable, conditional or 
unclassifiable, unlikely, possible, probable or certain). 
• Action taken or treatment given. 
• Outcome of adverse event (resolved or unresolved). 
• Follow-up. 
• Further details of the AE (if any). 
Severity (Intensity) of the adverse event, adverse reaction suspicion and adverse reactions, will 
be classified according to the clinical manifestation as: 
Mild: Signs and symptoms easily tolerable, which do not need treatment, do not prolong 
hospitalization and do not require medicine product suspension. 
Moderate: Interferes with usual activities (may cause work or school casualties), without 
directly threatening the patient's life. It requires pharmacological treatment and may or may 
not require the suspension of the causative drug.  
Severe: Interferes with usual activities (may cause work or school dropouts). It requires 
pharmacological treatment and the suspension of the causative drug. 
Adverse reactions are classified according to the assessment of causality as (see table 7): 
Table 7 Adverse Reaction Classification 
 
Causality 
Term 
Assessment Criteria 
Certain 
• Clinical event, including alterations in laboratory tests, which manifests 
itself with a plausible temporal sequence in relation to the 
administration of the drug. 
• It cannot be explained by the concurrent disease, or by other drugs or 
substances. 
• The response to drug suppression (withdrawal) must be clinically 
plausible. 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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Sponsor Code: 212969 
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Causality 
Term 
Assessment Criteria 
• Event shall be definitive pharmacologically or phenomenological, 
using, if necessary, a conclusive re-exposure procedure. 
Probable 
• Clinical event, including alterations in laboratory tests, which manifests 
itself with a reasonable temporal sequence in relation to the 
administration of the drug. 
• Unlikely to be attributed to the concurrent disease or by other drugs or 
substances, and that when the drug is withdrawn, a clinically reasonable 
response is presented. 
• It is not required to have information on re-exposure to assign this 
definition. 
Possible 
• Clinical event, including alterations in laboratory tests, which manifests 
itself with a reasonable temporal sequence in relation to the 
administration of the drug. 
• Could also be explained by the concurrent disease or by other drugs or 
substances. 
• Information on drug withdrawal may be lacking or unclear. 
Unlikely 
• Clinical event, including alterations in laboratory tests, manifested with 
an unlikely temporal sequence in relation to the administration of the 
drug. 
• It could be explained more plausibly by the concurrent disease, or by 
other drugs or substances. 
Conditional / 
Unclassifiable 
• Clinical event, including alterations in laboratory tests, reported as an 
adverse reaction, from which it is essential to obtain more data in order 
to make an appropriate evaluation, or additional data are under 
examination. 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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Sponsor Code: 212969 
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Causality 
Term 
Assessment Criteria 
Unassessable / 
Unclassifiable 
• Notification that suggests an adverse reaction, but that cannot be judged 
because the information is insufficient or contradictory and cannot be 
verified or completed with provided data. 
 
• 
Reporting of non-serious Adverse Events / non-serious Adverse Drug Reactions 
All non-serious, ADRs (expected or unexpected) and AEs occurred during the study 
conduction shall be notified to the REC/RC and the sponsor by the PI in the final study report 
according to SOP CP025 (Adverse Events and Serious Adverse Events Recording, 
Monitoring and Reporting). 
• 
Reporting of Serious Adverse Events / Serious Adverse Drug Reactions 
All SAEs and SADRs shall be reported immediately (within the first 24 hours after their 
occurrence) to the REC/RC, Sanitary Responsible and Sponsor’s responsible person either by 
telephone or written form.  
The information to the sponsor shall be sent in attention to:  
 
GlaxoSmithKline México, S.A. de C.V. 
Calzada México Xochimilco No. 4900  
Col.San Lorenzo Huipulco 14370 Ciudad de México 
Phone number: 
 
Email: 
 
The event must also be documented on the “Adverse Event” section in the CRF and in the 
clinical report. All SAEs must be transcribed in the CRF, whether or not there is a causal 
relationship with the drug or medicinal product being evaluated.  
PPD
PPD
PPD


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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Sponsor Code: 212969 
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The regulatory authorities (CNFV) shall be notified according to what is established in the 
“Pharmacovigilance guide for the notification of AE, SADR, ADR, and ESAVI or any safety 
problem related to the use of drugs” and according to the NOM-220-SSA1-2016, through the 
platform assigned by the CNFV for this purpose and in the Final Safety Report.  
The notification through the platform assigned by the CNFV for this purpose shall be 
performed according to the timelines stablished in the valid NOM-220-SSA1-2016. 
Notification to the CNFV of serious adverse events will be made by Avant Santé, using the 
current MedDRA terminology. [7-10] 
Actions to be taken if Pregnancy Occurs 
If a female subject becomes pregnant during their participation in the clinical study, she will 
be immediately withdrawn from the study and will be monitored throughout the pregnancy 
to assess drug AEs and ADRs in the mother / fetus or infant. The investigator must inform 
the Sponsor's safety division within 24 hours after being aware of a confirmed report of 
pregnancy fulfilling any of the following criteria: 
➢ Reports of congenital anomaly(ies) in fetus, child, 
➢ Reports of spontaneous abortion, 
➢ Reports of late fetal death, 
➢ Reports of ADRs in new born / neonate that is fatal, life threatening, resulting in persistent 
or significant disability / incapacity or resulting in or prolonging hospitalization, 
➢ When the medicinal products are known (or suspected) to induce teratogenic or foeto-toxic 
effects and are therefore contraindicated (or not recommended) in pregnant women, the 
circumstances relating to the pregnancy must be documented (e.g. patient “not aware” of the 
risk, contraception failure). Cases with all such drugs whether or not associated with any 
congenital anomaly and / or serious adverse drug reaction must always be considered serious 
and reported on expedited basis to regulatory authorities. Teratogenic potential of the drug 
must be determined from the safety section of the literature. 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
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All pregnancy reports not fulfilling the above criteria must be reported by the Principal 
Investigator at the earliest and no later than 3 working days of receipt of confirmed report of 
pregnancy.  
The Principal Investigator/ Designated personnel will follow up and collect pregnancy 
information as per the following schedule to determine outcome including spontaneous or 
voluntary terminations, details of birth, presence or absence of congenital anomalies, and 
maternal or newborn complications etc. 
Table 8 shows the follow-up schedule in case of pregnancies during the study. 
Table 8 Pregnancy follow up 
No. 
Follow up 
1 
Initial Contact 
2 
First Trimester (3 months Gestation) 
3 
Second Trimester (6 months Gestation) 
4 
Third Trimester (9 months Gestation) 
5 
At birth 
6 
30 days after birth 
7 
6 months after birth (In-case of congenital anomalies) 
The principal investigator / designee must obtain the minimum required information, with 
documentary evidence, if any, from the subject's Obstetrician / Gynecologist / Pediatrician. 
• 
Follow-Up of Adverse Events 
Classification of AE will be done by the PI, as well as causality relation. In case of SAE, 
causality will be confirmed by the sponsor (for test product). 
Subjects will be instructed to report at the clinical facility for any AE during the washout 
period. All the adverse events will be treated by the PI or CI at the clinical facility or in the 
contract hospital. All AEs will be followed up wherever possible until their resolution or until 
the CI or PI believes that there will be no further changes. This may involve additional visits. 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
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Follow-up and closure of adverse events will be done according to the procedure CP025 
(Adverse Events and Serious Adverse Events Recording, Monitoring and Reporting). 
12.0 
BIOANALYSIS 
12.1 Sample analysis 
The concentrations of Paroxetine in plasma samples will be quantified using a validated 
bioanalytical UPLC/MS-MS method (LOQ - 0.106 ng/mL) according to COFEPRIS 
guidelines, GLP and in-house SOPs. 
Method validation and subject sample analysis will be performed using same the 
anticoagulant (K2-EDTA) that will be used for blood sample collection in clinical phase. 
The use of reference substances of Paroxetine and internal standard, calibration curve spiking 
and control points as well as subject sample analysis shall be performed according to the 
stability periods mentioned in the Method SOP and according to the procedure BL004  
(Sample Analysis, Acceptance and Re-assay Analysis of Study Samples). Samples for 
reanalysis and its acceptance shall be performed according to the procedure BL004 and the 
cause of the same will be mentioned in the report. 
Quality control samples will be distributed throughout each batch of the study samples 
analyzed. The analyst will not have access to the randomization schedule, which is used for 
dispensing. 
12.2 Reporting of drug concentration data 
After completion of the analysis, all the concentration data will be transferred to the 
Pharmacokinetic and Biostatistics Department. All concentration values below the lower limit 
of quantification (LLOQ) will be reported as BLOQ and any missing samples will be reported 
as "NE". 
If the pre-dose concentration is above LLOQ, then pre-dose concentration will be reported as 
such for pharmacokinetic analysis. 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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Sponsor Code: 212969 
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All the concentration data should be reported in the bioanalytical report according to SOP: 
BL018 (Preparation of sample analysis report). 
Overall (mean) accuracy and precision of the QC samples of all accepted runs should be 
calculated at each concentration level and reported in the bioanalytical report according to 
SOP BL018 (Preparation of sample analysis report). 
13.0 PHARMACOKINETIC PARAMETERS 
Non-compartmental pharmacokinetic analysis will be performed on the observed plasma 
concentration of Paroxetine using WinNonlin® software (6.4 version or higher). 
➢ 
Any concentration below lower limit of quantification (BLOQ) including pre-dose 
concentrations will be converted to zero. 
➢ 
If the pre-dose concentration is ≤ 5% Cmax of the respective period and above LLOQ, 
then pre-dose concentration will not be converted to zero and the respective subject shall 
be considered for pharmacokinetic and statistical analysis. 
Missing samples will be reported as “NE” and will not be included for pharmacokinetic and 
statistical analysis. The process will be performed according to the procedure PB003 
(Procedure for Statistical Analysis using WinNonlin). 
The following pharmacokinetic parameters will be computed. 
Primary parameters 
Cmax 
: 
Maximum observed concentration following each treatment. 
AUC0-t 
 
