Twice-Daily Brinzolamide/Brimonidine Fixed

Combination versus Brinzolamide or

Brimonidine in Open-Angle Glaucoma or
Ocular Hypertension
Tin Aung, FRCS, PhD,1,2 Guna Laganovska, MD,3 Tania Josefina Hernandez Paredes, MD,4
James D. Branch, MD,5 Alexis Tsorbatzoglou, MD, PhD,6 Ivan Goldberg, AM, FRANZCO7,8,9

Purpose: To compare the intraocular pressure (IOP)-lowering efficacy and safety of brinzolamide 1% and
brimonidine 0.2% fixed combination (BBFC) with that of brinzolamide 1% or brimonidine 0.2% monotherapy, all
dosed 2 times per day (BID).
Design: Six-month, phase 3, randomized, multicenter, double-masked clinical trial.
Participants: A total of 560 patients with primary open-angle glaucoma or ocular hypertension who had
insufficient IOP reduction with their current therapeutic regimen or who were receiving
2 IOP-lowering
medications.
Intervention: Patients received BBFC (n ¼ 193), brinzolamide 1% (n ¼ 192), or brimonidine 0.2% (n ¼ 175)
BID.
Main Outcome Measures: The primary end point was mean change in diurnal IOP from baseline to month 3.
Supportive end points included mean diurnal IOP change from baseline at week 2, week 6, and month 6; and
mean IOP, mean IOP change from baseline, mean percentage IOP change from baseline, and percentage of
patients with IOP <18 mmHg at week 2, week 6, month 3, and month 6 at each assessment time point (i.e., 9 AM,
11 AM, and 4 PM). Adverse events were recorded throughout the study.
Results: Baseline diurnal IOP was similar among all groups (mean  standard deviation: BBFC, 25.90.19 mmHg;
brinzolamide, 25.90.20 mmHg; brimonidine, 26.00.19 mmHg). At month 3, BBFC lowered mean diurnal IOP from
baseline to a significantly greater extent than brinzolamide (least squares [LS] mean difference: 1.4 mmHg; P < 0.0001;
t test) and brimonidine (LS mean difference: 1.5 mmHg; P < 0.0001). All supportive end points corroborated the results
of the primary efficacy analysis. Mean percentage reductions in IOP from baseline were 26.7% to 36.0% with BBFC,
22.4% to 27.9% with brinzolamide, and 20.6% to 31.3% with brimonidine. The most common adverse drug reactions
were ocular side effects, including hyperemia, blurred vision, allergic-type reactions, and discomfort. The incidence of
hyperemia of the eye was slightly lower with brinzolamide than with BBFC and brimonidine, whereas blurred vision and
ocular discomfort were slightly more common with BBFC than with brinzolamide or brimonidine.
Conclusions: Brinzolamide 1% and brimonidine 0.2% fixed combination administered BID had a signifi-
cantly greater IOP-lowering effect than either brinzolamide or brimonidine alone and displayed a safety profile
consistent with its individual components. Ophthalmology 2014;-:1e8 ª 2014 by the American Academy of
Ophthalmology.

Supplemental material is available at www.aaojournal.org.

Intraocular pressure (IOP)-lowering medications, particu-
larly b-blockers and prostaglandin analogues, are typically
first-line therapies for the treatment of glaucoma.1 In many
instances, monotherapy with one of these drug classes
cannot lower IOP sufficiently,2 and combination therapy
with multiple IOP-lowering medications with differing
mechanisms of action may be indicated.1 Currently avail-
able fixed-combination formulations include a b-blocker
with another medication; therefore, no fixed-combination
therapy is currently available for patients who cannot or will
not use b-blockers.1
Successful treatment of glaucoma is in part tied to
compliance with medications.3 However, a retrospective
pharmacy claims database study estimated that, on the basis
of a refill period of 60 days, 71% of patients with glaucoma
experience at least 1 gap in their medication compliance per
year.4 Failure rate increases with the addition of multiple
medications,3,5 and cost and copays are also a usual issue.6
A fixed combination of the carbonic anhydrase inhibitor
brinzolamide 1% and the a2-adrenergic agonist brimonidine
0.2% (BBFC; SIMBRINZA, Alcon Laboratories, Inc, Fort
Worth, TX) was approved in the United States with 3 times

 2014 by the American Academy of Ophthalmology http://dx.doi.org/10.1016/j.ophtha.2014.06.022 1

