Bromfenac Ophthalmic Solution 0.

07%
Dosed Once Daily for Cataract Surgery
Results of 2 Randomized Controlled Trials
Thomas R. Walters, MD,1 Damien F. Goldberg, MD,2 James H. Peace, MD,3 James A. Gow, BSc(Med), MD,4
for the Bromfenac Ophthalmic Solution 0.07% Once Daily Study Group*

Purpose: To evaluate the efficacy and ocular safety of bromfenac ophthalmic solution 0.07% (Prolensa)
dosed once daily for the treatment of ocular inflammation and pain in subjects who underwent cataract surgery
with posterior chamber intraocular lens implantation.
Design: Two phase 3, randomized, double-masked, placebo-controlled, multicenter clinical trials.
Participants: Four hundred forty subjects (440 study eyes: 222 in the bromfenac group and 218 in the
placebo group).
Methods: Two phase 3, prospective, randomized, double-masked, placebo-controlled clinical trials were
conducted at 39 ophthalmology clinics in the United States. Subjects 18 years of age or older were randomized to
receive either bromfenac 0.07% or placebo dosed once daily beginning 1 day before cataract surgery, on the day
of surgery, and continuing for 14 days after surgery (for a total of 16 days). Subjects were evaluated on days 1, 3,
8, 15, and 22 after surgery. The primary efficacy end point was cleared ocular inflammation, as measured by the
summed ocular inflammation score of zero (anterior chamber cell count ¼ 0 and absence of flare) by day 15.
Secondary end points included cleared ocular inflammation at day 15 and the number of subjects who were pain
free at day 1. The data from the 2 clinical trials were integrated for analyses.
Main Outcome Measures: Summed ocular inflammation score and ocular pain.
Results: A significantly higher proportion of subjects treated with bromfenac 0.07% achieved complete
clearance of ocular inflammation by day 15 and at day 15 compared with placebo (P < 0.0001). A statistically
significantly higher proportion of subjects in the bromfenac 0.07% group were pain free at all study visits
compared with those in the placebo group (P < 0.0001). Fewer subjects in the bromfenac group (3.2%) dis-
continued investigational product early because of a lack of efficacy than in the placebo group (23.9%;
P < 0.0001). The incidence of adverse events was significantly lower in the bromfenac 0.07% group compared
with the placebo group (P ¼ 0.0041).
Conclusions: Bromfenac ophthalmic solution 0.07% dosed once daily was clinically safe and effective
compared with placebo for the treatment of ocular inflammation and pain in subjects who had undergone cataract
surgery and may be a beneficial addition to the current standard of care, which commonly includes ophthalmic
antibiotics and corticosteroids. Ophthalmology 2014;121:25-33 ª 2014 by the American Academy of Ophthal-
mology.

*Group members listed online in Appendix 1 (available at http://aaojournal.org).

Cataracts are the leading cause of blindness in the United
States and worldwide.1 Although approximately 10 million
cataract surgeries are performed annually worldwide,
untreated cataract-associated blindness is increasing by
approximately 1 million people per year, and those with
cataracts leading to a visual acuity of worse than 6/60 is
increasing by 4 to 5 million annually.2 By 2020, more than
30 million people in the United States will have a cataract.3
Numerous population-based studies have shown that age
and female gender are leading factors for the onset of cat-
aract3e7; the incidence of a nuclear cataract has been esti-
mated to occur in 40% of United States adults older than 75
years.8 Buch et al9,10 noted that cataract surgery can reduce
a patient’s visual impairment by more than one third.
Different medications have been developed to reduce
inflammation after cataract surgery, including corticoste-
roids and nonsteroidal anti-inflammatory drugs (NSAIDs).
Ophthalmic NSAIDs are used to reduce ocular pain and
inflammation in patients after cataract surgery, and in the
United States, it is becoming more prevalent to begin
NSAID dosing anywhere from 1 to 2 days before surgery.11
Nonsteroidal anti-inflammatory drugs inhibit cyclo-
oxygenase enzymes that synthesize prostaglandins via the
arachidonic acid pathway.12e15 Prostaglandins have a crucial

 2014 by the American Academy of Ophthalmology ISSN 0161-6420/14/$ - see front matter 25
Published by Elsevier Inc. http://dx.doi.org/10.1016/j.ophtha.2013.07.006
 Ophthalmology Volume 121, Number 1, January 2014
role in the onset of postoperative pain and inflammation.