: 
The area under the concentration versus time curve from time 
zero to the last measurable concentration using linear 
trapezoidal linear interpolation method. 
Secondary parameters 
Tmax 
: 
Time of the maximum measured concentration. 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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Sponsor Code: 212969 
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AUC0-inf 
: 
The area under the concentration versus time curve from time 
zero to infinity calculated; Where AUC0-inf = AUC0-t + Ct/ λz, 
Ct is the last measurable concentration and λz is the terminal 
elimination rate constant. 
AUC_% Extrap 
: 
The residual area in percentage [(AUC0-inf - AUC0-t)/ AUC0-inf] 
x 100 
Lambda_z 
(Kel) 
: 
First order rate constant associated with the terminal portion 
of the curve (log-lineal). This is estimated via linear regression 
of time vs. log concentration. This parameter will be calculated 
using at least three or more non-zero plasma concentration 
values. 
HL_Lambda_z (t½) 
: 
The elimination half-life will be calculated as 0.693/ λz 
Note: 
➢ For all the above computations, actual time points of the sample collection will be 
used in case of sample collection deviations i.e. beyond ± 2 minutes. 
➢ No value of Lambda_z (Kel), AUC0-inf, or HL_Lambda_z (t½) will be reported for 
cases who do not exhibit a terminal Log-linear phase in the concentration versus time 
profile. 
➢ Statistical methods used in the study will be mentioned in the Statistical Analysis Plan. 
14.0 STATISTICAL ANALYSIS 
Data from all treated subjects will be included in the statistical analysis. 
If any of the subject’s data is eliminated from the statistical analysis which meet the criteria 
of section 14.9 ‘Criteria for elimination of subject data from the statistical analysis’, statistical 
analysis shall be performed and presented with and without the data of eliminated subject’s 
data.  


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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Sponsor Code: 212969 
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The statistical analysis will be carried out according to the PB005 procedure (Procedure for 
Statistical Analysis for a cross-over design). 
Statistical analysis of PK parameters for establishing bioequivalence will be performed using 
the software SAS® (version 9.4 or higher). PROC GLM will be used for the estimation of the 
geometric least square mean differences (test - reference) of the test and reference 
formulations on the ln-transformed PK parameters Cmax and AUC0-t for Paroxetine and the 
corresponding standard errors of the differences will also be computed. Based on these 
parameters, 90% confidence intervals will be constructed for the geometric least square mean 
differences of ln-transformed Cmax and AUC0-t for Paroxetine. 
The anti-ln (or exponential) of the limits obtained from the ln-transformed data will give the 
90% confidence interval for the ratio of geometric least square means of test and reference 
formulations. 
 
14.1 Descriptive Statistics 
Geometric mean, arithmetic mean, median, minimum, maximum, standard deviation and 
coefficient of variation (arithmetic and geometric, respectively) will be calculated for each 
PK parameter (Cmax, AUC0-t and Tmax for Paroxetine), logarithmically transformed and 
untransformed. 
For PK parameters Cmax and AUC0-t for Paroxetine, the following shall be calculated: 
• 
Difference of test and reference drugs. 
• 
Quotient between test and reference drugs. 
• 
The natural logarithm of the quotient between test and reference drugs. 
• 
Histograms (ratios [A/B] and ln ratio [Ln (A/B)] will be performed. 
 
 
 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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14.2 Analysis of Variance 
The ln-transformed pharmacokinetic parameters (Cmax, AUC0-t for Paroxetine) will be 
analyzed using Type III sum of squares, with the main effects of formulation, period, 
sequence as fixed effects and subjects nested within sequence as a random effect. A separate 
ANOVA model will be used to analyze each of the parameters. The sequence effect will be 
tested at the 5% level of significance using the subjects nested within sequence mean square 
as the error term. Formulation and period effects will be tested at the 5% level of significance 
against the residual error (mean square error) from the ANOVA model as the error term. Each 
analysis of variance will include calculation of geometric least-squares means, the difference 
between the adjusted formulation means and the standard error associated with the difference. 
14.3 Statistical Model 
The statistical model used in this research is a general linear model, whose equation is: 
Yijkl = µ + Fi +Seqj + Pk + Sl (Seqj)+eijkl 
Where: 
Yijkl = Response of lth subject of jth Sequence when it received ith Formulation in kth Period 
µ = general mean 
Fi = fixed effect of ith formulation  
Seqj = fixed effect of jth sequence 
Pk = fixed effect of kth period 
Sl (Seqj)= random effect of lth subject nested within the jth sequence 
eijkl = random error 
14.4 Two One-Sided Test for Bioequivalence 
A two one-sided test (Schuirmann) for the differences of least squares means between the 
formulations (test/reference) will be calculated for ln-transformed data of the Cmax and  
AUC0-t for Paroxetine. 
The hypothesis approach for the Schuirmann two one-sided test is: 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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Null hypothesis  
H0: µtest / µref < (0.8) H0a: µtest / µref > (1.25) (not bioequivalent)  
Alternative hypothesis H1: µtest / µref ≥ (0.8) H1a: µtest / µref ≤ (1.25) (bioequivalent)  
Acceptance criteria: to support bioequivalence, the null hypothesis in both conditions shall 
be rejected with a significance level of 5% for each side. With regards to the classical 
generated 90% confidence interval, it shall fall within the bioequivalence range of 80.00% - 
125.00%. 
14.5 Statistical Power 
Statistical power is the probability of rejecting the null hypothesis when it is false. Power is 
1-Type II (where Type II error is the false negative error). The statistical power will be 
reported but considered only as informative when the test product is bioequivalent to the 
reference product. 
14.6 Ratio Analysis 
Ratio of geometric least squares means of the test and reference drugs will be computed for 
un-transformed and ln-transformed primary pharmacokinetic parameters Cmax and AUC0-t 
for Paroxetine. 
14.7 Intra-Subject Variability 
Intra-subject variability will be computed for un-transformed data and for ln-transformed 
Pharmacokinetic parameters Cmax and AUC0-t for Paroxetine. 
14.8 Analysis of Outliers  
The outliers shall be identified (< -2.00 and > +2.00) using a ±2 studentized residuals using 
the software SAS® version 9.4 or higher and their exclusion in the statistical analysis shall be 
justified (if applicable). 
The subject’s data will not be excluded from the statistical analysis exclusively due to 
mathematical or statistical reasons. 
If statistical analysis concluded after removing the outliers, the results shall be submitted with 
and without the inclusion of outliers with a justification. In this case, the persons responsible 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
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for the study, along with quality assurance personnel will investigate the possible causes of 
the appearance of outliers, and scientific evidence will be provided in addition to the statistical 
evidence.  
14.9 Criteria for elimination of subject data from the statistical analysis. 
No data shall be eliminated from statistical analysis, except for the following. 
a. Research (study) subjects with pre-dose concentrations in plasma: 
If the pre-dose concentration is 5% of Cmax in that research subject, the data can be 
included without adjustments in all pharmacokinetic measurements and calculations. In 
cases where the pre-dose sample is >5% of the Cmax, the research subject shall be 
eliminated from all bioequivalence assessments.  
b. Data elimination due to vomiting or diarrhea.  
Since the study drug is an immediate release product; the data from research subjects 
who experience vomiting or diarrhea occur before 2 times the median tmax or 2 times the 
value of tmax obtained in the research subject in a given period shall be eliminated from 
all bioequivalence assessments.  
c. A research subject who lacks measurable concentrations or with plasma concentrations 
well below that of the reference drug.  
A research subject is considered to have very low concentrations, if the AUC is less than 
5% of the AUC geometric mean of the reference drug (shall be calculated without 
inclusion of the atypical values of the research subject data). The exclusion of data due 
to this reason will be accepted only with a scientific justification and with prior review 
by COFEPRIS. 
d. Since the planned study is a crossover and balanced, subjects who did not complete in 
any of the study periods (subject that is discontinued or withdrawn) shall be eliminated 
from all bioequivalence assessments. 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
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The AUC0-t shall cover at least 80% of the AUC0-inf. The research subjects shall not be excluded 
for the statistical analysis if the AUC0-t covers less than 80% of the AUC0-inf.  
In case that a research subject elimination proceeds, according to the above-mentioned 
information, the excluded research subject samples shall be analyzed and the results shall be 
presented. Also, the statistical analysis shall be performed and shall be presented with and 
without the data of eliminated research subjects. 
14.10 Bioequivalence Criteria 
Based on the statistical results of classic 90% confidence interval for the ratio of the geometric 
least squares means for log-transformed PK parameters Cmax and AUC0-t for Paroxetine, a 
conclusion will be drawn for test product (A) vs. the reference product (B) under fasting 
conditions. 
The bioequivalence of the test product (A) with that of the reference product (B) under fasting 
conditions will be concluded if the 90% confidence interval of the ratio of the test and 
reference product (test/reference) falls within the acceptance range of 80.00 – 125.00% for 
ln-transformed PK parameters Cmax and AUC0-t of Paroxetine. 
15.0 
AMENDMENTS AND PROTOCOL DEVIATIONS 
A protocol deviation is an unintended excursion from the approved protocol. 
A major protocol deviation is a protocol deviation that may, as evaluated by the principal 
investigator, or person designated by the investigator impact the safety of the subject or the 
integrity of the trial.  Major deviations will lead to withdrawal of a subject from the study.. 
Deviations not classified as major are considered as minor protocol deviations. 
All protocol deviations should be reported to the sponsor by the Avant Santé and monitor (if 
present on site) at the earliest possible time.  The sponsor can propose to re-classify a protocol 
deviation (minor to major or vice versa) upon evaluation. In such case, the classification made 
by the sponsor prevails and will be communicated to Avant Santé together with a written 
justification. 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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Major protocol deviations will only be implemented after sponsor’s approval and obtaining 
approval or a favorable opinion from the Research Ethics Committee (REC) and Research 
Committee (RC) and COFEPRIS. 
The sponsor must be informed of minor protocol deviations, but before start of the following 
clinical study period or before start of the bioanalytical phase/ statistical phase. 
Minor protocol deviations will be reported sponsor and Committees if applicable, and will be 
reported in study report: 
• Logistic deviations (follow up visits that occurred outside the protocol required time 
frame because of the participant’s schedule etc.) 
• All post dose in-house blood samples collected beyond ± 2 minutes during housing 
period and ± 60 minutes for ambulatory samples from the scheduled collection time 
will be reported as protocol deviations. 
• Deviations related to meal consumption. 
• Administrative deviations (e.g. change of names). 
Protocol deviation notification and reports are submitted to Health Authorities and/or relevant 
Research Ethics Committee (REC) and Research Committee (RC) according to applicable 
requirements/guidelines/law. 
Procedure for documenting protocol deviations 
The Principal Investigator, or person designated by PI, should document and explain any 
deviation from the approved protocol. The notification of protocol deviation to sponsor can 
be in exceptional cases communicated by verbal means (if immediate action/notification is 
needed) and must be followed-up with written documentation (e.g. by e-mail; period update). 
All major protocol deviations, as well as time point deviations or meal plan, must be described 
in the final study report. 
 
