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Patient Preference and Adherence
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`6 r
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`A
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`Dove; ll
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`REVIEW
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`Bromfenac ophthalmic solution for the treatment
`of postoperative ocular pain and inflammation:
`safety, efficacy, and patient adherence
`This article was published in the following Dove Press ioiniat
`Patient Preference and Atlierence
`25 jute 20H
`
`Rajesh K Raipal
`Bryan R055
`sachin D Rama]
`Khoa H oang
`See Clearly Vision Group, McLean,
`VA’ USA
`
`Abstract Ophthalmic nonsteroidal anti-inflammatory drugs (NSAIDS) are commonly used
`by clinicians to manage ocular inflammation and pain following cataract surgery. Over the
`past decade, the US Food and Drug Administration has approved multiple topical NSAIDS for
`these purposes, including several reformulated products. One ofthese mediaitions, bromfenac
`ophthahnic solution, has a long and extensive history, with proven efficacy and safety in patients
`,
`,
`,
`,
`following cataract surgery. The evolution of bromfenac ophthalmic solution over the years has
`involved either lowering the concentration of the active ingredient or extending the dosing
`interval to improve patient adherence/compliance. This review will focus on the history and
`progression of bromfenac ophthalmic solution and report the available patient preference and
`adherence data regarding this ocular NSAID throughout its evolution.
`Keywords: cataract surgery, nonsteroidal anti—inflammatory drugs, COX inhibitors
`
`Introduction
`Cataracts are the leading cause of visual impairment and preventable blindness
`worldwide,” with bilateral age-related cataracts causing an estimated 43% of all
`cases of blindness worldwide.’ In the US, blindness or low vision is estimated to
`affect 1 in 28 people older than 40 years ofage.‘ The aging US population is expected
`to have a marked increase in these figures.‘ Phacoemulsification with intraocular
`lens implantation has become the primary surgery to remove cataracts. However,
`with the surgery comes the potential for postoperative pain and inflammation, which
`have long been deemed as acceptable risks given the numerous benefits of cataract
`surgery} The use ofnonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to
`reduce postoperative pain, reduce the risk ofpostoperative inflammation, and improve
`patient comfort.“l° Recent ophthalmic medications have been developed to improve
`product-related comfort, with the overall potential to improve patient preference and
`adherence.
`
`NSAIDs and postoperative inflammation
`NSAIDS have a long history as effective analgesics; their use in ophthalmic disorders
`has been well established. With respect to their mechanism of action, in short, NSAIDS
`inhibit cyclooxygenase (COX) at the site of inflammation.“ COX inhibitors act upon
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`the arachidonic acid pathway to inhibit the production of prostaglandins, thereby
`reducing inflammation.“"‘ Since NSAIDS act at later stages in the arachidonic acid
`pathway than corticosteroids, they can achieve similar anti-inflammatory effects without
`the adverse events (AE5) common with steroid use (eg, increased intraocular pressure
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`Rajpal et al
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`Dovepress
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`and, in phakic patients, cataract development).17–20 Historically,
` clinicians have viewed ophthalmic NSAIDs as an essen-
`tial component of the available treatment options for the man-
`agement of ocular postoperative pain and inflammation. In the
`US, in order to decrease both intraoperative and post-surgical
`inflammation, it is now becoming commonplace to extend oph-
`thalmic NSAID dosing to preoperative use as well, with clini-
`cians opting to dose patients beginning 1–2 days prior to ocular
`surgery, continuing on the day of surgery, and for 2 or more
`weeks post-surgery to reduce inflammation and minimize the
`risk of postoperative complications,21 in particular to prevent
`postoperative cystoid macular edema (CME). In the US, the
`use of NSAIDs for the prevention of CME remains off-label,
`although there is convincing evidence in the literature.22–26 In
`the European Union, nepafenac was the first NSAID granted
`marketing authorization for the prevention of CME.
