Clinical Ophthalmology
`
`Open access Full Text article
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`O r i g i n a l re s e a rCh
`
`The efficacy of bromfenac ophthalmic solution
`0.07% dosed once daily in achieving zero-to-
`trace anterior chamber cell severity following
`cataract surgery
`
`steven M silverstein 1
`Mitchell a Jackson 2
`Damien F Goldberg3
`Mauricio Muñoz4
`
`On behalf of the Bromfenac
`Ophthalmic solution 0.07%
`Once Daily study group
`1silverstein eye Centers, Kansas
`City, MO, Usa; 2Jacksoneye, inc., lake
`Villa, il, Usa; 3Wolstan & Goldberg
`eye associates, Torrance, Ca, Usa;
`4Bausch + Lomb, Irvine, CA, USA
`
`Correspondence: steven M silverstein
`Silverstein Eye Centers, 4240 Blue Ridge
`Blvd #100, Kansas City, MO, 64133 USA
`Tel +1 816 358 3600
`email ssilverstein@silversteineyecenters.
`com
`
`Purpose: To evaluate the efficacy of bromfenac ophthalmic solution 0.07% dosed once daily
`in achieving zero-to-trace (0–5 cells) anterior chamber cells, following cataract surgery with
`posterior chamber intraocular lens implantation.
`Methods: The study designed employed two Phase III, double-masked, placebo-controlled,
`multicenter clinical trials of 440 subjects, randomized to either bromfenac ophthalmic solution
`0.07% (n=222) or placebo (n=218). Subjects self-dosed once daily, beginning 1 day before
`undergoing cataract surgery with intraocular lens implantation (day −1) and again on the day
`of surgery (day 0) and for 14 days postoperatively. Follow-up was on days 1, 3, 8, and 15. The
`outcome measures included the percentage of subjects with zero-to-trace anterior chamber
`cells at each visit, as determined by the percentage of subjects with #5 anterior chamber cells,
`overall anterior chamber cell grades, and summed ocular inflammation score (SOIS) (combined
`anterior chamber cell and flare scores).
`Results: The proportion of subjects with zero-to-trace anterior chamber cells was significantly
`higher in the bromfenac 0.07% group compared with the placebo group as early as day 3
`(P=0.0007), continued at day 8 (P,0.0001), and through day 15 (P,0.0001). At day 15, 80.2%
`of subjects in the bromfenac 0.07% group achieved zero-to-trace anterior chamber cells compared
`with 47.2% of subjects who did so in the placebo group. The overall anterior chamber cell scores
`were significantly lower in the bromfenac 0.07% group compared with the placebo group at days 3,
`8, and 15 (P,0.0001 at each visit). The SOIS were also significantly lower in the bromfenac
`group compared with the placebo group at days 3, 8, and 15 (P,0.0001 at each visit).
`Conclusion: Bromfenac ophthalmic solution 0.07%, dosed once daily was clinically effective
`in achieving zero-to-trace anterior chamber cell severity after cataract surgery and was superior
`to placebo in all anterior chamber cell severity and inflammation outcome measures.
`Keywords: ocular inflammation, anterior chamber inflammation, non-steroidal anti- inflammatory,
`cells and flare
`
`Introduction
`Cataract surgery is the most frequently performed surgical procedure worldwide.1,2
`With improvements in surgical techniques, patients’ expectations have risen proportion-
`ally;3 however, differences in surgical technique impact the severity of surgical trauma
`and postsurgical recovery.2 The amount of postsurgical ocular pain and inflammation
`a patient has will play a significant role in his/her perception of the surgical success.