 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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16.0 
TERMINATION OF A STUDY 
If the Principal Investigator terminates or suspends a study due to safety concerns, 
investigator should inform the institution (Avant Santé) where applicable and the Principal 
Investigator/institution should promptly inform the sponsor, subjects and the REC & RC. 
If the sponsor terminates or suspends a study due to safety concerns to assure volunteers well-
being, the sponsor should promptly inform the institution/ Principal Investigator where 
applicable and the investigator/institution should promptly inform the REC / RC and subjects. 
If the REC / RC terminates or suspends its approval / favorable opinion of a trial / study, the 
Principal Investigator should inform the institution where applicable and notify the sponsor. 
The subjects would be informed on the reasons for the termination and compensated 
adequately. 
Reasons for termination of study: Principal Investigator / Sponsor / REC / RC / Sanitary 
Responsible may discontinue / terminate the study at any time before study is complete. Some 
of the reasons for these early terminations are:  
1. 
A significant number of subjects are withdrawn from the study due to adverse events. 
2. 
A significant number of subjects intermediately dropped out from the study / subjects 
withdrew their consents to continue in the study, which may affect the overall power of 
the study.  
In case the sponsor finds that the investigational drug presents an unreasonable and significant 
risk to subjects. In this case, the sponsor will discontinue the investigation as soon as possible, 
and not later than 5 working days after making the decision. This will be communicated to 
Principal Investigator, REC / RC and COFEPRIS. 
17.0 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The Quality Assurance (QA) personnel, Research Ethics Committee, Research Committee of 
Avant Santé Research Center S.A. de C.V., sponsor/monitor and applicable regulatory 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
Project No./Protocol No.: AS/BK/OCT-19/0055 
Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
Page 80 of  94 
 
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agencies (like Ministry of Health of México, COFEPRIS) will have access to the forms and 
other source documents during inspection and audits. 
Source documents 
• Monitoring details describing strategy including definition of study critical data items and 
processes, methods, responsibilities and requirements, including handling of noncompliance 
issues and monitoring techniques (central, remote, or on-site monitoring) are provided in the 
Monitoring Plan. 
• Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected.  Source documents are filed at the investigator’s site. 
• Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained.  The 
investigator may need to request previous medical records or transfer records, depending on 
the study.  Also, current medical records must be available. 
• Definition of what constitutes source data and its origin can be found in the Source Document 
Acknowledgment. 
• The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• Study monitors will perform ongoing monitoring (remote or on-site) as per the Monitoring 
Plan to confirm that data entered into the CRF by authorized site personnel are accurate, 
complete, and verifiable from source documents; that the safety and rights of participants are 
being protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable regulatory 
requirements. 
 
 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
Project No./Protocol No.: AS/BK/OCT-19/0055 
Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
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18.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
The raw data generated during the conduct of the study as well as the reports will undergo a 
thorough Quality Control check and retrospective Quality Assurance audits performed by QA 
personnel from Avant Santé Research Center, S.A. de C.V. to evaluate the conformity with 
this protocol and all the governing SOPs.  
The final report will contain a certification of the Quality Assurance Audit, duly signed by 
the head of the Quality Assurance department. 
19.0 
INVESTIGATOR AND DELEGATION OF DUTIES 
The Principal Investigator will ensure that the personnel involved in the study are adequately 
qualified, trained and informed about the protocol, any amendment(s) made, the study drugs, 
and their study-related duties and functions. 
The investigator will maintain a list of the clinical investigator(s) and other appropriately 
qualified personnel to whom he delegates significant study-related duties. The actual 
delegation of the activities will be documented in the respective form and archived in the 
RMF or trial master file. 
20.0 
ETHICAL CONSIDERATIONS 
20.1 Ethical Standards 
This study will be conducted in compliance with the requirements of NOM-177-SSA1-2013, 
COFEPRIS guidelines, ICH-GCP and principles of Declaration of Helsinki (Fortaleza, Brazil, 
October 2013).  
Protocol, Case Report Form (CRF) and the informed consent form (ICF) approval will be 
taken from the REC & RC, and COFEPRIS before initiation of the study. 
 
 
 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
Project No./Protocol No.: AS/BK/OCT-19/0055 
Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
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20.2 Research Ethics Committee and Research Committee 
This protocol, the informed consent form (ICF) and any other study-related material provided 
to the subject will be reviewed and approved by REC & RC and the corresponding regulatory 
agency. 
The study will commence only after obtaining the written approval of the study protocol by 
the REC/RC and COFEPRIS. Any modifications made to this protocol after its approval will 
be presented to the REC/RC and COFEPRIS in accordance with the corresponding SOP and 
any other regulatory requirement. A list of the changes in reference to the previous version 
will be generated and included in the protocol as a “Change History” (Attachment-III). 
20.3 Informed Consent Process 
The informed consent documents used during the informed consent process must be approved 
by the REC / RC before providing to the subjects. 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in 
this study. Extensive discussion of nature and objectives of the study, risks and possible 
benefits of this study will be provided to each subject or subject’s representative. 
The designated study person will explain the details of the study to the subject or subject’s 
representative in a language that the subject or subject legal representative comprehends and 
answer any questions that may arise. All volunteers shall sign the informed consent form 
before their participation in the study. Each subject will be informed that they may withdraw 
consent at any time throughout the course of the study.  
A duplicate of the informed consent document will be given to the subjects. The subject has 
the right to withdraw consent and discontinue further participation in the study. If the subject 
decides to withdraw the study, subject will not face any penalties or loss of benefits to which 
they may otherwise be entitled. 
 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
Project No./Protocol No.: AS/BK/OCT-19/0055 
Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
Page 83 of  94 
 
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20.4 Subject Participation Compensation 
The subjects will be compensated based on NOM 177-SSA1-2013 (COFEPRIS), and  
previous approval of   REC/RC) on account of their participation in the study. In case of 
dropout / withdrawal of a subject because of a cause or decision of Avant Santé Research 
Center, S.A. de C.V. before study is concluded, the subjects will receive the full 
compensation. In case the withdrawal is the result of any situation caused by the subject such 
as non-compliance, discipline etc. compensation will be according to the conditions 
established in the ICF, approved by the REC/RC. 
20.5 Subject’s Insurance 
If a subject suffers any discomfort or injury, temporary or permanent, as a result of an event 
associated with the study drugs’ administration, or that subject needs medical assistance, all 
the expenses will be met by the sponsor. through an insurance policy contracted by 
GlaxoSmithKline México, S.A. de C.V. Avant Santé Research Center S.A. de C.V. will 
ensure that if a subject needs emergency medical care, the same shall be provided at Tertiary 
care hospital, Swiss Hospital S.A.P.I. de C.V., contracted by Avant Santé Research Center 
S.A. de C.V. If required, ambulance of Emergencia Médica Profesional, S. C. [contracted by 
Avant Santé Research Center S.A. de C.V.] may be used for shifting the subject to Tertiary 
care hospital. 
If a subject suffers any discomfort or injury to medical practice will be covered by a valid 
civil liability insurance policy of Avant Santé Research Center S.A. de C.V. to the extent of 
sum assured mentioned in the policy. 
21.0 
DATA HANDLING AND RECORD KEEPING 
All clinical data generated during the conduct of the study will be entered directly in the 
source documents as per the SOPs of Avant Santé Research Center S.A. de C.V. Raw data 
information will be transcribed in to electronic Case Report Form (eCRFs) according with 
SOP CP064 Source Data Management. All study (raw data and transcribed data) documents 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
Project No./Protocol No.: AS/BK/OCT-19/0055 
Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
Page 84 of  94 
 
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will be reviewed for completeness by the PI or delegated personnel followed by QA personnel 
verification. The computer-generated data such as ECGs, randomization schedule, diagnostic 
lab reports will also be treated as raw data. All data related to the study will be in the custody 
of the PI until archived. All bioanalytical raw data generated and compiled by the study 
personnel during the conduct of the same will be reviewed for completeness. All data 
generated in the Bioanalytical Unit will be exported and transferred electronically based on 
C-DISC standards as recommended by GSK, to the Pharmacokinetics and Biostatistics 
department for further evaluation. 
21.1 Clinical Study Report 
The Clinical study report will be prepared as per NOM-177-SSA1-2013 (COFEPRIS), Guía 
de Farmacovigilancia en Estudios clínicos, and sponsor requirements, having all the clinical, 
bioanalytical, pharmacokinetic and statistical data subjected to Quality Assurance audits. 
21.2 Confidentiality of Data 
The data related to the subject identity will be kept confidential according to what it is 
described in the informed consent form and will be accessible only to the study personnel and 
if necessary, to the QA auditors, sponsor/monitors, REC/RC and COFEPRIS. 
21.3 Archiving 
The raw data and reports (this protocol, all data generated in connection to the study, along 
with a copy of this protocol, the signed ICFs, bioanalytical method validation report, 
concentration data, chromatograms and the final report) will be kept in the Trial Master Files 
together  with all the records and documents pertaining to  this study and they will be 
archived in the archives of Avant Santé Research Center S.A. de C.V.  for at least 30 years 
based on GSK SOP POL-GSK-506-GRS GSK Global Records Retention Schedule - Version 
7. 
Avant Santé Research Center S.A. de C.V. will not destroy/discard any document related to 
the study without written confirmation from the sponsor. 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
Project No./Protocol No.: AS/BK/OCT-19/0055 
Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
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21.4 Publication Policy 
All data and results, and all intellectual property rights in data and results of the study will be 
property of GlaxoSmithKline México, S.A. de C.V., who can use the same in different ways, 
such as to be submitted to regulatory authorities or for being sent to other investigators.  
The investigator, as long as he/she is free of using data from the study for scientific purposes, 
shall discuss any publication with GlaxoSmithKline México, S.A. de C.V. prior to the same 
and obtain the written consent from the sponsor regarding the publication.  
This will be reviewed briefly and approval will not be delayed unnecessarily. In case of a 
difference in opinion between sponsor and investigator(s), the content of publication will be 
discussed with the objective of finding a solution that satisfies both parties 
 
22.0 LIST OF ATTACHMENTS 
Attachment-I: “Flowchart of Activities” 
Attachment II: “Schedule of Events”. 
Attachment-III: “Change History”. 
 