Bromfenac, a well-studied NSAID, has been shown to be
a potent inhibitor of cyclooxygenase.16 The United States
Food and Drug Administration (FDA) has approved several
NSAIDs for the reduction of postoperative inflammation
after cataract surgery.17
Bromfenac sodium is designated chemically as sodium
2-amino-3-(4-bromobenzoyl) phenylacetate sesquihy-
drate.18 The additional bromine atom increases the
absorption into ocular tissue and increases the duration of
effect.19e21 In a preclinical14 study in New Zealand White
rabbits, bromfenac was detected in all ocular tissues 24
hours after a single dose of the 0.09% concentration.22
Bromfenac has been studied extensively in the Untied
States and Japan and has demonstrated effectiveness as
a topical agent.23e30 In 2000, bromfenac sodium hydrate
ophthalmic solution 0.1% (Bronuck; Senju Pharmaceuticals
Co, Osaka, Japan) was approved by the Japanese Ministry
of Health, Labour and Welfare and currently is approved for
twice-daily use in Japan as a treatment for blepharitis,
conjunctivitis, scleritis, and postoperative inflammation.31
Bromfenac ophthalmic solution 0.09% (Xibrom; ISTA
Pharmaceuticals, Inc, Irvine, CA) was approved by the
United States FDA in 2005 for twice-daily dosing in the
treatment of ocular inflammation after cataract surgery with
posterior chamber intraocular lens (IOL) implantation and
in 2006 for the treatment of postoperative ocular pain with
no predosing and twice-daily administration.32 The
Japanese and United States versions of bromfenac 0.09%
are identical; in computing concentrations, the Japanese
formulation is labeled as the sodium salt (0.1%), whereas
the United States formula is labeled as the free acid
concentration (0.09%).
The pivotal studies on which the FDA based the
approval of bromfenac ophthalmic solution 0.09%
(Xibrom) were 2 randomized, double-masked, vehicle-
controlled United States clinical trials evaluating bromfenac
0.09% instilled twice daily for 14 days; the results indicated
that bromfenac 0.09% had a significant effect on reducing
intraocular inflammation after cataract surgery (62%e66%,
compared with 40%e48% in the placebo group). Eighty
percent of bromfenac-treated subjects reported no ocular
pain on postoperative day 1; the bromfenac group also had
a statistically significant difference in median time to
resolution of ocular pain of 2 days compared with 4 days
for the placebo group.32
Once-daily dosing has the potential benefits of both
improved patient compliance and limited ocular exposure to
the active ingredient.33 After the FDA approval of bromfenac
ophthalmic solution 0.09%, researchers conducted dose-
ranging studies including bromfenac 0.09% dosed once
daily. Four randomized, double-masked, placebo- or active-
controlled clinical trials then were conducted to evaluate
bromfenac 0.09% dosed once daily for the same indications
as its twice-daily counterpart.26 As a result of those clinical
trials, a once-daily version of bromfenac 0.09% (Bromday;
Bausch and Lomb, Irvine, CA) was approved in the United
States in 2010 for the treatment of postoperative inflamma-
tion and reduction of ocular pain in patients who have
undergone cataract extraction.18
26
Researchers then reassessed the 0.09% once-daily
formulation to determine if a lower concentration of brom-
fenac ophthalmic solution would be effective in the treat-
ment of postoperative pain and inflammation associated
with cataract surgery. Bromfenac ophthalmic solution
0.07% was formulated using a more physiologic pH (7.8),
which has been shown to improve penetration into ocular
tissues.23 Limiting the ocular exposure to a medication may
result in decreased adverse events (AEs), which is important
because, historically, ocular NSAID use has resulted in
small numbers of corneal erosions or melts.34e37 We
hypothesized that bromfenac 0.07% dosed once daily would
be safe and effective as a treatment for ocular inflammation
and pain in subjects who underwent cataract surgery with
posterior chamber IOL implantation.
Methods
Patients
These 2 multicenter, prospective, randomized, double-masked,
placebo-controlled clinical trials received approval from an insti-
tutional review board (Sterling Institutional Review Board, Atlanta,
Georgia). These clinical trials were conducted in accordance and
adherence with the Declaration of Helsinki (Edinburgh 2000), the
Code of Federal Regulations, and the International Conference on
Harmonisation, including the maintenance of patient confidenti-
ality and compliance with the United States Health Insurance
Portability and Accountability Act. Both clinical trials were
registered with ClinicalTrials.gov (accessed July 2, 2013) with the
single identifier of NCT01367249. Written informed consent was
received from each subject at each of the 39 study sites across the
United States.