`Prospective studies assessing the incidence of postoperative pain have reported that
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`one-third of patients experience pain in the early hours
` following cataract surgery, and the majority of those patients
`(79%) continued to experience pain after leaving the surgical
`facility.4 Anterior chamber ocular inflammation, clinically
`assessed as anterior chamber cell counts and flare, is also
`common following cataract surgery. However, postoperative
`inflammation is frequently viewed as an acceptable risk that
`is largely outweighed by the numerous benefits of cataract
`surgery.3 The management of postoperative inflammation is
`essential, both to ensure rapid recovery following the surgery
`as well as to prevent or decrease the potential for long-term
`complications, such as cystoid macular edema.5
`Postoperative pain and inflammation following pha-
`coemulsification and intraocular lens (IOL) implantation are
`often managed with topical nonsteroidal anti-inflammatory
`drugs (NSAIDs). Recently, this management regimen has
`been extended to include dosing prior to and on the day of
`surgery, to potentially improve analgesia, reduce intra- and
`postoperative inflammation, and to minimize the risk of
`postoperative complications.6 Bromfenac ophthalmic solu-
`tion has been evaluated in numerous clinical studies in both
`Japan and the United States (US)7−14 and has been shown to
`be a potent inhibitor of cyclooxygenase (COX). The COX
`enzyme promotes prostaglandin synthesis by converting
`arachidonic acid into prostaglandin, a necessary component
`for the onset of inflammation.15−19 By blocking both COX-1
`and COX-2 enzymes, the release of potent inflammatory
`mediators located primarily in the iris and ciliary body,
`such as prostaglandin E2, is prevented. In vitro studies have
`shown the IC50 values (the concentration of NSAID needed
`to inhibit 50% of either COX-1 or COX-2) are even lower
`for COX-2, the inducible enzyme primarily responsible for
`prostaglandin E2, a potent inflammatory mediator in surgi-
`cal trauma.16,18 Bromfenac sodium is designated chemically
`as sodium 2-amino-3-(4-bromobenzoyl) phenylacetate ses-
`quihydrate.20 The addition of a bromine atom improves the
`absorption and penetration into ocular tissue and allows for an
`increased duration of effect.21,22 The inclusion of bromine also
`increases the potency against the COX-2 enzyme by provid-
`ing an approximate tenfold greater lipophilicity.23 Bromfenac
`ophthalmic solution was first commercially available in
`Japan as Bronuck® (Senju Pharmaceuticals Co, Ltd, Osaka,
`Japan) and was approved for the treatment of blepharitis,
`conjunctivitis, scleritis, and postoperative inflammation.24
`Bromfenac ophthalmic solution 0.09% (Xibrom™; ISTA
`Pharmaceuticals Inc., Irvine, CA, USA), with no predosing
`and twice-daily administration for 14 days, was granted
`approval by the US Food and Drug Administration (FDA), in
`
`March 2005, for the treatment of ocular inflammation after
`cataract surgery with posterior chamber IOL implantation;
`this was amended, in January 2006, to include the reduction
`of postoperative ocular pain.25 This initial bromfenac 0.09%
`solution was formulated with a pH of 8.3.
`The reduction of ocular inflammation in the bromfenac
`0.09% twice-daily clinical trials assessed zero-to-trace
`inflammation (0−5 cells and no flare in the anterior chamber).9
`Subsequent trials assessing the reduction of anterior chamber
`inflammation following cataract surgery, with bromfenac
`0.09% dosed once daily (which also had a pH of 8.3),
`found the agent to be effective in the complete clearance of
`inflammation at all-time points (days 3, 8, and 15) compared
`with placebo, as well as in reducing ocular inflammation to
`zero-to-trace levels.10 The US FDA approved bromfenac
`0.09% (Bromday®; ISTA Pharmaceuticals Inc.) on October
`16, 2010; this was the first once-daily ophthalmic NSAID
`for the treatment of postoperative ocular inflammation and
`reduction of ocular pain in patients who have undergone cata-
`ract extraction with posterior chamber IOL implantation.20
`Overall, since its initial approval, bromfenac has been a
`beneficial addition to the standard of care in the reduction
`of ocular inflammation.