 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
Project No./Protocol No.: AS/BK/OCT-19/0055 
Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
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23.0 
REFERENCES 
1. Summary of Product Characteristics (SmPC) of Paroxetine, film coated tablets 10 mg / 20 mg 
/ 
30 
mg, 
last 
update 
in 
13/09/2019, 
retrieved 
from 
https://www.medicines.org.uk/emc/product/7593 
2. Drug information of Paxil (Paroxetine) 20 mg tablets, last updated on 01/04/2017, retrieved 
from 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020031s074lbl.pdf  
3.  “INFORME FARMACOCINÉTICO – ESTADÍSTICO” of In-house study-AS/AO/ABR-
17/0012 (Paroxetine 20 mg). 
4. Bioequivalence Study of Paroxetine Hydrochloride Film-Coated Tablets; SHI Ai-ming, 
WANG Meng, ZHOU Wen-jia, ZHANG Quan-ying*(Department of Pharmacy, The Second 
Affiliated Hospital of Soochow University, Suzhou 215004, China) and retrieved from; 
http://en.cnki.com.cn/Article_en/CJFDTOTAL-ZGYX201205014.htm 
5. Oficio Circular CAS/OR/01/868/2013 "Lineamientos por los que se establecen los requisitos 
para cambio de fabricante de fármaco o inclusión de fabricantes en México. 
6. NORMA Oficial Mexicana NOM-059-SSA1-2015, Buenas prácticas de fabricación de 
medicamentos. 30/Jun/2015. 
7. NORMA Oficial Mexicana NOM-177-SSA1-2013, Que establece las pruebas y 
procedimientos para demostrar que un medicamento es intercambiable. Requisitos a que deben 
sujetarse los Terceros Autorizados que realicen las pruebas de intercambiabilidad. Requisitos 
para realizar los estudios de biocomparabilidad. Requisitos a que deben sujetarse los Terceros 
Autorizados, Centros de Investigación o Instituciones Hospitalarias que realicen las pruebas 
de biocomparabilidad, Sep, 2013. 
8. Guideline for Good Clinical Practice, E6 (R2), International Council on Harmonization of 
Technical Requirements for Registration of Pharmaceuticals for Human use, Current Step 4 
version, 09 November 2016. 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
Project No./Protocol No.: AS/BK/OCT-19/0055 
Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
Page 87 of  94 
 
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9. NORMA Oficial Mexicana NOM-220-SSA1-2016, Instalación y operación de la 
farmacovigilancia, 19/07/2017 y modificaciones a la NOM-220-SSA1-2016 con fecha de 
30/09/2020. 
10. Reglamento de la Ley General de Salud en Materia de Investigación, Feb, 1984. 
11. NORMA Oficial Mexicana NOM-012-SSA3-2012, Que establece los criterios para la 
ejecución de proyectos de investigación para la salud en seres humanos, 04/01/2013. 
12. “Guía de Farmacovigilancia en Investigación clínica”, vigente 
13. (Guía para Bioequivalencia) “Guía para sometimiento de protocolos de investigación para 
demostrar 
la 
intercambiabilidad 
de 
medicamentos” 
obtenido 
de  
http://www.cofepris.gob.mx/AS/Paginas/Mol%C3%A9culas%20nuevas/Tr%C3%A1mites-
PI.aspx 
14. EMEA-GUIDELINE ON THE INVESTIGATION OF BIOEQUIVALENCE- London, 20 
January 2010. 
15. Food and Drug Administration (FDA), Guidance for Industry: Statistical approaches to 
establishing bioequivalence 2001. 
16. Guidance on Study Design Considerations Related to COVID-19 for new GSK Clinical 
Trials_v1_26May20 
 
 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
Project No./Protocol No.: AS/BK/OCT-19/0055 
Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
Page 88 of  94 
 
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ATTACHMENT-I 
FLOWCHART OF ACTIVITIES 
 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
Project No./Protocol No.: AS/BK/OCT-19/0055 
Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
Page 89 of  94 
 
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ATTACHMENT-II 
SCHEDULE OF EVENTS 
SCREENING 
Day 
Hours 
Scheduled Time 
Activity 
-90 
days 
to 
day -
1 
N/A 
N/A 
Informed consent for screening and/or study. 
Recording of weight and height. 
Medical and Physical examination. Subject’s well-being assessment. 
Laboratory: hematology, blood chemistry, urinalysis; serology; 
alcohol testing, urine test for drugs; pregnancy test in urine: ECG. 
Evaluation of inclusion and exclusion criteria. 
-72 h 
N/A 
N/A 
RT-PCR test for the detection and diagnosis of SARS-COV-2 
 
PERIOD 1 
Day 
Hours 
Scheduled Time* 
Activity 
-1 
-20.00 – -10.50 
12:00 – 21:30 
Arrival in clinical facilities.  Evaluation of inclusion and exclusion 
criteria based on screening tests (demography, medical history, 
physical examination findings, ECG, laboratory tests and RT-PCR). 
a 
Breath alcohol testing, urine drug screen, urine pregnancy test for 
females, medical & physical examination, vital signs recording, prior 
and concomitant medication and well-being assessment and 
admission into clinics (Check-in). 
-10.50 to -10.00 
21:30– 22:00 
Dinner.  
1 
-3.00 
05:00 
Wakeup time, bath following by pre-dose Medical examination, Vital 
signs recording and well-being assessment. 
-1.50 to 0.00 
06:30 – 08:00 
Cannulation and 1st blood sample (pre-dose 0.00 h) collection 
- 1.00 to 2.00 
07:00 to 10:00 
Water restriction period. 
0.00 
08:00 
Dosing (administration of test or reference product) with 250 mL of 
water. 
0.00 to 2.00 
08:00 to 10:00 
Posture restriction period. 
00.50 
08:30 
2nd blood sample collection. 
01.00 
09:00 
3rd blood sample collection. 
01.50 
09:30 
4th blood sample collection 
02.00 
10:00 
5th blood sample collection, 
02.50 
10:30 
6th blood sample collection. 
03.00 
11:00 
7th blood sample collection, Vital signs recording and well-being 
assessment. 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
Project No./Protocol No.: AS/BK/OCT-19/0055 
Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
Page 90 of  94 
 
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Day 
Hours 
Scheduled Time* 
Activity 
03.50 
11:30 
8th blood sample collection.  
04.00 
12:00 
9th blood sample collection. Lunch. 
04.50 
12:30 
10th blood sample collection. 
05.00 
13:00 
11th blood sample collection, Vital signs recording and well-being 
assessment. 
05.50 
13:30 
12th blood sample collection. 
06.00 
14:00 
13th blood sample collection. 
06.50 
14:30 
14th blood sample collection 
07.00 
15:00 
15th blood sample collection.  
08.00 
16:00 
16th blood sample collection, Snacks. 
09.00 
17:00 
17th blood sample collection. 
10.00 
18:00 
18th blood sample collection.  
12.00 
20:00 
19th blood sample collection, Vital signs recording and well-being 
assessment, Dinner. 
2 
16.00 
00:00 
20th blood sample collection. 
24.00 
08:00 
21th blood sample collection. Medical examination with vital signs, 
well-being assessment and exit from clinics (Check-out). 
36.00 
20:00 
22nd blood sample collection, well-being assessment and vital signs 
recording. 
3 
48.00 
08:00 
23nd blood sample collection, well-being assessment and vital signs 
recording.    
4 
72.00 
08:00 
24nd blood sample collection, well-being assessment and vital signs 
recording. 
*The schedule of events may change according to the dosing time a: Update of changes since screening visit 
 
 PERIOD 2 
Day 
Hours 
Scheduled Time* 
Activity 
-1 
-20.00 – -10.50 
12:00 – 21:30 
Arrival in clinical facilities.  
Breath alcohol testing, urine drug screen, urine pregnancy test for 
females, medical & physical examination, vital signs recording, prior 
and concomitant medication and well-being assessment and 
admission into clinics (Check-in). 
-10.50 to -10.00 
21:30– 22:00 
Dinner.  
Washout 
Period 
There will be a washout period of at least 7 days between successive dosing. 
Subjects will be instructed to self-quarantine during the outpatient period of the 
study and to monitor at home their daily body temperature  
 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
Project No./Protocol No.: AS/BK/OCT-19/0055 
Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
Page 91 of  94 
 