`
`Chemical history of bromfenac
`Potency
`The bromfenac molecule has been evaluated extensively
`in Japan and the US.27–34 Bromfenac sodium is designated
`chemically as sodium 2-amino-3-(4-bromobenzoyl) phe-
`nylacetate sesquihydrate, with an empirical formula of
`C15H11BrNNaO3 · 1 ½ H2O.35 The addition of the bromine
`atom to the structure increases the potency and penetration
`of the molecule into ocular tissue.36–39 In preclinical stud-
`ies, bromfenac was substantially more potent than other
`analgesics (by a factor ranging from 1.8 to 44.2 times)
`in mice, rabbits, and dogs at suppressing both acute and
`chronic inflammation.37 Ruiz et al also showed the addition
`of bromine to the molecule increased the potency against the
`cyclooxygenase (COX)-2 enzyme by increasing lipophilicity
`almost ten-fold in log scale terms.40
`The potency of an NSAID is commonly measured as the
`necessary concentration of the drug to inhibit COX enzyme
`activity by 50% (IC50). Compared with other ophthalmic
`NSAIDs, bromfenac was shown to be approximately
`three-to-four times more potent at inhibiting COX-2, with
`an IC50 of 0.0075 μm compared with amfenac (0.0204 μm),
`ketorolac (0.0279 μm), and diclofenac (0.0307 μm).39
`
`Ocular penetration
`To be considered an effective topical ophthalmic NSAID,
`the medication needs to be able to penetrate the affected tis-
`sue and remain in the tissue at sufficient levels throughout
`the dosing interval to be clinically effective. As the potency
`and the ability to inhibit prostaglandin production vary
`among the NSAIDs, so does the ability of the available
`
`NSAIDs to penetrate ocular tissues. The pharmacokinetic
`properties associated with any particular NSAID are
`highly correlated with the molecular structure of the
`compound.41 Bromfenac has a chemical structure similar to
`amfenac (the active form of prodrug nepafenac), with the
`distinction of a bromine atom at the 4-position of the benzoyl
`ring.41 By halogenating the molecule, effective in vitro and
`in vivo potency and absorption across the cornea and into
`the ocular tissue have been demonstrated.41
`A 24-hour pharmacokinetic evaluation of a single 50 μL
`14C-bromfenac ophthalmic solution 0.09% administered into
`eyes of New Zealand White rabbits found that after 24 hours,
`the highest concentrations of bromfenac were in the cornea,
`the conjunctiva, and the sclera.41 Similar amounts were
`detected in the aqueous humor, the iris-ciliary body, the chor-
`oid, and, to a slightly lesser degree, the retina. Measurable
`amounts of bromfenac were detected in all samples at
`the 24-hour time point (0.001 μg equivalent/g). In a
`similar 12-hour pharmacokinetic study (Data on file, Bausch
`+ Lomb, Irvine, CA, USA), the eyes of New Zealand White
`rabbits were instilled with 50 μL of either 14C-labeled
` bromfenac 0.07%, pH 7.8 or 14C-labeled bromfenac 0.09%,
`pH 8.3. The highest concentrations of bromfenac-equivalent
`levels were found in the sclera, followed by the iris-ciliary
`body, the aqueous humor, the choroid, the retina, and the
`lens. The total amount of bromfenac-equivalents in all ocular
`tissues was higher in the eyes that received bromfenac 0.07%
`at four of five time points compared with those that received
`bromfenac 0.09%.
`
`Clinical history of bromfenac
`Bromfenac 0.09% (0.1%)
`Bromfenac ophthalmic solution 0.1% was approved as
`Bronuck (Senju Pharmaceutical Co., Ltd., Osaka, Japan)
`in Japan in 2000, and is presently approved in Japan for
`the treatment of postoperative inflammation and anterior
`inflammatory diseases such as blepharitis, conjunctivitis, and
`scleritis.42 Bromfenac ophthalmic solution 0.09%, the same as
`the hydrate-salt bromfenac 0.1% formulation, was approved
`in the US in 2005 as Xibrom (ISTA Pharmaceuticals Inc.,
`Irvine, CA, USA) for the treatment of postoperative inflam-
`mation in patients who have undergone cataract extraction.