`Following the approval of Xibrom and Bromday, an
`advanced formulation of bromfenac ophthalmic solution was
`developed to improve ocular penetration, thereby allowing
`for a reduction of the concentration of the active ingredi-
`ent, bromfenac, to 0.07%. The pH was reduced, from 8.3 in
`the 0.09% concentration to 7.8 in the 0.07% concentration,
`in order to increase the lipophilicity of the molecule. The
`reduction in pH to a more physiologic level, closer to that of
`normal tears, may also improve ocular comfort upon instil-
`lation. The hypothesis for the current clinical trials was that
`the once-daily bromfenac ophthalmic solution 0.07% would
`be effective in reducing ocular inflammation and pain after
`cataract surgery. The specific intent of the analysis was to
`evaluate the efficacy of bromfenac 0.07% for reducing the
`level of postoperative anterior chamber inflammatory cells
`to trace or better. Of note: at the time of these studies, bro-
`mfenac 0.09% once daily (Bromday) was marketed in the
`United States; since the US regulatory approval of bromfenac
`0.07% (PROLENSA®; Bausch + Lomb, Bridgewater, NJ,
`USA), Bromday has been discontinued.
`
`Subjects and methods
`Subjects and study design
`The current analyses comprised of two multicenter, pro-
`spective, randomized, double-masked, placebo-controlled,
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`Bromfenac 0.07% zero-to-trace cell severity
`
`clinical trials (ClinicalTrials.gov: NCT01367249;26 approval
`received from Sterling Institutional Review Board, Atlanta,
`GA, USA) that evaluated 440 subjects. The clinical trials27
`were split geographically into an east and a west region of the
`US (Study S00124-ER and Study S00124-WR, respectively).
`Each clinical trial enrolled subjects using separate randomiza-
`tion sequences, and each was comprised of a minimum of
`75 subjects in order to generate sufficient data to demonstrate
`statistical significance.
`The clinical trials were conducted in accordance and
`adherence with the Declaration of Helsinki (Edinburgh
`2000), the Code of Federal Regulations, and the Interna-
`tional Conference on Harmonisation, and maintained patient
`confidentiality and complied with the US Health Insurance
`Portability and Accountability Act.27 Written informed
`consent was received from each subject prior to any study-
`related procedure.
`
`sample size calculations
`A sample size of 75 subjects per treatment arm provided 80%
`power to detect a treatment effect equivalent to that seen with
`a previous bromfenac formulation.10 This calculation was
`based on a two-sided Fisher’s exact test of independent pro-
`portions conducted with an alpha =0.05 and was performed
`using PASS (version 2005; NCSS, Kaysville, UT, USA).
`In order to account for a potential dropout rate of 30%, the
`required sample size was increased to 200 subjects, 100 per
`group.
`This current study is a subset analysis of a larger study on
`the safety and efficacy of bromfenac 0.07% that used those
`same sample size calculation parameters.27
`
`study protocol
`These post hoc analyses were based on Phase III clinical tri-
`als conducted between May 2011 and July 2011; the results
`of the primary endpoints have been previously reported.27
`Briefly, all the subjects were randomized to receive either
`bromfenac 0.07% or placebo; the subjects and study per-
`sonnel were masked to treatment.27 Dosing of the test agent
`began 1 day prior to surgery (day −1), and continued on the
`day of surgery (day 0) and for 14 days after surgery, for a total
`of 16 drops of the investigational eye drop. Subjects self-
`instilled the topical eye drops into the inferior conjunctival
`cul de sac of the study eye. A follow-up visit was scheduled
`on days 1, 3 (±1), 8 (±1), and 15 (±1) after cataract surgery.
`A safety follow-up visit was performed on day 22 (±3) or
`on day 7 (±3) if the subject prematurely discontinued the
`eye drops.27
`
`Topical antibiotics were permitted per the investigators’
`standard practice of postcataract surgery treatment. No other
`ocular, topical, or systemic NSAIDs were allowed. Ocular,
`topical, or systemic gentamicin was not allowed. No form of
`opioid, narcotic or any other pain-relieving medication that
`could have interfered with the interpretation of the study
`results, (eg, gabapentin, pregabalin, or COX-2 inhibitors)
`was allowed. The use of acetaminophen (up to 4,000 mg/day)
`during the study and/or an opioid during surgery (ie, fentanyl)
`was allowed. Topical cyclosporine 0.05% was not allowed.
`The use of ocular, topical, inhaled, or oral corticosteroids
`within 15 days prior to the initiation of dosing with the inves-
`tigational study medication or depot corticosteroids within
`45 days prior to initiation of dosing with the investigational
`study medication or throughout the duration of the study
`was also prohibited.
