Investigator’s Brochure
1. COVER PAGE OF INVESTIGATOR’S BROCHURE ......................................1
2. INVESTIGATOR’S BROCHURE APPROVAL PAGE......................................2
3. TABLE OF CONTENTS........................................................................................3
4. SUMMARY............................................................................................................15
4.1 Physical, Chemical and Pharmaceutical Properties. Formulation......................15
4.2 Pharmacodynamic Profile in Experimental Animals and in vitro......................15
4.3 Pharmacokinetic Profile in Experimental Animals and in vitro ........................15
4.4 Safety / Toxicology Profile in Experimental Animals .......................................15
4.4.1 Undesirable Pharmacodynamic Effects on Physiological Functions …..........15
4.4.2 Main Toxicological Effects Identified in Conventional Toxicology Studies ..15
4.5 Pharmacokinetic Profile in Man and in vitro (Human Microsomes) ..................20
4.6 Proof of Concept Studies in Man ........................................................................20
4.7 Safety Profile in Man ..........................................................................................20
5. INTRODUCTION...................................................................................................23
6. PHYSICAL, CHEMICAL AND PHARMACEUTICAL PROPERTIES,
FORMULATION ........................................................................25
6.1 Active Ingredient (Drug Substance)....................................................................25
6.2 Formulation of Investigational Product in the Clinical Studies in Humans….....25
6.3 Instructions for Storage and Handling of Investigational Product.......................25
6.4 Incompatibilities and Interactions .......................................................................25
7. NON-CLINICAL STUDIES...................................................................................28
7.1 Introduction ........................................................................................................28
7.2 Pharmacology......................................................................................................28
7.2.1 Primary Pharmacodynamics..........................................................................28
7.2.1.1 Primary Pharmacodynamics: Overview..................................................28
7.2.1.2 Primary Pharmacodynamics: Studies and Results .................................28
7.2.1.3 Primary Pharmacodynamics: Discussion/Conclusions…………..…….28
7.2.2 Secondary Pharmacodynamics......................................................................28
7.2.3 Safety Pharmacology ...................................................................................38
7.2.3.1 Non-Clinical Safety Pharmacology: Overview.......................................38
7.2.3.2 Non-Clinical Safety Pharmacology: Studies and Results ......................38
7.2.3.3 Non-Clinical Safety Pharmacology: Discussion/Conclusion .................40
7.2.4 Pharmacodynamic Drug Interactions............................................................40
7.3 Pharmacokinetics ................................................................................................40
7.3.1 Overview.......................................................................................................40
7.3.2 Methods of Analysis ....................................................................................45
7.3.3 Absorption....................................................................................................45
7.3.4 Distribution ..................................................................................................45
7.3.5 Metabolism..................................................................................................45
7.3.6 Excretion .....................................................................................................55
7.3.7 Pharmacokinetic Drug Interactions..............................................................55
7.3.8 Pharmacokinetic/Pharmacodynamic Relationship........................................55
7.3.9 Toxicokinetics...............................................................................................55
7.3.10 Discussion/Conclusion................................................................................58
7.4 Toxicology ..........................................................................................................60
7.4.1
Overview...............................................................................................................60
7.4.2 Single Dose Toxicity: Studies and Results ...................................................60
7.4.2.1 Single Dose Oral Study in the Rat..........................................................63
7.4.3 Repeated Dose Toxicity: Studies and Results...............................................64
7.4.3.1 7-Day Oral Exploratory Study in the Wistar Rat ...................................64
7.4.3.2 2-Week Oral Toxicity Study in the Wistar Rat …………………..........64
7.4.3.3 4-Week Oral Toxicity Study in the Wistar Rat ......................................65
7.4.3.4 13-Week Oral Toxicity Study in the Wistar Rat with a 4-Week
Recovery Period..............................................................................66
7.4.3.5 26-Week Oral (Dietary and Gavage) Toxicity Study in the Wistar Rat..66
7.4.3.6 Assessment of the Morphology of the Preputial, Clitoral and Zymbal’s
Glands Following 2 and 4 Weeks Oral Gavage in the Wistar Rat….....76
7.4.3.7 Quantitative Evaluation by ELISA of -2 Microglobulin
Concentrations in Kidney Homogenates Following 2 Weeks Oral
Administration in Wistar Rats………………………………….….76
7.4.3.8 2-Week Oral (Dietary) Palatability Study in the Wistar Rat...................76
7.4.3.9 4-Week Oral (Dietary and Gavage) Range-Finding Toxicity Study
in the Wistar Rat .............................................................................76
7.4.3.10 7-Day Oral Exploratory Study in the Beagle Dog................................76
7.4.3.11 Single and 7-Day Oral MTD Study in the Beagle Dog……………….76
7.4.3.12 2-Week Range-Finding Toxicity Study in the Beagle Dog .................76
7.4.3.13 4-Week Oral Toxicity Study in the Beagle Dog ..................................76
7.4.3.14 13-Week Oral Toxicity Study in the Beagle Dog with a 4-Week
Recovery Period..............................................................................78
7.4.3.15 4-Week Oral Gavage (Three Times Daily) Rangefinding Toxicity
Study in the Beagle Dog....................................................................78
7.4.3.16 26-Week Oral Gavage (Three Times Daily) Toxicity Study in the
Beagle Dog......................................................................................79
7.4.3.17 Determination of the Single and 7-Day Maximum Tolerated Dose
by Oral Route in the Cynomolgus Monkey......................................82
7.4.3.18 2-Week Range-Finding Toxicity Study in the Cynomolgus Monkey..82