Published by Elsevier Inc. ISSN 0161-6420/12
 Ophthalmology Volume -, Number -, Month 2014
per day (TID) dosing in April 2013 and is indicated for the
reduction of elevated IOP in patients with primary open-
angle glaucoma or ocular hypertension. In phase 3 clinical
trials, the IOP-lowering efficacy of BBFC administered
TID was significantly greater than that of brinzolamide 1%
or brimonidine 0.2% alone, was demonstrated as early as
week 2, and continued for at least 6 months.7e10 Further-
more, the safety profile of BBFC administered TID was
similar to that of the individual components. The TID
dosing regimen used for BBFC in these trials is consistent
with the approved dosing regimen of brinzolamide and
brimonidine in the United States.
This study evaluated the safety and IOP-lowering effi-
cacy of BBFC administered 2 times per day (BID) compared
with each of its individual active components in patients
with primary open-angle glaucoma or ocular hypertension.
A BID dosing regimen is approved for brinzolamide and
brimonidine in the European Union and most countries.
Methods
Study Design
This phase 3, 6-month, randomized, multicenter, multinational,
double-masked trial evaluated the efficacy and safety of BBFC
versus each individual active component (i.e., brinzolamide 1%
and brimonidine 0.2%) for reduction of IOP in patients with pri-
mary open-angle glaucoma or ocular hypertension who were
insufficiently controlled on monotherapy in the opinion of the
investigator or who were receiving multiple IOP-lowering medi-
cations (ClinicalTrials.gov identifier, NCT01310777). The study
was approved by all institutional review boards and complied with
the ethical standards set forth by the Declaration of Helsinki and
Good Clinical Practice. All patients provided written informed
consent before study initiation.
This 7-visit study comprised 2 phases, including a screening/
eligibility phase with 1 screening visit and 2 eligibility visits and a
treatment phase with 4 on-therapy visits at week 2, week 6, month 3,
and month 6. During the initial screening visit, patients were eval-
uated for eligibility and provided informed consent and a medical
history. Eligible patients were asked to discontinue all ocular hy-
potensive medications before returning for the first eligibility visit.
The duration of this washout period depended on the medication
being discontinued:
5 days for miotics and oral or topical carbonic
anhydrase inhibitors,
14 days for alpha- or beta-agonists, and
28
days for beta-antagonists, prostaglandin analogues, and combina-
tion drugs. At both eligibility visits, IOP was measured in each eye
at 9 AM, 11 AM, and 4 PM. Baseline IOP at each time point was
calculated as the mean time-matched IOP over the 2 eligibility visits.
Eligible patients were randomized 1:1:1 at each investigational
center using an interactive web response system to receive BBFC,
brinzolamide alone, or brimonidine alone for up to 6 months.
Randomization was performed by the investigators after comple-
tion of the second eligibility visit using a block design and was
stratified by study center and baseline IOP in the study eye (i.e.,
IOP 24 to 27 mmHg or 28 to 36 mmHg, assessed at 9 AM at the
eligibility visit). The randomization code was concealed until after
database lock. Patients self-administered medication BID at 9 AM
(30 minutes) and 9 PM (30 minutes) except on study visit days.
On these days, study personnel instilled the medication at 9 AM
after safety and efficacy measurements were obtained, and patients
self-administered the second dose at home. Study medications were
provided in identical, masked 10-ml bottles and instilled in both
2
eyes unless application to both eyes was thought by the investi-
gator to present a potential safety issue. Because study medication
drops differed in appearance (suspension vs. solution), in-
vestigators were not permitted to instill eye drops in patients’ eyes
on study visit days; rather, drops were administered by designated
staff at each investigational center.
Patients
Patients from 63 centers in the Asia-Pacific region, European
Union, Latin America, Caribbean nations, and the United States
participated in this study, which was performed from May 2011 to
January 2013. Inclusion and exclusion criteria are provided in
Table 1 (available at www.aaojournal.org).
Outcomes
The primary efficacy end point for this study was mean diurnal IOP
change from baseline at month 3. Mean diurnal IOP change was
calculated as the IOP change from baseline to month 3 averaged over
the 9 AM, 11 AM, and 4 PM time points. Supportive efficacy end points
included mean diurnal IOP change from baseline at week 2, week 6,
and month 6, as well as mean IOP, mean IOP change from baseline,
mean percentage IOP change from baseline, and the percentage of
patients with IOP <18 mmHg at week 2, week 6, month 3, and
month 6 at each assessment time point (i.e., 9 AM, 11 AM, and 4 PM).
Intraocular pressure was measured in both eyes using a Gold-
mann applanation tonometer once at the screening visit; at 3 time
points (9 AM, 11 AM, and 4 PM) during each eligibility visit; and at the
week 2, week 6, month 3, and month 6 visits. Two or 3 consecutive
IOP measures were taken for each assessment; a third measurement
was taken only if the initial 2 measurements differed by >4 mmHg.
In instances requiring 3 measurements, the average IOP was
ascertained from the 2 closest values; if all values differed by similar
amounts, all 3 values were averaged to calculate the mean IOP. One
eye (the worse eye) was designated the “study eye,” and only data
from this eye were included in the efficacy analyses. If a patient
administered medication to only 1 eye during the trial, that eye was
designated the study eye. If both eyes received medication, the eye
with the higher mean IOP at 9 AM across both eligibility visits was
considered the study eye. If both eyes had equal mean IOP at 9 AM,
the study eye was the one that had the higher mean IOP at 11 AM
across eligibility visits. If both eyes continued to have equal IOP
values at 11 AM, then the right eye was selected for analysis.
Safety assessments consisted of adverse events (AEs) and
serious AEs (SAEs) collected through solicited and spontaneous
reports throughout the study. In addition, blood pressure, pulse
rate, best-corrected visual acuity (BCVA), and ocular signs were
evaluated at the screening visit; at both eligibility visits; and at
week 2, week 6, month 3, and month 6. The BCVA was performed
using a standardized Early Treatment Diabetic Retinopathy Study
chart. Ocular signs were evaluated through slit-lamp bio-
microscopy examination of the cornea, iris/anterior chamber, lens,
and eyelids/conjunctiva. Both BCVA and slit-lamp examinations
were performed on study visit days before measurement of IOP.
Automated perimetry assessments of visual field function were
performed at screening and at the month 6 visit. Dilated fundus
examination of the vitreous, retina, macula, choroid, and optic
nerve was performed on both eyes after measurement of IOP at
screening and at the month 6 visit.
Statistical Analyses
Demographic parameters and baseline characteristics were summa-
rized in the overall population using descriptive statistics. Efficacy
analyses were based on an observed case assessment; however, a
prespecified last observation carried forward sensitivity analysis also
 Aung et al 
Brinzolamide/Brimonidine Fixed Combination BID