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Day 
Hours 
Scheduled Time* 
Activity 
1 
-3.00 
05:00 
Wakeup time, bath following by pre-dose Medical examination, Vital 
signs recording and well-being assessment. 
-1.50 to 0.00 
06:30 – 08:00 
Cannulation and 1st blood sample (pre-dose 0.00 h) collection 
- 1.00 to 2.00 
07:00 to 10:00 
Water restriction period. 
0.00 
08:00 
Dosing (administration of test or reference product) with 250 mL of 
water. 
0.00 to 2.00 
08:00 to 10:00 
Posture restriction period. 
00.50 
08:30 
2nd blood sample collection. 
01.00 
09:00 
3rd blood sample collection. 
01.50 
09:30 
4th blood sample collection 
02.00 
10:00 
5th blood sample collection, 
02.50 
10:30 
6th blood sample collection. 
03.00 
11:00 
7th blood sample collection, Vital signs recording and well-being 
assessment. 
03.50 
11:30 
8th blood sample collection.  
04.00 
12:00 
9th blood sample collection. Lunch. 
04.50 
12:30 
10th blood sample collection. 
05.00 
13:00 
11th blood sample collection, Vital signs recording and well-being 
assessment. 
05.50 
13:30 
12th blood sample collection. 
06.00 
14:00 
13th blood sample collection. 
06.50 
14:30 
14th blood sample collection 
07.00 
15:00 
15th blood sample collection.  
08.00 
16:00 
16th blood sample collection, Snacks. 
09.00 
17:00 
17th blood sample collection. 
10.00 
18:00 
18th blood sample collection.  
12.00 
20:00 
19th blood sample collection, Vital signs recording and well-being 
assessment, Dinner. 
2 
16.00 
00:00 
20th blood sample collection. 
24.00 
08:00 
21th blood sample collection. Medical examination with vital signs, 
well-being assessment and exit from clinics (Check-out). 
36.00 
20:00 
22nd blood sample collection, well-being assessment and vital signs 
recording. 
3 
48.00 
08:00 
23nd blood sample collection, well-being assessment and vital signs 
recording. 
4 
72.00 
08:00 
24nd blood sample collection, well-being assessment and vital signs 
recording.  
Final Compensation for subjects (applicable only for period 2). 
Seven (7) to 9 days after the collection of 72-h blood sample in second period or after the withdrawal, a 
telephone call will be made to each subject by the personnel designated by the PI to monitor any serious adverse 
event, specifically, subjects will be questioned about any symptoms related to COVID-19. 
*The schedule of events may change according to the dosing time 
 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
Project No./Protocol No.: AS/BK/OCT-19/0055 
Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
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ATTACHMENT-III 
CHANGE HISTORY 
Current 
Version No. 
Supersedes, 
Effective Date 
Changes Made 
01 
N/A 
N/A 
02 
01, 
10/Jan/2020 
1. Format number “CPF127-02E” of the protocol is 
modified to “CPF127-03E” 
2. The Sanitary Responsible of Clinical Unit is modified 
on page 6. 
3. COVID-19, SARS-CoV-2 and RT-PCR are added to 
abbreviations. 
4. The address of the Clinical Diagnostic Laboratory is 
modified in section 2.3. 
5. Real-time (RT-PCR) test for the detection and 
diagnosis of SARS-COV-2 is added in section 1.0 and 
8.1 Screening (selection and enrollment). 
6.  “Have a negative test for active COVID-19, within 72 
hours prior to the first period check-in. The testing 
should be done using a molecular (RT-PCR) approved 
by the country regulatory authorities” is added in 
section 8.3 (Inclusion criteria). 
7.  “Subjects with symptoms suggestive of active 
COVID-19 infection (i.e. fever, cough, respiratory 
difficulties) within 14 days of inpatient admission” and 
“Subjects with known COVID-19 positive contacts* 
within the past 14 days prior to the first period check-
in. *Positive Contact; this means, if the subject has 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
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Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
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been living, providing, care, being within 1.5 m for at 
least 15 min or having exposure to respiratory 
secretions with/to a person who has COVID-19” is 
added in section 8.3 (Exclusion criteria). 
8. In section 8.5, criteria b is added “In case a subject is 
positive for COVID-19 or has a related symptom (i.e. 
fever, cough, respiratory difficulties), they shall be 
isolated for 14 days and they shall be discontinued In 
case any other subject was exposed to a COVID-19 
patient, they must report this to Avant Santé, GSK 
and/or their primary care provider”. 
9. In section 9.3 is added “Recommendations during 
washout period and visits to the center (ambulatory 
samples)”. 
10. “Subjects will be instructed to self-quarantine during 
the outpatient period of the study i.e. until 72 h blood 
sample collection in period-2 or until withdrawal, 
whichever is earlier, and to monitor at home their daily 
body temperature” is added in section 1.0 and 9.4 
(Housing). 
11. The assessment of vital signs at the time of ambulatory 
samples is added in section 1.0 and 11.1 (Assessment 
of safety). 
12. “ Seven (7) to 9 days after the collection of 72-h sample 
in second period or after withdrawal, a telephone call 
will be made to each subject by the personnel 


 
 
Format No.: CPF127-03E                                                                                                    No. Reference SOP: CP006 
 
Bioequivalence Pivotal Study Protocol of Paroxetine tablets 20 mg under fasting conditions. 
 
Project No./Protocol No.: AS/BK/OCT-19/0055 
Sponsor Code: 212969 
Version No: 02 (12/Oct/2020) 
Page 94 of  94 
 
                             CONFIDENTIAL 
      Avant Santé Research Center S.A. de C.V 
designated by the PI to monitor any adverse event, 
specifically, subjects will be questioned about any 
symptoms related to COVID-19” is added in section 
1.0 and 11.1 (Assessment of safety).  
13. The period of recording AEs “(i.e., within 7 or 9 days 
after the last sample collection or after withdrawal)” is 
added in section 11.2 (Recording of AEs). 
14. The section 11.2 “The notification through the 
platform assigned by the CNFV for this purpose shall 
be performed as soon as possible but no more than 7 
calendar days * from the time of awareness” is 
modified by “The notification through the platform 
assigned by the CNFV for this purpose shall be 
performed according to the timelines stablished in the 
valid NOM-220-SSA1-2016”. 
15. Typo errors are corrected in section 14.4. 
16. Information regarding “source documents” was added 
in section 17.0. 
17. In section 20.3 "a copy of the informed consent ..." is 
modified by "a duplicate of the informed consent ..." 
18. Reference 9 is updated and reference 16 is added. 
19. Attachment-I (Flowchart of activities) is updated. 
20. Attachment-II (Schedule of events) is updated based 
on the new information provided above. 
 

SAP_001.pdf: 
1 
 
 
 
Statistical Analysis Plan  
Study ID:  212969 
Official Title of Study:  An oral single-dose, randomized, balanced, open-label, two-sequence, two-
treatment, two-period, crossover bioequivalence study of Paroxetine tablets 20 mg of GlaxoSmithKline 
Pharmaceuticals S.A, with that of P AXIL (Paroxetine) tablets 20 mg of GlaxoSmithKline Mexico S.A. de 
C.V., in healthy adult male and female subjects under fasting conditions. 
Date of Document: 21-JAN-2021 


o<S Avant Sante 
Format No.: PBF031-00E 
Reference SOP No.: PB016 
Statistical Analysis Plan of Bioequivalence Pivotal Study of Paroxetine tablets 20 mg under 
fasting conditions. 
TITLE 
An oral single-dose, randomized, balanced, open-label, two-sequence, two-treatment, two-
period, crossover bioequivalence study of Paroxetine tablets 20 mg of GlaxoSmithKline 
Pharmaceuticals S.A, with that of P AXIL (Paroxetine) tablets 20 mg of GlaxoSmithKline 
Mexico S.A. de C.V., in healthy adult male and female subjects under fasting conditions. 
Author 
Document type: 
Document Status: 
Date of issue: 
PROTOCOL NO: AS/BK/OCT-19/0055 
SPONSOR CODE: 212969 
Statistician, Dr. 
Statistical Analysis Plan 
Final 
21/JAN/2021 
Project No. I Protocol No.: AS/BK/OCT-19/0055 
Sponsorcode:212969 
Version No: 01 
CONFIDENTIAL 
Avant Sante Research Center S.A. de C.V. 
Page 2 of 20 
PPD


o(S Avant Sante 
Format No.: PBF031-00E 
Reference SOP No.: PB016 
Statistical Analysis Plan of Bioequivalence Pivotal Study of Paroxetine tablets 20 mg under 
fasting conditions. 
TABLE OF CONTENTS 
1.0 
Introduction 
2.0 
Study Objective 
3.0 
Hypothesis of the study 
4.0 
Study design 
5.0 
Randomization 
6.0 
Sample size 
7.0 
Justification of the Sample Size 
8.0 
Washout period 
9.0 
Duration of the study 
10.0 Test and Reference Products 
11.0 Sampling Schedule 
12.0 Assessment of efficacy 
13.0 Pharmacokinetic parameters 
14.0 Statistical analysis 
15.0 Amendments and Protocol Deviations 
16.0 References 
17.0 Change history 
Project No. / Protocol No.: AS/BK/OCT-I 9/0055 
Sponsorcode: 212969 
Version No: 0 I 
CONFIDENTIAL 
Avant Sante Research Center S.A. de C.V. 
4 
4 
4 
5 
6 
6 
7 
8 
8 
9 
10 
10 
11 
12 
17 
19 
20 
Page 3 of 20 