`This initial approval was then expanded in 2006 to include
`the reduction of ocular pain after cataract extraction.43
`Formulated at pH 8.3, bromfenac 0.09% dosed twice-
`daily showed superior clinical efficacy over placebo in
`achieving zero-to-trace anterior chamber inflammation
`(0–5 cells and the absence of flare)32 (Table 1). In 2010,
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`Once-daily bromfenac for ocular inflammation and pain
`
`Donnenfeld et al29
`
`Silverstein et al32
`
`Gow et al45,*
`
`Table 1 Bromfenac stud es eva uat ng zero to trace anterior chamber nflammat on
`Study
`Treatments
`Number of eyes
`(patients)
`N= 527 (527)
`Patients with postoperative
`SOiS 3 were treated for 14 days
`starting the day after surgery
`N=455 (455)
`Dosing began 1 day before
`surgery, on the day of surgery,
`and for 14 days following surgery
`N= 440 (440)
`Dosing began 1 day before
`surgery, on the day of surgery,
`and for 14 days following surgery
`Note: *Poster presented at the 2013 Association for Research in vision and Ophthalmolog meeting
`Abbreviations: SOIS, summed ocular inflammation score; vs, versus.
`
`Bromfenac 0.09%, twice daily
`(n=356)
`Placebo (n=171)
`
`Bromfenac 0.09%, once daily
`(n=230)
`Placebo (n=225)
`
`Bromfenac 0.07%, once daily
`(n=222)
`Placebo (n=218)
`
`Zero-to-trace inflammation
`(0–5 cells with 0 flare)
`64% (bromfenac) vs 43.3%
`(placebo) at study day 15
`(P0.0001)
`
`73.9% (bromfenac) vs 40.4%
`(placebo) by day 15
`(P0.0001)
`
`71.2% (bromfenac) vs 39.4%
`(placebo) by day 15
`(P0.0001)
`
`a once-daily formulation of bromfenac 0.09% (Bromday;
`ISTA Pharmaceuticals Inc.) was developed; this was the
`first once-daily ophthalmic NSAID in the US approved
`for the treatment of postoperative ocular inflammation and
`reduction of ocular pain in patients who have undergone
`cataract extraction with posterior chamber intraocular lens
`implantation.35 A study evaluating bromfenac 0.09% dosed
`once daily, also with a pH of 8.3, found that 73.9% of the
`bromfenac 0.09% once-daily group reached zero-to-trace
`anterior chamber inflammation by day 15 compared with
`only 40.4% in the placebo group; the once-daily formulation
`provided similar efficacy to that of the bromfenac 0.09%
`twice-daily formulation.32
`
`Bromfenac 0.07%
`A lower concentration of bromfenac, 0.07%, dosed once
`daily was then evaluated to determine efficacy in the treat-
`ment of postoperative pain and inflammation associated with
`cataract surgery. The lower concentration included a more
` physiologic pH (7.8) to improve penetration into ocular tis-
`sues; the reduced pH also may improve comfort upon instilla-
`tion for some patients. Limiting acute ocular surface exposure
`to a medication also may have an added benefit of a reduced
`incidence of AEs. This may be especially important with the
`use of NSAIDs, as in the past NSAID use has resulted in
`corneal erosions or melts – albeit a low incidence.44
`The advanced formulation of bromfenac 0.07% was
`also effective in reducing ocular inflammation following
`cataract surgery, with significantly higher proportions of
`subjects having zero-to-trace anterior chamber inflamma-
`tion compared with the placebo group as early as day 3 and
`through day 15.45 At day 15, 71.2% of subjects in the
`
`bromfenac 0.07% group achieved zero-to-trace anterior
`chamber inflammation compared with 39.4% of subjects in
`the placebo group.45 Based in part on results of the Phase III
`clinical trials, on April 5, 2013 the US Food and Drug
`Administration approved once-daily use of bromfenac 0.07%
`(Prolensa; Bausch and Lomb Inc., Irvine, CA, USA) for
`the treatment of postoperative inflammation and reduction
`of ocular pain in patients who have undergone cataract
`surgery.6
`Throughout the history of ophthalmic bromfenac, each
`new iteration has reduced either the dosing regimen (from
`twice daily to once daily) or the concentration and pH levels
`(from 0.09%, pH 8.3 to 0.07%, pH 7.8). The only other
`NSAID approved for once-daily dosing is nepafenac, which
`has triple the drug concentration of its three-times-daily
`formulation.
