RESIDENTS AND FELLOWS
`
`Section Editor: Sumit "Sam" Garg, MD
`
`Topical Corticosteroid
`and NSAID Therapies
`for Ocular Inflammation
`
`A concise overview for clinical practice.
`
`BY GARRICK CHAK, MD: AMANDA E. KIELY, MD; AND PRATAP CHALLA, MD
`
`-
`
`
`
`When beginning to prescribe anti-inflammatory medications, it is common to be confizsed with respect to the
`various preparations that are commercially available What is the dlference in potency between prednisolone,
`loteprednol, and djfluprednate? How do I choose which nonsteroidal drop to usefor my patient? In this second
`installmentfrom Dr. Garrick Chak and colleagues, they review the basics and intricacies ofophthalmic steroidal
`and nonstemidalformulations. Knowledge of the specfics detailed here will allow you to better tailor your medical manage-
`ment ofpatients. As always, you have any recommendationfor "Residents and Fellows," please let me know.
`—Sumit "Sam" Carg. MD, section editor
`
`opical corticosteroids and nonsteroidal anti-
`inllammatory drugs (NSA|Ds) are often used to
`treat ocular inflammation. An appreciation of
`the subtle differences may help physicians deter-
`mine which medication to prescribe as they strive to
`offer patient-centered care.
`
`via corticosteroids)? Corticosteroid therapies disrupt the
`inflammatory cascade by inhibiting the release of arachi-
`donic acid from cell membrane phospholipids, thus pre-
`venting the formation of prostaglandins (cyclooxygenase
`[COX] pathway) as well as leukotrienes and other inflam-
`matory mediators (lipoxygenase pathways).
`
`PEARLS FOR TOPICAL CORTICOSTEROIDS
`
`EFFICACY VERSUS POTENCY
`
`Topical ophthalmic corticosteroid agents can be clas-
`sified as ketone steroids (prednisolone, difluprednate,
`dexamethasone, fluorometholone, and rimexolone)
`or ester steroid (loteprednol) based on phannacologic
`design. Loteprednol is formulated with an ester instead of
`a ketone group at the C-20 position.‘ Thought to be cata-
`ractogenic, the C-20 ketone group forms a covalent bond
`with lens proteins that are found only in steroid-induced
`cataracts.‘ Although this is a widely accepted hypothesis
`for steroid-induced cataracts, other mechanisms may exist.
`In clinical practice, corticosteroids are often grouped
`broadly by anti-inflammatory potency, defined as the
`binding affinity of the drug to the glucocorticoid receptor.
`As a brief review, the corticosteroid binds to a glucocorti-
`coid receptor that is located in the cytosol. Once bound,
`the glucocorticoid receptor is activated and migrates into
`the nucleus where it modulates signaling pathways and
`protein expression (more than 5,000 genes are targeted
`
`The anti—inflammatory potency of a drug is a phar-
`macologically relative term—in some instances relative
`to hydrocortisone’ and in other instances relative to
`dexamethasone‘—and is not necessarily tantamount
`to its clinical efficacy topically. For instance, topical
`dexamethasone alcohol 0.1% is known to have a sixfold
`
`higher potency and double the half-life of topical pred-
`nisolone acetate 1% (Table 1). Even so, the latter attained
`a peak aqueous concentration that was more than 21 to
`36 times higher than the former and also persisted with
`a detectable drug aqueous concentration after 24 hours
`(whereas the former was undetectable) because of supe-
`rior penetration of the drug.‘ Thus, when selecting the
`appropriate corticosteroid for the patient, the eye care
`provider should note that the efficacy of a topical corti-
`costeroid comprises a combination of variables such as
`potency, vehicle, drug concentration, duration of action,
`and ocular penetration.