`
`Outcome measures
`Efficacy
`The outcome measures in the analyses included the
`proportion of subjects with #5 anterior chamber cells,
`overall anterior chamber cell grades, anterior chamber cell
`grades by frequency/severity, and overall anterior chamber
` inflammation. Anterior chamber cell grades were determined
`twice per study visit and were based on a manual count of
`cells using a slit lamp biomicroscope (Table 1). Each of
`the aforementioned endpoints was assessed at days 1, 3, 8,
`and 15.
`
`safety
`As with the earlier published study,27 the safety factors were
`assessed by the incidence and frequency of ocular and sys-
`temic adverse events (AEs), ophthalmological evaluations
`(visual acuity, slit lamp examination, intraocular pressure
`[IOP], and dilated funduscopic examination), as well as the
`Ocular Comfort Grading Assessment (OCGA) that subjects
`completed within 1 hour after instilling the investigational
`product into their study eye.
`
`Table 1 Ocular inflammation grading scale
`Anterior chamber cells
`Anterior chamber flare
`Grade
`Cell count
`Grade
`Flare count
`0
`0
`0
`Complete absence
`0.5
`1–5 cells (trace)
`–
`–
`1
`6–15
`1
`Very slight (barely detectable)
`2
`16–25
`2
`Moderate (iris and lens clear)
`3
`26–50
`3
`Marked (iris and lens hazy)
`4
`4
`Intense (fibrin clot)
`.50
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`inclusion and exclusion criteria
`For this analysis, the inclusion and exclusion criteria were
`the same as in the pivotal Phase III clinical trials.27 Some key
`inclusion criteria included subjects $18 years of age sched-
`uled for unilateral cataract surgery with posterior chamber
`IOL implantation and no other concurrent ophthalmic surgi-
`cal procedures. Visual acuity at baseline had to be logarithm
`of the minimum angle of resolution (logMAR) 0.6 or better
`in the nonstudy eye. The primary exclusion criterion was
`extraocular/intraocular inflammation (any cell or flare in the
`anterior chamber, as assessed using slit lamp biomicroscopy
`examination) in either eye at screening, including ongoing,
`unresolved uveitis. Subjects were also excluded if they had
`administered ocular, topical, or systemic NSAIDs within 1
`week of the study initiation or administered ocular, topical,
`inhaled, or systemic corticosteroids within 15 days of the
`study initiation. Finally, the IOP had to be between 5−22
`mmHg in the study eye at screening.
`
`study medications
`The study medications were provided by the study sponsor
`(Bausch + Lomb) and included bromfenac 0.07% (Bausch +
`Lomb) and placebo (vehicle-controlled ophthalmic solution;
`Bausch + Lomb and JHP Pharmaceuticals, LLC, Parsippany,
`NJ, USA). The ophthalmic solutions were identically for-
`mulated, with the exception that the placebo did not include
`bromfenac. The study medications were supplied in identi-
`cal 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 and
`investigators.
`
`adverse events, safety, and analysis
`The AEs included the incidence and frequency of both ocular
`and systemic AEs. Safety was assessed on study day 22 and
`included all subjects who received at least one dose of the
`study medication. All subjects were included in the intent-
`to-treat population; investigators used the last observation
`carried forward (LOCF) for efficacy outcomes if a follow-up
`visit was missed.
`
`statistical analysis
`The statistical analysis was performed, comparing the brom-
`fenac 0.07% once daily data with placebo data, at each study
`visit. The P-values were derived from a Fisher’s exact test,
`adjusted for multiple comparisons using Hochberg’s method.
`The treatment difference was calculated by subtracting the
`placebo percentage from the bromfenac percentage.
`
`Results
`A total of 440 subjects were enrolled and randomized to
`receive bromfenac 0.07% (n=222) or placebo (n=218). The
`disposition of the subjects has been previously reported.27
`The mean age in the bromfenac 0.07% arm was 68.4 years
`compared with 68.5 years in the placebo arm; these were not
`statistically different. There were significantly more females
`enrolled in both arms (141/222 in the bromfenac arm and
`146/218 in the placebo arm). Table 2 provides an overview
`of the completion rates in the two arms.
