Clinical trial NCT03896633
Conditions: Glaucoma Open Angle or Ocular Hypertension
Sponsor: Bausch & Lomb Incorporated
Start date: 2018-02-28; Completion date: 2018-11-17
Enrollment: 637 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main purpose of this prospective study is to demonstrate the therapeutic equivalence of topical brinzolamide compared with AzoptTM

Detailed description:
The main purpose of this prospective study is to demonstrate the therapeutic equivalence of topical brinzolamide dosed three times daily compared with AzoptTM (brinzolamide ophthalmic suspension 1%) dosed three times daily in IOP reduction in patients with POAG or OH.

Arms: arm 1: Ophthalmic suspension arm 2: ophthalmic suspension
Interventions: intervention 1: brinzolamide 1% ophthalmic suspension intervention 2: Azopt 1%
Intervention descriptions: intervention 1: brinzolamide 1% ophthalmic suspension intervention 2: Azopt 1%, RLD

Protocol documents:
Prot_SAP_000.pdf: 
Brinzolamide 1% Ophthalmic Suspension 
Study S0883 
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1 TITLE PAGE 
Clinical Study Protocol 
Brinzolamide 1% Ophthalmic Suspension 
A RANDOMIZED, DOUBLE-MASKED, ACTIVE-CONTROLLED, PARALLEL 
GROUP, MULTI-CENTER BIOEQUIVALENCE STUDY OF THE GENERIC 
BRINZOLAMIDE 1% OPHTHALMIC SUSPENSION COMPARED TO 
REFERENCE LISTED DRUG AZOPT® (BRINZOLAMIDE) OPHTHALMIC 
SUSPENSION 1% IN SUBJECTS WITH PRIMARY OPEN ANGLE GLAUCOMA OR 
OCULAR HYPERTENSION 
Protocol S0883 
Developmental phase of study: 
Bioequivalence, pivotal 
Study design: 
A multi-center, randomized, double-
masked, active-controlled, parallel 
bioequivalence study of both eyes in 
subjects with primary open angle 
glaucoma or ocular hypertension 
Date: Original 
Amendment 1  
11 JAN 2018 
12 APR 2018 
Sponsor representative 
 
 
 
 
 
Sponsor  
Valeant Pharmaceuticals North America 
LLC  
400 Somerset Corporate Blvd, 
Bridgewater NJ 08807  
Main office: (866) 246-8245 
 
CONFIDENTIAL 
Nothing herein is to be disclosed without prior approval of the sponsor. 
This clinical investigation will be conducted in accordance with the protocol and in compliance with 
Good Clinical Practice, including the archiving of essential documents. ™/® are trademarks of Valeant 
Pharmaceuticals North America LLC or its affiliates. All other brand names/product names are 
trademarks of their respective owners. The information in the following document is confidential. The 
information contained herein will not be disclosed to others without written authorization from Valeant 
Pharmaceuticals North America LLC. 
 




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Personnel Responsible for Conducting the Study 
 
A RANDOMIZED, DOUBLE-MASKED, ACTIVE-CONTROLLED, PARALLEL 
GROUP, MULTI-CENTER BIOEQUIVALENCE STUDY OF THE GENERIC 
BRINZOLAMIDE 1% OPHTHALMIC SUSPENSION COMPARED TO 
REFERENCE LISTED DRUG AZOPT® (BRINZOLAMIDE) OPHTHALMIC 
SUSPENSION 1% IN SUBJECTS WITH PRIMARY OPEN ANGLE GLAUCOMA 
OR OCULAR HYPERTENSION 
Protocol S0883 
 
 
  
  
 
 
 
Contract Research Organization 
 
 
 
 
 
 
Lexitas Pharma Services 
313 Foster St 
Durham, NC, 27701 
 
 
  
 


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Principal Investigator Protocol Agreement Page 
I agree: 
 To assume responsibility for the proper conduct of this clinical study at this site and to 
conduct the study in compliance with this protocol, any future amendments, and with 
any other study conduct procedures provided by the sponsor. 
 That I am aware of, and will comply with, the internationally recognized code of Good 
Clinical Practices (GCP) and all other applicable regulatory requirements to obtain 
written and dated approval from the Institutional or Central Review Board (IRB) or 
Independent Ethics Committee (IEC) for the study protocol, written informed consent, 
consent-form updates, subject-recruitment procedures (eg, advertisements), and any 
other written information to be provided to the subjects, before initiating this clinical 
study. 
 Not to implement any changes to, or deviations from the protocol without prior 
agreement from the sponsor and review and documented approval from the IRB/IEC, 
except to eliminate an immediate hazard to the study subjects, or when change(s) 
involves only logistical or administrative aspects of the clinical study. 
 To permit direct monitoring and auditing by the sponsor or sponsor’s representatives 
and inspection by the appropriate regulatory authority (ies). 
 That I am thoroughly familiar with the appropriate use of the investigational 
products(s), as described in this protocol, and any other information provided by the 
sponsor or designee, including, but not limited to, the current investigator Brochure or 
equivalent document and approved product label (if applicable). 
 To provide sufficient time and adequate numbers of qualified staff and facilities for the 
foreseen duration of the clinical study to conduct the study properly, ethically, and 
safely. 
 To ensure that all persons assisting in this study are adequately informed about the 
protocol, investigational product(s), and their clinical study-related duties and 
functions. 
 
 
Principal Investigator (print name) 
 
 
 
 
Principal Investigator (signature) 
 
Date 
 


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Synopsis 
Name of Sponsor/Company: Valeant Pharmaceuticals North America LLC  
Name of Investigational Product (test product): Brinzolamide 1% Suspension 
Name of Active Ingredient: Brinzolamide 1% Suspension 
Title of Study: A randomized, double-masked, active-controlled, parallel group, multicenter 
bioequivalence study of the generic brinzolamide 1% ophthalmic suspension compared to Reference 
Listed Drug Azopt® (brinzolamide) ophthalmic suspension 1% in subjects with primary open angle 
glaucoma or ocular hypertension. 
Number of clinical centers: Approximately 32 Sites, United States only 
Objectives:  
Primary: 
 
To establish that the generic brinzolamide 1% suspension is bioequivalent to brinzolamide 1% 
suspension (AZOPT®), the selected Reference Listed Drug. 
Secondary: 
 
To compare the safety and tolerability of the generic brinzolamide 1% suspension to 
brinzolamide 1% suspension (AZOPT®). 
Methodology:  
This repeat study will be prospective, randomized, double masked and will follow Food and Drug 
Administration (FDA) guidance, revised as of March 2015, for demonstrating bioequivalence of the 
generic brinzolamide 1% ophthalmic suspension compared to brinzolamide 1% Ophthalmic Suspension 
(AZOPT®) for the treatment of elevated intraocular pressure (IOP) in patients  with Primary Open Angle 
Glaucoma (POAG) or Ocular Hypertension (OH). 
Number of patients planned: Approximately 624 subjects will be randomized to ensure that 560 
subjects complete the 42 days (6 weeks) of dosing. 
Diagnosis and main criteria for inclusion:  
1. Subjects must be of legal age (at least 18 years) on the date the Informed Consent Form (ICF) is 
signed.  
2. Subjects must be able to read, understand, and provide written informed consent on the 
Institutional Review Board (IRB)/Ethics Committee (EC)-approved ICF and provide 
authorization as appropriate for local privacy regulations. 
3. Subjects who are willing and able to comply with scheduled visits, treatment plan, and other 
study procedures. 
4. Male subjects able to father children and female subjects of childbearing potential and at risk 
for pregnancy must agree to use a highly effective method of contraception throughout the 
study and for at least 28 days after last dose of assigned treatment. 
Acceptable contraceptive methods for female subjects (need at least one):  
a) Hormonal methods of contraception (including oral and transdermal contraceptives, 
injectable progesterone, progestin subdermal implants, progesterone-releasing intrauterine 
devices [IUDs]) initiated at least 14 days prior to the first dose of study drug  
b) True abstinence: when this is in line with the preferred and usual lifestyle of the subject. 
Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception  
c) Placement of a copper-containing IUD  
d) Condom with spermicidal foam/gel/film/cream/suppository  
e) Postmenopausal at least 12 months (365 days) prior to the first dose of study drug or 
permanently sterilized (eg, tubal occlusion, hysterectomy, bilateral salpingectomy)  
f) Male partner who has had a vasectomy for at least 3 months (90 days) prior to the first dose 


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of study drug or is surgically sterile  
 
Acceptable contraceptive methods for male subjects with partners of childbearing potential 
(need at least one):  
a) True abstinence: when this is in line with the preferred and usual lifestyle of the subject. 
Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception.  
b) Vasectomy for at least 3 months (90 days) prior to the first dose of study drug or surgically 
sterile  
c) Without a vasectomy, must use a condom with spermicidal 
foam/gel/film/cream/suppository  
 
5. Female subjects who are not of childbearing potential must meet at least one of the following 
criteria: 
a) Have undergone a documented hysterectomy and/or bilateral oophorectomy, and/or tubal 
ligation 
b) Have  a medically confirmed ovarian failure, or; 
c) Achieved postmenopausal status, defined as follows: cessation of regular menses for at 
least 12 consecutive months with no alternative pathological or physiological causes  
6. Diagnosis of primary-open angle glaucoma (including pigmentary or pseudoexfoliative) or 
ocular hypertension and requires treatment in both eyes. 
7. Adequate wash-out period prior to baseline of any ocular hypotensive medication (see Table 1). 
In order to minimize potential risk to patients due to intraocular pressure (IOP) elevations 
during the washout period, the investigator may choose to substitute a parasympathomimetic or 
carbonic anhydrase inhibitor in place of a sympathomimetic, alpha-agonist, beta-adrenergic 
blocking agent, or prostaglandin; however, all patients must have discontinued all ocular 
hypotensive medication for the minimum washout period provided in Table 1.  
8. Baseline (Day 1/hour 0) IOP ≥22 mmHg and ≤34 mmHg in both eyes and ≤5 mmHg IOP 
difference between eyes. 
9. Screening and Baseline/Visit 1 BCVA equivalent to 20/200 or better in each eye. 
10. Negative urine pregnancy test at screening and baseline for women of childbearing potential. 
Key exclusion criteria:  
1. Subjects who are investigational site staff members directly involved in the conduct of the study 
and their family members, site staff members otherwise supervised by the investigator, 
subjects who are Sponsor employees directly involved in the conduct of the study, or 
household members of current subjects in the study. 
2. Subjects participating in any clinical investigation within 30 days prior to Screening. 
3. Any severe, acute, or chronic medical or psychiatric condition that may increase the risk 
associated with the study participation or investigational product administration or could 
interfere with the interpretation of study results and, in the judgment of the investigator, could 
make the patient inappropriate for entry in to this study.   
4. Pregnant female subjects; breastfeeding female subjects; male subjects with partners currently 
pregnant; male subjects able to father children and female subject of childbearing potential 
who are unwilling or unable to use highly effective method of contraception as outlined in this 
protocol for the duration of the study and for at least 28 days after the last dose of 
investigational product. 
5. Current or past history of severe hepatic or renal impairment. 


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6. Current or history within two months prior to baseline of significant ocular disease (eg, macular 
degeneration, hypertensive retinopathy, diabetic retinopathy, corneal edema, uveitis, ocular 
infection, or ocular trauma in either eye) that may increase the risk associated with the study 
participation or investigational product administration or could interfere with the interpretation 
of study results and, in the judgment of the investigator, could make the patient inappropriate 
for entry in to this study.   
7. Current corneal abnormalities or any condition that would prevent accurate IOP readings with 
the Goldmann applanation tonometer. 
8. Functionally significant visual field loss in either eye, measured within 6 months prior to 
screening. 
9. At screening advanced glaucoma defined by horizontal and vertical cup/disc ratio >0.8 in either 
eye.  
10. Contraindication of brinzolamide or sulfonamide therapy known hypersensitivity to any 
component of brinzolamide or sulfonamide therapy. 
11. Use at any time prior to baseline of an intraocular corticosteroid implant. 
12. Use within one week prior to baseline of contact lenses. 
13. Use within two weeks prior to baseline of: 1) topical ophthalmic corticosteroid; 2) topical 
corticosteroid; 3) systemic corticosteroid, or 4) high dose salicylate therapy (defined as stable 
daily doses exceeding 325 mg aspirin or equivalent) 
14. Use within six months prior to baseline intravitreal or subtenon injection of ophthalmic 
corticosteroid. 
15. Intraocular or refractive surgery (eg, cataract surgery, LASIK, etc.) within six months prior to 
Screening. 
16. IOP lowering surgery (eg, Trabeculectomy, Laser trabeculoplasty, tube shunts, etc.) within 12 
months prior to baseline. 
17. History of severe dry eye in either eye. 
18. Persons with Central Corneal Thickness (CCT) >600um in either eye. 
19. Anticipate the need to initiate or modify medication (systemic or topical) that is known to 
affect IOP or blood pressure (eg, adrenergic antagonists, -adrenergic agonists, calcium 
channel blockers, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II 
receptor blockers) during the study period. 
20. Subjects with very narrow angles (3 quadrants with less than Grade 2 according to Shaffer's 
anterior chamber angle grading system) and subjects with angle closure, congenital, and 
secondary glaucoma, and subjects with history of angle closure in either eye. 
21. Subjects with known or suspected drug or alcohol abuse. 
Investigational product, dosage and mode of administration: Subjects who meet all 
include/exclusion criteria will be randomized to receive the generic brinzolamide 1% suspension or 
brinzolamide 1% suspension (AZOPT®) using computer generated, blocked treatment assignments in a 
1:1 ratio stratified by investigational site. 
 
Arm 1: One eye drop of the generic brinzolamide 1% suspension in each eye at approximately 8:00 AM, 
4:00 PM and 10:00 PM Daily 
 
Arm 2: One eye drop of brinzolamide 1% suspension (AZOPT®) in each eye at approximately 8:00 
AM, 4:00 PM and 10:00 PM Daily 
 


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Note: the test article must be manufactured compliant to cGMP and meet the proposed 
ANDA specifications. 
Duration of treatment: 42 days (6 weeks) after start of administration of study drug 
Reference therapy, dosage and mode of administration:  
Brinzolamide (AZOPT®) 1% Ophthalmic Suspension 
Criteria for evaluation: 
Efficacy: The primary endpoint is the mean difference in IOP of both eyes between the two treatment 
groups at four time points, eg, at approximately 8:00 a.m. (hour 0; before the morning drop) and 10:00 
a.m. (hour 2) at the Day 14 (week 2) and Day 42 (week 6) visits.  
 