Study Design
The FDA requires that phase 3 clinical trials in this therapeutic area
be properly controlled by including a placebo control group. This
phase 3 trial was inclusive of 2 pivotal studies that were conducted
under the same protocol. Study S00124-ER (ER) enrolled United
States clinical sites east of the Mississippi River and study S00124-
WR (WR) enrolled United States clinical sites west of the Mis-
sissippi River. The sample size was determined based on previous
studies26 assessing the use of bromfenac ophthalmic solution
0.09% with identical study designs in which 27.4% of subjects
in the control group and 51.1% of subjects in the bromfenac
group achieved complete clearance of ocular inflammation by
day 15. Separate randomization sequences were used in each
study, and each of the 4 groups (ER bromfenac, ER placebo,
WR bromfenac, and WR placebo) enrolled at least 75 subjects to
generate sufficient data to demonstrate statistical significance. A
sample size of 75 subjects per treatment arm would provide 80%
power to detect a treatment effect, and the calculation was based
on a 2-sided Fisher exact test of independent proportions con-
ducted with a ¼ 0.05 and was performed using PASS version 2005
(NCSS Statistical Software, Kaysville, UT). To account for
a potential dropout rate of 30%, the required sample size was
increased to 200 subjects, 100 per group. A total of 220 subjects
were enrolled in the ER study and 220 in the WR study and were
included in the intent-to-treat group; 416 subjects received at least
1 dose of either bromfenac 0.07% or placebo and are included in
the safety analysis.
 Walters et al 
Once Daily Bromfenac 0.07%
Study Protocol
All subjects were enrolled between May 2011 and July 2011. All
subjects were screened anywhere from 1 to 8 days before study
enrollment; subjects who signed the informed consent and met all
inclusion and exclusion criteria were randomized to receive either
bromfenac 0.07% or placebo. The enrolled subjects were assigned
sequentially according to a computer-generated randomization list
to receive either bromfenac ophthalmic solution 0.07% or placebo
in a 1:1 ratio. The study investigators, staff, and subjects were
appropriately masked to the identity of the investigational product
(IP). Subjects were exposed only to the IP that they were provided.
Dosing began 1 day before surgery, continued on the day of
surgery, and then continued for 14 days after surgery (for a total of
16 days). The subjects were instructed to instill one drop of the IP
into the lower conjunctival cul de sac of the study eye. Concom-
itant medications (i.e., ophthalmic antibiotics) were allowed per the
investigators’ postoperative standard of care with the exception of
those listed in the exclusion criteria. Although ophthalmic corti-
costeroids commonly may be used in the management of pain and
inflammation after cataract surgery, their use was not allowed to
assess the effect of the IP properly compared with placebo. Follow-
up was at days 1, 31, 81, and 151 after surgery. Subjects then
were seen on day 22 (þ3) after cataract surgery or, if the subject
prematurely discontinued the test agent, on day 7 (þ3) after the
subject’s last dose. The IP could have been discontinued because of
an AE, lack of efficacy, the use of disallowed medications, or other
reasons (i.e., cataract surgery did not occur, informed consent was
withdrawn before the first dose, etc.). For subjects in whom the IP
was discontinued, attempts were made to have the subject return
for a safety follow-up visit. Rescue medications consisted only of
ophthalmic NSAIDs, corticosteroids, or both and were given only
after the subject discontinued because of an AE or because of lack
of efficacy.
Outcome Measures
Efficacy. The primary efficacy outcome was cleared intraocular
inflammation, defined as the proportion of subjects who achieved
a summed ocular inflammation score (SOIS) of grade 0 by day 15
(Table 1). The SOIS was assessed by adding the subject’s anterior
chamber cells and flare grades with the minimum score of
0 and a maximum score of 8; this protocol has been described
previously.26,28
A secondary end point was the proportion of subjects who
achieved complete clearance of ocular inflammation (SOIS ¼ 0) at
day 15. The difference between the “at” and “by” day results is that
the “at” day results included only the subjects who were observed
to have complete clearance at that visit. Another secondary efficacy
outcome was ocular pain as evaluated by the ocular comfort
grading assessment (OCGA) reported in the subjects’ diaries.
Subjects recorded their ocular pain as none, mild, moderate, or
severe at screening and throughout all study days. Subjects
completed their assessment of the 7 symptoms (eye pain, tearing,
itching, foreign body sensation, photophobia, eye discharge, and
haziness) within 1 hour after instilling the drop into the study eye.
A subject was considered to be pain free at a particular visit if there
was a score of none on the pain scale of the OCGA in the subject
diary at that visit. The end point determined the proportion of
subjects who were pain free at day 1. Only the ocular pain data
from the OCGA was integrated from the 2 trials.
Other secondary efficacy outcomes included the proportion of
subjects who achieved an SOIS of grade 0 by and at day 1, day 3,
and day 8, and the proportion of subjects who achieved an ocular
pain score of none at day 3, at day 8, and at day 15.