Figure 1. Patient disposition. BBFC ¼ brinzolamide 1%/brimonidine 0.2% fixed combination; IOP ¼ intraocular pressure; ITT ¼ intent-to-treat.

was conducted to assess the effect of missing data. Pairwise com-
parisons of between-group differences for continuous variables,
including the primary end point, were based on the least squares
(LS) means derived from a statistical model that accounted for
correlated intrapatient IOP measurements and were made using
2-sided t tests. The superiority of BBFC over brinzolamide or bri-
monidine in mean diurnal IOP change from baseline was determined
using a pairwise test at month 3. Between-group differences for
categoric parameters were analyzed across investigation center and
baseline IOP strata using a CochraneManteleHaenszel test. The
supportive efficacy assessments of mean diurnal IOP change from
baseline at week 2, week 6 (not shown), and month 6 were con-
ducted similar to the primary end point; however, the P values for
these end points should be considered descriptive in nature. For the
remaining IOP end points, descriptive statistics were provided, and
observations of numeric differences were not intended to imply
statistical significance. All safety data were summarized for the
safety population (i.e., all patients who were exposed to study drug)
using descriptive statistics. All analyses were performed using SAS
software (SAS Inc, Cary, NC).
The primary efficacy end point was evaluated in the intent-to-
treat (ITT) population (i.e., all patients who received study drug
and completed
1 scheduled on-therapy study visit). Efficacy
evaluations also were performed in the per-protocol population
(i.e., all patients who met study eligibility requirements, received
study drug, and completed
1 on-therapy study visit) to support
the primary analysis. By assuming a standard deviation for mean
IOP of 3.5 to 3.9 mmHg, this study provided 90% power to detect a
mean IOP difference of
1.5 mmHg between groups, assuming
enrollment of
143 patients in each treatment group. Therefore,
approximately 175 patients per treatment group were planned for
enrollment to provide sufficient data.

Table 2. Patient Demographics and Baseline Disease Characteristics

Characteristics BBFC (n [ 193) Brinzolamide (n [ 191) Brimonidine (n [ 175)

Mean  SD age, yrs 64.912.2 64.111.2 64.311.6
Age
65 yrs, n (%) 102 (52.8) 104 (54.5) 96 (54.9)
Sex, n (%)
Male 87 (45.1) 90 (47.1) 73 (41.7)
Female 106 (54.9) 101 (52.9) 102 (58.3)
Race, n (%)
White 133 (68.9) 138 (72.3) 123 (70.3)
Black or African American 20 (10.4) 14 (7.3) 14 (8.0)
Asian 16 (8.3) 16 (8.4) 14 (8.0)
Multiracial 4 (2.1) 2 (1.0) 3 (1.7)
Other 20 (10.4) 21 (11.0) 21 (12.0)
Diagnosis, n (%)
Ocular hypertension 44 (22.8) 38 (19.9) 28 (16.0)
Open-angle glaucoma 142 (73.6) 145 (75.9) 134 (76.6)
Open-angle glaucoma with pigment dispersion 1 (0.5) 4 (2.1) 4 (2.3)
Open-angle glaucoma with pseudoexfoliation 6 (3.1) 4 (2.1) 9 (5.1)
Mean  SE baseline IOP, mmHg
9 AM 27.00.18 27.00.18 27.00.19
11 AM 25.90.21 25.90.22 26.20.22
4 PM 24.80.23 24.80.24 24.90.21
Diurnal IOP* 25.90.19 25.90.20 26.00.19

BBFC ¼ brinzolamide 1%/brimonidine 0.2% fixed combination; IOP ¼ intraocular pressure; SD ¼ standard deviation; SE ¼ standard error.
*Average of 9 AM, 11 AM, and 4 PM time points.