`
`NOVEMBER/DECEMBER 2014 CATARACT B4 REFRACTIVE SURGERY TODAY 15
`
`PAGE 1 OF 5
`
`SENJU EXHIBIT 2155
`
`INNOPHARNIA v SENJU
`
`IPR2015—00903
`
`

`
`RESIDENTS AND FELLOWS
`
`TABLE 1. TOPICAL CORTICOSTEROIDS IN THE UNITED STATES
`
`Topical Potency
`(Clinical Efficacy)
`
`Anti—inflammatory Potency
`(Relative to Hydrocortisone)
`
`Average IOP Rise, mm Hg
`
`Highest
`
`Difl uprednate
`
`Highest
`
`Higher
`
`Higher
`
`High
`
`Moderate
`
`Moderate
`
`Moderate
`
`Prednisolone
`acetate
`
`Dexamethasone
`acetate
`
`Prednisolone
`phosphate
`
`Loteprednol
`etabonate
`
`Rimexolone
`
`Dexamethasone
`
`phosphate
`Fluorometholone
`acetate
`
`178
`
`10.0 + 1.7
`
`22.0 + 2.9
`
`1.7% with spike > 10 mm Hg
`(901 patients)
`
`2% with spike > 10 mm Hg
`(98 patients)
`
`4
`
`25
`
`4
`
`25
`
`2S
`
`25
`
`40-50
`
`61 + 1.4
`
`Half-life of
`
`Drug, hrs
`
`2x as long as
`betamethasone
`
`18—36
`
`3664
`
`18-36
`
`36-54
`
`— 1-0+1-3 K
`Mild
`Fluorometholone
`40—S0
`alcohol
`
`3-2+1-4
`@—
`
`SOLUBILITY. PENETRATION, AND
`CONVENIENCE
`
`Within a class of corticosteroids, the acetate, the phos-
`phate, or the alcohol form—somewhere in between
`acetate and phosphate in the solubility spectrum—gives
`physicians an idea of the drug's propensity for corneal
`penetration and may change the relative anti—inflam matory
`efficacy of the drug. Aqueous humor samples have shown
`that prednisolone acetate achieves higher drug concen-
`trations than prednisolone sodium phosphate in the
`presence of an intact corneal epithelium.‘ The acetate
`form is more lipophilic and available as a suspension,
`which leads to longer contact time and better penetra-
`tion. The phosphate form is more hydrophilic, however,
`and is available as a solution. Topical prednisolone sodi-
`um phosphate 1% is less effective than topical predniso-
`lone acetate 1% due to bioavailability and penetration
`(lower ability to achieve high aqueous humor concentra-
`tion of the drug through an intact corneal epithelium)?
`Generally, a suspension (for instance, prednisolone
`acetate) must be shaken vigorously for the medication to
`be homogenous upon application,“ whereas a solution
`(eg, prednisolone sodium phosphate), an emulsion
`
`(eg. difluprednate), or a gel (eg, loteprednol etabonate)
`removes this responsibility from those who find shaking
`agitating. Even among prednisolone acetate suspensions,
`a generic version has been shown to have poorer dose
`uniformity and may require more shaking in order to
`achieve the same dose uniformity as a brand-name ver-
`sion.9 Besides the convenience of not requiring shaki ng.
`difluprednate 0.05% does not contain benzalkonium
`chloride (BAK); instead, it uses sorbic acid as a preserva-
`tive. Alternative topical corticosteroids without BAK
`include preservative-free dexamethasone 0.1%, preserva—
`tive—free loteprednol 0.5%, and compounded preserva-
`tive-free methylprednisolone 1%. Table 1 provides a quick
`reference list of topical corticosteroids that are frequently
`prescribed in the United States.“”“
`
`RISK AND REWARDS, IOP ELEVATION
`With corticosteroid therapy, higher anti—inflammatory
`rewards do not come without the potential for higher
`risk, such as IOP elevation, cataractogenesis, epithelial
`breakdown into a geographic ulcer if administered in the
`presence of a herpetic dendritic ulcer, and fungal infec-
`tion with |ong—term corticosteroid use. Generally, the risk
`
`16 CATARACT 84 REFRACTIVE SURGERY TODAY NOVEMBER/DECEMBER 2014
`
`PAGE 2 OF 5
`
`

`
`RESIDENTS AND FELLOWS
`
`TABLE 2. NSAIDS IN THE UNITED STATES
`
`pm3
`-E2
`Bromday 0.09%
`Bausch + Lomb - BAK 0.005%
`Prolensa 0.07%
`Bausch + Lomb ‘ BAK 0.005%
`Voltaren 0.1%
`Alcon
`0.085
`BAK 0.005%
`
`Diclofenac
`
`Thimerosal 0.004%
`
`Preservative free
`
`0.102
`
`Thimerosal 0.005%
`
`BAK 0.01%
`
`BAK 0.006%
`
`Preservative free
`
`BAK 0.005%
`
`BAK 0.005%
`
`Ophtha co
`Voltaren 0 1%
`
`Ophtha
`
`Dicloftil 0.1%
`
`Alcon
`
`Farrnigea
`(not available in the United States)
`
`EEi
`
`Ketorolac
`
`Nepafanac
`
`for a steroid—re|ated IOP spike is correlated to the poten-
`cy of the topical steroid; other influencing factors include
`the duration and frequency of the drug's administration
`as well as the susceptibility of the individual.