`
`Safety profile
`The safety of the bromfenac molecule has remained consistent
`throughout the various formulations, and AEs have been
` minimal in most studies. Patient-reported comfort and reduced
`dosing frequency may aid patient compliance.46 Over a 7-year
`time frame (from 2000 to 2006), approximately 7.8 million
`patients were treated with bromfenac ophthalmic solution in
`Japan; a total of 16 serious AEs were reported during that
`period, representing an incidence of 0.0002%.47 Since the
`initial approval of bromfenac ophthalmic solution in Japan
`and the US, more than 26 million prescriptions of bromfenac
`have been reported.47
`In the bromfenac 0.09% twice-daily study,29 the most
`common ocular AEs included iritis, abnormal sensations in
`the eye, eye pain, pruritus, posterior capsule opacification,
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`ocular irritation, redness, or conjunctival hyperemia. For the
`majority of these AEs, the incidence was lower in the bro-
`mfenac group than in the placebo group. Only eye pruritus
`was reported in a higher proportion in the bromfenac group
`compared with the placebo group (3.9% versus [vs] 2.9%).29
`No serious ocular AEs were reported in either group.
`In the bromfenac 0.09% once-daily study, the overall
`incidence of AEs in the bromfenac 0.09% group
`(35.1%, [196/559]) was significantly lower compared
`with those in the placebo group (55.0%, [153/278];
`P0.0001).30 Common AEs included eye inflammation,
`conjunctival hyperemia, eye pain, and foreign-body
`sensation.30 The incidence of these AEs also occurred more
`frequently in the placebo group compared with the brom-
`fenac group; only conjunctival hyperemia occurred in a
`higher proportion of subjects in the bromfenac group com-
`pared with the placebo group (8.5% vs 3.7%, respectively).
`The bromfenac group also had a lower incidence of macular
`edema (confirmed by clinician, optical coherence tomo-
`graphy, or fluorescein angiography) compared with the
`placebo group (0.7% vs 1.4%).30
`In the bromfenac 0.07% once-daily study, the incidence
`of adverse events was also significantly lower in the brom-
`fenac 0.07% group compared with the placebo group (28.8%
`vs 42.6%; P=0.0041).44 The most commonly reported
`AEs were eye pain, anterior chamber inflammation, and
` foreign-body sensation, all of which occurred more frequently
`in the placebo group than in the bromfenac group.44
`To date, there are no studies on the use of bromfenac
`0.07% in the treatment of CME or as prophylaxis against
`CME. However, published studies evaluating the use of
`bromfenac 0.09% (in both once- and twice-daily formulas)
`and bromfenac 0.1% have generally found the use of bro-
`mfenac to result in less central retinal thickening and less
`change in macular volume compared with nepafenac;22,48 to
`be efficacious in preventing CME following cataract
` surgery – particularly in patients with nonproliferative dia-
`betic retinopathy;23 and to be more successful at preventing
`CME than fluorometholone 0.1%, dexamethasone 0.1%, or
` betamethasone (all steroids).23,26
`
`Patient preference
`As part of the safety analysis of bromfenac 0.07%, patient
`symptoms were assessed using the Ocular Comfort Grading
`Assessment (OCGA), a nonvalidated set of seven symp-
`toms rated on a 0 to 3 severity scale. Subjects assessed and
`rated each of seven symptoms (eye pain, tearing, itching,
`foreign-body sensation, photophobia [light sensitivity], eye
`
`discharge, and haziness) as 0= none, 1= mild, 2= moderate,
`and 3= severe. A portion of the OCGA results were originally
`published in Walters et al,44 which integrated the results
`from two individual studies for safety and efficacy analyses.