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 Ophthalmology Volume -, Number -, Month 2014

Figure 2. The least squares (LS) mean changes in diurnal intraocular pressure (IOP) (i.e., average of IOP at 9 AM, 11 AM, and 4 PM time points) from
baseline throughout the study (intent-to-treat [ITT] population). Error bars represent standard errors. P values for the primary efficacy end point (between-
group differences at month 3) and descriptive P values for supportive efficacy end points (i.e., between-group differences at week 2 and month 6) are
provided. BBFC ¼ brinzolamide 1%/brimonidine 0.2% fixed combination. *P  0.0001. yPrimary end point.

Results
Patients
A total of 560 patients (BBFC, n ¼ 193; brinzolamide, n ¼ 192;
brimonidine, n ¼ 175) were enrolled and randomized to treatment
(Fig 1). One patient in the brinzolamide group did not complete
any on-therapy follow-up visits and was excluded from the ITT
population (BBFC, n ¼ 193; brinzolamide, n ¼ 191; brimonidine,
n ¼ 175). Most patients in the ITT population (86.4%) completed
the study. A similar percentage of patients discontinued from the
study in the BBFC and brimonidine groups (17.1% for both),
whereas a smaller percentage discontinued from the brinzolamide
group (6.8%). Patient demographics, including baseline IOP, were
similar among treatment groups (Table 2); patients were predom-
inantly white and female.
Efficacy
The IOP-lowering efficacy of BBFC was superior to both brinzola-
mide and brimonidine alone on the basis of mean diurnal IOP change
from baseline at the month 3 primary end point (Fig 2); the mean
change in diurnal IOP from baseline at month 3 was significantly
greater with BBFC versus brinzolamide (LS mean difference for
BBFC minus brinzolamide: 1.4 mmHg; P < 0.0001) and brimoni-
dine (LS mean difference for BBFC minus brimonidine: 1.5 mmHg;
P < 0.0001). This outcome was supported by the results of similar
analyses within the per-protocol population (data not shown).
The greater diurnal IOP-lowering efficacy of BBFC compared
with brinzolamide or brimonidine was observed at week 2 (the first
on-therapy visit) and was maintained throughout the study (Fig 2),
including the week 6 visit (data not shown). On all study days and
at all individual time points, the reduction in mean IOP was

Figure 3. Mean change in intraocular pressure (IOP) from baseline at all time points at week 2, month 3, and month 6 visits (intent-to-treat [ITT]
population). Error bars represent standard errors. BBFC ¼ brinzolamide 1%/brimonidine 0.2% fixed combination.