`In the LOCF population, at day 15, the proportion of
`subjects with #5 anterior chamber cells was significantly
`higher in the bromfenac 0.07% group (80.2%) compared
`with those in the placebo group (47.2%) (P,0.0001). The
`proportion of subjects with #5 anterior chamber cells was
`also significantly higher in the bromfenac 0.07% group at
`days 3 and 8 compared with the placebo group (P=0.0007
`and P,0.0001 respectively) (Figure 1).
`The overall anterior chamber cell grades were signifi-
`cantly lower in the bromfenac group by as early as day 3 and
`continued through days 8 and 15 (all P,0.0001) (Figure 2).
`When the anterior chamber cell grades were assessed by
`severity, a significantly higher proportion of subjects in the
`bromfenac group had low severity scores at days 3, 8, and 15
`compared with subjects in the placebo group (all P,0.001).
`Conversely, there was a significantly higher proportion of
`subjects in the placebo group with high severity scores at
`days 3, 8, and 15 compared with those in the bromfenac
`group (Figure 3). Finally, the summed ocular inflammation
`score (SOIS), which took into account anterior chamber cell
`count and flare, were significantly lower in the bromfenac
`group at days 3, 8, and 15 compared with the placebo group
`(all P,0.0001) (Figure 4).
`
`safety endpoints
`There were 416 subjects who met the criteria for inclusion
`in the safety analysis (received at least one eye drop). The
`safety and tolerability of bromfenac 0.07% has been previ-
`ously reported;27 the incidence of AEs was significantly
`
`Table 2 Subject completion
`Parameter
`Bromfenac 0.07%,
`n (%)
`213/222 (95.9%)
`143/222 (64.4%)
`
`Overall study completion
`Full treatment (16 doses)
`received
`75.9%b
`91.2%
`Percent compliance
`Notes: aThis was statistically significant (P=0.0001); bthis was statistically significant
`(P,0.0001).
`
`Placebo,
`n (%)
`202/218 (92.7%)
`100/218 (45.8%)a
`
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`Bromfenac 0.07% zero-to-trace cell severity
`
`Bromfenac 0.07% (N=222)
`
`Placebo (N=218)
`
`80.2*
`
`68.0*
`
`44.6*
`
`43.1
`
`47.2
`
`19.4
`
`18.8
`
`27.5
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Percentage of subjects
`
`1
`
`3
`
`8
`
`15
`
`Study visit day
`
`Figure 1 Trace anterior chamber cells (cell count ≤5) at each visit day.
`Notes: *P-values statistically significant; days 8 and 15, P,0.0001; day 3, P,0.0007.
`
`lower in the bromfenac 0.07% group than in the placebo
`group (P=0.0041).
`
`adverse events
`Overall, 31.3% (130/416) of subjects experienced an AE
`affecting the study eye. There was a significantly lower
`incidence of AEs affecting the study eye in the bromfenac
`
`0.07% group (48/212 [22.6%]) than in the placebo group
`(82/204 [40.2%]) (P=0.0001). A lower proportion of
`subjects in the bromfenac 0.07% group (15/212 [7.1%])
`experienced AEs related to the eye drop in the study
`eye compared with those in the placebo group (21.6%,
`44/204). Ocular AEs related to the instilled drops occurred
`in $2% of subjects, as follows: eye pain (7.8%, placebo;
`
`2.2
`
`2.2
`
`2.0
`
`1.6*
`
`Bromfenac 0.07% (N=222)
`
`Placebo (N=218)
`
`1.8
`
`1.6
`
`1.1*
`
`0.7*
`
`2.5
`
`2
`
`1.5
`
`1
`
`0.5
`
`0
`
`Transformed anterior chamber cell grade
`
`1
`
`3
`
`8
`
`15
`
`Study visit day
`
`Figure 2 Transformed anterior chamber cell grade at each study visit.
`Notes: Transformed anterior chamber cell grade was transformed as follows: 0=0, 0.5=1, 1=2, 2=3, 3=4 and 4=5. P-value for bromfenac versus placebo for continuous score
`was derived from a Student’s t-test, adjusted for multiple comparisons using Hochberg’s method. *P,0.0001.