Safety: The safety and tolerability of the generic brinzolamide 1% suspension and brinzolamide 1% 
suspension (AZOPT®) will be evaluated by monitoring of blood pressure and pulse, ophthalmic exams 
(BCVA, refraction, biomicroscopy, and ophthalmoscopy), and monitoring of treatment related adverse 
events. 
Statistical methods: A comprehensive Statistical Analysis Plan (SAP) will be finalized and approved 
prior to the unmasking of the trial.  
The primary endpoint is the mean difference in IOP of both eyes between the two treatment groups at 
four time points, eg, at approximately 8:00 a.m. (hour 0; before the morning drop) and 10:00 a.m. (hour 
2) at the Day 14 (week 2) and Day 42 (week 6) visits. The endpoint will be analyzed using the per-
protocol population, which will include all randomized subjects who meet all inclusion/exclusion 
criteria, instilled 75% to 125% of the planned doses for the entire duration of the study, as verified by 
patient diaries, and who did not miss the scheduled applications for more than 3 consecutive days, and 
completed evaluations at Day 14 and Day 42 within the designated visit window (± 4 days) with no 
protocol deviations that would affect the treatment evaluation. 
In order to establish equivalence of the two treatments: 
1. The limits of each two-sided 95% CI of the treatment difference (test – reference) for mean IOP 
of both eyes (continuous variable) at all four follow-up points (eg, at approximately 8:00 AM 
(hour 0; before the morning drop) and 10:00 AM (hour 2) at the Day 14 (week 2) and Day 42 
(week 6) visits must be within ± 1.5 mm Hg; and 
2. For the majority of the time points [3 out of 4 follow-up time points; eg, at approximately 8:00 
AM (hour 0; before the morning drop) and 10:00 AM (hour 2) at the Day 14 (week 2) and Day 
42 (week 6) visits) measured], the limits of each two-sided 95% CI of the differences in the 
mean IOP of both eyes between the two treatment groups is within ± 1.0 mmHg 
The point estimates of the difference between the two treatment groups and the two-sided 95% CIs will 
be presented. Since both of the above conditions have to be satisfied to establish equivalence, the type I 
error (α), will not be adjusted to account for multiple comparisons. 
The safety and tolerability of the generic brinzolamide 1% suspension and brinzolamide 1% suspension 
(AZOPT®) will be evaluated by monitoring of blood pressure and pulse, ophthalmic exams (BCVA, 
refraction, biomicroscopy, and ophthalmoscopy), and monitoring of adverse events. 
Sample size calculations: 
A mean treatment difference of 0 mmHg, a standard deviation of 3.3 mmHg, and a correlation 
coefficient of 0.565 between any 2 different follow-up time points was assumed for the sample size 
calculation. To confirm the lower and the upper bounds of the two-sided 95% confidence interval (CI) of 
the treatment difference is within the range of ± 1.0 mmHg for at least 3 (out of 4) follow-up time points 
(at approximately 8:00 AM and 10:00 AM on days 14 and 42), and to confirm that the lower and the 
upper bounds of the two-sided 95% CI of the treatment difference at all 4 follow-up time points are 
within ±1.5 mmHg, a minimum number of 280 evaluable patients for each treatment group will be 
needed to achieve 90% power. To account for 10% attrition, a total of 624 subjects (312 subjects per 
group) will need to be randomized.  
 


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3 
Table of Contents  
1 
TITLE PAGE ...........................................................................................................1 
2 
SYNOPSIS ...............................................................................................................6 
3 
TABLE OF CONTENTS .......................................................................................10 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................13 
5 
INTRODUCTION .................................................................................................14 
6 
STUDY OBJECTIVES AND ENDPOINTS .........................................................15 
6.1 
Primary objective .......................................................................................15 
6.2 
Secondary objectives .................................................................................16 
6.3 
Primary Endpoint .......................................................................................16 
6.4 
Safety Endpoints ........................................................................................16 
7 
INVESTIGATIONAL PLAN ................................................................................16 
7.1 
Overall Study Design and Plan: Description .............................................16 
8 
SUBJECT SELECTION ........................................................................................19 
8.1 
Subject Inclusion Criteria ..........................................................................20 
8.2 
Subject Exclusion Criteria .........................................................................22 
8.3 
Subject Withdrawal Criteria ......................................................................24 
9 
TREATMENT PLAN ............................................................................................26 
9.1 
Study Treatments .......................................................................................26 
9.1.1 Methods of Assigning Subjects to Treatment Groups ...................26 
9.1.2 Treatment Replacement .................................................................27 
9.2 
Masking......................................................................................................27 
9.3 
Concomitant Medications ..........................................................................27 
9.4 
Treatment Compliance ...............................................................................29 
9.5 
Protocol Deviations ....................................................................................29 
10 
STUDY DRUG MATERIALS AND MANAGEMENT ......................................30 
10.1 
Brinzolamide 1% Suspension ....................................................................30 
10.1.1 Packaging and Labeling .................................................................30 
10.1.1.1 Retention of Study Drug Samples .................................31 
10.1.2 Storage, Handling, and Disposal of Study Drug ............................31 
10.1.3 Study Drug Preparation and Dispensing ........................................32 
10.1.4 Administration ...............................................................................33 
10.2 
Study Drug Accountability ........................................................................33 
10.3 
Destruction of Investigational Product Supplies........................................34 
11 
STUDY PROCEDURES AND EVALUATIONS ................................................34 


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11.1 
Schedule of Evaluations and Procedures ...................................................34 
11.1.1 Screening Visit ...............................................................................34 
11.1.2 Visit 1 (Day 1) ...............................................................................36 
11.1.3 Visit 2 (Day 14) .............................................................................37 
11.1.4 Visit 3 (Day 21) .............................................................................38 
11.1.5 Visit 4 (Day 42) .............................................................................38 
11.1.6 Post Study Follow-up Visit ............................................................39 
11.2 
Blood Pressure and Pulse ...........................................................................40 
11.3 
Visual Fields ..............................................................................................41 
11.4 
Best Corrected Visual Acuity ....................................................................41 
11.5 
Refraction ...................................................................................................41 
11.6 
Iris Color ....................................................................................................42 
11.7 
Biomicroscopy ...........................................................................................42 
11.8 
Intraocular Pressure ...................................................................................42 
11.9 
Ophthalmoscopy ........................................................................................42 
11.10 Gonioscopy ................................................................................................43 
11.11 Pachymetry ................................................................................................44 
12 
METHODS AND TIMING FOR ASSESSING, RECORDING, AND 
ANALYZING SAFETY PARAMETERS. ...........................................................44 
12.1 
Adverse Event Reporting ...........................................................................44 
12.1.1 Adverse Events ..............................................................................44 
12.1.2 Reporting Period ............................................................................45 
12.1.3 Definition of an Adverse Event .....................................................45 
12.2 
Serious Adverse Events .............................................................................46 
12.2.1 Protocol-Specified Serious Adverse Events ..................................48 
12.2.2 Hospitalization ...............................................................................48 
12.2.3 Severity Assessment ......................................................................48 
12.3 
Causality Assessment.................................................................................49 
12.4 
Exposure during Pregnancy .......................................................................50 
12.5 
Withdrawal Due to Adverse Events ...........................................................50 
12.6 
Reporting Requirements ............................................................................51 
12.6.1 Serious Adverse Event Reporting Requirements ...........................51 
12.6.2 Non-serious Adverse Event Reporting Requirements ...................51 
12.6.3 Sponsor’s Reporting Requirements to Regulatory Authorities .....51 
13 
STATISTICS .........................................................................................................51 
13.1 
Sample Size Determination........................................................................52 
13.2 
Efficacy Analysis .......................................................................................52 


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13.2.1 Analysis of the Primary Endpoint ..................................................52 
13.3 
Safety Analysis ..........................................................................................54 
13.4 
Data Monitoring Committee ......................................................................55 
14 
QUALITY CONTROL AND QUALITY ASSURANCE .....................................55 
14.1 
Study Monitoring .......................................................................................56 
14.2 
Audits and Inspections ...............................................................................56 
14.3 
Data Quality Assurance .............................................................................56 
15 
DATA HANDLING AND RECORD KEEPING .................................................57 
15.1 
Inspection of Records ................................................................................57 
15.2 
Record Retention .......................................................................................58 
16 
ETHICS..................................................................................................................59 
16.1 
Institution Review Board/Ethics Committee .............................................59 
16.2 
Ethical Conduct of the Study .....................................................................60 
16.3 
Written Informed Consent .........................................................................60 
16.4 
Subject Data Protection..............................................................................61 
16.5 
Reporting of Safety Issues and Serious Breaches of the Protocol ICH 
GCP ............................................................................................................61 
16.6 
Confidentiality/Publication of the Study ...................................................61 
16.7 
Investigator Obligations .............................................................................62 
16.8 
Changes to the Protocol .............................................................................62 
17 
DEFINITION OF END OF TRIAL .......................................................................62 
17.1 
End of Trial in All Participating Countries ................................................62 
18 
SPONSOR DISCONTINUATION CRITERIA ....................................................63 
19 
REFERENCES ......................................................................................................63 
20 
APPENDICES .......................................................................................................64 
21.1 
Appendix A. Current Full Prescribing Information of AZOPT® ..............64 
 
LIST OF TABLES 
Table 1 
Minimum Washout Periods for Ocular Hypotensive Medications.................17 
Table 2 
Study Design and Schedule of Assessments ..................................................19 
 
LIST OF FIGURES 
Figure 1 
Study Design ...................................................................................................18 
 
  


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List of Abbreviations and Definitions of Terms 
 
Abbreviation or specialist term 
Definition or Explanation 
AE 
ACE 
BCVA 
BP 
CA II 
CAI 
CCT 
CI 
CRF 
CSR 
DU 
EC 
EDP 
ETDRS 
FDA 
Adverse event 
Angiotensin-converting enzyme 
Best corrected visual acuity 
Blood Pressure 
Carbonic anhydrase II 
Carbonic anhydrous inhibitors 
Central Corneal Thickness 
Confidence interval 
Case report form 
Clinical study report 
Dispensable unit 
Ethics committee 
Exposure during pregnancy 
Early treatment of diabetic retinopathy study 
Food and Drug Administration (United States) 
GCP 
Good Clinical Practice 
ICH 
ID 
International Conference on Harmonization 
Identification 
IEC 
IOP 
ORS 
IUD 
Independent Ethics Committee 
Intraocular Pressure 
Oracle Randomization and Supply Management System 
Intrauterine device 
IRB 
IWR 
LSLV 
mmHG 
Institutional Review Board 
Interactive web response 
Last subject last visit 
Millimeters of mercury 
OAG 
POAG 
Open angle glaucoma 
Primary open angle glaucoma 
SAE 
SAP 
SRSD 
TEAE 
US 
USPI 
Serious adverse event 
Statistical analysis plan 
Single reference safety document 
Treatment emergent adverse event 
United States 
United States package insert 
 
In this protocol, “sponsor duties” refer to responsibilities that will be performed by the 
Sponsor, the sponsor’s designee, or the sponsor’s designated contract research organization. 
In this protocol, “investigator” refers to the principal investigator or his/her designee, who is 
responsible for performing the study procedures and assessments. 


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Introduction 
Mechanism of Action 
Brinzolamide is a carbonic anhydrous inhibitor indicated for the reduction of intraocular 
pressure (IOP) in patients with primary open angle glaucoma (POAG) and ocular 
hypertension (OH). 
Background and Rationale 
Brinzolamide belongs to a class of heterocyclic sulfonamide carbonic anhydrous inhibitors 
(CAIs) that is topically active for reducing IOP. It has high affinity and inhibitory potency 
against human CA II, an isoenzyme of carbonic anhydrase found in the ciliary epithelia, 
which are involved with aqueous humor secretion. Branded brinzolamide is formulated as an 
ophthalmic 1% aqueous suspension with a physiologic pH (AZOPT®). AZOPT® is well 
tolerated and does not produce many of the side effects associated with the CAIs that are 
given systemically, making it an attractive treatment for patients with glaucoma, in whom 
compliance with therapy can be an issue. It reduces IOP from baseline in a statistically 
significant and clinically relevant manner in the majority of patients when used for primary 
or adjunctive therapy (Sall K. 2000) (Shin D. 2000). 
Complete information for this compound may be found in the single reference safety 
document (SRSD), which for this study is the (AZOPT®) United States Package Insert 
(USPI, version date 07/2015). 
Clinical Studies 
The safety and efficacy of brinzolamide 1% ophthalmic suspension have been evaluated in 
several previous clinical studies (reference to Section 20). 
In two, three-month clinical studies, brinzolamide 1% ophthalmic suspension in subjects with 
elevated IOP, produced significant reductions in IOP (4-5 mmHg) (Sall K. 2000) (Silver LH. 
1998). These IOP reductions were statistically equivalent (confidence limit less than 1.5 
mmHg) to the reductions observed with dorzolamide 2% hydrochloride ophthalmic solution 
(Sall K. 2000) (March WF, Ochsner KI 2000). The studies also demonstrated that 


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brinzolamide was associated with significantly less ocular discomfort (burning and stinging) 
than dorzolamide (Sall K. 2000) (Silver LH. 1998). 
In a double masked, randomized, adjunctive study, 108 patients received brinzolamide 1% or 
placebo in addition to ocular timolol 0.5% for primary open-angle glaucoma (POAG) or 
ocular hypertension (OH). Adding topical ocular brinzolamide to timolol therapy further 
reduced IOP. Over the 3-month study, IOP changes ranged from -3.3 mmHg to -4.1 mmHg 
in the brinzolamide group compared to -0.9 mmHg to -2.5 mmHg in the placebo group (p 
<0.03, brinzolamide vs. placebo) (Shin D. 2000). 
In a long-term study, brinzolamide 1% ophthalmic suspension induced significant IOP 
reductions and caused less ocular discomfort than topical timolol 0.5%, in patients with 
open-angle glaucoma (OAG) or OH (March WF, Ochsner KI 2000). Patients treated with 
timolol attained a significantly greater mean reduction of 5.2 mmHg in IOP compared with 
patients receiving brinzolamide (p <0.0002). There were no significant adverse events 
(March WF, Ochsner KI 2000). 
In a 12 week InnoPharma/Pfizer (previous sponsor) bioequivalence study of the generic 
brinzolamide 1% suspension and brinzolamide 1% suspension (AZOPT®) in 256 patients 
with POAG or OH, the 95% confidence limits on the mean difference in IOP between 
treatment groups were within 1.5 mmHg at each time point with comparable safety and 
tolerance (InnoPharma Inc. 2012).  
This repeat study will be prospective, randomized, double masked and will follow Food and 
Drug Administration (FDA) guidance for demonstrating bioequivalence of the generic 
brinzolamide 1% ophthalmic suspension (test article) compared to brinzolamide 1% 
ophthalmic suspension (AZOPT®; reference listed drug, reference article) to treat elevated  
IOP in patients with POAG or OH. 
6 
Study Objectives and Endpoints 
6.1 
Primary objective  
 To establish that the generic brinzolamide 1% suspension is bioequivalent to 
brinzolamide 1% suspension (AZOPT®). 


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6.2 
Secondary objectives 
 To compare the safety and tolerability of the generic brinzolamide 1% suspension to 
brinzolamide 1% suspension (AZOPT®). 
6.3 
Primary Endpoint 
 The mean difference in intraocular pressure (IOP) of both eyes between the two 
treatment groups at four time points, eg, at approximately 8:00 am (hour 0; before the 
morning drop) and 10:00 AM (hour 2) at the Day 14 (week 2) and Day 42 (week 6) 
visits. 
6.4 
Safety Endpoints 
 The safety and tolerability of the generic brinzolamide 1% suspension and 
brinzolamide 1% suspension (AZOPT®) will be evaluated by monitoring of blood 
pressure and pulse, ophthalmic exams (BCVA, refraction, biomicroscopy, and 
ophthalmoscopy), and monitoring of treatment related adverse events. 
7 
Investigational plan 
7.1 
Overall Study Design and Plan: Description 
Study S0883 is a 42 day, multi-center, randomized, double-masked, active-controlled, 
parallel bioequivalence study of both eyes in subjects with primary open angle glaucoma or 
ocular hypertension who, following a washout of 4 to 28 days (depending on pre-study 
treatment) have an IOP mmHg and mmHg, mmHg IOP difference between eyes 
and best corrected visual acuity (BCVA) better than or equal to 20/200 in each eye. 
The screening visit will be conducted 4 to 42 days before the baseline visit (Day 1). All 
subjects must be washed out of topical or systemic ocular hypotensive medications prior to 
the baseline visit. 