4
 Aung et al 
Brinzolamide/Brimonidine Fixed Combination BID

Table 3. Mean Intraocular Pressure at Week 2, Month 3, and both analyses. Mean diurnal IOP change from baseline at month 3
Month 6 Study Visits with BBFC was superior to that observed with brinzolamide
(LS mean difference for BBFC minus brinzolamide: 1.5 mmHg;
BBFC Brinzolamide Brimonidine P < 0.0001) or brimonidine (LS mean difference for BBFC minus
Time Point n* Mean  SE n* Mean  SE n* Mean  SE brimonidine: 1.3 mmHg; P < 0.0001); statistically greater IOP-
lowering efficacy of BBFC over brinzolamide and brimonidine was
Week 2 also observed at all other study visits (P < 0.0001 for all pairwise
9 AM 191 19.80.28 191 20.60.30 174 21.40.31 comparisons; data not shown).
11 AM 189 17.00.26 191 19.40.29 174 18.50.25
4 PM 188 17.80.26 191 19.10.26 173 19.70.29 Safety
Month 3
9 AM 176 19.30.27 182 20.00.29 161 20.70.34 The safety profile of BBFC was consistent with the known safety
11 AM 173 16.40.22 182 18.70.26 159 17.80.31 profile of its individual components; BBFC did not pose any
4 PM 172 17.10.22 180 18.40.27 159 19.10.31 additional risk to patients relative to the individual components.
Month 6 The overall incidences of SAEs were numerically similar among
9 AM 160 19.30.28 178 20.00.31 145 20.50.34 treatment groups (BBFC, n ¼ 5 [2.6%]; brinzolamide, n ¼ 2
11 AM 160 16.60.24 178 18.50.29 145 18.20.32 [1.0%]; brimonidine, n ¼ 3 [1.7%]), and all SAEs were considered
4 PM 160 17.30.26 178 18.10.28 144 18.70.30 by the investigator to be unrelated to the study medication. The
SAEs included the following: cellulitis, cervical carcinoma,
BBFC ¼ brinzolamide 1%/brimonidine 0.2% fixed combination; SE ¼ cholelithiasis, pancreatic carcinoma, renal cell carcinoma, vascular
standard error. pseudoaneurysm, and breast cancer with BBFC (n ¼ 1 each);
*Number of evaluable patients at each time point; excludes patients urethral calculus and cholecystitis with brinzolamide (n ¼ 1 each);
without data collection at the specified time point or those who dis- and carotid artery occlusion, concussion, headache, cystitis, and
continued from the study. macular degeneration with brimonidine (n ¼ 1 each). Three pa-
tients discontinued from the study because of SAEs: 2 in the BBFC
group (1 cervical carcinoma and 1 pancreatic carcinoma) and 1 in
numerically greater with BBFC (7.2e9.3 mmHg) than with brin- the brimonidine group (macular degeneration). The most
zolamide (5.7e7.2 mmHg) or brimonidine (5.2e8.1 mmHg) frequently reported AEs (
5% incidence in any group) were ocular
(Fig 3). Mean IOP values were numerically lower at all study visits hyperemia (BBFC, 5.7%; brinzolamide, 1.6%; brimonidine, 5.1%),
and time points in the BBFC group compared with brinzolamide or conjunctivitis (BBFC, 5.7%; brinzolamide, 1.0%; brimonidine,
brimonidine alone (Table 3). Across all visits and time points, 1.1%), blurred vision (BBFC, 5.7%; brinzolamide, 0.5%; brimo-
including the week 6 visit (data not shown), mean percentage IOP nidine, 1.7%), eye pain (BBFC, 5.7%; brinzolamide, 1.6%; bri-
reductions from baseline were 26.7% to 36.0% with BBFC, 22.4% monidine, 0.0%), dysgeusia (BBFC, 5.7%; brinzolamide, 2.1%;
to 27.9% with brinzolamide (mean difference from BBFC, 2.7%e brimonidine, 1.1%), and dry mouth (BBFC, 3.6%; brinzolamide,
9.5%), and 20.6% to 31.3% with brimonidine (mean difference 1.0%; brimonidine, 5.1%).
from BBFC, 4.8%e7.6%) (Table 4). The percentages of patients The majority of adverse drug reactions were ocular side effects
with IOP <18 mmHg were numerically greater in the BBFC group with a known association with brinzolamide or brimonidine
versus brinzolamide or brimonidine alone at most study visits and (Table 5). These included ocular hyperemia, blurred vision, ocular
time points (Fig 4), including the week 2 and week 6 visits (data allergic-type reactions, and ocular discomfort. The incidences of
not shown). adverse drug reactions for ocular hyperemia and conjunctival hy-
Overall, the results of the last observation carried forward sensi- peremia were 5.7% and 0.5% with BBFC, respectively, 4.6% and
tivity analysis were similar to those of the observed case evaluation. 2.3% with brimonidine, respectively, and 0.5% and 1.6% with
The LS mean diurnal IOP values at each study visit were similar with brinzolamide, respectively. Treatment-related transient blurred

Table 4. Percentage Change in Intraocular Pressure from Baseline at Week 2, Month 3, and Month 6 Study Visits

BBFC Brinzolamide Brimonidine

Percentage  SE Change Percentage  SE Change Percentage  SE Change
Time Point n* from Baseline n* from Baseline n* from Baseline
Week 2
9 AM 191 26.70.88 191 23.60.94 174 20.60.98
11 AM 189 34.10.89 191 25.00.88 174 29.00.84
4 PM 188 27.90.99 191 22.41.00 173 20.71.05
Month 3
9 AM 176 28.10.91 182 25.50.96 161 22.71.11
11 AM 173 36.00.84 182 26.90.94 159 31.31.07
4 PM 172 29.80.93 180 24.51.14 159 22.21.14
Month 6
9 AM 160 27.70.95 178 25.61.03 145 23.61.14
11 AM 160 35.00.89 178 27.91.06 145 30.01.16
4 PM 160 28.81.01 178 25.81.14 144 23.61.23

BBFC ¼ brinzolamide 1%/brimonidine 0.2% fixed combination; SE ¼ standard error.

*Number of evaluable patients at each time point; excludes patients without data collection at the specified time point or those who discontinued from the study.

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 Ophthalmology Volume -, Number -, Month 2014

Figure 4. Percentage of patients who achieved intraocular pressure (IOP) <18 mmHg (intent-to-treat [ITT] population). BBFC ¼ brinzolamide
1%/brimonidine 0.2% fixed combination.

