William F. Mieler, MD

University of Illinois at Chicago

Chicago, IL

Advisory Board • Genentech

Data and Safety Monitoring Committee • ThromboGenics (in the past)

• Acucela

Corticosteroids and NSAIDs are the mainstay in the treatment of postoperative pain and inflammation

NSAIDs are one of the most widely prescribed classes of medications worldwide

Ophthalmic formulations of the NSAIDs are

designed to • Enhance mydriasis

• Reduce postoperative pain and inflammation

• Treat and possibly prevent postoperative CME (not an FDA approved indication)

Other indications for NSAIDs include • Decreasing pain and photophobia following

refractive surgery, and scatter photocoagulation

• Alleviate itching associated with allergic conjunctivitis

Potential benefits may also be seen in the treatment of • Diabetic retinopathy

• AMD

• Choroidal neovascularization

• Ocular tumors

Cyclooxygenase (COX), an important group of

enzymes active in the inflammatory process,

catalyzes the biosynthesis of eicosanoids from

arachidonic acid to produce prostaglangins

(PGs) and thromboxanes

NSAIDs are potent inhibitors of COX enzymes,

and thereby the synthesis of PGs

Within the eye, PGs cause visodilation,

disruption of the blood-ocular barrier and

leukocyte migration

Two main isoforms

• COX-1 – expressed in the GI tract, kidneys, platelets,

and in vascular endothelium. Plays role in normal

physiologic function

• COX-2 – inducible enzyme expressed throughout the

body, primarily during inflammatory responses

COX-2 is the predominant isoform in human RPE cells, and is upregulated in response to pro-inflammatory cytokines • Present in CNV

• Present in other vascularized diseases

• Increased in diabetic retinopathy

• PGs interact and amplify other soluable mediators (VEGF)

Preferential inhibitors of COX-2 are preferred [yet cardiovascular (refecoxib) and GI concerns have been noted]

Topical formulations are relatively water soluable (acetic and/or propionic acids)

Acetic acids

Diclofenac 0.1% QID

Ketorolac 0.4% and 0.45% QID/BID Bromfenac 0.09% BID/once daily Nepafenac 0.1% and 0.3% TID/once daily

Propionic acids

Flurbiprofen 0.03% QID

Bromfenac is potentially a 3 to 18 times more potent inhibitor of COX-2 (though this needs to be verified)

Prednisolone acetate

Dexamethasone

Difluprednate

Loteprednol

Good supportive evidence that NSAIDs reduce

postoperative inflammation and pain after

cataract surgery

Four medications approved for this indication

• Diclofenac

• Ketorolac

• Nepafenac

• Bromfenac

Henderson BA, Gayton JL, Chandler SP, Gow JA, Klier SM, McNamara TR: Bromfenac Ophthalmic Solution

(Bromday) Once Daily Study Group. Safety and efficacy of bromfenac ophthalmic solution (Bromday)

dosed once daily for postoperative ocular inflammation and pain. Ophthalmol 2011;118:2121-7

Donnenfeld ED, Nichamin LD, Hardten DR, Raizman MB, Trattler W, Rajpal RK, Alpern LM, Felix C,

Bradford RR, Villanueva L, Hollander DA, Schiffman RM: Twice-daily, preservative-free ketorolac 0.45%

for treatment of inflammation and pain after cataract surgery. Am J Ophthalmol 2011;151:420-6.

Several studies suggest a measurable impact

on visual acuity and CME following cataract

and retina surgery

In many studies, it is difficult to separate the

effects of NSAIDs from corticosteroids

NSAIDs appear to better stabilize the blood

ocular barrier (as assessed via measurement of

flare)

Kim SJ, Lo WR, Hubbard GB 3rd, et al: Topical ketorolac in vitreoretinal surgery; a prospective, randomized, placebo

controlled, double-masked trial. Arch Ophthalmol 2008;126:1203-9.

Donnenfeld ED, Perry HD, Wittpenn JR, et al: Preoperative ketorolac tromethamine 0.4% in phacoemulsification

outcomes: pharmacokinetic-response curve. J Cataract Refract Surg 2006;32:1474-82

Most important is the direct visual impact on the patient

Analysis of costs of CME in the USA

• 139,759 Medicare cataract patients from 1997-2001

Patients stratified into two groups for up to 1 year from date of surgery

• Diagnosis of CME (cases)

• No Diagnosis of CME (control)

Ophthalmic claims alone were $3,298 higher for cases vs. control

• There is a substantial cost associated with CME

Matthews GP, et al. Evaluation of costs for cystoid macular edema among patients following cataract surgery. Invest

Ophthalmol Vis Sci. 2006; 4409: B168.