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Table 1 
Minimum Washout Periods for Ocular Hypotensive Medications 
 
Medication 
Minimum 
Washout 
Periods 
Parasympathomimetics [eg, pilocarpine (Isopto® Carpine), 
carbachol (Isopto® Carbachol)] 
4 days 
Carbonic anhydrase inhibitors (systemic or topical) [eg, 
acetazolamide (Diamox®), dorzolamide hydrochloride (Trusopt®), 
brinzolamide (AZOPT®)] 
4 days 
Sympathomimetics [eg, dipivefron (Propine®), epinephrine 
(Epifrin®)] 
2 weeks 
Alpha-agonists [eg, apraclonidine (Iopidine®) brimonidine tartarate 
(Alphagan®, Alphagan® P), brimonidine and brinzolamide 
(Simbrinza®)] 
2 weeks 
Beta-adrenergic blocking agents [eg, timolol (Timoptic®, 
Betimol®, Timoptic XE®, Isatol®), timolol maleate and 
dorzolamide hydrochloride (Cosopt®), timolol maleate and 
brimonidine tartrate (Combigan®), levobunolol (Akbeta®, 
Betagan®), betaxolol (Betoptioc®, Betoptic-S®), metipranolol 
(Opti-Pranolol®), careteolol (Ocupress®)] 
4 weeks 
Prostaglandin analogs [eg, latanoprost (Xalatan®), travoprost 
(Travatan®), bimatoprost (Lumigan®), tafluprost (ZioptanTM)] 
4 weeks 
 
To account for 10% attrition, approximately 624 subjects will be randomized in order to 
ensure that 560 subjects complete the 42 days (6 weeks) of dosing. Subjects who meet all 
inclusion/exclusion criteria will be randomized to receive the generic brinzolamide 1% 
suspension or brinzolamide 1% suspension (AZOPT®) using computer generated, blocked 
treatment assignments in a 1:1 ratio stratified by investigational site. Investigational product 
will be administered at approximately 8:00 AM, 4:00 PM and 10:00 PM in both eyes for 42 
days, with exception of Visit 1 (Day 1) dose administered at only 4:00PM and 10:00PM. IOP 
assessments will be performed at approximately 8:00 AM and 10:00 AM on days 1 
(baseline), 14, 21, and 42. IOP will be performed a second time (at approximately 10:00AM) 
on Days 1 (baseline), 14, 21, and 42. For subjects who discontinue the study before the end 


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of the treatment period, an Early Termination visit will be conducted within approximately 
one week after last study dose. 
Figure 1 Study Design  
 
 
The generic brinzolamide 1% 
suspension 
Brinzolamide 1% suspension 
(AZOPT) 
Sample Size 
624 
Washout -4 to -28 Days 
Visit 
Screening (Day -4 to -42) 
Baseline Day 1 Day 14 Day 21 
Day 42 


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Table 2 
Study Design and Schedule of Assessments 
Visit identifier 
Screening 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Early 
Termination 
Visit Window 
Day -42 
to  
-4  
 Day 1 
Day 14 
±4 days 
Day 21 ±4 
days 
Day 42 ±4 days 
Approximately 
within 7 days 
after last dose 
Informed Consent 
X 
  
  
  
  
 
Obtain Subject ID 
X 
  
  
  
  
 
Randomization  
  
X 
  
  
  
 
Inclusion/Exclusion 
criteria 
X 
X 
  
  
  
 
Demographics 
X 
  
  
  
  
 
Medical History 
X 
 
  
  
  
 
Prior and Concomitant 
medications 
X 
X 
X 
X 
X 
X 
AE Monitoring  
X 
X 
X 
X 
X 
X 
Check dosing diary 
  
  
X 
X 
X 
X 
Collect unused 
investigational product 
  
  
  
X 
X 
X 
Collect dosing diary 
  
  
  
 X 
X 
X 
BP and Pulse (sitting) 
X 
X 
X 
X 
X 
X 
Visual Field Testing 
Xc 
 
 
 
 
 
Refraction 
X 
X* 
X* 
X* 
X* 
X* 
BCVA 
X 
X 
X 
X 
X 
X 
Biomicroscopy 
X 
X 
X 
X 
X 
X 
Intraocular Pressure 
X 
X B 
X B 
X B 
X B 
X 
Gonioscopy 
XD 
 
Pachymetry 
X 
 
 
 
 
 
Ophthalmoscopy 
X 
X 
X 
X 
X 
X 
Urine Pregnancy Test 
 X 
X 
X 
X 
Dispense Investigational 
Product 
 
X 
 
X 
 
 
Dispense Dosing Diary 
 
X 
 
X 
 
 
Self-Administer 
Investigational Drug A  
 
 
X A 
X A 
X A 
 
A : indicates dosing will be self-administered at the site on visits 2, visit 3, and visit 4 after 8:00AM IOP measurement  
B: IOP measurement will occur twice (within ± 30 minutes of) 8:00AM and 10:00AM) at visit 1, visit 2, visit 3, and visit 4 
c: Visual Field testing to be conducted if no documentation within 6 months prior to screening 
D: Gonioscopy testing to be conducted if no documentation within 6 months prior to screening 
*: Refraction to be performed if there was a two line decrease in BCVA from the previous assessment 
Table 2 above, should be followed in order as schedule of assessments 
8 
Subject Selection 
The following eligibility criteria are designed to select subjects for whom participation in the 
study in considered appropriate. All relevant medical and nonmedical conditions should be 


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taken into consideration when deciding whether a particular subject is suitable for this 
protocol.  
8.1 
Subject Inclusion Criteria 
Subject eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before subjects are included in the study. 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment in to 
the study: 
1. Subjects must be of legal age (at least 18 years) on the date the Informed Consent 
Form (ICF) is signed.  
2. Subjects must be able to read, understand, and provide written informed consent on 
the Institutional Review Board (IRB)/Ethics Committee (EC)-approved ICF and 
provide authorization as appropriate for local privacy regulations. 
3. Subjects who are willing and able to comply with scheduled visits, treatment plan, 
and other study procedures. 
4. Male subjects able to father children and female subjects of childbearing potential and 
at risk for pregnancy must agree to use a highly effective method of contraception 
throughout the study and for at least 28 days after last dose of assigned treatment. 
 
Acceptable contraceptive methods for female subjects (need at least one):  
a) Hormonal methods of contraception (including oral and transdermal 
contraceptives, injectable progesterone, progestin subdermal implants, 
progesterone-releasing intrauterine devices [IUDs]) initiated at least 14 days prior 
to the first dose of study drug  
b) True abstinence: when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception  
c) Placement of a copper-containing IUD  
d) Condom with spermicidal foam/gel/film/cream/suppository  


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e) Postmenopausal at least 12 months (365 days) prior to the first dose of study drug 
or permanently sterilized (eg, tubal occlusion, hysterectomy, bilateral 
salpingectomy)  
f) Male partner who has had a vasectomy for at least 3 months (90 days) prior to the 
first dose of study drug or is surgically sterile  
 
Acceptable contraceptive methods for male subjects with partners of childbearing 
potential (need at least one):  
a) True abstinence: when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception.  
b) Vasectomy for at least 3 months (90 days) prior to the first dose of study drug or 
surgically sterile  
c) Without a vasectomy, must use a condom with spermicidal 
foam/gel/film/cream/suppository  
 
5. Female subjects who are not of childbearing potential must meet at least 1 of the 
following criteria: 
a. Have undergone a documented hysterectomy and/or bilateral oophorectomy, 
and/or tubal ligation; 
b. Have medically confirmed ovarian failure; or 
c. Achieved postmenopausal status, defined as follows: cessation of regular 
menses for at least 12 consecutive months with no alternative pathological or 
physiological cause  
6. Diagnosis of primary-open angle glaucoma (including pigmentary or 
pseudoexfoliative) or ocular hypertension and requires treatment in both eyes. 
7. Adequate wash-out period prior to baseline of any ocular hypotensive medication (see 
Table 1). In order to minimize potential risk to patients due to intraocular pressure 
(IOP) elevations during the washout period, the investigator may choose to substitute 
a parasympathomimetic or carbonic anhydrase inhibitor in place of a 


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sympathomimetic, alpha-agonist, beta-adrenergic blocking agent, or prostaglandin; 
however, all patients must have discontinued all ocular hypotensive medication for 
the minimum washout period provided in Table 1.  
8. Baseline (Day 1/hour 0) IOP 22 mmHg and 34 mmHg in both eyes and 5 mmHg 
IOP difference between eyes. 
9. Screening and Baseline/Visit 1 BCVA equivalent to 20/200 or better in each eye. 
10. Negative urine pregnancy test at screening and baseline for women of childbearing 
potential. 
8.2 
Subject Exclusion Criteria 
Subjects with any of the following characteristics/conditions will not be included in the 
study: 
1. Subjects who are investigational site staff members directly involved in the conduct 
of the study and their family members, site staff members otherwise supervised by the 
investigator, subjects who are Sponsor employees directly involved in the conduct of 
the study, or household members of current subjects in the study. 
2. Subjects participating in any clinical investigation within 30 days prior to Screening.  
3. Any severe, acute, or chronic medical or psychiatric condition that may increase the 
risk associated with the study participation or investigational product administration 
or could interfere with the interpretation of study results and, in the judgment of the 
investigator, could make the patient inappropriate for entry in to this study.   
4. Pregnant female subjects; breastfeeding female subjects; male subjects with partners 
currently pregnant; male subjects able to father children and female subject of 
childbearing potential who are unwilling or unable to use highly effective method of 
contraception as outlined in this protocol for the duration of the study and for at least 
28 days after the last dose of investigational product. 
5. Current or past history of severe hepatic or renal impairment. 


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6. Current or history within two months prior to baseline of significant ocular disease 
(eg, macular degeneration, hypertensive retinopathy, diabetic retinopathy, corneal 
edema, uveitis, ocular infection, or ocular trauma in either eye) that may increase the 
risk associated with the study participation or investigational product administration 
or could interfere with the interpretation of study results and, in the judgment of the 
investigator, could make the patient inappropriate for entry in to this study.   
7. Current corneal abnormalities or any condition that would prevent accurate IOP 
readings with the Goldmann applanation tonometer. 
8. Functionally significant visual field loss in either eye, measured within 6 months 
prior to screening. 
9. At the screening visit, advanced glaucoma defined by both a horizontal and vertical 
cup/disc ratio >0.8 in either eye.  
10. Contraindiction to brinzolamide or sulfonamide therapy or known hypersensitivity to 
any component of brinzolamide or sulfonamide therapy. 
11. Use at any time prior to baseline of an intraocular corticosteroid implant. 
12. Use within one week prior to baseline of contact lenses. 
13. Use within two weeks prior to baseline of: 1) topical ophthalmic corticosteroid; 2) 
topical corticosteroid; 3) systemic corticosteroid, or 4) high dose salicylate therapy 
(defined as stable daily doses exceeding 325 mg aspirin or equivalent) 
14. Use within six months prior to baseline intravitreal or subtenon injection of 
ophthalmic corticosteroid. 
15. Intraocular or refractive surgery (eg, cataract surgery, LASIK, etc.) within six 
months prior to Screening. 
16.  IOP lowering surgery (eg, Trabeculectomy, Laser trabeculoplasty, tube shunts, etc.) 
within 12 months prior to baseline. 
17. History of severe dry eye in either eye. 
18. Persons with Central Corneal Thickness (CCT) >600um in either eye. 


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19. Anticipate the need to initiate or modify medication (systemic or topical) that is 
known to affect IOP or blood pressure (eg, adrenergic antagonists, -adrenergic 
agonists, calcium channel blockers, angiotensin-converting enzyme (ACE) 
inhibitors, and angiotensin II receptor blockers) during the study period. 
20. Subjects with very narrow angles (3 quadrants with less than Grade 2 according to 
Shaffer's anterior chamber angle grading system) and subjects with angle closure, 
congenital, and secondary glaucoma, and subjects with history of angle closure in 
either eye. 
21. Subjects with known or suspected drug or alcohol abuse. 
8.3 
Subject Withdrawal Criteria 
Withdrawal of consent: Subjects who wish to discontinue study treatment will remain in the 
study and must continue to be followed for protocol specified follow-up procedures. The 
only exception to this is when the subject specifically withdraws consent for any further 
contact with him or her or any persons previously authorized by the subject to provide 
information. Subjects are completely free to refuse to enter the study or to withdraw at any 
time, without giving a reason. The withdrawal of consent should be explained in detail in the 
medical records of the investigator, as to whether the withdrawal is only from further 
treatment of investigational product or also from study procedures and/or post treatment 
study follow-up, and entered on the appropriate CRF page. In the event that vital status 
(whether the subject is alive or dead) is being measured, publicly available information 
should be used to determine vital status only as appropriately directed in accordance with 
local law. 
 
For subjects that are lost to follow-up, all reasonable efforts must be made to locate subjects 
to determine and report their ongoing status. This includes follow-up with persons authorized 
by the subject as noted above. Prior to discontinuing a subject, every effort should be made to 
contact the subject, schedule a final study visit, obtain as much follow-up data as possible, 
and to retrieve all study materials. All attempts should be documented in the subject’s 
medical records. If it is determined that the subject has died, the site will use permissible 


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local methods to obtain the date and cause of death. If the investigator’s use of a third-party 
representative to assist in the follow-up portion of the study has been included in the 
subject’s informed consent, then the investigator may use a sponsor-retained third-party 
representative to assist site staff with obtaining the subject’s contact information or other 
public vital status data necessary to complete the follow-up portion of the study. The site 
staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information. If, after all attempts, 
the subject remains lost to follow-up, then the last-known-alive date as determined by the 
investigator should be reported and documented in the subject’s medical records. 
 
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety or behavioral 
reasons, or the inability of the subject to comply with the protocol required schedule of study 
visits or procedures at a given study site. 
 
Subjects whose condition worsens (eg, IOP 36 mmHg in either eye) and require alternate or 
supplemental therapy for the treatment of their primary open angle glaucoma or ocular 
hypertension during the study should be discontinued from the study, excluded from the per-
protocol population analysis, and provided with effective treatment. 
 
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject. All attempts to contact the subject and information received during contact attempts 
must be documented in the subject’s medical record. In any circumstance, every effort should 
be made to document subject outcome, if possible. The investigator should inquire about the 
reason for withdrawal, request that the subject return all unused investigational product(s), 
request that the subject return for a final visit, if applicable, and follow up with the subject 
regarding any unresolved AEs. Where possible, the same assessments as Day 42 (Section 
(11.1.5), should be completed if the subject withdraws from the study early. If the subject 
withdraws from the study, and also withdraws consent for disclosure of future information, 
no further evaluations should be performed, and no additional data should be collected. The 
sponsor may retain and continue to use any data collected before such withdrawal of consent. 