vision (4.7%, 0.5%, and 1.1% in the BBFC, brinzolamide, and Overall, the efficacy and safety of BBFC BID dosing were
brimonidine groups, respectively), eye pain (5.7%, 1.6%, 0% in the similar to those of the previously published TID posology
BBFC, brinzolamide, and brimonidine groups, respectively), eye studies over the measured diurnal time points,7e10 although
pruritus (3.6%, 1.6%, 2.3% in the BBFC, brinzolamide, and bri-
monidine groups, respectively), and foreign body sensation in eyes
(2.1%, 1.0%, 1.1% in the BBFC, brinzolamide, and brimonidine Table 5. Safety Characteristics
groups, respectively) were numerically more common in the BBFC
BBFC Brinzolamide Brimonidine
group than in the brinzolamide or brimonidine groups.
Parameter, n (%) (n [ 193) (n [ 191) (n [ 175)
Changes associated with the eyelids/conjunctiva (e.g., local
ocular hyperemia and ocular allergic reactions) were the most Deaths 0 0 0
common ocular abnormalities observed during slit-lamp examina- Patients with SAEs 5 (2.6) 2 (1.0) 3 (1.7)
tion; a greater percentage of patients experienced eyelid/conjunc- Discontinuation because of 20 (9.3) 1 (0.5) 13 (7.4)
tival changes in the BBFC and brimonidine groups (14.0% and a nonserious,
13.8%, respectively) than in the brinzolamide group (6.8%). No treatment-related AE
other meaningful or unexpected treatment group differences were Patients with
1 ADR 55 (28.5) 22 (11.5) 40 (22.9)
ADRs
observed for the other measured ocular or cardiovascular safety
Ocular hyperemia 11 (5.7) 1 (0.5) 8 (4.6)
parameters.
Eye pain 11 (5.7) 3 (1.6) 0
Dysgeusia 11 (5.7) 4 (2.1) 2 (1.1)
Blurred vision 9 (4.7) 1 (0.5) 2 (1.1)
Discussion Dry mouth 7 (3.6) 2 (1.0) 9 (5.1)
Somnolence 7 (3.6) 0 4 (2.3)
In this randomized phase 3 trial, BBFC administered BID Conjunctivitis 7 (3.6) 0 1 (0.6)
reduced IOP to a significantly greater extent than brinzola- Eye pruritus 7 (3.6) 3 (1.6) 4 (2.3)
Foreign body sensation 4 (2.1) 2 (1.0) 2 (1.1)
mide or brimonidine monotherapy after 3 months of treat- in eyes
ment in patients with primary open-angle glaucoma or Allergic conjunctivitis 3 (1.6) 0 3 (1.7)
ocular hypertension. This increased efficacy of BBFC Eye allergy 3 (1.6) 0 2 (1.1)
versus monotherapy with each of its individual components Eye irritation 2 (1.0) 4 (2.1) 3 (1.7)
was observed at the week 2 visit and was maintained Headache 2 (1.0) 1 (0.5) 2 (1.1)
through 6 months of treatment. The safety profile of BBFC Eyelid edema 2 (1.0) 0 0
Photophobia 2 (1.0) 0 0
was consistent with the known safety profile of each of its
Nasal dryness 2 (1.0) 0 0
individual components (brinzolamide and brimonidine) and Conjunctival hyperemia 1 (0.5) 3 (1.6) 4 (2.3)
did not demonstrate any unexpected findings. Dry eye 1 (0.5) 1 (0.5) 3 (1.7)
Previous studies in the United States have demonstrated Asthenopia 1 (0.5) 0 2 (1.1)
the efficacy and safety of BBFC versus brinzolamide and Increased lacrimation 1 (0.5) 0 2 (1.1)
brimonidine when administered according to accepted Hypotension 1 (0.5) 0 2 (1.1)
dosing standards for the comparator medications (i.e., TID Punctate keratitis 0 1 (0.5) 2 (1.1)
Dizziness 0 1 (0.5) 3 (1.7)
dosing).7e10 In the European Union and many other coun-
tries, brinzolamide and brimonidine are approved for BID
dosing; therefore, the current study addressed the compa- ADR ¼ adverse drug reaction; AE ¼ adverse event; BBFC ¼ brinzolamide
1%/brimonidine 0.2% fixed combination; SAE ¼ serious adverse event.
rable efficacy and safety of BBFC using BID dosing.