Table 1. Ocular Inflammation Grading Scale for the Calculation
of the Summed Ocular Inflammation Score
Anterior Chamber Cells* Anterior Chamber Flarey
Grade Cell Count Grade Flare Count
0 0 0 Complete absence
0.5 1e5 cells (trace)
1 6e15 1 Very slight (barely detectable)
2 16e25 2 Moderate (iris and lens clear)
3 26e50 3 Marked (iris and lens hazy)
4 >50 4 Intense (fibrin clot)
The summed ocular inflammation score was calculated by adding the
subject’s anterior chamber cells and flare grades with the minimum score of
0 indicating the absence of inflammation and a maximum score of 8. A
subject could not be enrolled in the trial if there was the presence of cell or
flare at the screening visit in either eye.
*To evaluate, investigators were instructed to use the following methods:
slit-lamp biomicroscope, use 16 magnification; 11-mm oblique high-
intensity beam; aim central cornea in pupillary axis; focus in anterior
aqueous humor; at plane of focus, perform first count of cells; do not focus
on multiple planes; move focus to central cornea; refocus in anterior
aqueous humor; at plane of focus, perform second count of cells; convert
each cell count to a grade (see grading scale above); sum the 2 grades,
divide by 2 to determine the average final cell score; try to score white
blood cells only.
y
To evaluate, investigators were instructed to use the following methods:
slit-lamp biomicroscope, use 16 magnification; 11-mm oblique high-
intensity beam; aim central cornea in pupillary axis; focus in anterior
aqueous humor; single determination; convert flare analysis to grade (see
grading scale above); record the flare grade.
Safety. The safety for these clinical trials was assessed by the
incidence and frequency of ocular and systemic AEs using the
MedDRA version 14.0 (MedDRA MSSO, McLean, VA). The
ophthalmologic evaluations included visual acuity, slit-lamp
examination, intraocular pressure (IOP) assessment, and dilated
funduscopic examination. The OCGA also was used.
Inclusion Criteria
After completion of the informed consent process, male and female
subjects 18 years of age or older were eligible for participation in
the clinical trial if they were scheduled for unilateral cataract
surgery (phacoemulsification or extracapsular cataract extraction)
with posterior chamber IOL implantation without other ophthalmic
surgical procedures (such as limbal relaxing incisions, iridectomy,
or conjunctival excisions). At clinical trial entry, baseline medical
and ophthalmic histories were obtained. The key inclusion criteria
were visual acuity of 0.6 logarithm of the minimum angle of
resolution units or better in the nonstudy eye; no ocular, topical, or
systemic NSAIDs within 1 week of investigational product initia-
tion; no ocular, topical, inhaled, or systemic corticosteroids within
15 days of the IP initiation; and an IOP between 5 and 22 mmHg in
the study eye at screening. For women of childbearing potential,
a negative urine pregnancy test result and agreement to use
a medically acceptable form of birth control for the study period,
including 1 week before and 1 week after completion of the clinical
trial, was necessary.
Exclusion Criteria
Subjects were excluded at the screening visit if they had a known
hypersensitivity to bromfenac or any component of the investiga-
tional products, procedural medications, salicylates, sulfites, or
27
 Ophthalmology Volume 121, Number 1, January 2014
other NSAIDs; had extraocular or intraocular inflammation (i.e.,
any cells or flare in the anterior chamber as assessed using slit-lamp
examination) in either eye at screening, including ongoing, unre-
solved uveitis; had ocular pain (greater than none) on the pain scale
of the OCGA in either eye at the screening visit; had any active or
chronic or recurrent ocular or systemic disease that was uncon-
trolled and was likely to affect wound healing; had an uncontrolled
systemic disease including a bleeding disorder; or had taken anti-
coagulants within 7 days of initiating dosing for this study.
Additional exclusion criteria included the use of ocular, topical, or
systemic NSAIDs or gentamicin within the 7 days before initiation
of dosing with IP or throughout the study; any use of opioid,
narcotic, or other pain-relieving medication that could bias study
results (with the exception of up to 4000 mg/day of acetaminophen
or use of an opioid during surgery within 7 days before initiation of
dosing with the IP or throughout the study); the use of immuno-
modulators such as topical cyclosporine 0.05% within 7 days
before initiation of dosing with the IP or throughout the study; the
use of any corticosteroid within 15 days before initiation of dosing
with the IP or throughout the study; the use of tamsulosin, silo-
dosin, afluzoxin, or finasteride; or the use of any medication within
7 days before initiation of dosing with the IP or throughout the
study that could have interfered with normal lacrimation.