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9 
Treatment Plan 
9.1 
Study Treatments 
For the purpose of this study, and per International Conference on harmonization (ICH) 
guidelines investigational product is defined as a pharmaceutical form of an active ingredient 
or placebo being tested or used as a reference in a clinical trial, including a product with a 
marketing authorization when used or assembled (formulated or packaged) in a way different 
from the approved form, or when used to gain further information about an approved use 
(ICH E6 1.33). 
9.1.1 
Methods of Assigning Subjects to Treatment Groups 
Subjects who meet all inclusive/exclusive criteria will be randomized to receive the generic 
brinzolamide 1% suspension or brinzolamide 1% suspension (AZOPT®) using computer 
generated, block treatment assignments in a 1:1 ratio stratified by investigational site. 
Arm 1: One eye drop of the generic brinzolamide 1% ophthalmic suspension in 
each eye at approximately 8:00 AM, 4:00 PM and 10:00 PM Daily 
Arm 2: One eye drop of brinzolamide 1% ophthalmic suspension (AZOPT®) in 
each eye at approximately 8:00 AM, 4:00 PM and 10:00 PM Daily 
 
Allocation of subjects to treatment groups will proceed through the use of a randomization 
and supply management  system (Oracle Randomization and Supply Management System 
[ORS]) (interactive Web-based response [IWR]). The site personnel (study coordinator or 
specified designee) will be required to enter or select information including but not limited to 
the user’s identification (ID) and password, the protocol number, the subject number and the 
date of birth of the subject. The site personnel will then be provided with a treatment 
assignment and Kit Number or container number when drug is being supplied via the ORS 
system. The ORS system will provide a confirmation report containing the subject number  
or container number assigned. The confirmation report must be stored in the site files.  


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There is a 24-hour-a-day, 365-days-a-year ORS helpdesk available for any questions or 
issues. The study specified ORS reference manual will provide the contact information and 
further details on the use of the ORS system. 
Note: The ORS is the source of the subject number. The ORS system will provide 
the subject number at the end of the first ORS subject transaction.  
9.1.2 Treatment Replacement  
In the event that a subject’s original container is lost, damaged, or consumed prior to the end of 
treatment, the Investigator will use the ORS, which will specify a new Kit Number to be 
dispensed to that subject from the supplies already available at the site.  
9.2 
Masking  
The study subject, investigational staff, investigator, and sponsor personnel will be masked 
with respect to treatment group. The investigational site will employ procedures to avoid 
accidental unmasking of the masked staff. A sealed copy of the randomization scheme will 
be retained at the investigational site and will be available at the time of the site inspection to 
allow for verification of the treatment identity of each subject. 
Masking codes should be broken only in emergency situations for reasons of subject safety. 
Whenever possible, the investigator or sub-investigator will consult with a member of the 
study team prior to breaking the mask. When the masking code is broken, the reason must be 
fully documented. At the initiation of the study, the study site will be instructed on the 
method for breaking the masking. The method will either be a manual or an electronic 
process.  
9.3 
Concomitant Medications 
Subjects must abstain from the concomitant medications prohibited in the Exclusion Criteria 
(Section 8.2) of this protocol. 
 
All medications taken during the study must be recorded with indication, daily dose, and start 
and stop dates of administration. All subjects will be questioned about concomitant 
medications at each clinic visit.  


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Subjects who anticipate the need to initiate or modify medication (systemic or topical) that is 
known to affect IOP or blood pressure (BP) (eg, ß-adrenergic antagonists, α-adrenergic 
agonists, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, and 
angiotensin II receptor blockers) during the study period should not be enrolled.  
 
The following prescription and over-the-counter drug products, procedures, and activities are 
prohibited during the study: 
 
 Ocular hypotensive drug product other than study treatment, eg, acetazolamide 
(Diamox®), betaxolol (Betoptic®, Betopic-S®), betaxolol and pilocarpine 
(Betoptic® Pilo), bimatoprost (Lumigan®), brimonidine tartrate (Alphagan®, 
Alphagan® P), brimonidine tartrate and brinzolamide (Simbrinza®), brimodidine 
tartrate and timolol maleate (Combigan®), carbachol (Miostat®), carteolol 
(Ocupress®), dorzolamide hydrochloride (Trusopt®), dorzolamide hydrochloride 
and timolol maleate (Cosopt®), epinephrine (Epifrin®), latanoprost (Xalatan®), 
levobetaxolol (Betaxon®), levobunolol (Akbeta®, Betagan®), mannitol 
(Osmitrol®), metipranolol (OptiPranolol®), pilocarpine (Isopto® Carpine, Pilopine 
HS®), tafluprost (ZioptanTM), timolol (Betimol®, Istalol®, Timoptic®, Timoptic 
XE®), travoprost (Travatan®, Travatan Z®); 
 Ophthalmic over-the-counter or prescription product, other than study treatment and 
the occasional use of artificial tears; 
 Oral carbonic anhydrase inhibitor; 
 High-dose salicylate therapy; defined as stable daily doses exceeding 325 mg aspirin 
or equivalent 
 Topical Corticosteroid  
  Systemic corticosteroid; 
 Topical ophthalmic corticosteroid; 
 Intraocular corticosteroid implant; 
 Intravitreal or subtenon injection of ophthalmic corticosteroid; 


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 Marijuana (any form) 
 Change in concurrent treatment or initiation of treatment with agents potentially 
affecting IOP, eg, antihypertensive medication; 
 Ocular surgery during the study. 
Administration of all medications used up to 30 days prior to study entry (date ICF signed) 
through study exit must be recorded in the source documentation and in the Concomitant 
Medications eCRF. Indications for these medications should be recorded in the subject's 
Medical History eCRF, as applicable. 
9.4 
Treatment Compliance 
Subjects should be instructed that if they miss a dose, this should be recorded in their dosing 
diary and discussed with the investigational site personnel at the next contact or visit. 
Subject’s knowledge and understanding of the dosing diary completion must be verified 
before the subject leaves the investigator site at each visit. 
Compliance of outpatient dosing will be assessed by site personnel at Day 14, Day 21, and 
Day 42 by review of the subject’s dosing diary. 
The dosing diary along with the investigational product, in its masked external packaging, 
will be collected from the subject at Visit 3 and also at the end of the subject’s participation 
in the study. 
9.5 
Protocol Deviations  
A deviation from the protocol is an unintended and/or unanticipated departure from the 
procedures and/or processes approved by the sponsor and the IRB/IEC and agreed to by the 
investigator. Deviations usually have an impact on individual patients or a small group of 
patients and do not involve inclusion/exclusion or primary endpoint criteria.  
The investigator or designee must document and explain in the patients’ source 
documentation any deviation from the approved protocol. The investigator may implement a 
deviation from, or a change of, the protocol to eliminate an immediate hazard to study 
patients without prior IRB/IEC approval. As soon as possible after such an occurrence, the 


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implemented deviation or change, the reasons for it, and any proposed protocol 
amendment(s) should be submitted to the IRB/IEC for review and approval, to the sponsor 
for agreement, and to the regulatory authorities, if required. 
10 
Study Drug Materials and Management 
All study medication will be dispensed by the pharmacy or an appropriately qualified 
member of the study staff assigned by the investigator to this task. 
10.1 Brinzolamide 1% Suspension  
10.1.1 
Packaging and Labeling 
The generic brinzolamide 1% suspension and brinzolamide 1% suspension (AZOPT®) will 
be provided by the Sponsor as 10 mL topical ophthalmic solutions. Each mL of the generic 
brinzolamide 1% suspension and Brinzolamide 1% suspension (AZOPT®) contains 10 mg of 
brinzolamide (1% w/v) and one drop of each medication (approximately 0.03 ml) contains 
approximately 0.3 mg of brinzolamide. The generic brinzolamide 1% suspension and 
brinzolamide 1% suspension (AZOPT®) will be supplied in eyedropper bottles that are in 
masked external packaging. Investigational product will be dispensed on Day 1 and on Day 
21. Investigational product will be labeled according to local regulatory requirements with 
appropriate dosing and storage information as well as a unique container number that will be 
used to assign the medication to the subject according to their treatment assignment. 
Investigational product will be supplied in sufficient quantities to allow unopened containers 
to be kept as bioequivalence retains.  Bioequivalence retains should be stored in accordance 
with protocol-specified requirements for at least 5 years following the date on which the 
application or supplemental application is approved, or, if such application or supplemental 
application is not approved, at least 5 years following the date of completion of a 
bioavailability or bioequivalence study. The quantity and storage of bioequivalence retains 
will be outlined in separate instructions to the site. 


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10.1.1.1 
Retention of Study Drug Samples 
At the time of receipt of the investigational product by the investigator, the sponsor will 
specify the appropriate number of containers or units to select for retention by the 
investigator. The total amounts of reserve samples will, at a minimum, be equivalent to five 
times the quantity of investigational product (test product and reference product) required for 
release testing. The total amount of reserve samples will be divided among all study sites 
participating in this study. The number of retain samples per site is subject to change, if the 
total number of sites change. 
 
The sponsor will also specify the conditions of sample storage, the required duration of 
sample retention and the provisions for returning the investigational product. When retention 
samples are selected, containers or units should be placed in packaging with a tamper evident 
seal. The packaging should be clearly identified as to its content (that it contains retention 
samples) and the investigational product should be stored in a restricted area with limited 
access. 
10.1.2 
Storage, Handling, and Disposal of Study Drug  
The investigator, or an approved representative, eg, pharmacist, will ensure that all 
investigational products, including any comparator and/or marketed products, are stored in a 
secured area with controlled access under required storage conditions in accordance with 
applicable regulatory requirements. 
All investigational product must be stored at 4º to 30ºC (39-86 ºF) in accordance with the 
conditions specified on the study label. The storage location at the clinical site must have 
limited access, available to study site personnel only. Subjects must be instructed regarding 
proper storage. Investigational product should be stored in its original container and in 
accordance with the label.  
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated and/or room temperature products) for business 
days only. This should be captured from the time of investigational product receipt 


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throughout the study. Even for continuous monitoring systems, a log or site procedure that 
ensures active daily evaluation for excursions should be available. The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure it is maintained in working order. 
Any excursions from the investigational product label storage conditions should be reported 
upon discovery. The site should actively pursue options for returning the investigational 
product to the storage conditions as described in the labeling, as soon as possible. Deviations 
from the storage requirements, including any actions taken, must be documented and 
reported to the sponsor. Once an excursion is identified, the investigational product must be 
quarantined and not used until the sponsor provides documentation of permission to use the 
investigational product.  
Specific details regarding information the site should report for each excursion will be 
provided to the site.  
Receipt of materials, door opening and closing, and other routine handling operations where 
the investigational product is briefly out of the temperature range described in the labeling 
are not considered excursions. More specific details will be provided to the sites separately in 
an investigational product manual or equivalent, including storage conditions and actions to 
be taken when conditions are outside the specified range. 
Investigational site staff will instruct subjects on the proper storage requirements for take 
home investigational products. 
Retention samples of investigational product will be stored in accordance with Sponsor 
procedures and FDA regulations. 
10.1.3 
Study Drug Preparation and Dispensing  
Investigational product should not be used more than 28 days after opening. It will be 
dispensed using ORS on Day 1 and Day 21 to ensure the subject has a sufficient amount of 
investigational product for the duration of treatment. A qualified and experienced member of 
the investigational site staff will dispense the investigational product in masked external 
packaging provided throughout the course of dosing. Investigational site staff must not be in 


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the room whenever the treatment is taken out of the masked external packaging.  The bottle 
that is dispensed on Day 1 will be returned to the site in the masked external packaging on 
Day 21(Visit 3), at which time a second bottle (again, in masked external packaging) will be 
dispensed to the subject; unused investigational product that was dispensed on Day 21 must 
be returned in the masked external packaging at the end of the Day 42 (Visit 4)(eg, after all 
assessments are performed). Note: The subject should also bring their bottle to Visit 2 for 
purposes of the in-office dose. 
10.1.4 
Administration 
Administration instructions should be followed, which are on the investigational product 
label. 
Each dose of investigational product (one eye drop) will contain 0.3 mg brinzolamide in 
either the generic brinzolamide 1% suspension or brinzolamide 1% suspension (AZOPT®). 
One drop of investigational product should be instilled in each eye at approximately 8:00 
AM, 4:00PM, and 10:00PM daily.On Day 1, the first day of dosing, only the 4pm and 
10:00PM should be administered. On Day 42, the last day of dosing, only the 8:00AM dose 
is administered.  
Subjects will self-administer investigational product daily on an outpatient basis; however, 
on Day 14, Day 21, and Day 42 the 8:00AM dose will be self-administered at the 
investigational site, following the 8:00AM IOP. The dose must be self-administered in a 
secluded room without any investigational site staff present within 30 minutes of 8:00 AM. 
Investigational site staff must not be in the room whenever the treatment is taken out of the 
masked external packaging or the subject is dosed with investigational product.  
Subject knowledge and understanding of the dosing requirements must be verified before the 
subject leaves the investigator site at each visit.  
10.2 Study Drug Accountability 
The investigative site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies, Unused investigational product that 
was dispensed on Day 1 must be returned in the masked external packaging to the 


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investigator at the Day 21 visit at which time another bottle (again, in masked external 
packaging) will be dispensed to the subject; unused investigational product that was 
dispensed on Day 21 must be returned in the masked external packaging at the end of the 
Day 42 visit (eg, after all assessments are performed and 8:00AM dose is instilled). The 
investigational site will employ procedures to avoid accidental unmasking of the masked 
staff. Investigational product accountability will be discussed in the study monitoring plan.  
At various time points throughout the study and/or upon completion of the study, Valeant or 
representative of Valeant will review and verify the Investigator's accountability records. 
Following verification, and as directed by Valeant, all used and unused product must be 
returned to Valeant at the addresses below, or with Valeant’s permission, disposed of at the 
site in an appropriate manner. 
10.3 Destruction of Investigational Product Supplies 
Following verification of investigational product accountability, and as directed by Sponsor, 
all used and unused product must be returned to 
 
, or with the Sponsor’s 
permission, disposed of at the site in an appropriate manner.  
11 
Study Procedures and Evaluations 
11.1 Schedule of Evaluations and Procedures 
11.1.1 
Screening Visit 
Subjects will be screened from 4 to 42 days prior to administration of investigational product 
to confirm that they meet the subject selection criteria for the study. If the time between 
screening and dosing exceeds 6 weeks as a result of unexpected operational delays (eg, 
delayed drug shipment), then subjects do not require re-screening if at the baseline visit (Day 
1) the patient meets the eligibility criteria.  
The following procedures will be completed: 
 Obtain informed consent; 


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 Obtain Subject Specific Identification  
 Review inclusion/exclusion criteria; 
 Collect demography; 
 Complete medical history; 
 Complete history of all prescription or nonprescription drugs, and dietary 
supplements taken within 30 days prior to signing the ICF; 
 Blood pressure/pulse rate (sitting for 5 minutes); 
 Visual field testing; if performed within 6 months (183 days) prior to screening 
and was documented in subject’s records, no additional visual field testing is 
necessary  
 Refraction 
 Best corrected visual acuity; 
 Collect Iris color: blue, brown, gray, green, hazel, or specify other; 
 Biomicroscopy  
 IOP 
 Ophthalmoscopy  
 Pachymetry  
 Gonioscopy: (must use anesthesia): if performed within 6 months (183 days) prior 
to screening and was documented in subject’s records, no additional screening 
gonioscopy examination is necessary  
 Urine hCG for all females of childbearing potential; 
If the subject meets the inclusion criteria: 
 Discontinue topical and/or systemic ocular antihypertensives; 


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 Schedule the subject to return in 4 to 42 days (depending on washout time 
necessary for previous ocular hypotensive medication(s), Table 1, for the 
eligibility visit, Baseline (Day 1). 
 Record any AEs that occur from the time the subject signs the ICF  
 
To prepare for study participation, subjects will be instructed on use of Concomitant 
Medications (Section 9.3). 
11.1.2 
Visit 1 (Day 1) 
Subjects must continue to satisfy all inclusion/exclusion criteria in order to be eligible for 
randomization. 
The following procedures will be completed: 
 Re-check inclusion/exclusion criteria (only those eligibility criteria that apply at Day 
1); 
 Review prior/concomitant treatments; 
 Blood pressure/pulse rate (sitting); 
 Best corrected visual acuity; 
NOTE: Refraction must be performed if a decrease in VA of two or more lines from the 
previous assessment occurs. 
 Biomicroscopy  
 IOP at 8:00 AM ± 30 minutes and 10:00 AM ± 30 minutes; 
 Ophthalmoscopy  
 Assess and record adverse events (AEs); 
 Urine hCG for all females of childbearing potential; 
 Randomize the subject to a treatment group; 


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 To prepare for study participation, subjects will be instructed on the use of 
Concomitant Medications (Section 9.3); 
 Dispense dosing diary and instruct subject on completion; 
 Dispense investigational product in masked external packaging and instruct subject 
on self-administration, storage, and return. 
 First dose will be self-administered at 4pm, then followed by 10pm dose. 
 