o(S Avant Sante 
Format No.: PBF031-00E 
Reference SOP No.: PB016 
Statistical Analysis Plan of Bioequivalence Pivotal Study of Paroxetine tablets 20 mg under 
fasting conditions. 
1.0 Introduction 
Paroxetine is an antidepressants drug. It is the hydrochloride salt of a phenylpiperidine 
compound 
identified 
chemically 
as 
(-)-trans-4R-( 4'fluorophenyl)-3S-[(3',4'-
methylenedioxyphenoxy) methyl] piperidine hydrochloride hemihydrate and has the 
empirical formula ofC19H20FNO3•HCl•l/2H2O. 
Paroxetine is indicated for the treatment of: 
• 
Major depressive disorder. 
• 
Obsessive Compulsive Disorder (OCD). 
• 
Panic disorder with and without agoraphobia. 
• 
Social anxiety disorders/social phobia. 
• 
Generalised anxiety disorder. 
• 
Post-traumatic stress disorder. 
2.0 Study Objective 
Primary Objective 
To evaluate and compare the single oral dose bioavailability of Paroxetine tablets 20 mg 
manufactured by GlaxoSmithKline Pharmaceuticals S.A. for GlaxoSmithKline Mexico, 
S.A. de C.V. with that of P AXIL (Paroxetine) tablets 20 mg of GlaxoSmithKline Mexico, 
S.A. de C.V. in healthy, adult, male and female subjects under fasting conditions. 
Secondary Objective 
To evaluate the safety and tolerability of single oral dose of Paroxetine 20 mg tablets in 
healthy adult male and female subjects under fasting conditions. 
3.0 Hypothesis of the study 
Null hypothesis: Ho: mean test / mean reference < Lor mean test I mean reference > U 
Paroxetine tablets 20 mg manufactured by GlaxoSmithKline Pharmaceuticals S.A. and 
P AXIL (Paroxetine) tablets 20 mg of GlaxoSmithKline Mexico, S.A de C.V. are not 
bioequivalent. 
Project No. I Protocol No.: AS/BK/OCT-19/0055 
Sponsor code: 212969 
Version No: 01 
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Page 4 of20 


o(S Avant Sante 
Format No.: PBF031-00E 
Reference SOP No.: PB016 
Statistical Analysis Plan of Bioequivalence Pivotal Study of Paroxetine tablets 20 mg under 
fasting conditions. 
Alternative hypothesis: H1: L :S mean test / mean reference :S U 
Paroxetine tablets 20 mg manufactured by GlaxoSmithKline Pharmaceuticals S.A. and 
PAXIL (Paroxetine) tablets 20 mg of GlaxoSmithKline Mexico, S.A. de C.V. are 
bioequivalent. 
Two one-sided t-tests will be carried out on each PK parameter of Paroxetine using least 
squares means (LSM) values for geometric LSMs of the primary PK parameters (mean test 
or mean reference = LSM value of the corresponding PK parameter for test or reference 
product). The type I error will be set to a = 5% and therefore 90% (two-tailed) confidence 
intervals will be provided together with the indication whether the null hypothesis of 
nonequivalence for the appropriate parameter can be rejected. 
Probabilities p(t) of Schuirmann, left tail (t,) and right tail (tr) values will be calculated for 
the lower limit L = 0.80 and upper limit +U = 1 / 0.80 = 1.25 for geometric LSM of 
pharmacokinetic parameters Gnax and AUCo-1. 
4.0 Study design 
An oral, single-dose, randomized, balanced, open-label, two-sequence, two-treatment two-
period, crossover comparative bioavailability study under fasting conditions. 
The study design is presented in Figure 1 below. 
I 
;z; 
0 
~ 
Sequence I 
Reference 
i-; 
E--< 
> 
N 
Subjects 
i-; 
~ ~ 
Sequence2 
0 
A z 
~ 
Test 
Figure 1. Study Design Diagram 
Project No. I Protocol No.: AS/BK/OCT-19/0055 
Sponsorcode:212969 
Version No: 01 
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Avant Sante Research Center S.A. de C.V. 
Period 
II 
E--
Test 
~ 
0 = 
r:,:i < 
~ 
Reference 
Page 5 of 20 


c,(S Avant Sante 
Format No.: PBF031-00E 
Reference SOP No.: PB016 
Statistical Analysis Plan of Bioequivalence Pivotal Study of Paroxetine tablets 20 mg under 
fasting conditions. 
5.0 Randomization 
The order of receiving the test and reference products for each subject during each period of 
the study will be determined according to a randomization, generated by using SAS® 
software (version 9.4 or higher). This randomization will be balanced for the test product 
(A) and reference product (B). All the subjects should be divided into blocks of equal size 
and two-sequence "AB" and "BA" will be used for assignment of treatment in the respective 
study period (refer Figure-I). Analysts will not have access to the period randomization 
schedule. 
Randomization will be performed according to the procedure PB009 (Procedure for 
Randomization Schedule Generation). 
Blinding 
This study is an open label study; the subjects and the investigators will not be blinded 
towards the identity of the study treatments. Analysts (bioanalytical personnel) will be 
blinded with regard to the sequence of administration of test and reference products. 
6.0 Sample size 
At least 34 healthy adult male and female subjects are required to meet at least a statistical 
power of 90% at 5% level of significance to achieve the bioequivalence results within 80.00-
125.00% in this study. In addition, a maximum of 4 subjects will be dosed in account for 
withdrawal and dropouts. 
Hence, a maximum of 38 subjects will be randomized and dosed. No subjects should be 
replaced after administered with the study treatment. 
If possible, a maximum of two additional standby subjects (Stand by-I, Stand by-II) will be 
enrolled to replace any subject, who is withdrawn or dropped due to any reason prior to 
administration of study medication in period-I. 
Project No. / Protocol No.: AS/BK/OCT-19/0055 
Sponsorcode:212969 
Version No: OJ 
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Page 6 of20 


o(S Avant Sante 
Format No.: PBF031-00E 
Reference SOP No.: PB016 
Statistical Analysis Plan of Bioequivalence Pivotal Study of Paroxetine tablets 20 mg under 
fasting conditions. 
7.0 Justification of the Sample Size 
Based on the in-house study data [l l J, a maximum intra subject variability of coefficient of 
variation (ISCV %) of 23.l was observed for Cnax of Paroxetine. According to NOM-l 77-
SSAl-2013, section 8.5.1.1, the statistical power must not be less than 80%. Based on the 
observed maximum ISCV% of 23 .1 % and assuming the test/reference ratio of 95%, the 
inclusion of 34 subjects in the study is required to meet at least a statistical power of 80% at 
5% level of significance to achieve the results within 80.00-125.00% for 2-way crossover 
study. 
Using the intra-subject variability and the expected test/reference ratio from above 
paragraph, the sample size is estimated from the following equation: 
ni2::2 [t1-a,n-2+t1.p, n-2]2[CV/(-ln(eL)- (-ln (0))]2 where 0 :S 1 
a: Probability of Type I error (0.05) 
~: Probability of Type II error (0.1) 
CV: Intra Subject Variability (0.231) 
e: Expected T/R ratio (0.95) 
0L: Lower bioequivalence limit (0.80) 
Assuming the minimum sample size required (n) as 12, the sample size is estimated as 
follows: 
n2 2 [t1--0.os, 12-2+t1 --0.1, 12-2]2 [0.231/ (-In (0.8) - (-In (0.95))]2 
n2 3 7 
Using the estimated sample size fonn previous iteration (n=37) from the above estimation, 
the sample size is again estimated as follows: 
ni2::2 [t1.o.os, 37.2+t1 --0.1, 31.2]2 [0.231/ (-In (0.8) - (-ln (0.95))]2 
ni2::32 
Using the estimated sample size form previous iteration (n=32) from the above estimation, 
the sample size is again estimated as follows: 
Project No. I Protocol No.: AS/BK/OCT-19/0055 
Sponsor code: 212969 
Version No: 01 
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Page 7 of20 


c,(S Avant Sante 
Format No.: PBF031-00E 
Reference SOP No.: PB016 
Statistical Analysis Plan of Bioequivalence Pivotal Study of Paroxetine tablets 20 mg under 
fasting conditions. 
ni.22 [t1-o os, 32.2+t1-0.1, 32.2]2 [0.231/ (-ln (0.8) - (-In (0.95))]2 
ni2:33 
Using the estimated sample size form previous iteration (n=33) from the above estimation, 
the sample size is again estimated as follows: 
ni2:2 [t1-o.os, 33.2+t1.o 1, 33.2]2 [0.231/ (-ln (0.8) - (-In (0.95))]2 
n2:33 
Convergence has reached and the estimated sample size is at least 34 (round to equal 
number) subjects to meet at least a statistical power of 80% at 5% level of significance to 
achieve the results within 80.00-125.00% for 2-way crossover study. 
8.0 Washout period 
There will be a washout period of at least 7 days between successive dosing. 
9.0 Duration of the study 
The expected duration of the subjects' participation in the study will be at-least 12 days, 
including a wash-out period of 7 days between each dosing. 
Project No. I Protocol No.: AS/BK/OCT-19/0055 
Sponsorcode:212969 
Version No: 01 
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Page 8 of20 


o(S Avant Sante 
Format No.: PBF031-00E 
Reference SOP No.: PB016 
Statistical Analysis Plan of Bioequivalence Pivotal Study of Paroxetine tablets 20 mg under 
fasting conditions. 
10.0 
Test and Reference Products 
a e . nves •~a 10na 
T bl 1 I 
f 
f 
ro UC 
ea s 
IP d tDtil 
IP Details 
Reference Product (B) 
Test Product (A) 
Distinctive Name 
PAXIL 
NIA 
Paroxetine 
Paroxetine 
Generic name 
[Paroxetine as Paroxetine 
[Paroxetine as Paroxetine 
hydrochloride hemihydrate) 
hydrochloride hemihydrate] 
Pharmaceutical 
Tablets 
Tablets 
form 
Formulation 
Immediate release 
Immediate release 
Strength 
20mg 
20mg 
Dose 
20mg 
20mg 
Lot / Batch No. 
1930200023 
YC4M 
Expiry date / Re-
Oct/2021 
28/Nov/2021 
test date 
Storage 
Store at 25°C (77°F): excursions Store at 25°C (77°F): excursions 
permitted to l 5-30°C (59-
permitted to 15- 30°C (59-
Conditions 
86°F). 
86°F). 
Manufactured by: 
GlaxoSmithKline 
GlaxoSmithKline Mexico, S.A. 
Pharmaceuticals S.A. 
Nameofthe 
manufacturer 
deC.V. 
Manufactured for: 
GlaxoSmithKline Mexico, S.A. 
deC.V. 
Sanitary 
008M93SSA 
Not applicable (I ) 
Registration 
Number 
I: The test drug will be evaluated for obtaining COFEPRlS registration. 
Project No. I Protocol No.: AS/BK/OCT-19/0055 
Sponsorcode:212969 
Version No: 01 
CONFIDENTIAL 
Avant Sante Research Center S.A. de C.V. 
Page 9 of20 