Exclusionary eye pathologic features included any active
corneal pathologic feature in either eye at screening that was
nonstable or worse than mild or that would compromise assessment
of the safety or efficacy of treatment (with the exception of
superficial punctate keratitis in the nonstudy eye), or use of anterior
capsule staining for capsulorrhexis. Subjects also were excluded if
they had undergone corneal transplantation or corneal refractive
surgery in the study eye within the 2 years before study enrollment.
Study Medications
All study participants were instructed to self-instill 1 drop once
daily into their study eye for a maximum total of 16 days (day
before surgery, day of surgery, and 14 days after surgery). All IPs
were provided by the study sponsor (ISTA Pharmaceuticals, Inc)
and included bromfenac 0.07% and vehicle-controlled ophthalmic
solution (placebo; Bausch and Lomb, Inc). These solutions were
formulated identically, with the exception that the vehicle did not
include bromfenac. Bromfenac sodium is a yellow to orange
crystalline powder that may have caused a slight difference in color
between the active and the placebo solutions; all other character-
istics of the solutions were indistinguishable. All drops were
supplied in identical bottles with trial-specific labels, and each of
the bottles was placed into a tamper-evident carton. Both the
bottles and the cartons were masked to all study participants.
Adverse Event Reporting
Adverse events included the incidence and frequency of both
ocular and systemic events and were collected by the study
investigators. Event information was collected for any subject who
had instilled at least 1 dose of the IP. MedDRA version 14.0 was
used to standardize reporting of the AEs.
Data Analysis and Statistical Methods
All randomized subjects were included in the intent-to-treat pop-
ulation. If a subject missed a follow-up appointment, the investi-
gators used the last observation carried forward for efficacy
outcomes. The safety population included all randomized subjects
who had instilled at least 1 dose of the IP. All data from the
bromfenac 0.07% groups were pooled for the integrated analyses,
as were all data from the placebo groups. All data in this summary
analysis are based on the pooled data. The bromfenac 0.07%
28
treatment group and the placebo group were compared using the
chi-square or Fisher exact test for dichotomous or nonordered
categorical response measures and the t test or Wilcoxon rank-sum
test for continuous variable and ordered categorical response
measures.
Results
Demographics and Treatment Allocation
In the 2 clinical trials, a total of 440 subjects were randomized to
bromfenac ophthalmic solution 0.07% (n ¼ 222 subjects) or to
placebo (n ¼ 218; Fig 1). Overall, approximately two-thirds of
subjects in each group were female and approximately three-
quarters were white (Table 2). The proportion of subjects in the
intent-to-treat population who completed treatment (defined as
receiving 16 doses of either the bromfenac 0.07% or placebo) was
significantly higher in the bromfenac 0.07% group than in the
placebo group in the pooled data (64.4% [143/222] v. 45.9% [100/
218]; P ¼ 0.0001). The mean proportion of patient compliance,
calculated as the number of doses received multiplied by 100 and
divided by 16, also was significantly higher in the bromfenac
0.07% group compared with the placebo group (91.2% vs. 76.0%,
respectively; P < 0.0001).
Efficacy End Points
The primary efficacy end point, the proportion of subjects who
achieved complete clearance (SOIS of 0) of ocular inflammation by
day 15, was significantly higher in the bromfenac 0.07% group
(48.6% [108/222]) than in the placebo group (24.3% [53/218];
P < 0.0001; Fig 2). The proportion of subjects who had cleared
ocular inflammation as determined by an SOIS score of 0 was
significantly greater in the bromfenac 0.07% group than in the
placebo group by day 8 (29.7% [66/222] vs. 11.9% [26/218],
respectively; P < 0.0001), and this continued through the
remaining study visits. A significantly higher proportion of
subjects in the bromfenac 0.07% group, compared with those in
the placebo group, also achieved complete clearance (SOIS of 0)
at day 8 (27.0% [60/222] vs. 10.1% [22/218], respectively;
P < 0.0001) and at day 15 (45.5% [101/222] vs. 20.6% [45/218],
respectively; P < 0.001; Fig 3). A secondary efficacy outcome
was the proportion of subjects who were pain free at each study
visit. A significantly greater proportion of subjects were pain free
in the bromfenac 0.07% group than in the placebo group at day 1
(78.8% [175/222] vs. 49.5% [108/218], respectively; P < 0.0001),
and this continued through the remaining follow-up visits (Fig 4).
The mean pain scores in the bromfenac 0.07% group were
significantly lower than those in the placebo group at all follow-
up visits (P < 0.0001 for all comparisons).