11.1.3 
Visit 2 (Day 14) 
The following procedures will be completed on Day 14 ±4 days: 
 Review concomitant treatments; 
 Check dosing diary; 
 Blood pressure/pulse rate (sitting for 5 minutes); 
 Best corrected visual acuity; 
NOTE: Refraction must be performed if a decrease in VA of two or more lines from the 
previous assessment occurs. 
 Biomicroscopy; 
 IOP at ±30 minutes of 8:00 AM (prior to 8:00 AM dose of investigational product) 
and 10:00 AM. The 8:00 AM dose must be self-administered within 30 minutes of 
8:00 AM in a secluded room without any investigational site staff present. 
Investigational site staff must not be in the room whenever the treatment is taken out 
of the masked external packaging or the subject is dosed with investigational product. 
Subject knowledge and understanding of the dosing requirements must be verified 
before the subject leaves the investigator site at each visit 
 Ophthalmoscopy  
 Assess and record AEs. 


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11.1.4 
Visit 3 (Day 21) 
The following procedures will be completed on Day 21 ±4 days: 
 Review concomitant treatments; 
 Collect dosing diary, and dispense new dosing diary; 
 Blood pressure/pulse rate (sitting for 5 minutes); 
 Best corrected visual acuity; 
NOTE: Refraction must be performed if a decrease in VA of two or more lines from the 
previous assessment occurs. 
 Biomicroscopy; 
 IOP at ±30 minutes 8:00 AM (prior to 8:00 AM dose of investigational product) and 
10:00 AM. The 8:00 AM dose must be self-administered  within 30 minutes of 8:00 
AM in a secluded room without any investigational site staff present. Investigational 
site staff must not be in the room whenever the treatment is taken out of the masked 
external packaging or the subject is dosed with investigational product. Subject 
knowledge and understanding of the dosing requirements must be verified before the 
subject leaves the investigator site at each visit; 
 Ophthalmoscopy  
 Assess and record AEs; 
 Collect the unused investigational product in the first bottle; 
 Dispense investigational product in masked external packaging and instruct subject 
on the self-administration, storage, and return of product at visit 4. 
11.1.5 
Visit 4 (Day 42) 
The subject has completed the study when Visit 4 (Day 42) has been completed and the 
subject has been exited. Subjects who require further follow-up for an AE will be followed 
according to Section 11.1.6. 
The following procedures will be completed on Day 42 ±4 days: 


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 Review concomitant treatments; 
 Check dosing diary; 
 Collect dosing diary; 
 Blood pressure/pulse rate (sitting for 5 minutes); 
 Best corrected visual acuity; 
NOTE: Refraction must be performed if a decrease in VA of two or more lines from the 
previous assessment occurs. 
 Biomicroscopy; 
 IOP at ±30 minutes 8:00 AM (prior to 8:00 AM dose of investigational product) and 
10:00 AM. The 8:00 AM dose must be self-administered within 30 minutes of 8:00 
AM in a secluded room without any investigational site staff present. Investigational 
site staff must not be in the room whenever the treatment is taken out of the masked 
external packaging or the subject is dosed with investigational product. Subject 
knowledge and understanding of the dosing requirements must be verified before the 
subject leaves the investigator site at each visit; 
 Ophthalmoscopy  
 Assess and record AEs; 
 Urine hCG for all females of childbearing potential; 
 Collect the unused investigational product in the second bottle; 
11.1.6 
Post Study Follow-up Visit 
A post study follow-up telephone call (conducted by the study coordinator or other delegated 
site staff) will occur approximately 28 days ±4 days after the last dose of investigational 
product was taken. All outstanding unresolved adverse events and serious adverse events will 
be followed-up at this time. Concomitant treatments will also be recorded. The follow-up 
telephone call should be noted and documented in the subject’s primary source records. If the 
subject had no new or ongoing adverse events, serious adverse events, or concomitant 


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treatments during this time, this should also be noted and added to the subject’s primary 
source records. Any serious adverse event should be reported to Sponsor within 24 hours. 
 
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator that may make it unfeasible to 
perform a test. In these cases the investigator will take all steps necessary to ensure the safety 
and well-being of the subject. When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible. The 
study team will be informed of these incidents in a timely fashion. 
11.2 Blood Pressure and Pulse 
Blood pressure measurements will be taken using a mercury sphygmomanometer, a recently 
calibrated aneroid manometer, or a validated electronic device. Both systolic and diastolic 
blood pressure should be recorded. The first appearance of sound (phase 1) should be used to 
define systolic blood pressure and the disappearance of sound (phase 5) should be used to 
define diastolic blood pressure. Preferably, the same device should be used throughout the 
study and the same individual should record blood pressure throughout the study. An 
appropriate cuff size with a bladder encircling at least 80 percent of the arm should be used 
to ensure accurate measurement. Blood pressure should be measured in the sitting position 
after the patient has remained seated for at least 5 minutes, using the same arm at each visit. 
 
Pulse measurements will be recorded using a full 60-second count while the patient is in the 
seated position. 
 
Any clinically significant change in blood pressure or pulse measurements, in the 
investigator’s judgment, compared to the screening values should be reported as an adverse 
event. 


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11.3 Visual Fields 
Perform visual fields assessments following the study site’s standard practices. If a visual 
field assessment was performed within 6 months (183 days) prior to screening and is 
documented in subject’s records, no additional screening visual field examination is 
necessary. 
11.4 Best Corrected Visual Acuity 
Preferably, the same visual acuity examiner should perform each best corrected visual acuity 
measurement for a given subject. Best corrected visual acuity (BCVA) will be assessed using 
an Early Treatment Diabetic Retinopathy Study (ETDRS) eye chart (placed at 13 feet or 4 
meters) or equivalent eye chart. BCVA should be performed prior to any exam requiring 
contact with the eye or drops to dilate or anesthetize the eye. If most of the letters are read on 
a line, then that line will be counted. For example, if the patient reads 20/25 +3, 20/20 will be 
recorded. Only the nearest Snellen line will be reported without plus and minus letters. 
 
A decrease in BCVA of 3 lines or more from the screening visit will be reported as an 
adverse event. If visual acuity at screening is better than 20/20, any decrease in visual acuity 
will be calculated from 20/20. 
 
The BCVA will be assessed at all visits as indicated in the Schedule of Activities. 
11.5 Refraction 
At the screening visit, the manifest refraction will be measured and recorded. The sphere will 
be noted, cylinder and axis of the refraction will be recorded. Plano will be recorded as 0.00 
as it applies to the sphere and/or cylinder. Refraction must be performed at subsequent visits 
(1, 2, 3 and/or 4) only if a decrease in visual acuity (VA) of two or more lines from the 
previous assessment occurs.  If refraction must be re-measured due to a decrease in BCVA 
from the previous assessment, the BCVA should also be repeated using the updated 
refraction values.  


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11.6 Iris Color 
At screening, report iris color as blue, brown, gray, green, hazel, or other (with specification). 
All iris colors are desired to be enrolled, and the investigator’s  will not randomize, include 
or exclude subjects based on iris color. 
11.7 Biomicroscopy 
Biomicroscopic examination of the lids, conjunctiva, sclera, cornea, anterior chamber, iris 
and lens will be performed. Anterior chamber inflammation will be graded as follows: 
 
 
 
Examination of the anterior chamber for cells must be performed before either dilation or 
applanation tonometry. The light intensity of the slit lamp is to be turned to the maximum 
tolerated by the patient. 
11.8 Intraocular Pressure 
IOP will be measured by an MD or DO only, using a Goldmann applanation tonometer. Both 
eyes will be tested, with the right eye preceding the left eye. The operator will initially set the 
dial at 10 mmHg, then look through the slit lamp and adjust the dial to take the reading, and 
then record the results. The procedure will be repeated on the same eye twice consecutively. 
If the measurements are within 2 mmHg or less of each other, the mean of the 2 readings will 
be reported as the IOP at that time point. If the 2 readings are more than 2 mmHg apart from 
each other, a third (consecutive) reading will be taken and the median (middle) IOP will be 
reported as the IOP at that time point. Preferably, the same operator will measure IOP and the 
same tonometer will be used at each visit for a given patient. 
11.9 Ophthalmoscopy  
Ophthalmoscopy will be performed at the time points indicated in Table 2, to examine the 
vitreous body, retina, and optic nerve head. Ophthalmoscopic assessments will be recorded 


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as normal or abnormal. Any abnormalities and pathologic findings will be graded as mild, 
moderate, or severe. The cup /disc ratio will be recorded horizontally and vertically for each 
examination, and reported in 0.1 increments. 
Vitreous, Retina, Macula, Choroid: Assess for abnormalities in the retina, macula and 
choroid.  
0 = Normal  
1 = Abnormal  
Optic Nerve: Assess for abnormalities in the optic nerve.  
0 = Normal  
1 = Abnormal  
Cup/Disc Ratio: Assess the cup/disc vertical and horizontal ratio.  
Optic Disc Hemorrhage:  
0 = Absent  
1 = Present  
Rim Loss:  
0 = Absent  
1 = Present  
Retinal Nerve Fiber Layer (RNFL) Defect:  
0 = Absent  
1 = Present 
11.10 Gonioscopy 
Gonioscopy should be performed after application of a topical anesthetic with a low level of 
illumination throughout that is consistent with standard clinical practice. If performed within 
6 months (183 days) prior to screening and was documented in subject’s records, no 
additional screening gonioscopy examination is necessary. Any observation of peripheral 
anterior synechiae should be noted. All four quadrants of the angle (superior, inferior, nasal, 
and temporal) should be evaluated using Shaffer’s anterior chamber angle grading system:  
 
Grade 4 (35°-45°): Ciliary body can be visualized.  
Grade 3 (20°-35°): At least scleral spur can be identified.  


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Grade 2 (20°): Moderately narrow angle in which only the trabeculum can be identified.  
Grade 1 (10°): Very narrow angle in which only the Schwalbe’s line, and perhaps also the 
top of the trabeculum, can be identified.  
Grade 0 (0°): Closed angle resulting from iridocorneal contact. 
11.11 Pachymetry 
Measurements of central corneal thickness will be performed for each participating subject, 
by using a calibrated ultrasonic pachymeter. It should be done after VA, refraction, and slit-
lamp examination. Three measurements should be taken per eye with the subject in the 
sitting position and fixating on a target straight ahead. The probe should be removed from the 
cornea between measurements. All measurements from the right eye should be completed 
before taking any measurements from the left eye. The mean of the 3 recorded central 
corneal thickness measurements should be used to assess subject eligibility, as the mean will 
most likely reflect perpendicular placement of the pachymeter probe. 
12 
Methods and timing for assessing, recording, and analyzing safety 
parameters. 
12.1 Adverse Event Reporting 
12.1.1 
Adverse Events 
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections. 
 
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as a 
serious adverse event (SAE) requiring immediate notification to Sponsor or its designated 
representative. For all AEs, sufficient information should be obtained by the investigator to 
determine the causality of the AE. The investigator is required to assess causality. Follow-up 
by the investigator may be required until the event or its sequelae resolve or stabilize at a 
level acceptable to the investigator, and Sponsor concurs with that assessment. 


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As part of ongoing safety reviews conducted by the sponsor, any non-serious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE. To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study. 
12.1.2 
Reporting Period 
For SAEs, the active reporting period to Sponsor or its designated representative begins from 
the time that the subject provides informed consent, which is obtained prior to the subjects 
participation in the study, eg, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 30 calendar days after the last 
administration of the investigational product. SAEs occurring to a subject after the active 
reporting period has ended should be reported to the Designee/Sponsor if the investigator 
becomes aware of them; but will not be entered on a case report form; at a minimum, all 
SAEs that the investigator believes have at least a reasonable possibility of being related to 
investigational product are to be reported to the Designee/Sponsor. 
12.1.3 
Definition of an Adverse Event  
Adverse Event is defined as any untoward medical occurrence in a subject participating in a 
clinical study which does not necessarily have a causal relationship with the study protocol or 
with the study treatment.  
 Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease with onset following the signing of informed consent through 
study exit, whether or not considered related to the study.  
 An AE can also include a progression/worsening of underlying disease and 
hypersensitivity.  
 Events occurring from drug overdose, whether accidental or intentional, events 
occurring from drug abuse, drug misuse, drug interactions, drug dependency, events 
occurring from drug withdrawal, and medication errors.  


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A Treatment Emergent Adverse Event (TEAE) will be defined as an AE with a start date on 
or after the first dose of study drug, or that worsened following first administration of study 
drug.  
12.2 Serious Adverse Events 
A serious adverse event is any untoward medical occurrence at any dose that: 
 
 Results in death; 
 Is life-threatening (immediate risk of death); 
 Requires inpatient hospitalization or prolongation of existing hospitalization; 
 Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions); 
 Results in congenital anomaly/birth defect. 
 
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event. An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization. However, if it is determined that the event may jeopardize 
the subject, or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious. 
 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse. 
 