`The individual studies are: bromfenac 0.07% – west US
`region; and bromfenac 0.07% – east US region. Results from
`the individual studies for all symptoms are summarized in
`the next sections.
`The proportion of subjects who were pain free at
`day 1 was significantly higher in the bromfenac 0.07%
`group than in the placebo group in both regions. Addi-
`tionally, change from baseline mean ocular pain in the
`bromfenac 0.07% group was significantly lower than in the
`placebo group in four of four visits in the west region and
`three of four visits in the east region. Mean photophobia
`demonstrated similar results – significantly less photopho-
`bia compared with placebo in four of four visits in the west
`region and three of four visits in the east region. At all four
`study visits (days 1, 3, 8, and 15) for both the west and east
`region studies, the bromfenac 0.07% group demonstrated
`significantly lower tearing severity compared with placebo.
`Foreign-body sensation was significantly less in the brom-
`fenac 0.07% group compared with placebo at three of
`four visits in each region. The bromfenac 0.07% group was
`also better than placebo at three of four visits in the east
`region when change from baseline itching was evaluated.
`The bromfenac 0.07% group had similar changes from base-
`line in both mean eye discharge scores and mean haziness
`scores compared with the placebo group at any visit in both
`regions. Patients preferred bromfenac 0.07% over placebo
`for a majority of symptoms at most time points, which sup-
`ports the comfort of bromfenac 0.07%.
`
`Bromfenac compliance
`and adherence
`Cataract surgery is typically performed in an older population
`already known for poor medication compliance in other oph-
`thalmic disorders.49–52 Commonly prescribed post-surgical
`ophthalmic medications with varying dosing schedules can
`be particularly troublesome for these patients to manage,
`especially if accompanied by stinging and/or burning upon
`instillation. Topical medications that maintain or improve
`upon the efficacy while reducing the medication treatment
`burden of their predecessors are likely to have a beneficial
`effect on patient adherence/compliance.47
`Patient compliance or lack thereof can affect the safety
`and efficacy of a medication during study trials as well as
`in real-world settings. Questions raised range from whether
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`Once-daily bromfenac for ocular inflammation and pain
`
`Table 2 D scont nuat on rates due to ack of efficacy
`Study
`Bromfenac group
`Donnenfeld et al29
`3.1% (11/356)
`Bromfenac 0.09% BiD
`Henderson et al30
`Bromfenac 0.09% QD
`walters et al44
`Bromfenac 0.07% QD
`Abbreviations: BID, twice daily; QD, once daily.
`
`2.9% (17/584)
`
`3.2% (7/222)
`
`Placebo group
`21.6% (37/171)
`
`32.6% (94/288)
`
`23.9% (52/218)
`
`P-value
`P0.0001
`
`P0.0001
`
`P0.0001
`
`the drug is efficacious or has only a limited effect to whether
`the dose is inadequate to demonstrate efficacy to whether
`lower levels of adherence may be due to adverse experi-
`ences. Insufficient medication adherence has been estimated
`to cost between $100 billion and $289 billion in the US and
`€125 billion in the European Union.53
`Patient adherence and compliance is a hotly debated topic.