c,(S Avant Sante 
Format No.: PBF031-00E 
Reference SOP No.: PB016 
Statistical Analysis Plan of Bioequivalence Pivotal Study of Paroxetine tablets 20 mg under 
fasting conditions. 
11.0 
Sampling Schedule 
In each period, a total of 24 blood samples ( 4 mL each) will be collected from each 
subject as per the following schedule: 
• The first blood sample will be collected within 1.50 hours prior to the dosing (00.00 
hours / pre-dose). 
• The remaining samples will be collected after the dosing of the test or reference drug at 
00.50, 01.00, 01.50, 02.00, 02.50, 03.00, 03.50, 04.00, 04.50, 05.00, 05.50, 06.00, 
06.50, 07.00, 08.00, 09.00, 10.00, 12.00, 16.00, 24.00, 36.00, 48.00 and 72.00 hours. 
• The samples corresponding to 36.00, 48.00 and 72.00 hours post dose will be collected 
on separate visits as ambulatory sample in each period of the study. 
• Blood samples shall be collected not earlier or later than (±) 2 minutes of the specified 
sampling time for all the in-house samples and not earlier or later than (±) 60 minutes 
of the specified sampling time for ambulatory samples. Blood sampling will be 
registered in the respective source documents. 
• If blood samples are collected earlier or later than this period from the scheduled time, 
this shall be reported as a deviation from this protocol. 
• If any subject misses any blood sampling point, it will be considered as missing sample. 
• The same will be denoted as (M), it will be considered as protocol deviation and 
mentioned in the clinical study report. 
12.0 
Assessment of efficacy 
As this is a bioequivalence study, no efficacy assessment will be performed. The 
pharmacokinetic parameters of the test and reference formulations will be assessed. 
Project No. I Protocol No.: AS/BK/OCT-19/0055 
Sponsorcode:212969 
Version No: 01 
CONFIDENTIAL 
Avant Sante Research Center S.A. de C. V. 
Page 10 of20 


o(S Avant Sante 
Format No.: PBF031-00E 
Reference SOP No.: PB016 
Statistical Analysis Plan of Bioequivalence Pivotal Study of Paroxetine tablets 20 mg under 
fasting conditions. 
13.0 
Pharmacokinetic parameters 
Non-compartmental phannacokinetic analysis will be performed on the observed plasma 
concentration of Paroxetine using WinNonlin® software (6.4 version or higher). 
• 
Any concentration below lower limit of quantification (BLOQ) including pre-dose 
concentrations will be converted to zero. 
• If the pre-dose concentration is :S 5% Cmax of the respective period and above 
LLOQ, then pre-dose concentration will not be converted to zero and the respective 
subject shall be considered for pharmacokinetic and statistical analysis. 
Missing samples will be reported as "NE" and will not be included for pharmacokinetic 
and statistical analysis. The process will be performed according to the procedure PB003 
(Procedure for Statistical Analysis using WinNonlin). 
The following phannacokinetic parameters will be computed. 
Primary parameters 
Cmax 
AUCo-1 
Secondary parameters 
Tmax 
AUCo-inf 
AUC_% Extrap 
Lambda z 
(Ke1) 
Maximum observed concentration following each treatment. 
The area under the concentration versus time curve from time 
zero to the last measurable concentration using linear trapezoidal 
linear interpolation method. 
Time of the maximum measured concentration. 
The area under the concentration versus time curve from time 
zero to infinity calculated; Where AU Co-inf = AUCo-1 + C1/ AZ, Ct 
is the last measurable concentration and AZ is the terminal 
elimination rate constant. 
The residual area in percentage [(AUCo-inf - AUCo-1)/ AUCo-inr] x 
100 
First order rate constant associated with the terminal portion of 
the curve (log-lineal). This is estimated via linear regression of 
Project No. I Protocol No.: AS/BK/OCT-19/0055 
Sponsor code: 212969 
Version No: 01 
Page 11 of 20 
CONFIDENTIAL 
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o(S Avant Sante 
Format No.: PBF031-00E 
Reference SOP No.: PB016 
Statistical Analysis Plan of Bioequivalence Pivotal Study of Paroxetine tablets 20 mg under 
fasting conditions. 
HL Lambda z (t½) 
-
-
Note: 
time vs. log concentration. This parameter will be calculated 
using at least three or more non-zero plasma concentration 
values. 
The elimination half-life will be calculated as 0.693/ ')...,z 
• For all the above computations, actual time points of the sample collection will be 
used in case of sample collection deviations i.e. beyond± 2 minutes. 
• No value of Larnbda_z (Ke1), AUCo-inf, or HL_Lambda_z (ty,) will be reported for 
cases who do not exhibit a terminal Log-linear phase in the concentration versus 
time profile. 
• Statistical methods used in the study will be mentioned in the following section. 
14.0 
Statistical analysis 
Data from all treated subjects will be included in the statistical analysis. 
If any of the subject's data is eliminated from the statistical analysis which meet the 
criteria of section 14.9 'Criteria for elimination of subject data from the statistical 
analysis', statistical analysis shall be performed and presented with and without the data 
of eliminated subject's data. 
The statistical analysis will be carried out according to the PB005 procedure (Procedure 
for Statistical Analysis for a cross-over design). 
Statistical analysis of PK parameters for establishing bioequivalence will be performed 
using the software SAS® (version 9.4 or higher). PROC GLM will be used for the 
estimation of the geometric least square mean differences (test - reference) of the test 
and reference formulations on the In-transformed PK parameters Cinax and AUCo-1 for 
Paroxetine and the corresponding standard errors of the differences will also be 
computed. Based on these parameters, 90% confidence intervals will be constructed for 
Project No. I Protocol No.: AS/BK/OCT-19/0055 
Sponsorcode:212969 
Version No: 01 
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Page 12 of20 


o<S Avant Sante 
Format No.: PBF031-00E 
Reference SOP No.: PB016 
Statistical Analysis Plan of Bioequivalence Pivotal Study of Paroxetine tablets 20 mg under 
fasting conditions. 
the geometric least square mean differences of In-transformed C.nax and AUCo-1 for 
Paroxetine. 
The anti-In ( or exponential) of the limits obtained from the ln-transfonned data will give 
the 90% confidence interval for the ratio of geometric least square means of test and 
reference formulations. 
14.1 Descriptive Statistics 
Geometric mean, arithmetic mean, median, minimum, maximum, standard deviation and 
coefficient of variation (arithmetic and geometric, respectively) will be calculated for 
each PK parameter (C.nax, AUCo-1 and T max for Paroxetine), logarithmically transformed 
and untransformed. 
For PK parameters Cmax and AUCo-1 for Paroxetine, the following shall be calculated: 
• 
Difference of test and reference drugs. 
• 
Ratio between test and reference drugs. 
• 
The natural logarithm of the Ratio between test and reference drugs. 
• 
Histograms (ratios [A/B] and In ratio [Ln (A/B)] will be perfonned. 
14.2 Analysis of Variance 
The In-transformed phannacokinetic parameters (C.nax, AUCo-1 for Paroxetine) will be 
analyzed using Type III sum of squares, with the main effects of formulation, period, 
sequence as fixed effects and subjects nested within sequence as a random effect. A 
separate ANOV A model will be used to analyze each of the parameters. The sequence 
effect will be tested at the 5% level of significance using the subjects nested within 
sequence mean square as the error term. Formulation and period effects will be tested at 
the 5% level of significance against the residual error (mean square error) from the 
ANOV A model as the error term. Each analysis of variance will include calculation of 
geometric least-squares means, the difference between the adjusted formulation means 
and the standard error associated with the difference. 
Project No. / Protocol No.: AS/BK/OCT-19/0055 
Sponsorcode:212969 
Version No: 01 
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Page 13 of20 


o(S Avant Sante 
Format No.: PBF031-00E 
Reference SOP No.: PB0 16 
Statistical Analysis Plan of Bioequivalence Pivotal Study of Paroxetine tablets 20 mg under 
fasting conditions. 
14.3 Statistical Model 
The statistical model used in this research is a general linear model, whose equation is: 
YijkI = µ + Fi +Seqj + Pk + S, (Seqj)+eijkl 
Where: 
YijkI = Response of Ith subject of j'h Sequence when it received ith Formulation in k1h 
Period 
µ = general mean 
Fi = fixed effect of ith formulation 
Seqj = fixed effect of j'11 sequence 
Pk = fixed effect ofkth period 
S, (Seqj)= random effect oflth subject nested within the j th sequence 
eijkl = random error 
In addition, as the study was conducted in groups, group effect will be tested for 
informative purpose using the below mentioned model. 
Where: 
Yijklm = Response of Ith subject of j1
11 Sequence when it received ith Fomrnlation in kth 
Period for mth group 
µ = general mean 
Fi = fixed effect of ith formulation 
Seqj = fixed effect of j1h sequence 
Pk = fixed effect ofkth period 
Gm = fixed effect of mth group 
St(SeqJ x Gm) = random effect oflth subject nested within the j th sequence for mth group 
Fix Gm= effect of ith formulation for mth group 
ei.ikI = random error 
Project No./ Protocol No.: AS/BK/OCT-19/0055 
Sponsor code: 212969 
Version No: OJ 
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Page 14 of20 