Safety End Points
Of the 440 subjects enrolled in these clinical trials, 416 subjects
received at least 1 eye drop and were included in the safety
analysis.
Adverse Events
A total of 148 (35.6%) of 416 subjects included in the safety
analysis experienced an AE. There were a total of 276 AEs re-
ported, 170 of which were unique (i.e., excluding repeated reports
by of the same AE by a subject). The incidence of AEs was
significantly lower in the bromfenac 0.07% group (28.8% [61/
212]) than in the placebo group (42.6% [87/204]; P ¼ 0.0041).
Overall, 31.3% of subjects (n ¼ 130) experienced an AE affecting
 Walters et al 
Once Daily Bromfenac 0.07%

Figure 1. Subject disposition flow diagram (consolidated standards of reporting trials [CONSORT]).

the study eye. The incidence of AEs affecting the study eye by
subjects in the bromfenac 0.07% group (22.6% [48/212]) was
significantly lower than in the placebo group (40.2% [82/204]; P ¼
0.0001). Three subjects in the bromfenac 0.07% group (1.4%) and
4 subjects in the placebo group (2.0%) experienced a serious AE.
The number of subjects who experienced an AE related to the
instilled eye drop was lower in the bromfenac 0.07% group (7.1%
[15/212]) than in the placebo group (21.6% [44/204]).
Among the subjects treated with bromfenac 0.07%, eye pain,
anterior chamber inflammation, and foreign body sensation were
the most frequently reported AEs in the study eye (5.7%, 4.7%, and
Table 2. Subject Demographics
3.3%, respectively). Among the placebo-treated subjects, eye pain,
anterior chamber inflammation, conjunctival hyperemia, photo-
phobia, and corneal edema were the most frequently reported AEs
in the study eye (9.8%, 8.8%, 7.4%, 5.4%, and 4.9%, respectively).
Other reported AEs in the bromfenac 0.07% group included blur-
red vision and photophobia (each 1.9%); conjunctival hyperemia,
increased IOP, and pruritus (each 1.4%); and corneal edema and
increased lacrimation (each 0.9%). Other reported AEs in the
placebo group included foreign body sensation (3.9%); increased
lacrimation (3.4%); ocular hyperemia (2.9%); vitreous floaters
(2.5%); and blurred vision, ocular pruritus, and increased IOP
(each 2.0%).
Overall, 5.3% (22/416) of subjects experienced a systemic AE.
The bromfenac 0.07% group and the placebo treatment group did

Pooled Pooled
Parameter Bromfenac 0.07% Placebo
Intent-to-treat population, no. of subjects 222 218
Age (yrs)
Mean (standard deviation) 68.4 (10.70) 68.5 (9.68)
Gender, n (%)
Male 81 (36.5) 72 (33.0)
Female 141 (63.5) 146 (67.0)
Race, n (%)
American Indian or Alaska Native 1 (0.5) 0 (0%)
Asian 4 (1.8) 8 (3.7)
Black/African American 22 (9.9) 17 (7.8)
White 167 (75.2) 162 (74.3)
Other 28 (12.6) 31 (14.2)
Iris color (study eye), n (%)
Black 0 (0) 0 (0)
Blue 57 (25.7) 65 (29.8)
Brown 109 (49.1) 93 (42.7)
Gray 1 (0.5) 5 (2.3)
Green 24 (10.8) 21 (9.6)
Hazel 31 (14.0) 33 (15.1)
Other 0 (0) 1 (0.5) Figure 2. Graph showing the percentage of subjects with summed ocular
inflammation score (SOIS) of grade 0 by each study visit.

29
 Ophthalmology Volume 121, Number 1, January 2014
Figure 3. Graph showing the percentage of subjects with summed ocular
inflammation score (SOIS) of grade 0 at each study visit.
not differ significantly in the incidence of systemic AEs (5.7% [12/
212] vs. 4.9% [10/204]; P ¼ 0.83).
Discontinuation Rates
Of the enrolled subjects, 34 (15.3%) in the bromfenac 0.07% group
discontinued the IP early compared with 96 (44.0%) in the placebo
group. The 44% early discontinuation rate in the placebo group was
attributed to the following reasons: AE, 13.3%; lack of efficacy,
23.9%; the use of a disallowed medication, 0.9%; and other reasons
(i.e., cataract surgery was not performed, informed consent was
withdrawn, etc.), 6.0%. A significantly higher proportion of subjects
in the placebo group (13.3%; n ¼ 29) than in the bromfenac 0.07%
group (5.0%; n ¼ 11) discontinued the IP early because of an AE
(P ¼ 0.0026). The proportion of subjects in the placebo group
(23.9%; n ¼ 52) who discontinued the IP because of lack of efficacy
also was significantly higher (P < 0.0001) than in the bromfenac
0.07% group (3.2%; n ¼ 7; Table 3). The proportion of subjects who
discontinued from either of the studies and required rescue
medications was significantly higher (P < 0.05) in the placebo
group (39.0% [85/218]) compared with the bromfenac 0.07%
group (11.3% [25/222]). When rescue medications were needed,
prednisolone acetate suspension and bromfenac ophthalmic
solution 0.09% were the most commonly used medications.