A serious injury that can cause a serious deterioration in state of health can include: 
 a life-threatening illness, even if temporary in nature; 
 a permanent impairment of a body function or permanent damage to a body structure; 
 a condition necessitating medical or surgical intervention to prevent the above 2 
bulleted items 


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- 
Examples: clinically relevant increase in the duration of a surgical procedure; a 
condition that requires hospitalization or significant prolongation of existing 
hospitalization; 
 any indirect harm as a consequence of an incorrect diagnostic or in vitro diagnostic 
device test results when used within the manufacturer’s instructions for use; 
 fetal distress, fetal death, or any congenital abnormality or birth defects. 
 
All SAEs, whether related or unrelated to study drug, must be immediately reported to the 
designee within 24 hours of the investigator’s awareness of the event. All SAEs must be 
reported via confirmed email/facsimile transmission and must be submitted on a written SAE 
report form signed by the investigator within 24 hours of the investigator’s awareness of the 
event.  
 The fax number for reporting an SAE is: 
 
  
 
 
 
 
 
 
 
Investigators should not wait to receive additional information to fully document the event 
before notifying Medical Monitor of an SAE. If only limited information is initially 
available, follow-up reports are required. Additional relevant information such as hospital 
records and autopsy reports should be provided to designee as soon as they are available. 
Should the investigator become aware of an SAE (regardless of its relationship to 
investigational product) that occurs within 30 days after stopping the study drug, the SAE 
must be reported in accordance with procedures specified in this protocol.  
The investigator should take all appropriate measures to ensure the safety of the subjects, 
notably he/she should follow a subject with an SAE until the event has resolved or the 
condition has stabilized. This may imply that follow-up will continue after the subject has 
left the study, and that additional investigations may be requested by the sponsor. 
 


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The Designee will review forms and documents for completeness and forward to Sponsor 
within 24hrs of receipt via email:  
 
12.2.1 
Protocol-Specified Serious Adverse Events 
There are no protocol-specified SAEs in this study. All SAEs will be reported by the 
investigator as described in previous sections, and will be handled as SAEs in the safety 
database (see the section on Serious Adverse Event Reporting Requirements). 
12.2.2 
Hospitalization 
Hospitalization is a criterion for assessment of seriousness. If a subject is retained in the 
emergency room greater than 24 hours, but not admitted for medical care, these cases should 
not be considered as “hospital admissions,” but evaluated individually, as criteria such as 
“medically significant” may also apply.  
 
Hospitalization without a medical AE should not be considered either serious, or an AE. 
Examples include:  
 Admission for treatment of a pre-existing condition not associated with the 
development of a new AE or with worsening of the pre-existing condition (eg, for 
work-up of persistent pre-treatment lab abnormality)  
 Hospitalization for a purpose unrelated to the study (eg, "planned" or elective surgery 
scheduled prior to study participation) would not ordinarily need to be reported, 
unless a complication occurred that otherwise caused prolongation of this 
hospitalization  
 Protocol-specified admission or procedure (eg, cataract surgery required by a study 
protocol)  
 Social admission (eg, social hospitalization for purposes of respite care)  
12.2.3 
Severity Assessment 
 


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Note the distinction between the severity and the seriousness of an AE. A severe event is not 
necessarily an SAE. For example, a headache may be severe (interferes significantly with the 
subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above. 
12.3 Causality Assessment 
The investigator’s assessment of causality must be provided for all AEs (serious and non-
serious) Related or Not Related to the study drug; the investigator must record the causal 
relationship in the CRF, as appropriate, and report such an assessment in accordance with the 
SAE reporting requirements if applicable. An investigator’s causality assessment is the 
determination of whether there exists a reasonable possibility that the investigational product 
caused or contributed to an AE; generally the facts (evidence) or arguments to suggest a 
causal relationship should be provided.  The following should be taken into account when 
assessing SAE causality: 
 Positive temporal relationship to study drug, such as if the study drug was withdrawn 
and the SAE resolved or the event recurred after re introduction.  
 If there is a reasonable possibility that the AE is associated with an underlying or 
concomitant illness.  
 Possible association with previous or concomitant therapy.  
 No temporal relationship to the study drug and/or a more likely alternative etiology 
exists.  
 If the AE is directly related to study procedures or there is a lack of efficacy.  
 


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If the investigator does not know whether or not the investigational product caused the event, 
then the event will be handled as “related to investigational product” for reporting purposes, 
as defined by the sponsor (see the section on Reporting Requirements).  
 
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable. 
 
12.4 Exposure during Pregnancy  
In the event that a study subject or a study subject’s partner becomes pregnant, the study site 
should notify the study Medical Monitor and the Global Safety and Vigilance contact within 
24 hours of the time the event was reported to the Investigator, regardless of whether an 
AE/SAE was reported. The study site should also notify the Valeant Study Manager listed in 
the Personnel and Facilities section and the IRB of pregnancy, in accordance with IRB 
requirements. All pregnancies will be followed to term (in the event that a study subject’s 
partner becomes pregnant, permission to follow the pregnancy needs to be granted by the 
partner). Every effort will be made to obtain the health status of the mother and infant or the 
fetus (including cases of miscarriage or therapeutic abortion). 
12.5 Withdrawal Due to Adverse Events 
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page. 
 
When a subject withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below. 


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12.6 Reporting Requirements  
Each AE is to be assessed to determine if it meets the criteria for SAEs. If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate. 
12.6.1 
Serious Adverse Event Reporting Requirements  
Any SAE must be reported to Valeant Global Safety and Vigilance, independent of the 
circumstance or suspected cause, within 24 hours from the time the event was reported to the 
Investigator. All SAEs experienced from the date of consent through approximately 30 days 
after the last dose of study drug or discontinuation from the study must be reported to 
Valeant regardless of the relationship to the study drug. Following the approximately 30-day 
period after the last dose of study drug or discontinuation from the study, or for any 
timeframe afterward deemed medically significant, only SAEs considered related to study 
drug should be reported promptly to Valeant Global Safety and Vigilance.  
Within 24 hours of notification the Investigator will fax a completed Serious Adverse Event 
Report to the Valeant contact noted below. For SAEs with fatal outcomes, a summary of 
available autopsy findings should be submitted as soon as possible.  
12.6.2 
Non-serious Adverse Event Reporting Requirements  
All AEs will be reported on the AE page(s) of the CRF. It should be noted that the form for 
collection of SAE information is not the same as the AE CRF. Where the same data are 
collected, the forms must be completed in a consistent manner. For example, the same AE 
term should be used on both forms. AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information. 
12.6.3 
Sponsor’s Reporting Requirements to Regulatory Authorities  
AE reporting, including suspected unexpected serious adverse reactions will be carried out in 
accordance with applicable local regulations. 
13 
Statistics 
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a statistical analysis plan (SAP), which will be maintained by the 


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sponsor. The SAP may modify the plans outlined in the protocol; however, any major 
modifications of planned analyses will be reflected in a protocol amendment if it is modified 
before data unmasking.  
13.1 Sample Size Determination 
The sample size was determined to assess the bioequivalence of the generic brinzolamide 1% 
suspension compared to brinzolamide 1% suspension (AZOPT®) in patients with primary 
open angle glaucoma or ocular hypertension. Based on the IOP lowering effect of the generic 
brinzolamide 1% suspension and brinzolamide 1% suspension (AZOPT®) observed in the 
previous study performed by InnoPharma,6  a mean treatment difference of 0 mmHg, a 
standard deviation of 3.3 mmHg and a correlation coefficient of 0.565 between any 2 
different follow-up time points was assumed for the sample size calculation. To confirm the 
lower and the upper bounds of the two-sided 95% confidence interval (CI) of the treatment 
difference are within the range of ±1.0 mmHg for at least 3 (out of 4) follow-up time points 
(at approximately 8:00 AM and 10:00 AM on days 14 and 42), and to confirm that the lower 
and the upper bounds of the two-sided 95% CI of the treatment difference at all 4 follow-up 
time points are within ±1.5 mmHg, a minimum number of 280 evaluable subjects for each 
treatment group will be needed to achieve 90% power. To account for 10% attrition, a total 
of 624 subjects (312 per group) will need to be randomized.  
13.2 Efficacy Analysis  
13.2.1 
Analysis of the Primary Endpoint  
The primary endpoint is the mean difference in IOP of both eyes between the two treatment 
groups at four time points, eg, at approximately 8:00 a.m. (hour 0; before the morning drop) 
and 10:00 a.m. (hour 2) at the Day 14 (week 2) and Day 42 (week 6) visits. The endpoint will 
be analyzed using the per-protocol population, which will include all randomized subjects 
who meet all inclusion/exclusion criteria, instilled 75% to 125% of the planned doses for the 
entire duration of the study, as verified by patient diaries, and who did not miss the scheduled 
applications for more than 3 consecutive days, and completed evaluations at Day 14 and Day 


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42 within the designated visit window (± 4 days) with no protocol deviations that would 
affect the treatment evaluation. 
 
In addition to the deviations described in the previous paragraph, the following protocol 
deviations will be considered important and will result in exclusion from the per-protocol 
population. 
 Use of the wrong treatment (eg, misrandomization) 
 Use of prohibited prescription and over-the-counter drug products, procedures, and 
activities as outlined in Section 9.3 
 Raised IOP requiring treatment, defined as subjects whose condition worsens (eg, 
IOP 36 mmHg in either eye) and who require alternate or supplemental therapy for 
the treatment of their primary open angle glaucoma or ocular hypertension during the 
study 
 Additional criteria may be added prior to unmasking of the treatment assignments 
 
In order to establish equivalence of the two treatments: 
 
1. The limits of each two-sided 95% CI of the treatment difference (test – reference) for 
mean IOP of both eyes (continuous variable) at all four follow-up points [(eg, at 
approximately 8:00 AM (hour 0; before the morning drop) and 10:00 AM (hour 2) at 
the Day 14 (week 2) and Day 42 (week 6) visits] must be within ± 1.5 mm Hg; and 
 
2. For the majority of the time points [3 out of 4 follow-up time points; eg, at 
approximately 8:00 AM (hour 0; before the morning drop) and 10:00 AM (hour 2) at 
the Day 14 (week 2) and Day 42 (week 6) visits)] measured, the limits of each two-
sided 95% CI of the difference in the mean IOP of both eyes between the two 
treatment groups must be within ± 1.0 mmHg 
 
The point estimates of the differences between the two treatment groups and the two-sided 
95% CIs will be presented. Since both of the above conditions have to be satisfied to 


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establish equivalence, the type I error (α), will not be adjusted to account for multiple 
comparisons. 
13.3 Safety Analysis 
The safety and tolerability of the generic brinzolamide 1% suspension and brinzolamide 1% 
suspension (AZOPT®) will be evaluated by monitoring of blood pressure and pulse, 
ophthalmic exams (BCVA, refraction, biomicroscopy, and ophthalmoscopy), and monitoring 
of adverse events. 
 
The “Safety Analysis Set” will include all subjects who receive at least 1 dose of study 
medication. Safety data will be summarized and presented in tabular and/or graphical format. 
 
In addition to standard safety displays, a 3-tier approach will be used to summarize AEs. 
Under this approach, AEs are classified into 1 of 3 tiers. Subjects in the Safety Analysis Set 
will have their safety data included in the tiered analysis below. There are no Tier-1 events 
for this study; only Tier-2 and Tier-3 events will be reported. 
 
 Tier-2 events: These are events that are not tier-1 but are “common”. A MedDRA 
Preferred Term (PT) is defined as a tier-2 event if there at least ≥ 5% of patients in 
any treatment group reporting an event. 
 
 Tier-3 events: These are events that are neither tier-1 nor tier-2 events. 
 
Tier-2 events will be reported using risk difference and 95% CI; tier-3 events will be reported 
using frequency tables. 
 
For all other safety endpoints, continuous variables will be summarized using means, 
standard deviations, median, minimum, and maximum. Categorical variables will be 
summarized using frequencies and percentages. 
 


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13.4 Data Monitoring Committee  
This study will not use a data monitoring committee.  
14 
Quality Control and Quality Assurance 
Sponsor or its agent will conduct periodic monitoring visits during study conduct to ensure 
that the protocol and Good Clinical Practices (GCPs) are being followed. The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate. The 
investigator and institution will allow Sponsor monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification. This 
verification may also occur after study completion. 
 
During study conduct and/or after study completion, the study site may be subject to review 
by the institutional review board (IRB)/ethics committee (EC), and/or to quality assurance 
audits performed by Sponsor, or companies working with or on behalf of Sponsor, and/or to 
inspection by appropriate regulatory authorities. 
 
The investigator(s) will notify Sponsor or its agents immediately of any regulatory inspection 
notification in relation to the study. Furthermore, the investigator will cooperate with 
Sponsor or its agents to prepare the study site for the inspection and will allow Sponsor or its 
agent, whenever feasible, to be present during the inspection. The investigator will promptly 
provide copies of the inspection findings to Sponsor or its agent. Before response submission 
to the regulatory authorities, the investigator will provide Sponsor or its agents with an 
opportunity to review and comment on responses to any such findings. 
 
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process. 


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14.1 Study Monitoring  
An Investigator Meeting or an initiation visit will be conducted with the principal 
investigator and study coordinators by sponsor and/or its designee. During this meeting, an 
extensive review and discussion of the protocol, the role of the study technician, all study 
procedures, source documents, and eCRFs will be conducted. 
 
The study monitors/clinical research associates will be trained prior to study initiation. 
Following this training, an overview of the study disease and study material background will 
be understood. Specific monitoring guidelines and procedures to be followed during 
monitoring visits will also be utilized. During the course of the study, all data will be 100% 
source document verified by the monitors. All subject source records must be made available 
to the monitors. 
 
The conduct of the study will be closely monitored by the sponsor following GCP guidelines. 
The reports of these verifications will also be archived with the study report. In addition, 
inspections or on site audits may be carried out by local authorities or by the sponsor's 
Quality Assurance Department. The investigators will allow the sponsor's representatives and 
any regulatory agency to examine all study records, corresponding subject medical records, 
clinical dispensing records and storage area, and any other documents considered source 
documentation. The investigators agree to assist the representative, if required. 
14.2 Audits and Inspections  
Audits of clinical research activities in accordance with the Valeant’s internal Standard 
Operating Procedures (SOPs) to evaluate compliance with the principles of GCP may take 
place. A regulatory authority may also wish to conduct an inspection (during the study or 
after its completion). If an inspection is requested by a regulatory authority and/or IRB/EC, 
the Investigator must inform the Sponsor immediately that this request has been made. 
14.3 Data Quality Assurance 
All assessments performed will be accurately documented in the subject’s source documents 
and eCRFs. The investigator or designee will enter the information required by the protocol 


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into the source documents and eCRFs provided by the sponsor or designee. Subjects will be 
identified in the eCRFs by their assigned subject number and initials only. 
 
The investigators must read the protocol thoroughly and must follow the instructions exactly. 
Any deviations should be agreed to by prior discussion between the sponsor and the 
investigator, with appropriate written protocol amendments made prior to implementing the 
agreed changes. Any amendment containing major modifications (particularly if it may 
involve an increased risk to the subjects) will be approved by the IRB before it may be 
implemented. No change in the conduct of the study can be instituted without written 
approval from the sponsor. 
15 Data Handling and Record Keeping 
15.1 Inspection of Records 
Investigators must maintain detailed records on all study subjects who are enrolled in the 
study or undergo screening. Data will be recorded in the subject’s source documents and in 
applicable study logs provided by the sponsor. Source documents include subject medical 
records, hospital charts, clinic charts, investigator subject study files, as well as the results of 
diagnostic tests (eg, laboratory tests). All required data should be recorded in the study 
documentation completely for prompt data review. Upon study completion or at any other 
time specified by the sponsor or designee, the appropriate study documents must be 
submitted. 
 