7.4.3.19 4-Week Oral Toxicity Study in the Cynomolgus Monkey...................82
7.4.3.20 39-Week Oral Toxicity Study in the Cynomolgus Monkey.................84
7.4.4 Genotoxicity: Studies and Results ...............................................................84
7.4.4.1 Bacterial Mutation Assay (Ames Test) ..................................................84
7.4.4.2 Mouse Lymphoma Mutation Assay .......................................................84
7.4.4.3 Chromosome Aberration Assay in CHO Cells.......................................84
7.4.4.4 Micronucleus Induction Assay in Bone Marrow Erythrocytes from
Orally Dosed Wistar Rats....................................................................88
7.4.4.5 Cytotoxicity Studies ..............................................................................88
7.4.5 Carcinogenicity ............................................................................................88
7.4.6 Reproductive and Developmental Toxicity ..................................................89
7.4.6.1 Oral Embryo-Fetal Toxicity Dose Range Finding Study in the Rat…...89
7.4.6.2 Oral Embryo-Fetal Toxicity Study in the Rat.........................................91
7.4.6.3 Oral Fertility and Early Embryonic Development Study in the Rat.......92
7.4.6.4 Oral Maximum Tolerated Dose Study in the Rabbit…………………...97
7.4.6.5 Oral Embryo-Fetal Toxicity Dose Range-Finding Study in the Rabbit..97
7.4.6.6 Oral Embryo-Fetal Toxicity Study in the Rabbit ...................................97
7.4.7 Discussion/Conclusion..................................................................................97
7.5 References of Preclinical Reports - Bibliography...............................................98
8. CLINICAL STUDIES...........................................................................................112
8.1 Overview ..........................................................................................................112
8.2 Pharmacokinetics and Product Metabolism in Humans....................................115
8.2.1 Summary ....................................................................................................115
8.2.2 Methods of Analysis ..................................................................................115
8.2.3 Absorption - Influence of Food...................................................................115
8.2.4 Distribution ................................................................................................115
8.2.5 Metabolism.................................................................................................115
8.2.6 Elimination.................................................................................................116
8.2.7 Special Populations ...................................................................................116
8.2.7.1 Pharmacokinetic Studies in Elderly.....................................................116
8.2.7.2 Pharmacokinetic Studies in Subjects with Renal Impairment .............116
8.2.8 Pharmacokinetic Drug Interactions............................................................120
8.2.8.1 Interaction Studies with Oral Contraceptives...... ...............................120
8.2.8.2 Interaction Studies with carbamazepine in Healthy Subjects and
in Patients ………………………………………………………...….120
8.2.8.3 Interaction Study with phenytoin .........................................................120
8.3 Safety.................................................................................................................121
8.3.1 Healthy Subjects’ Studies ..........................................................................128
8.3.2 Studies in Special Populations ...................................................................128
8.3.3 Patients’ Studies..........................................................................................129
8.3.4 Adverse Drug Events .................................................................................131
8.4 Efficacy ............................................................................................................133
8.5 Marketing Experience ......................................................................................133
8.6 References of Clinical Reports - Bibliography ................................................133
9. SUMMARY OF DATA AND GUIDANCE FOR THE INVESTIGATOR.....136
9.1 Investigational Medicinal Product ...................................................................136
9.2 Clinical Particulars ...........................................................................................136
9.2.1 Therapeutic Indications...............................................................................136
9.2.2 Posology and Method of Administration ...................................................138
9.2.3 Contraindications .......................................................................................138
9.2.4 Special Warnings and Special Precautions for Use ....................................138
9.2.5 Interaction with Other Medicinal Products and Other Forms of
Interaction…………………………………………………………………141
9.2.6 Pregnancy and Lactation.............................................................................141
9.2.7 Effects on Ability to Drive and Use Machines .............................. ............141
9.2.8 Undesirable Effects (Adverse Events Considered to be Drug Related)......141
9.2.9 Overdose ....................................................................................................141
9.3 Pharmacological Properties...............................................................................141
9.3.1 Pharmacodynamic Properties......................................................................141
9.3.2 Pharmacokinetic Properties.........................................................................143
9.3.2.1 In Man .................................................................................................143
9.3.2.2 In Animals ...........................................................................................143
9.3.3 Preclinical Safety Data................................................................................145
9.4 Pharmaceutical Particulars ...............................................................................152
9.4.1 List of Excipients (Br+++++++ Capsules and Tablets)…………………..152
9.4.2 Incompatibilities..........................................................................................152
9.4.3 Shelf Life............................................................... ....................................152
9.4.4 Special Precautions for Storage ........................................... ......................152
9.4.5 Nature and Contents of Container..... .........................................................152
9.4.6 Instructions for Use and Handling .................. ...........................................152
9.4.7 Sponsor........................................................................... ...........................152