Figure 4. Graph showing percentage of subjects with ocular pain score of
0 at each study visit.
30
Discussion
These integrated efficacy and safety clinical results are
consistent with the individual study findings of bromfenac
ophthalmic solution 0.07% showing significant improve-
ments in both primary and secondary end points (Klier SM,
et al. Phase III clinical trial of low concentration bromfenac
ophthalmic solution dosed once daily for postoperative
ocular inflammation and pain. Paper presented at: Annual
American Society of Cataract and Refractive Surgery
Symposium on Cataract, IOL, and Refractive Surgery, April
21-24, 2012; Chicago. Klier SM, et al. Efficacy of low-
concentration, modified bromfenac ophthalmic solution
administered once daily for ocular inflammation and pain
associated with cataract surgery. Paper presented at: Asso-
ciation for Resarch in Vision and Ophthalmology Annual
Meeting, May 6-10, 2012; Fort Lauderdale, FL). In these 2
clinical trials, a significantly greater proportion of subjects
randomized to bromfenac 0.07% achieved clearance of
ocular inflammation by day 15 and were pain free at day 1,
compared with subjects randomized to placebo. The
differences between the “at” versus “by” results for the
percentage of subjects with an SOIS of grade 0 at each study
visit were minimal. The subjects treated with bromfenac
0.07% also had significantly lower numbers of AEs and
significantly lower IP discontinuation rates compared with
participants in the placebo group.
The results with bromfenac 0.07% dosed once daily are
similar to those reported with the use of bromfenac
ophthalmic solution 0.09% with either once- or twice-daily
dosing. In previous clinical trials,24,25,38e40 bromfenac
ophthalmic solution 0.09% dosed twice daily effectively
reduced ocular inflammation and resolved ocular pain more
rapidly than placebo. Studies of once-daily dosing of
bromfenac 0.09%26,28 also found the NSAID to treat ocular
inflammation and pain associated with cataract surgery
effectively. However, the results reported herein involved
a lower concentration of the active ingredient delivered in
a modified formulation. Although all of the bromfenac once-
daily trials used a similar study design, direct comparisons
between the studies cannot be made. The consistency of the
results between bromfenac 0.09% dosed twice daily,
bromfenac 0.09% dosed once daily, and now bromfenac
0.07% dosed once daily emphasizes the clinical usefulness
and potency of the bromfenac molecule. The results with the
modified formulation of bromfenac 0.07% reported in our
studies indicate that ocular penetration and clinical efficacy
can be maintained, and possibly improved, while reducing
the amount of the NSAID on the ocular surface. Another
key finding in our trials included the safety results: Subjects
in the bromfenac 0.07% consistently experienced fewer AEs
compared with subjects in the placebo group, highlighting
the safety profile of this product.
There are potential benefits of a medication that can be
dosed once daily, including the potential for improved
patient compliance, a more favorable safety profile, and
decreased exposure of excipients. The benefits of once-daily
topical dosing have been documented in a glaucoma pop-
ulation33 and in patients with ocular allergies,41 but similar
 Walters et al
Table 3. Proportion of Subjects Who Discontinued Investigational Product Early Because of Lack of Efficacy
Subjects who discontinued the investigational product early because of lack of efficacy
Subjects who discontinued investigational product because of lack of efficacy (by study visit)
Day 0 (day of surgery)
Day 1 (first day after surgery)
Day 3
Day 8
Day 15
benefits can be extrapolated to a cataract surgery population.
Compliance is an important factor in cataract surgery because
patients commonly are prescribed several medications, and
compliance with once-daily dosing has been shown to
improve in patients taking concurrent medications.26,33,38,41
An additional benefit of once-daily dosing is the reduced
exposure of the cornea to benzalkonium chloride,
a commonly used preservative in ophthalmic medications
that has been associated with tear deficiency syndrome and
corneal epithelial dysfunction in higher concentrations.42,43
With the advancements in ophthalmic technology, patient
expectations continue to increase with respect to outcomes;
any benefits in reducing the disruption of natural tear film
could be an important aspect in the management of patients
who have undergone cataract surgery. The bromfenac
ophthalmic solution 0.07% used in our clinical trials contains
benzalkonium chloride at levels no higher than most
currently available preserved ophthalmic NSAIDs.