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 Aung et al 
Brinzolamide/Brimonidine Fixed Combination BID
a true head-to-head trial would be necessary to thoroughly
compare the efficacy of the 2 dosing regimens. Taken
together, data from TID and BID dosing trials suggest that
both BBFC dosing regimens may offer patients an effica-
cious treatment alternative to manage their elevated IOP.
Although reductions in diurnal IOP with BBFC were su-
perior to brinzolamide or brimonidine alone, the effect of
BBFC was not completely additive, perhaps because of the
overlapping mechanisms of action of brinzolamide and
brimonidine. No SAEs were observed with TID or BID
dosing that were considered by the investigators to be drug
related; neither dosing schedule raised new safety concerns
given those previously associated with individual brinzola-
mide or brimonidine.7e10 In the current study, the percent-
age of patients who discontinued because of a nonserious,
treatment-related AE with BBFC (9.3%) was higher than
brinzolamide (0.5%) and slightly higher than brimonidine
(7.4%); however, the majority of the AEs that led to
discontinuation were associated with the types of local
ocular events that have been associated with the individual
components of the medication (e.g., blurred vision, ocular
discomfort, ocular hyperemia, and ocular allergies).
Furthermore, the severities of these AEs were similar among
treatment groups. The incidence of treatment-related blurred
vision with BBFC was similar with TID (4.5%) and BID
(4.7%) dosing after 6 months of treatment.9 Such effects
were transient and may relate to the viscosity of BBFC.
Fixed-combination therapies may offer several advantages
over concurrent administration of 2 separate medications.
Regular instillation of eye drops may be challenging for some
patients, with the challenges increasing as the dosing regimen
becomes more complicated11,12; therefore, limiting the num-
ber of eye drops administered or simplifying the administra-
tion schedule may increase patient adherence and persistence
with therapy.13,14 With dosing of 2 separate medications, there
is the potential for washout of the first medication by instil-
lation of the second if the interval between drops is insuffi-
cient.15 Furthermore, increased exposure to preservatives used
in ophthalmic solutions may be an issue, given that use of
multiple eye drops containing preservatives has been associ-
ated with increased frequency of AEs and ocular surface dis-
ease.16 Costs may increase with the purchasing of 2 bottles
rather than 1.12,17 Fixed-combination therapies, including
BBFC, can alleviate these concerns. For the first time, BBFC
offers patients a fixed-combination alternative therapy without
b-blockers, which are contraindicated in a substantial number
of patients with glaucoma.
Study Limitations
The IOP was not measured over a 24-hour period; therefore,
IOP reductions in late-day or nocturnal time points cannot
be inferred. However, IOP-lowering efficacies of brinzola-
mide and brimonidine at various time points have been
published.18 Because we compared the efficacy of a fixed-
combination product with its 2 constituent monotherapy
treatments, we cannot compare the efficacy of BBFC with
that of other fixed-combination therapies or concomitant but
separate administration of these individual IOP-lowering
agents. However, a phase 3 study comparing the efficacy of
BBFC administered BID with concomitant brinzolamide
and brimonidine was recently completed (ClinicalTrials.gov
identifier, NCT01309204).
In conclusion, brinzolamide 1% and brimonidine 0.2%
fixed combination administered BID lowered IOP to a
greater extent than either brinzolamide or brimonidine
monotherapy throughout this 6-month study and was not
associated with unexpected safety concerns. The safety and
IOP-lowering efficacy provided by BID dosing of BBFC
may be advantageous to patients with an inadequate
response to monotherapy or in whom b-blockers are con-
traindicated, especially those who would benefit from a less
complex medication schedule.
Acknowledgments. Preparation of the initial draft and addi-
tional medical writing assistance were provided by Jillian Gee,
PhD, CMPP, of Complete Healthcare Communications, Inc.
(Chadds Ford, PA), and were funded by Alcon.
References
1. European Glaucoma Society. Terminology and Guidelines for
Glaucoma. 3rd ed. Savona, Italy: Editrice DOGMA; 2008:122–45.
Available at: http://www.eugs.org/eng/EGS_guidelines.asp.
Accessed June 9, 2014.
2. McCarty CA, Mukesh BN, Kitchner TE, et al. Intraocular
pressure response to medication in a clinical setting: the
Marshfield Clinic Personalized Medicine Research Project.
J Glaucoma 2008;17:372–7.
3. Vorwerk C, Thelen U, Buchholz P, Kimmich F. Treatment of
glaucoma patients with insufficient intraocular pressure con-
trol: a survey of German ophthalmologists in private practice.
Curr Med Res Opin 2008;24:1295–301.
4. Lee PP, Walt JG, Chiang TH, et al. A gap analysis approach to