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`100
`
`*
`
`*
`
`*
`
`3.0–4.0
`
`1.0–2.0
`
`0–0.5
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Percentage of subjects obtaining score
`
`Day 1
`
`Day 3
`
`Day 8
`
`Day 15
`
`Day 1
`
`Day 3
`
`Day 8
`
`Day 15
`
`Bromfenac 0.07%
`N=222
`
`Placebo
`N=218
`
`Figure 3 Severity of anterior chamber cell scores.
`Note: *P,0.001.
`
`2.8%, bromfenac), anterior chamber inflammation (5.4%,
` placebo; 2.4%, bromfenac), conjunctival hyperemia (3.9%,
`placebo; 0.9%, bromfenac), photophobia (3.9%, placebo;
`0.5%, bromfenac), corneal edema (2.5%, placebo; 0.5%,
`bromfenac), increased lacrimation (2.5%, placebo; 0.5%,
`bromfenac), foreign body sensation (2.5%, placebo; 0%,
`bromfenac), and ocular hyperemia (2%, placebo; 0%
`bromfenac).
`
`Discussion
`Physicians are aware that clinical FDA studies mandate
`that the efficacy endpoint of NSAID trials include the
`proportion of subjects with an SOIS of 0, yet in practical
`daily experience, a noteworthy percentage of patients have
`1−5 anterior chamber cells for longer than 2 weeks following
`cataract surgery. By reporting trace cell data, this study more
`aptly reflects the experience of the nontrial environment.
`
`3.2
`
`3.1
`
`3.1
`
`2.3*
`
`Bromfenac 0.07% (N=222)
`Placebo (N=218)
`
`2.8
`
`2.5
`
`1.5*
`
`1.0*
`
`3.5
`
`3
`
`2.5
`
`2
`
`1.5
`
`1
`
`0.5
`
`0
`
`Mean summed ocular inflammation score
`
`1
`
`3
`
`Study visit day
`
`8
`
`15
`
`Figure 4 Mean transformed summed ocular inflammation score.
`Notes: Transformed anterior chamber cell grade was transformed as follows: 0=0, 0.5=1, 1=2, 2=3, 3=4 and 4=5. P-value for bromfenac versus placebo for continuous score
`was derived from a Student’s t-test, adjusted for multiple comparisons using Hochberg’s method. Transformed summed ocular inflammation score is the sum of the flare and
`transformed cell grades. *P,0.0001.
`
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`Bromfenac 0.07% zero-to-trace cell severity
`
`In these analyses of the zero-to-trace anterior chamber cell
`severity and inflammation in the bromfenac 0.07% Phase III
`clinical trials, the findings consistently demonstrated that
`bromfenac 0.07% effectively reduced anterior chamber
`cell and flare compared with placebo, beginning as early as
`study visit day 3 and continuing through study visit day 15.
`Additionally, there were significantly fewer AEs reported in
`the bromfenac 0.07% group compared with participants in
`the placebo group.
`The clinical results are similar to other trials evaluating
`higher concentrations of bromfenac.9,10,28 In a twice-daily dos-
`ing study, bromfenac 0.09% was able to reduce ocular inflam-
`mation to trace or cleared levels by day 3.9 In a more recent
`study evaluating bromfenac 0.09% dosed once daily, a post hoc
`analysis found that 78.7% of the bromfenac 0.09% once-daily
`group reached zero-to-trace inflammation by day 15, compared
`with only 42% who did so in the placebo group.10
`Direct comparisons of bromfenac 0.07% with other ver-
`sions of bromfenac are not possible as other currently approved
`formulations are of a higher concentration, have different pH
`levels, and/or the clinical trials on those formulations did not
`necessarily include predosing. However, the overall results
`with both the once- and twice-daily versions of bromfenac
`0.09%, as well as the once-daily dosing of bromfenac 0.07%,
`reconfirm the potency of the bromfenac molecule in reducing
`inflammation in the postcataract surgery population. This
`analysis also indicates that a lower concentration of bromfenac
`solution could be as efficacious in reducing cell and flare as
`a higher concentration of bromfenac solution.