o(S Avant Sante 
Format No.: PBF031-00E 
Reference SOP No.: PB016 
Statistical Analysis Plan of Bioequivalence Pivotal Study of Paroxetine tablets 20 mg under 
fasting conditions. 
14.4 Two One-Sided Test for Bioequivalence 
A two one-sided test (Schuirmann) for the differences of least squares means between 
the fonnulations (test/reference) will be calculated for In-transformed data of the Cmax 
and AUCo-t for Paroxetine. 
The hypothesis approach for the Schuirmann two one-sided test is: 
Null hypothesis 
Ho: µtest/ µref< (0.8) Hoa: µtest / µref > (1.25) (not bioequivalent) 
Alternative hypothesis H 1: µtest I µref 2'.: (0.8) H 1a: µtest/ µref ~ ( 1.25) (bioequivalent) 
Acceptance criteria: to support bioequivalence, the null hypothesis in both conditions 
shall be rejected with a significance level of 5% for each side. With regards to the 
classical generated 90% confidence interval, it shall fall within the bioequivalence range 
of 80.00% - 125.00%. 
14.5 Statistical Power 
Statistical power is the probability of rejecting the null hypothesis when it is false. 
Power is I-Type II (where Type II error is the false negative error). The statistical power 
will be reported but considered only as informative when the test product is 
bioequivalent to the reference product. 
14.6 Ratio Analysis 
Ratio of geometric least squares means of the test and reference drugs will be computed 
for un-transformed and In-transformed primary pharmacokinetic parameters Cmax and 
AUCo-t for Paroxetine. 
14.7 Intra-Subject Variability 
Intra-subject variability will be computed for un-transformed data and for In-
transformed Pharmacokinetic parameters Cmax and AUCo-t for Paroxetine. 
14.8 Analysis of Outliers 
The outliers shall be identified (< -2.00 and > +2.00) using a ±2 studentized residuals 
using the software SAS® version 9.4 or higher and their exclusion in the statistical 
analysis shall be justified (if applicable). 
Project No. I Protocol No.: AS/BK/OCT-19/0055 
Sponsorcode:212969 
Version No: 01 
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Page 15 of20 


o(S Avant Sante 
Format No.: PBF031-00E 
Reference SOP No.: PB016 
Statistical Analysis Plan of Bioequivalence Pivotal Study of Paroxetine tablets 20 mg under 
fasting conditions. 
The subject's data will not be excluded from the statistical analysis exclusively due to 
mathematical or statistical reasons. 
If statistical analysis concluded after removing the outliers, the results shall be submitted 
with and without the inclusion of outliers with a justification. In this case, the persons 
responsible for the study, along with quality assurance personnel will investigate the 
possible causes of the appearance of outliers, and scientific evidence will be provided in 
addition to the statistical evidence. 
14.9 Criteria for elimination of subject data from the statistical analysis. 
No data shall be eliminated from statistical analysis, except for the following. 
a. Research (study) subjects with pre-dose concentrations in plasma: 
If the pre-dose concentration is 5% of Cnax in that research subject, the data can be 
included without adjustments in all pharmacokinetic measurements and 
calculations. In cases where the pre-dose sample is >5% of the Cmax, the research 
subject shall be eliminated from all bioequivalence assessments. 
b. Data elimination due to vomiting or diarrhea. 
Since the study drug is an immediate release product; the data from research 
subjects who experience vomiting or diarrhea occur before 2 times the median T max 
or 2 times the value of Tmax obtained in the research subject in a given period shall 
be eliminated from all bioequivalence assessments. 
c. A research subject who lacks measurable concentrations or with plasma 
concentrations well below that of the reference drug. 
A research subject is considered to have very low concentrations, if the AUC is less 
than 5% of the AUC geometric mean of the reference drug (shall be calculated 
without inclusion of the atypical values of the research subject data). The exclusion 
of data due to this reason will be accepted only with a scientific justification and 
with prior review by COFEPRIS. 
Project No. I Protocol No.: AS/BK./OCT-19/0055 
Sponsor code: 2 I 2969 
Version No: 01 
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o<S Avant Sante 
Format No.: PBF031-00E 
Reference SOP No.: PB016 
Statistical Analysis Plan of Bioequivalence Pivotal Study of Paroxetine tablets 20 mg under 
fasting conditions. 
d. Since the planned study is a crossover and balanced, subjects who did not complete 
in any of the study periods (subject that is discontinued or withdrawn) shall be 
eliminated from all bioequivalence assessments. 
The AUCo-1 shall cover at least 80% of the AU Co-inf. The research subjects shall not 
be excluded for the statistical analysis if the AUCo-1 covers less than 80% of the 
AUCo-mr. 
In case that a research subject elimination proceeds, according to the above-
mentioned information, the excluded research subject samples shall be analyzed 
and the results shall be presented. Also, the statistical analysis shall be performed 
and shall be presented with and without the data of eliminated research subjects. 
14.l0Bioequivalence Criteria 
Based on the statistical results of classic 90% confidence interval for the ratio of the 
geometric least squares means for log-transformed PK parameters Cmax and AUCo-1 for 
Paroxetine, a conclusion will be drawn for test product (A) vs. the reference product (B) 
under fasting conditions. 
The bioequivalence of the test product (A) with that of the reference product (B) under 
fasting conditions will be concluded if the 90% confidence interval of the ratio of the 
test and reference product (test/reference) falls within the acceptance range of 80.00 -
125.00% for In-transformed PK parameters C.nax and AUCo-1 of Paroxetine. 
15.0 
Amendments and Protocol Deviations 
A protocol deviation is an unintended excursion from the approved protocol. 
A major protocol deviation is a protocol deviation that may, as evaluated by the 
principal investigator, or person designated by the investigator impact the safety of the 
subject or the integrity of the trial. Major deviations will lead to withdrawal of a subjecl 
from the study. Deviations not classified as major are considered as minor protocol 
deviations. 
Project No. I Protocol No.: AS/BK/OCT-19/0055 
Sponsorcode:212969 
Version No: 01 
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o(S Avant Sante 
Format No.: PBF031-00E 
Reference SOP No.: PB016 
Statistical Analysis Plan of Bioequivalence Pivotal Study of Paroxetine tablets 20 mg under 
fasting conditions. 
All protocol deviations should be reported to the sponsor by the Avant Sante and 
monitor (if present on site) at the earliest possible time. The sponsor can propose to re-
classify a protocol deviation (minor to major or vice versa) upon evaluation. In such 
case, the classification made by the sponsor prevails and will be communicated to Avant 
Sante together with a written justification. 
Major protocol deviations will only be implemented after sponsor's approval and 
obtaining approval or a favorable opinion from the Research Ethics Committee (REC) 
and Research Committee (RC) and COFEPRIS. 
The sponsor must be informed of minor protocol deviations, but before start of the 
following clinical study period or before start of the bioanalytical phase/ statistical 
phase. 
Minor protocol deviations will be reported sponsor and Committees if applicable, and 
will be reported in study report: 
• 
Logistic deviations (follow up visits that occurred outside the protocol required 
time frame because of the participant's schedule etc.) 
• 
All post dose in-house blood samples collected beyond ± 2 minutes during 
housing period and ± 60 minutes for ambulatory samples from the scheduled 
collection time will be reported as protocol deviations. 
• 
Deviations related to meal consumption. 
• 
Administrative deviations (e.g. change of names). 
Protocol deviation notification and reports are submitted to Health Authorities and/or 
relevant Research Ethics Committee (REC) and Research Committee (RC) according to 
applicable requirements/ guidelines/law. 
Procedure for documenting protocol deviations 
The Principal Investigator, or person designated by PI, should document and explain any 
deviation from the approved protocol. The notification of protocol deviation to sponsor 
can be in exceptional cases communicated by verbal means (if immediate 
Project No. I Protocol No.: AS/BK/OCT-19/005 5 
Sponsor code:212969 
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c,(S Avant Sante 
Format No.: PBF031-00E 
Reference SOP No.: PB016 
Statistical Analysis Plan of Bioequivalence Pivotal Study of Paroxetine tablets 20 mg under 
fasting conditions. 
action/notification is needed) and must be followed-up with written documentation ( e.g. 
by e-mail; period update). All major protocol deviations, as well as time point deviations 
or meal plan, must be described in the final study report. 
16.0 
References 
1. Protocol of the study AS/BK/OCT-19/0055 Version 01 
2. Protocol of the study AS/BK/OCT-19/0055 Version 02 
3. NORMA Oficial Mexicana NOM-177-SSAJ-2013, Que establece las pruebas y 
procedimientos para demostrar que un medicamento es intercambiable. Requisites a 
que deben sujetarse los Terceros Autorizados que realicen las pruebas de 
intercambiabilidad. Requisites para realizar los estudios de biocomparabilidad. 
Requisitos a que deben sujetarse los Terceros Autorizados, Centres de Investigaci6n o 
lnstituciones Hospitalarias que rea!icen las pruebas de biocomparabilidad, Sep, 2013. 
4. Guideline for Good Clinical Practice, E6 (R2), International Council on 
Harmonization of Technical Requirements for Registration of Pharmaceuticals for 
Human use, Current Step 5 version, 15 December 2016. 
5. Food and Drug Administration (FDA), Guidance for Industry: Statistical approaches 
to establishing bioequivalence 2001. 
6. Schuirman, D. J. A comparison of the two one-sided tests procedure and the power 
approach for assessing the equivalence of average bioavailability. J. Pharmacokin. 
Biopharm., 1987, 715:657-680. 
7. Hauck, W.W., Anderson, S. A New Statistical Procedures for testing equivalence in 
two group comparative bioavailability trials. J. Pharmacokin. Biopharm., 1984, 
12:83-91. 
8. SOP PB009, Generation of Randomization Schedule). 
9. SOP PB003, Statistical Analysis for Bioequivalence Studies Using Winnonlin® 
Software. 
10. SOP PB005, Procedure for Statistical Analysis of Crossover Design. 
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Sponsorcode: 212969 
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o<S Avant Sante 
Format No.: PBF031-00E 
Reference SOP No.: PB016 
Statistical Analysis Plan of Bioequivalence Pivotal Study of Paroxetine tablets 20 mg under 
fasting conditions. 
11. "INFORME FARMACOCINETICO -
ESTADiSTICO" of In-house study-
AS/ AO/ ABR-17/0012 (Paroxetine 20 mg). 
17 .0 
Change history 
Current 
Supercedes 
Version No. 
(Version No.) 
Changes Made 
00 
NIA 
NIA 
1. Section 14.3: The statistical model 
00, 26/Nov/2020 
is included to evaluate the Group 
01 
Effect by means of ANOV A, after 
conducting the study in groups. 
Project No. / Protocol No.: AS/BK/OCT-19/0055 
Sponsor code: 212969 
Version No: 01 
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