`About one—third of the general population are potential
`moderate steroid responders (IOP increase of 6-15 mm
`Hg). About 5% to 6% of the general population, in addition
`to the 33% mentioned previously, are severe responders
`(IOP increase > 15 mm Hg. with many havinga marked
`IOP increase of > 31 mm Hg after 4-6 weeks of topical ste-
`roid LLse).‘5-‘° Despite proper tapering of topical corticoste-
`roid therapy, IOP may not necessarily decrease in steroid-
`responsive patients who are at increased risk of developing
`open—angle glaucoma. Also, topical corticosteroids may
`yield a crossover effect with IOP elevation in the fellow eye
`from systemic absorption." The provider should be aware
`that corticosteroid use may lead to a dose-dependent IOP
`spike that occurs more frequently, more severely, and more
`rapidly in children than in adults.“
`Due to the potential IOP elevation with the stronger
`corticosteroids, "softer" corticosteroids have been stra-
`tegically designed to reduce the risk of IOP elevation.
`Loteprednol and rimexolone are rapidly hydrolyzed into
`their respective inactive metabolite, and fluorometho—
`|one—despite a surprisingly high pharmacologic poten-
`cy—is considered a soft steroid because of its limited
`corneal penetration.‘ P|acebo—contro| led trials have been
`
`conducted, but there has not been a randomized head-
`to-head comparison of the softer steroids.
`By knowing the profile of each corticosteroid, an oph-
`thalmic provider can select the most appropriate anti-
`inflammatory medication for the patient.
`
`N SA I D P EA R L S
`
`NSA|Ds produce a variety of ocular effects. The grow-
`ing body of scientific evidence suggests they may be
`beneficial in diabetic retinopathy, diabetic macular
`edema, age-related macular degeneration, and even ocu-
`lar tumors. The longest-standing and most widespread
`uses of NSA|Ds, however, are for reducing postoperative
`inflammation and preventing and treating cystoid macu-
`lar edema (CME) associated with intraocular surgery.
`This article focuses on those applications
`NSA|Ds reduce inflammation by inhibiting COX
`enzymes (COX-1 and COX-2), thereby limiting the produc-
`tion of prostaglandins via the arachidonic acid cascade.
`Prostaglandins mediate multiple inflammatory changes,
`increasing vasodilation and vascular permeabi|ity.‘°'2° In the
`eye, the drugs also disrupt the b|ood—aqueous barrier, lead-
`ing not only to iritis but also increasing the risk of CME as
`inflammatory mediators leak into the eye. Topical NSA|Ds
`have been shown to be more effective than corticosteroids
`
`in re-establishing the blood-aqueous barrier and can thus
`play a critical role in the management of postoperative
`
`18 CATARACT &- REFRACTIVE SURGERY TODAY NOVEMBER/DECEMBER 2014
`
`PAGE 3 OF 5
`
`Bromfenac
`
`Xibrom 0.09%
`
`Fomierly Ista Pharmaceuticals; now
`
`0.023
`
`Benzalkonium
`
`

`
`RESIDENTS AND FELLOWS
`
`and other ophthalmic inflammation." When choosing an
`NSAID, several factors are worth considering.
`
`E F FICA CY
`As a rule, the inhibition of COX-2—inducib|e in inflam-
`
`matory conditions—determines the clinical efficacy of
`an ophthalmic NSAID (Table 2).""-3 Interestingly, how-
`ever, evidence does not support a direct correlation
`between in vitro potency, measured by the ICSO (the
`concentration required to reduce enzyme activity to
`half), and either bioavailability or medication effective-
`ness.“ Flach et al compared the anti-inflammatory effects
`of diclofenac (ICSO = 0.085 um) and ketorolac (ICSO =
`0.12 pm) in a double-masked study of 120 postoperative
`patients using both a laser cell and flare meter and clinical
`observation. The investigators found the two treatments
`to be equivalent.” Bromfenac has the lowest ICSO of the
`group (0.023 pm), indicating greatest potency. A 2007
`study, however, com pared the in vivo concentration and
`in vitro PGE2 inhibition of amfenac, its prodrug nepaf-
`enac (nepafanac is converted to bioactive amfenac pri-
`marily by ocular tissue hydrolasesz‘), ketorolac, and brom-
`fenac. Nepafenac proved to be most bioavailable with
`the shortest time to peak concentration and the highest
`peak aqueous humor concentration. Amfenac was more
`potent at COX-2 inhibition than either bromfenac or
`ketorolac (the most potent COX-1 inhibitor)?’