`In some disease states adherence is critical to survival rates,
`yet some degree of nonadherence is likely in a relatively high
`percentage of patients.54 Hauber et al found that patients are
`willing to pay for additional improvement not only in dosing
`frequency, but also in efficacy and side effects.55 In instances
`where long-term medical therapy is necessary to achieve
`desired outcomes, treatment efficacy can be compromised
`by suboptimal adherence, compliance, and persistence with
`the treatment in general. This occurs both in ophthalmology
`and in other clinical therapeutic areas.56
`In all of the bromfenac studies reported here, the most
`common reasons for discontinuation of the test agent were
`lack of efficacy and adverse events. In the bromfenac 0.09%
`twice-daily study, 81.5% of subjects completed all 28 doses
`of bromfenac compared with 54.4% in the placebo
`group.32 A significantly higher proportion of subjects in
`the placebo group discontinued the test agent due to an
`adverse event compared with the bromfenac group (14.6%
`[25/171] vs 2.8% [10/356]; P0.0001). Also, in the placebo
`group, 21.6% (37/171) of the subjects discontinued the test
`agent due to lack of efficacy compared with only 3.1%
`(11/356) in the bromfenac group (P0.0001) (Table 2).
`Similar results were seen in the bromfenac 0.09% once-
`daily study,33 where early discontinuations from treatment
`occurred less frequently in the bromfenac group compared
`with the placebo group. Of the subjects in the placebo
`group, 16.2% (45/278) discontinued the test agent due to the
`occurrence of an AE compared with only 5.2% (29/559) in
`the bromfenac group (P0.0001). In the bromfenac 0.07%
`once-daily study, the mean proportion of patient compli-
`ance, calculated as the number of doses received multiplied
`by 100 and divided by 16, was significantly higher in the
`
`bromfenac 0.07% group compared with the placebo group
`(91.2% vs 76.0%, respectively; P0.0001).44 As with the
`bromfenac 0.09% study, the primary causes for discontinu-
`ation in the placebo group in the bromfenac 0.07% study
`were lack of efficacy and occurrence of an adverse event.
`A significantly higher number of subjects in the placebo
`group discontinued the study agent due to the occurrence
`of an adverse event than in the bromfenac group (13.3%
`[29/218] vs 5.0% [11/222]; P=0.0026). Furthermore, more
`subjects in the placebo group (23.9% [52/218]) discontinued
`use early due to lack of efficacy than in the bromfenac group
`(3.2% [7/222]; P0.0001).
`
`Conclusion
`The use of topical NSAIDs in ophthalmology has become
`well accepted because of their anti-inflammatory effects as
`well as their potential in improving patient comfort follow-
`ing surgery. Clinical studies on bromfenac have consistently
`confirmed the compound’s potency, both in terms of pene-
`tration into ocular tissue and COX inhibition. Large cohort
`studies also have added to the literature on bromfenac’s
`safety profile.
`The lower concentration of bromfenac 0.07% combined
`with its once-daily dosing may help further improve patient
`adherence and compliance. Clinically, patients have been
`able to benefit from the easier administration and clini-
`cians appreciate bromfenac’s continued efficacy as an anti-
`inflammatory medication that assists in achieving the best
`outcomes possible.
`In conclusion, bromfenac is a molecule with a long his-
`tory of effectively treating pain and inflammation following
`cataract surgery and should be viewed as a valuable tool in
`the ophthalmic NSAID armamentarium.
`
`Acknowledgments
`The authors wish to acknowledge the following contribu-
`tions: Michelle Dalton, BS, ELS, for her medical writing; and
` Mauricio Munoz, PharmD, and Linda Wang, PharmD, for
`data review, verification, and editorial assistance.
`
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`Disclosure
`Bausch + Lomb provided financial assistance and edi-
`torial support in the preparation of this manuscript.
`RR is a consultant for Bausch + Lomb. The authors report
`no other conflicts of interest in this work.
`
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`submit your manuscript | www.dovepress.com
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`Patient Preference and Adherence 2014:8
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