`Most importantly, by maintaining the efficacy of already-
`approved bromfenac 0.09% formulations and potentially
`improving the absorption across the hydrophobic corneal
`barrier, via the pH adjustment, to a more physiologic pH,
`once-daily bromfenac 0.07% solution may improve comfort
`and tolerability, particularly at the corneal and/or ocular
`surface level. The incidence of adverse events was sig-
`nificantly lower in the bromfenac 0.07% group than in the
`placebo group and similar to those of earlier formulations
`of bromfenac.
`Safety profiles among ophthalmic NSAIDs are important
`as the early 1990s taught us a valuable lesson about topical
`NSAID safety in terms of corneal AEs, such as corneal
`melts.29 Corneal infiltrates and ulcerative keratolysis were
`associated, in 117 cases, to either diclofenac (27%−61%)
`or ketorolac (12%) in the early 2000s.6 The reported inci-
`dence of serious AEs over the course of 6 years in patients
`who used bromfenac has been found to be extremely low,
`at 0.0002%.30,31
`
`The limitations of the current clinical trials have been previ-
`ously reported27 and include a smaller sample size than in other
`clinical trials evaluating higher concentrations of bromfenac
`and an overwhelming number of Caucasian subjects in the
`bromfenac 0.07% arm. These factors prevent us from making
`direct comparisons with other clinical trial results.
`In summary, the clinical trials clearly demonstrated
`that the proportion of subjects with zero-to-trace anterior
`chamber cells was significantly higher in the bromfenac
`0.07% group, while the overall anterior chamber cell severity
`and SOIS were significantly lower in the bromfenac 0.07%
`group compared with placebo. Based in part on these results
`of the Phase III clinical trials, on April 5, 2013, the US
`FDA approved once-daily use of bromfenac 0.07% (PRO-
`LENSA®) for the treatment of postoperative inflammation
`and reduction of ocular pain in patients who have undergone
`cataract surgery.32 In future clinical assessments, bromfenac
`0.07% may be further evaluated in other ocular inflammatory
`disorders where NSAID use may be potentially beneficial.
`
`Acknowledgments
`The authors thank Sharon M Klier, MD, for contributions to
`the protocol conception and design, and data acquisition; and
`Michelle Dalton, BS, ELS, for medical writing assistance.
`These clinical trials were supported by Bausch + Lomb.
`The Bromfenac Ophthalmic Solution 0.07% Once Daily
`Study Group members were:
`S00124-WR; Jason Bacharach, MD; Donald Beahm, MD;
`James Boyce, MD; E Randy Craven, MD; Jung Dao, MD;
`Michael Depenbusch, MD; Eran Duzman, MD; Joseph Gira,
`MD; Damien Goldberg, MD; Kerry Hagen, MD; Michael
`Korenfeld, MD; Ryan McKinnon, MD; Karl Olsen, MD;
`James Peace, MD; Kenneth Sall, MD; David L Schwartz,
`MD; Steven Silverstein, MD; Robert Smyth-Medina, MD;
`Jon-Marc Weston, MD.
`S00124-ER; Mark Bergmann, MD; Robert Berry,
`MD; Leonard Cacioppo, MD; David Cooke, MD; Thomas
`Elmer, MD; William Flynn, MD; Ronald Frenkel, MD;
`Marvin Greenberg, MD; Brennan Greene, MD; Mitchell
`Jackson, MD; Lawrence Katzen, MD; John Lim, MD; Parag
` Majmudar, MD; Bernard Perez, MD; Francis Price, Jr, MD;
`Eugene Protzko, MD; Harvey Reiser, MD; Stephen Smith,
`MD; W Colby Stewart, MD; Thomas Walters, MD.
`
`Disclosure
`Study support was provided by Bausch + Lomb, Irvine, CA,
`USA. The sponsor participated in the design of the study, data
`collection, data management, data analyses, data interpretation,
`
`Clinical Ophthalmology 2014:8
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`submit your manuscript | www.dovepress.com
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`preparation, review, and approval of the manuscript. The
`authors report no other conflicts of interest.
`
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