`On the other hand, another study conducted that
`same year suggested ketorolac was as effective as nepaf-
`enac clinically (assessed using BCVA, anterior chamber
`inflammation on examination, and pain control) and
`perhaps better tolerated, with greater reported satisfac-
`tion and compliance among patients.’“9
`Although flurbiprofen reduces intraoperative miosis
`and inflammation after cataract surgery, the weight of
`the scientific evidence suggests it is less effective than
`other available NSA|Ds.3°
`
`DOSING SCHEDULE
`
`While maximizing drug effect may be necessary in
`some patients (eg, those with persistent macular edema),
`in many routine cases, it is just as important that ease
`of drop use facilitates patients’ adherence to therapy.
`Several studies have examined reduced dosing schedules
`for bromfenac, ketorolac, and nepafenac. Among dosing
`schedules for nepafenac, dosing three times a day resulted
`in better pain control on day 1 after cataract surgery. By
`postoperative day 3, patients using nepafenac only once
`daily were equally comfortable, however, and by day 14,
`there was no measureable difference in inflammation."
`
`A more recent small study suggested that bromfenac
`administered just once daily was equivalent to nepafenac
`
`closed three times daily after cataract surgery, based
`on measures of anterior chamber inflammation, BCVA,
`macular volume/retinal thickness, and IOP." Twice-daily
`dosing of ketorolac has been evaluated versus placebo
`but not head-to-head with other agents.
`
`SIDE EFFECTS
`
`In the 19905, reports of corneal melting associated with
`topical NSAID use caused significant concern in the oph-
`thalmology community. Most cases were associated with
`a now-discontinued diclofenac product (DSOS) and felt
`to be related to the vitamin E-based solubilizer tocopher-
`solan it containedm’ However, a few cases of corneal
`melt have since been associated with other formulations
`
`of ophthalmic diclofenac. One proposed mechanism is
`depletion of the neuropeptide substance P within the cor-
`neal epithelium, which is associated with delayed wound
`healing and a risk of neurotrophic keratopathy.“ It is also
`speculated that diclofenac increases the production of
`lipoxygenase-derived LTB4, a polymorphonuclear chemo-
`tactic, leading to corneal inflammation and melting.”
`
`CO N C L U S I O N
`
`In general, the ophthalmic practitioner should consider
`the patient's profile when prescribing topical corticosteroids
`or NSAlDs. With corticosteroids, matching the penetration
`and potency of the drug with consideration of clinical con-
`text, contraindications monitoring of the potential devel-
`opment of open-angle glaucoma, and the patient's physical
`limitations guides selection of the topical corticosteroid
`that is most appropriate for the patient Before prescribing
`an NSAID, it behooves practitioners to determine whether
`a patient is predisposed to delayed wound healing (as in
`diabetes, rheumatoid arthritis, or other autoimmune inflam-
`
`matory conditions) or has likely comeal denervation (as in
`severe ocular surface disease, a history of herpetic keratitis,
`or after multiple complex ocular surgeries). Certainly, as
`with topical steroids, patients should not follow a pro-
`longed, unsupervised course of topical NSA|Ds. I
`
`Section Editor Sumit “Sam” Garg, MD, is the medical direc-
`tor, vice chair ofclinical ophthalmology, and an assistant
`profiessor of ophthalmology at the Gavin Herbert Eye Institute
`at the University of Calfibmia, Irvine, School ofMedicine. He
`also serves on the ASCRS Young Physicians and Residents
`Clinical Committee and is involved in re5idents'andfiellows'
`education Dr. Garg may be reached at gargs@uci.edu.
`Garrick Chak, MD, and Amanda
`E Kiely, MD, are glaucoma fellows
`at the Duke Eye Center in Durham,
`North Carolina. They both acknowl-
`edged no financial interest in the
`
`
`
`20 CATARACT & REFRACTIVE SURGERY TODAY NOVEMBER/DECEMBER 2014
`
`PAGE 4 OF 5
`
`

`
`products or companies mentioned herein. Dr. Chak may
`be reached at garriclcchak@dmduke.edu, and Dr. Kiely
`may be reached at amanda.kiely@dm.duke.edu.
`Pratap Challa, MD, is the director of the
`ophthalmology residency program and an
`associate professor of ophthalmology at the
`Duke Eye Center in Durham, North Carolina.
`He acknowledged no financial interest in the
`products or companies mentioned herein. Dr. Challa may
`be reached at pratap.challa@dm.duke.edu.
`
`
`
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`PAGE 5 OF 5