The investigator must keep accurate separate records (source documentation) of all subject 
visits, being sure to include all pertinent study related information. At a minimum, this 
includes the following information: 
 
A statement indicating that the subject has been enrolled in the study and the subject 
number 
 
Date that informed consent was obtained 
 
Evidence that the subject meets study eligibility requirements (eg, medical 
history, screening evaluations) 


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 
Dates of all study related visits and results of any evaluations/procedures 
performed, including who performed each assessment at each visit 
 
Use of any concurrent medications during the study 
 
Documentation of study drug accountability 
 
Any and all side effects and AEs must be thoroughly documented to conclusion 
 
Results of any diagnostic tests conducted during the study 
 
The date the subject exited the study and a statement indicating that the subject 
completed the study or was discontinued early, including the reason for   
discontinuation 
Notes describing telephone conversations and all electronic mail with the subject or the 
sponsor (sponsor’s designee) concerning the study must be recorded or kept on file. All 
source documents must be made available to the sponsor and the sponsor’s designated 
monitor upon request. 
15.2 Record Retention 
Subject data recorded on eCRFs during the study will be documented in a coded fashion. The 
subject will only be identified by the subject initials,  subject number, and year of birth. 
Confidentiality of subject records must be maintained to ensure adherence to applicable local 
privacy regulations.  
 
The Investigator must retain essential documents indefinitely after the completion of the 
study, unless otherwise notified by Valeant. The Investigator agrees to adhere to the 
document retention procedures when signing the protocol Investigator Statement of 
Approval.  
 
Essential documents include but are not limited to the following:  
• IRB/EC approvals for the study protocol, all amendments, ICF(s), and advertisements  
• IRB/EC annual study review, if applicable  
• IRB/EC correspondence and reports (eg, SAE reports, protocol deviations, and safety 
updates)  


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• Regulatory documents (eg, financial disclosure and delegation of authority forms)  
• All source documents  
• Archive of eCRFs  
• Subject’s signed ICF  
• FDA Form 1572 (or equivalent forms)  
• Accountability records for the study drugs  
• Correspondence from and to Valeant   
• Any other documents relevant to the conduct of the study  
 
In the event that the Investigator withdraws from the study (eg, retirement, relocation), study 
records will be transferred to a mutually agreed upon designee (eg, another Investigator, site 
IRB/EC). The Investigator will provide notice of such transfer in writing to Valeant  Global 
Clinical Operations. 
16 Ethics 
16.1 Institution Review Board/Ethics Committee 
In the US, the Investigator, or in the EU, Valeant or legal representative, should ensure that 
participation in the study, in addition to the protocol, subject recruitment materials (written 
information or materials including web pages, radio advertisements, television spots or 
written text developed to encourage subject enrollment) and the ICF to be used in this study 
are approved by their institution IRB/EC, or if not using their institution's IRB/EC, approved 
by the reviewing central IRB/EC prior to entering any subjects in the study. Documentation 
of IRB/EC approval of the study protocol and informed consent must be provided to Valeant 
prior to initiation of the study. In addition, in the US, the Investigator, or in the EU, Valeant 
or legal representative, must ensure that the reviewing IRB/EC has provided approval for any 
protocol amendments prior to implementation. If the amendment necessitates a revision to 
the ICF, the Investigator should ensure the revised form is also submitted to and approved by 
Valeant and the IRB/EC prior to implementation.  


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16.2 Ethical Conduct of the Study 
This study will be conducted in accordance with the ethical principles originating from the 
Declaration of Helsinki, ICH guidelines, GCP, and in compliance with local regulatory 
requirements. The investigator agrees, when signing the protocol, to adhere to the 
instructions and procedures described in it and thereby to adhere to the principles of GCP. 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws. 
16.3 Written Informed Consent  
Written informed consent, in accordance with local clinical investigation regulations, must be 
obtained prior to participation in the study. The investigator or designee will discuss the 
purpose of the study with each subject, and provide a description of the study drug (including 
any potential and possible side effects) and the study procedures. Information must be given 
both in oral and written form. Subject information will be provided in a language 
understandable to the subject and may not include any language that appears to waive any of 
the subject‘s legal rights or appears to release the investigator, the sponsor or the institution 
from liability or negligence. 
 
The investigator will provide the prospective subject sufficient time to consider whether or 
not to participate, minimizing the possibility of coercion or undue influence and will discuss 
any questions the subject may have. The investigator will explain to the subject that 
participation in the study is voluntary and that withdrawal from the study is possible at any 
time without detriment to care. The consent must include acknowledgment that medical 
records and medical data derived from the study may be forwarded to the sponsor or to 
responsible local or federal authorities. 
 
No subject can enter the study or have any study related procedures performed before his/her 
written informed consent has been obtained. The original signed and dated informed consent 
form will be retained with the study records, and a copy of the signed form will be given to 
the subject. 


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An informed consent template will be supplied by the sponsor. Any changes to the informed 
consent form must be agreed to by the sponsor or designee prior to submission to the 
IRB/IEC, and a copy of the approved version must be provided to the sponsor or designee 
after IRB/IEC approval. 
16.4 Subject Data Protection 
Subject data will be protected by ensuring that no captured data contain subject names, 
addresses, telephone numbers, email addresses, or other direct personally identifying 
information. It is acknowledged that subject initials, demographics (including birthdates), 
medical histories, and prior concomitant medication uses, along with the name and address of 
the enrolling investigator may allow for personal identification of study participants. Other 
than where necessary to meet regulatory requirements, all data collected in this study will be 
presented in tabulated (eg, aggregate) form and listings containing information that could be 
used to identify an individual subject will not be included in any public disclosures of the 
study data or the study results. 
16.5 Reporting of Safety Issues and Serious Breaches of the Protocol ICH GCP 
In the event of any prohibition or restriction imposed (eg, clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Sponsor should be informed immediately. 
 
In addition, the investigator will inform Sponsor immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of. 
16.6 Confidentiality/Publication of the Study 
 All study data generated as a result of this study will be regarded as confidential, until 
appropriate analysis and review by Valeant or its designee and the Investigator(s) are 
completed. The results of the study may be published or presented by the Investigator(s) after 


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the review by, and in consultation and agreement with the Valeant, and such that confidential 
or proprietary information is not disclosed.  
Prior to publication or presentation, a copy of the final text should be forwarded by the 
Investigator(s) to the Valeant or its designee, for comment. Such comments shall aim to 
ensure the scientific integrity of the proposed publications and/or presentations and ensure 
that the data and material referring to Valeant Incorporated products and activities receive 
fair, accurate, and reasonable presentation. Financial disclosures will be obtained from all 
investigators in order to document any potential conflicts of interest. 
16.7 Investigator Obligations 
The investigator agrees, when signing the protocol, to adhere to the instructions and 
procedures described in it and thereby to adhere to the principles of Good Clinical Practice 
(GCP). 
16.8 Changes to the Protocol 
The investigators must read the protocol thoroughly and must follow the instructions exactly. 
Whenever possible, any planned deviations should be agreed to by prior discussion between 
the sponsor and the investigator, with appropriate documentation of sponsor approval prior to 
effecting the changes agreed upon. Any amendment to the protocol containing major 
modifications (particularly if it may involve an increased risk to the subjects) will be 
approved by the IRB before it may be implemented. No change in the conduct of the study 
can be instituted without written approval from the sponsor. 
17 Definition of End of Trial 
17.1 End of Trial in All Participating Countries 
This study will only be performed in the USA. The end of the trial is defined as last subject 
last visit (LSLV). 


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18 
Sponsor Discontinuation Criteria  
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Sponsor. In addition, Sponsor retains the right to discontinue development of 
brinzolamide 1% suspension at any time. 
If a study is prematurely terminated or discontinued, Sponsor will promptly notify the 
investigator. After notification, the investigator must contact all participating subjects and the 
hospital pharmacy (if applicable) within 48 hours. As directed by Sponsor, all study materials 
must be collected and all CRFs completed to the greatest extent possible. 
19 
References 
AZOPT®. United States Product Insert (USPI). NDA 20-816/S-009 
 
FDA. Draft Guidance on brinzolamide. Office of Generic Drugs, 2014 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Gida
nces/UCM384099.pdf 
 
InnoPharma, Inc. A multicenter, double-masked, randomized, parallel-assignment study 
to determine the therapeutic equivalence of generic brinzolamide 1% ophthalmic 
suspension manufactured by InnoPharma, Inc. with respect to AZOPT® (Brinzolamide 
1% Ophthalmic Suspension) in patients with primary open-angle glaucoma or ocular 
hypertension. Clinical Study Report. CD-11-265, 30 October 2012. 
 
March WF, Ochsner KI. The long-term safety and efficacy of brinzolamide 1.0% 
(AZOPT®) in patients with primary open-angle glaucoma or ocular hypertension. The 
Brinzolamide Long-Term Therapy Study Group. Am J Ophthalmol. 2000;129:1360- 143. 
 
Sall K. The efficacy and safety of brinzolamide 1 % ophthalmic suspension (AZOPT®) 
as a primary therapy in patients with open-angle glaucoma or ocular hypertension. 
Brinzolamide Primary Therapy Study Group. Surv Ophthalmol 2000; 44: S155-S162. 
 
Shin D. Adjunctive therapy with brinzolamide 1 % ophthalmic suspension (AZOPT®) in 
patients with open-angle glaucoma or ocular hypertension maintained on timolol therapy. 
Surv Ophthalmol 2000; 44: S163-S168. 
 
Silver LH. Clinical efficacy and safety of brinzolamide (AZOPT®), a new topical 
carbonic anhydrase inhibitor for primary open-angle glaucoma and ocular hypertension. 
Brinzolamide Primary Therapy Study Group. Am J Ophthalmol. 1998;126:400–8 


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20 
Appendices 
21.1 
Appendix A. Current Full Prescribing Information of AZOPT® 
*On following page 


___________________________________________________________________________________________________________ 
____________________________________________________________________________________________________________ 
HIGHLIGHTS OF PRESCRIBING INFORMATION 
These highlights do not include all the information needed 
to use AZOPT† safely and effectively. See full prescribing 
information for AZOPT. 
AZOPT (brinzolamide ophthalmic suspension) 1% 
Sterile topical ophthalmic drops 
Initial U.S. Approval: 1998 
------------------INDICATIONS AND USAGE------------------
AZOPT is a carbonic anhydrase inhibitor indicated for in the treatment of 
elevated intraocular pressure in patients with ocular hypertension or 
open-angle glaucoma (1). 
--------------DOSAGE AND ADMINISTRATION-------------
•
Instill one drop in the affected eye(s) three times daily (2). 
•
If more than one topical ophthalmic drug is being used, the drugs 
should be administered at least (10) minutes apart (2). 
------------DOSAGE FORMS AND STRENGTHS------------
Solution containing 10 mg/mL brinzolamide (3) 
---------------------CONTRAINDICATIONS---------------------
Hypersensitivity to any component of this product. (4) 
---------------WARNINGS AND PRECAUTIONS-------------
•
Sulfonamide hypersensitivity reactions (5.1). 
•
Corneal edema may occur in patients with low endothelial cell 
counts (5.2). 
----------------------ADVERSE REACTIONS---------------------
Most common adverse reactions are blurred vision and bitter, sour or 
unusual taste (6.1). 
To report SUSPECTED ADVERSE REACTIONS, contact Alcon 
Laboratories, Inc. at 1-800-757-9195 or www.alconlabs.com or FDA 
at 1-800-FDA-1088 or www.fda.gov/medwatch. 
---------------------DRUG INTERACTIONS---------------------
• 
There is a potential additive effect of the known systemic effects of 
carbonic anhydrase inhibition in patients receiving both oral and 
topical carbonic anhydrase inhibitors (7.1). 
• 
Rare instance of acid-base alterations have occurred with high-dose 
salicylate therapy (7.2) 
See 17 for PATIENT COUNSELING INFORMATION 
Revised: 7/2015 
FULL PRESCRIBING INFORMATION: CONTENTS* 
1 
INDICATIONS AND USAGE 
2 
DOSAGE AND ADMINISTRATION 
3 
DOSAGE FORMS AND STRENGTHS 
4 
CONTRAINDICATIONS 
5 
WARNINGS AND PRECAUTIONS 
5.1 
Sulfonamide Hypersensitivity Reactions 
5.2 
Corneal Endothelium 
5.3 
Severe Renal Impairment 
5.4 
Acute Angle-Closure Glaucoma 
5.5 
Contact Lens Wear 
6 
ADVERSE REACTIONS 
6.1 
Clinical Studies Experience 
7 
DRUG INTERACTIONS 
7.1 
Oral Carbonic Anhydrase Inhibitors 
7.2 
High-Dose Salicylate Therapy 
8 
USE IN SPECIFIC POPULATIONS 
8.1 
Pregnancy 
8.3 
Nursing Mothers 
8.4 
Pediatric Use 
8.5 
Geriatric Use 
10 
OVERDOSAGE 
11 
DESCRIPTION 
12 
CLINICAL PHARMACOLOGY 
12.1 
Mechanism of Action 
12.3 
Pharmacokinetics 
13 
NONCLINICAL TOXICOLOGY 
13.1 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
16 
HOW SUPPLIED/STORAGE AND HANDLING 
17 
PATIENT COUNSELING INFORMATION 
17.1 
Sulfonamide Reactions 
17.2 
Temporary Blurred Vision 
17.3 
Avoiding Contamination of the Product 
17.4 
Intercurrent Ocular Conditions 
17.5 
Concomitant Topical Ocular Therapy 
17.6 
Contact Lens Wear 
*Sections or subsections omitted from the full prescribing 
information are not listed. 
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FULL PRESCRIBING INFORMATION 
1 
INDICATIONS AND USAGE 
AZOPT† (brinzolamide ophthalmic suspension) 1% is a carbonic anhydrase inhibitor indicated 
in the treatment of elevated intraocular pressure in patients with ocular hypertension or open-
angle glaucoma. 
2 
DOSAGE AND ADMINISTRATION 
The recommended dose is one drop of AZOPT (brinzolamide ophthalmic suspension) 1% in the 
affected eye(s) three times daily. AZOPT (brinzolamide ophthalmic suspension) 1% may be used 
concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If more 
than one topical ophthalmic drug is used, the drugs should be administered at least ten (10) 
minutes apart. 
3 
DOSAGE FORMS AND STRENGTHS 
Solution containing 10 mg/mL brinzolamide. 
4 
CONTRAINDICATIONS 
AZOPT (brinzolamide ophthalmic suspension) 1% is contraindicated in patients who are 
hypersensitive to any component of this product. 
5 
WARNINGS AND PRECAUTIONS 
5.1 
Sulfonamide Hypersensitivity Reactions 
AZOPT (brinzolamide ophthalmic suspension) 1% is a sulfonamide and although administered 
topically it is absorbed systemically. Therefore, the same types of adverse reactions that are 
attributable to sulfonamides may occur with topical administration of AZOPT (brinzolamide 
ophthalmic suspension) 1%. Fatalities have occurred, although rarely, due to severe reactions to 
sulfonamides including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant 
hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. Sensitization may 
recur when a sulfonamide is re-administered irrespective of the route of administration. If signs 
of serious reactions or hypersensitivity occur, discontinue the use of this preparation. 
5.2 
Corneal Endothelium 
Carbonic anhydrase activity has been observed in both the cytoplasm and around the plasma 
membranes of the corneal endothelium. There is an increased potential for developing corneal 
edema in patients with low endothelial cell counts. Caution should be used when prescribing 
AZOPT (brinzolamide ophthalmic suspension) 1% to this group of patients. 
5.3 
Severe Renal Impairment 
AZOPT (brinzolamide ophthalmic suspension) 1% has not been studied in patients with severe 
renal impairment (CrCl < 30 mL/min). Because AZOPT (brinzolamide ophthalmic suspension) 
1% and its metabolite are excreted predominantly by the kidney, AZOPT (brinzolamide 
ophthalmic suspension) 1% is not recommended in such patients. 
5.4 
Acute Angle-Closure Glaucoma 
The management of patients with acute angle-closure glaucoma requires therapeutic 
interventions in addition to ocular hypotensive agents. AZOPT (brinzolamide ophthalmic 
suspension) 1% has not been studied in patients with acute angle-closure glaucoma. 
Reference ID: 3843548 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
5.5 
Contact Lens Wear 
The preservative in AZOPT (brinzolamide ophthalmic suspension) 1%, benzalkonium chloride, 
may be absorbed by soft contact lenses. Contact lenses should be removed during instillation of 
AZOPT (brinzolamide ophthalmic suspension) 1%, but may be reinserted 15 minutes after 
instillation. 
6 
ADVERSE REACTIONS 
6.1 
Clinical Studies Experience 
Because clinical studies are conducted under widely varying conditions, adverse reaction rates 
observed in the clinical studies of a drug cannot be directly compared to the rates in the clinical 
studies of another drug and may not reflect the rates observed in practice. 
In clinical studies of AZOPT (brinzolamide ophthalmic suspension) 1%, the most frequently 
reported adverse reactions reported in 5 to 10% of patients were blurred vision and bitter, sour or 
unusual taste. Adverse reactions occurring in 1 to 5% of patients were blepharitis, dermatitis, dry 
eye, foreign body sensation, headache, hyperemia, ocular discharge, ocular discomfort, ocular 
keratitis, ocular pain, ocular pruritus and rhinitis. 
The following adverse reactions were reported at an incidence below 1%: allergic reactions, 
alopecia, chest pain, conjunctivitis, diarrhea, diplopia, dizziness, dry mouth, dyspnea, dyspepsia, 
eye fatigue, hypertonia, keratoconjunctivitis, keratopathy, kidney pain, lid margin crusting or 
sticky sensation, nausea, pharyngitis, tearing and urticaria. 
7 
DRUG INTERACTIONS 
7.1 
Oral Carbonic Anhydrase Inhibitors 
There is a potential for an additive effect on the known systemic effects of carbonic anhydrase 
inhibition in patients receiving an oral carbonic anhydrase inhibitor and AZOPT (brinzolamide 
ophthalmic suspension) 1%. The concomitant administration of AZOPT (brinzolamide 
ophthalmic suspension) 1% and oral carbonic anhydrase inhibitors is not recommended. 
7.2 
High-Dose Salicylate Therapy 
Carbonic anhydrase inhibitors may produce acid-base and electrolyte alterations. These 
alterations were not reported in the clinical trials with brinzolamide. However, in patients treated 
with oral carbonic anhydrase inhibitors, rare instances of acid-base alterations have occurred 
with high-dose salicylate therapy. Therefore, the potential for such drug interactions should be 
considered in patients receiving AZOPT (brinzolamide ophthalmic suspension) 1%. 
8 
USE IN SPECIFIC POPULATIONS 
8.1 
Pregnancy 
Pregnancy Category C: Developmental toxicity studies with brinzolamide in rabbits at oral 
doses of 1, 3, and 6 mg/kg/day (20, 62, and 125 times the recommended human ophthalmic dose) 
produced maternal toxicity at 6 mg/kg/day and a significant increase in the number of fetal 
variations, such as accessory skull bones, which was only slightly higher than the historic value 
at 1 and 6 mg/kg. In rats, statistically decreased body weights of fetuses from dams receiving 
oral doses of 18 mg/kg/day (375 times the recommended human ophthalmic dose) during 
gestation were proportional to the reduced maternal weight gain, with no statistically significant 
effects on organ or tissue development. Increases in unossified sternebrae, reduced ossification 
of the skull, and unossified hyoid that occurred at 6 and 18 mg/kg were not statistically 
Reference ID: 3843548 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
  