There are limitations as well as advantages regarding the
integrated results of the bromfenac 0.07% clinical trials. The
current trials included a smaller sample size than in other
clinical trials evaluating higher concentrations of bromfe-
nac, making direct comparisons difficult. There were an
overwhelming number of white subjects in the bromfenac
0.07% clinical trials, which may not be representative of
other clinical settings. Our clinical trials enrolled only
subjects in whom cataract surgery was expected to be
uneventful, and therefore, it is not known if our results
would be different in complicated cataract cases or in cases
where concurrent ocular disease exists. The advantages of
the bromfenac 0.07% clinical trials includes the geographic
diversity of the clinical practices involved and proper
masking of the IP, eliminating potential bias in reported
clinical outcomes.
In conclusion, compared with placebo, bromfenac
ophthalmic solution 0.07% dosed once daily was demon-
strated to be clinically safe and effective for the treatment of
ocular inflammation and pain in subjects undergoing cataract
surgery. Bromfenac ophthalmic solution 0.07% could be
a valuable addition to surgeons’ standard of care after cataract
surgery, which may include ophthalmic antibiotics and
corticosteroids. This advanced formulation of bromfenac,
with a lower concentration of active ingredient, has a similar
efficacy profile as higher concentrations of bromfenac
previously approved by the FDA in the United States and
a safety profile with consistently lower incidence rates than

Once Daily Bromfenac 0.07%
Pooled Pooled
Bromfenac 0.07%, n (%) Placebo, n (%)
7 (3.2) 52 (23.9)
0 0
1 (14.3) 1 (1.9)
3 (42.9) 28 (53.8)
3 (42.9) 23 (44.2)
0 0
those seen in the placebo group. Part of the results from these
clinical trials formed the basis of the FDA approval on April
5, 2013, of bromfenac ophthalmic solution 0.07% as Pro-
lensa.44 The authors recommend that bromfenac 0.07% be
evaluated further in other ocular inflammatory conditions in
which the use of NSAIDs has been demonstrated to be
potentially beneficial.
Acknowledgments. The authors thank Mauricio Muñoz,
PharmD, and Karen Gertz, BA, of Bausch and Lomb, Inc, Irvine,
California, for data review and verification; and Michelle Dalton,
BS, ELS, of Dalton & Associates, Reading, Pennsylvania, for
editorial assistance with scientific content.
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Footnotes and Financial Disclosures
Originally received: January 26, 2013.
Final revision: July 2, 2013.
Accepted: July 9, 2013.
Available online: September 9, 2013. Manuscript no. 2013-147.
1
Texan Eye, Austin, Texas.
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2
Wolstan Eye Associates, Torrance, California.
3
United Medical Research Institute, Inglewood, California.
4
Bausch and Lomb, Inc, Irvine, California.
*See Appendix 1 (available at http://aaojournal.org) for members of the
Bromfenac Ophthalmic Solution 0.07% Once Daily Study Group.
 Walters et al 
Once Daily Bromfenac 0.07%
Presented in part at: 38th Symposium on Cataract, IOL, and Refractive
Surgery of the American Society of Cataract and Refractive Surgery, April
21e24, 2012, Chicago, Illinois; Association for Research in Vision and
Ophthalmology Annual Meeting, May 6e10, 2012, Fort Lauderdale,
Florida; American Academy of Ophthalmology Annual Meeting and Joint
Meeting of the Asia-Pacific Academy of Ophthalmology, November 2012,
Chicago, Illinois.
Financial Disclosure(s):
The author(s) have made the following disclosure(s):
Thomas R. Walters:
Principal Investigator and ConsultantdBausch and Lomb, Inc.
Damien F. Goldberg:
Principal InvestigatordBausch and Lomb, Inc.
James H. Peace:
Principal Investigator and ConsultantdBausch and Lomb, Inc.
James A. Gow:
EmployeedBausch and Lomb, Inc.
Sponsored by Bausch and Lomb, Inc, Irvine, California, which participated
in the design of the study and data analyses and interpretation and super-
vised the preparation of the manuscript and approved the final version. The
authors had full access to all study data and take responsibility for the
integrity of the data and the accuracy of the data analysis. All authors
participated in the interpretation of the study findings and in the drafting or
critical revision of the manuscript, or both.
Correspondence:
James A. Gow, MD, Bausch and Lomb, Inc., 50 Technology Drive, Irvine,
CA 92618e2301.
33