assess patient persistence with glaucoma medication. Am J
Ophthalmol 2007;144:520–4.
5. Higginbotham EJ, Hansen J, Davis EJ, et al. Glaucoma
medication persistence with a fixed combination versus mul-
tiple bottles. Curr Med Res Opin 2009;25:2543–7.
6. Higginbotham EJ, Olander KW, Kim EE, et al; United States
Fixed-Combination Study Group. Fixed combination of lata-
noprost and timolol vs individual components for primary
open-angle glaucoma or ocular hypertension: a randomized,
double-masked study. Arch Ophthalmol 2010;128:165–72.
7. Katz G, Dubiner H, Samples J, et al. Three-month randomized
trial of fixed-combination brinzolamide, 1%, and brimonidine,
0.2%. JAMA Ophthalmol 2013;131:724–30.
8. Nguyen QH, McMenemy MG, Realini T, et al. Phase 3 ran-
domized 3-month trial with an ongoing 3-month safety
extension of fixed-combination brinzolamide 1%/brimonidine
0.2%. J Ocul Pharmacol Ther 2013;29:290–7.
9. Whitson JT, Realini T, Nguyen QH, et al. Six-month results
from a phase III randomized trial of fixed-combination brin-
zolamide 1% þ brimonidine 0.2% versus brinzolamide or
brimonidine monotherapy in glaucoma or ocular hypertension.
Clin Ophthalmol 2013;7:1053–60.
10. Realini T, Nguyen QH, Katz G, Dubiner H. Fixed-combina-
tion brinzolamide 1%/brimonidine 0.2% vs monotherapy with
brinzolamide or brimonidine in patients with open-angle
glaucoma or ocular hypertension: results of a pooled analysis
of two phase 3 studies. Eye (Lond) 2013;27:841–7.
11. Kerr NM, Patel HY, Chew SS, et al. Patient satisfaction with
topical ocular hypotensives. Clin Experiment Ophthalmol
2013;41:27–35.
7
 Ophthalmology Volume -, Number -, Month 2014
12. Sleath B, Robin AL, Covert D, et al. Patient-reported behavior
and problems in using glaucoma medications. Ophthalmology
2006;113:431–6.
13. Djafari F, Lesk MR, Harasymowycz PJ, et al. Determinants of
adherence to glaucoma medical therapy in a long-term patient
population. J Glaucoma 2009;18:238–43.
14. Olthoff CM, Schouten JS, van de Borne BW, Webers CA.
Noncompliance with ocular hypotensive treatment in patients
with glaucoma or ocular hypertension: an evidence-based re-
view. Ophthalmology 2005;112:953–61.
15. Chrai SS, Makoid MC, Eriksen SP, Robinson JR. Drop
size and initial dosing frequency problems of topically
Footnotes and Financial Disclosures
Originally received: March 6, 2014.
Final revision: April 3, 2014.
Accepted: June 13, 2014.
Available online: ---. Manuscript no. 2014-365.
1
Singapore National Eye Centre, Singapore.
2
National University of Singapore, Singapore.
3 prietary or commercial interest in any materials discussed in this article.
Pauls Stradins Clinical University Hospital, Riga, Latvia.
4 This study was funded by Alcon Laboratories, Inc, Fort Worth, Texas.
Oftalmica PAHE, Mexico City, Mexico.
5
Private Practice, Winston-Salem, North Carolina.
6
Szabolcs-Szatmár-Bereg County Hospital, Nyíregyháza, Hungary.
7
Discipline of Ophthalmology, University of Sydney, Sydney, Australia.
8
Glaucoma Unit, Sydney Eye Hospital, Sydney, Australia.
9
Eye Associates, Sydney, Australia.
Presented in part at: the American Academy of Ophthalmology Annual
Meeting, November 16e19, 2013, New Orleans, Louisiana.
Financial Disclosure(s):
The author(s) have made the following disclosure(s): T.A.: Grant support
eAlcon Laboratories, Inc, Allergan, Santen Pharmaceutical Co, Ltd, Ellex,
Ocular Therapeutix, Inc; Consulting feeseAlcon Laboratories, Inc,
applied ophthalmic drugs. J Pharm Sci 1974;63:
333–8.
16. Pisella PJ, Pouliquen P, Baudouin C. Prevalence of ocular
symptoms and signs with preserved and preservative free
glaucoma medication. Br J Ophthalmol 2002;86:418–23.
17. Higginbotham EJ. Considerations in glaucoma therapy: fixed
combinations versus their component medications. Clin Oph-
thalmol 2010;4:1–9.
18. van der Valk R, Webers CA, Schouten JS, et al. Intraocular
pressure-lowering effects of all commonly used glaucoma
drugs: a meta-analysis of randomized clinical trials. Ophthal-
mology 2005;112:1177–85.
Allergan, Santen Pharmaceutical Co, Ltd, Pfizer, Merck Sharp & Dohme,
Bausch & Lomb, Quark Pharmaceuticals; Travel supporteAlcon Labora-
tories, Inc, Allergan, Santen Pharmaceutical Co, Ltd, Pfizer, Ellex. I.G.:
Consultant and advisory board membereAlcon Laboratories, Inc, Allergan,
ForSight, Merck, Pfizer; Speakers bureauseAlcon Laboratories, Inc; Travel
supporteAlcon Laboratories, Inc, Pfizer. The other authors have no pro-
Alcon participated in the design and conduct of the study, data manage-
ment, data analysis, interpretation of the data, and preparation and approval
of the manuscript.
Abbreviations and Acronyms:
AE ¼ adverse event; BBFC ¼ brinzolamide 1% and brimonidine 0.2%
fixed combination; BCVA ¼ best-corrected visual acuity; BID ¼ 2 times
per day; IOP ¼ intraocular pressure; ITT ¼ intent-to-treat; LS ¼ least
squares; SAE ¼ serious adverse event; SD ¼ standard deviation; TID ¼ 3
times per day.
Correspondence:
Tin Aung, FRCS, PhD, Singapore National Eye Centre, 11 Third Hospital
Ave., Singapore 168751. E-mail: aung.tin@snec.com.sg.