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
  
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
  
 
  
   
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
significant. No treatment-related malformations were seen. Following oral administration of 
14C-brinzolamide to pregnant rats, radioactivity was found to cross the placenta and was present 
in the fetal tissues and blood. 
There are no adequate and well-controlled studies in pregnant women. AZOPT (brinzolamide 
ophthalmic suspension) 1% should be used during pregnancy only if the potential benefit 
justifies the potential risk to the fetus. 
8.3 
Nursing Mothers 
In a study of brinzolamide in lactating rats, decreases in body weight gain in offspring at an oral 
dose of 15 mg/kg/day (312 times the recommended human ophthalmic dose) were seen during 
lactation. No other effects were observed. However, following oral administration of 14C­
brinzolamide to lactating rats, radioactivity was found in milk at concentrations below those in 
the blood and plasma. 
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in 
human milk and because of the potential for serious adverse reactions in nursing infants from 
AZOPT (brinzolamide ophthalmic suspension) 1%, a decision should be made whether to 
discontinue nursing or to discontinue the drug, taking into account the importance of the drug to 
the mother. 
8.4 
Pediatric Use 
A three-month controlled clinical study was conducted in which AZOPT (brinzolamide 
ophthalmic suspension) 1% was dosed only twice a day in pediatric patients 4 weeks to 5 years 
of age. Patients were not required to discontinue their IOP-lowering medication(s) until initiation 
of monotherapy with AZOPT. IOP-lowering efficacy was not demonstrated in this study in 
which the mean decrease in elevated IOP was between 0 and 2 mmHg. Five out of 32 patients 
demonstrated an increase in corneal diameter of one millimeter. 
8.5 
Geriatric Use 
No overall differences in safety or effectiveness have been observed between elderly and 
younger patients. 
10 
OVERDOSAGE 
Although no human data are available, electrolyte imbalance, development of an acidotic state, 
and possible nervous system effects may occur following oral administration of an overdose. 
Serum electrolyte levels (particularly potassium) and blood pH levels should be monitored. 
11 
DESCRIPTION 
AZOPT (brinzolamide ophthalmic suspension) 1% contains a carbonic anhydrase inhibitor 
formulated for multidose topical ophthalmic use. Brinzolamide is described chemically as: (R)­
(+)-4-Ethylamino-2-(3-methoxypropyl)-3,4-dihydro-2H-thieno [3,2-e]-1,2-thiazine-6­
sulfonamide-1,1- dioxide. Its empirical formula is C12H21N3O5S3, and its structural formula is: 
Reference ID: 3843548 


 
  
 
 
 
 
  
 
 
 
 
    
 
 
  
  
 
 
  
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
Brinzolamide has a molecular weight of 383.5 and a melting point of about 131°C. It is a white 
powder, which is insoluble in water, very soluble in methanol and soluble in ethanol. 
AZOPT (brinzolamide ophthalmic suspension) 1% is supplied as a sterile, aqueous suspension of 
brinzolamide which has been formulated to be readily suspended and slow settling, following 
shaking. It has a pH of approximately 7.5 and an osmolality of 300 mOsm/kg. 
Each mL of AZOPT (brinzolamide ophthalmic suspension) 1% contains: Active ingredient: 
brinzolamide 10 mg. Preservative: Benzalkonium chloride 0.1 mg. Inactives: mannitol, 
carbomer 974P, tyloxapol, edetate disodium, sodium chloride, purified water, with hydrochloric 
acid and/or sodium hydroxide to adjust pH. 
12 
CLINICAL PHARMACOLOGY 
12.1 
Mechanism of Action 
Carbonic anhydrase (CA) is an enzyme found in many tissues of the body including the eye. It 
catalyzes the reversible reaction involving the hydration of carbon dioxide and the dehydration 
of carbonic acid. In humans, carbonic anhydrase exists as a number of isoenzymes, the most 
active being carbonic anhydrase II (CA-II), found primarily in red blood cells (RBCs), but also 
in other tissues. Inhibition of carbonic anhydrase in the ciliary processes of the eye decreases 
aqueous humor secretion, presumably by slowing the formation of bicarbonate ions with 
subsequent reduction in sodium and fluid transport. The result is a reduction in intraocular 
pressure (IOP). 
AZOPT (brinzolamide ophthalmic suspension) 1% contains brinzolamide, an inhibitor of 
carbonic anhydrase II (CA-II). Following topical ocular administration, brinzolamide inhibits 
aqueous humor formation and reduces elevated intraocular pressure. Elevated intraocular 
pressure is a major risk factor in the pathogenesis of optic nerve damage and glaucomatous 
visual field loss. 
12.3 
Pharmacokinetics 
Following topical ocular administration, brinzolamide is absorbed into the systemic circulation. 
Due to its affinity for CA-II, brinzolamide distributes extensively into the RBCs and exhibits a 
long half-life in whole blood (approximately 111 days). In humans, the metabolite N-desethyl 
brinzolamide is formed, which also binds to CA and accumulates in RBCs. This metabolite binds 
mainly to CA-I in the presence of brinzolamide. In plasma, both parent brinzolamide and N­
desethyl brinzolamide concentrations are low and generally below assay quantitation limits (<10 
ng/mL). Binding to plasma proteins is approximately 60%. Brinzolamide is eliminated 
predominantly in the urine as unchanged drug. N-Desethyl brinzolamide is also found in the 
urine along with lower concentrations of the N-desmethoxypropyl and O-desmethyl metabolites. 
Reference ID: 3843548 


 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
  
 
 
  
   
 
 
 
 
 
  
 
 
 
 
 
 
 
 
   
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
   
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
An oral pharmacokinetic study was conducted in which healthy volunteers received 1 mg 
capsules of brinzolamide twice per day for up to 32 weeks. This regimen approximates the 
amount of drug delivered by topical ocular administration of AZOPT (brinzolamide ophthalmic 
suspension) 1% dosed to both eyes three times per day and simulates systemic drug and 
metabolite concentrations similar to those achieved with long-term topical dosing. RBC CA 
activity was measured to assess the degree of systemic CA inhibition. Brinzolamide saturation of 
RBC CA-II was achieved within 4 weeks (RBC concentrations of approximately 20 mcM). N-
Desethyl brinzolamide accumulated in RBCs to steady-state within 20 to 28 weeks reaching 
concentrations ranging from 6 to30 mcM. The inhibition of CA-II activity at steady-state was 
approximately 70 to 75%, which is below the degree of inhibition expected to have a 
pharmacological effect on renal function or respiration in healthy subjects. 
13 
NONCLINICAL TOXICOLOGY 
13.1 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
Brinzolamide caused urinary bladder tumors in female mice at oral doses of 10 mg/kg/day and in 
male rats at oral doses of 8 mg/kg/day in 2 year studies. Brinzolamide was not carcinogenic in 
male mice or female rats dosed orally for up to 2 years. The carcinogenicity appears secondary to 
kidney and urinary bladder toxicity. These levels of exposure cannot be achieved with topical 
ophthalmic dosing in humans. The following tests for mutagenic potential were negative: (1) in 
vivo mouse micronucleus assay; (2) in vivo sister chromatid exchange assay; and (3) Ames E. 
coli test. The in vitro mouse lymphoma forward mutation assay was negative in the absence of 
activation, but positive in the presence of microsomal activation. In reproduction studies of 
brinzolamide in rats, there were no adverse effects on the fertility or reproductive capacity of 
males or females at doses up to 18 mg/kg/day (375 times the recommended human ophthalmic 
dose). 
14 
CLINICAL STUDIES 
In two, three-month clinical studies, AZOPT® (brinzolamide ophthalmic suspension) 1% dosed 
three times per day in patients with elevated intraocular pressure (IOP), produced significant 
reductions in IOPs (4 to 5 mmHg). These IOP reductions are equivalent to the reductions 
observed with TRUSOPT* (dorzolamide hydrochloride ophthalmic solution) 2% dosed three 
times per day in the same studies. 
In two clinical studies in patients with elevated intraocular pressure, AZOPT (brinzolamide 
ophthalmic suspension) 1% was associated with less stinging and burning upon instillation than 
TRUSOPT* 2%. 
16 
HOW SUPPLIED/STORAGE AND HANDLING 
AZOPT (brinzolamide ophthalmic suspension) 1% is supplied in plastic DROP-TAINER† 
dispensers with a controlled dispensing-tip as follows: 
10 mL NDC 0065-0275-10 
15 mL NDC 0065-0275-15 
Storage and Handling 
Store AZOPT (brinzolamide ophthalmic suspension) 1% at 4-30°C (39-86°F). Shake well before 
use. 
17 
PATIENT COUNSELING INFORMATION 
Reference ID: 3843548 


 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
  
 
 
 
 
 
 
 
 
17.1 
Sulfonamide Reactions 
Advise patients that if serious or unusual ocular or systemic reactions or signs of hypersensitivity 
occur, they should discontinue the use of the product and consult their physician. 
17.2 
Temporary Blurred Vision 
Vision may be temporarily blurred following dosing with AZOPT (brinzolamide ophthalmic 
suspension) 1%. Advise patients to exercise care in operating machinery or driving a motor 
vehicle. 
17.3 
Avoiding Contamination of the Product 
Instruct patients to avoid allowing the tip of the dispensing container to contact the eye or 
surrounding structures or other surfaces, since the product can become contaminated by common 
bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of 
vision may result from using contaminated solutions. 
17.4 
Intercurrent Ocular Conditions 
Advise patients that if they have ocular surgery or develop an intercurrent ocular condition (e.g., 
trauma or infection), they should immediately seek their physician's advice concerning the 
continued use of the present multidose container. 
17.5 
Concomitant Topical Ocular Therapy 
If more than one topical ophthalmic drug is being used, the drugs should be administered at least 
ten minutes apart. 
17.6 
Contact Lens Wear 
The preservative in AZOPT (brinzolamide ophthalmic suspension) 1%, benzalkonium chloride, 
may be absorbed by soft contact lenses. Contact lenses should be removed during instillation of 
AZOPT (brinzolamide ophthalmic suspension) 1%, but may be reinserted 15 minutes after 
instillation. 
©2000-2009, 2011-2012, 2015 Novartis 
† 
Trademark of Novartis 
U.S. Patent Nos: 6,071,904.  
*TRUSOPT is a registered trademark of Merck & Co., Inc.  
Distributed By:  
ALCON LABORATORIES, INC. 
Fort Worth, Texas 76134 USA 
Reference ID: 3843548