Topical

• NSAIDs (COX-2 inhibitors)

• Corticosteroids

• Combination therapy

Periocular corticosteroids

Intravitreal injections

• Corticosteroids

• Anti-VEGF agents (bevacizumab,

ranibizumab,aflibercept)-all off label

Kim SJ, Flack AJ, Jampol LM: Nonsteroidal anti-inflammatory drugs in ophthalmology. Surv Ophthalmol 2010;55:108-

133

Need to recognize the natural history of CME

Also there is no FDA approved treatment in the

prevention or treatment of postoperative CME

However, numerous studies have been

completed (including a meta-analysis)

A treatment benefit is likely

Rossetti L, Chaudhuri J, Dickersin K: Medical prophylaxis and treatment of cystoid macular edema after cataract

surgery. The results of a meta-analysis. Ophthalmol 1998;105:397-405

Flach (Am J Ophthalmol 1991) reported

significant improvement in chronic CME with

topical ketorolac 0.5% for three months

Flach AJ, Jampol LM, Weinberg D, et al: Improvement in visual acuity in chronic aphakic and pseudophakic cystoid

macular edema after treatment with topical 0.5% ketorolac tromethamine. Am J Ophthalmol 1991;112:514-9

Flach (Ophthalmol 1998) and Rho (J Cat Refract

Surg 2003) have shown that diclofenac 0.1% and

ketorolac 0.5% are equally effective in:

• Treating acute/simple post-operative CME

• Treating post-operative inflammation

Flach AJ et al. Comparative Effect of diclofenac 0.1% and ketorolac 0.5% on inflammation after cataract.

Ophthalmol1998;105: 1775-9.

Rho DS. Treatment of Acute Pseudophakic Cystoid Macular Edema: Diclofenac versus Ketorolac. J Cataract Refract

Surg. 2003;29:2378-84.

Heier (Ophthalmol 2000) reported that

combination therapy (ketorolac and

prednisolone) was more effective than

corticosteroids alone

• Treatment applied for three months or until

resolution of CME, then tapered for three weeks

• Only combination treated eyes improved two Snellen

lines of vision

Heier JS, Topping TM, et al. Ketorolac versus prednisolone versus combination therapy in treatment of acute

pseudophakic cystoid macular edema. Ophthalmol 2000;107:2034-9.

Warren (Retina 2010) reported the treatment of 39

patients with pseudophakic CME

All patients received intravitreal corticosteroids and

bevacizumab at study entry, then one of four NSAIDs

were added in (diclofenac, ketorolac, nepafenac, and/

or bromfenac)

At 12 and 16 weeks, nepafenac and bromfenac showed

a significant reduction in retinal thickness compared to

placebo

Nepafenac treated patients showed a sustained

improvement in visual acuity

Warren KA, Bashrani H, Fox JE: NSAIDs in combination therapy for the treatment of chronic pseudophakic cystoid

macular edema. Retina 2010;30:260-6

Donnenfeld (Am J Ophthalmol 2011) reported the use of

ketorolac 0.45% employed BID in patients undergoing

cataract surgery

Well tolerated and efficacious in the treatment of ocular

inflammation and pain

Donnenfeld ED, Nichamin LD, Hardten DR, Raizman MB, Trattler W, Rajpal RK, Alpern LM, Felix C, Bradford RR,

Villanueva L, Hollander DA, Schiffman RM: Twice-daily, preservative-free ketorolac 0.45% for treatment of

inflammation and pain after cataract surgery. Am J Ophthalmol 2011;151:420-6

Henderson (Ophthalmol 2011) reported a multi-center

study of bromfenac 0.09% dosed once daily in 872

subjects undergoing cataract surgery

Found to be effective in control of ocular pain and

inflammation, as measured by the summed ocular

inflammation score (SOIS)

Inflammation cleared quickly (as measured on day 15),

visual improvement was noted, and there were no

safety concerns

Silverstein SM, Cable MG, Sadri E, Peace JH, Fong R, Chandler SP, Gow JA, Klier SM, McNamara TR: Bromfenac

Ophthalmic Solution Once Daily (Bromday) Study Group. Curr Med Res Opin 2011;27:1693-1703

Henderson BA, Gayton JL, Chandler SP, Gow JA, Klier SM, McNamara TR, Bomfenac solution (Bromday) dosed once

daily for postoperative ocular inflammation and pain. Ophthalmol 2011;119:2120-7

Modi (J Cataract Refract Surg 2013) reported a multi-

center prospective phase 3 trial of the use of once daily

nepafenac 0.3%, administered day 1 through 14 post-

cataract surgery

817 patients received nepafenac 0.3% daily, 819

patients received nepafenac 0.1%, TID with controls

receiving the vehicles

Nepafenac 0.3% was non-inferior for control of

postoperative pain and inflammation

Modi SS, Lehmann RP, Walters TR, Fong R, Christie WC, Roel l, Nethery D, Sager D, TsorbatzoglouA, Philipson B,

Traverso CE, Reiser H: Once-daily nepafenac ophthalmic suspension 0.3% to prevent and trreat ocular

inflammation and pain after cataract surgery. Phase 3 study. J Cataract Refract Surg 2013 (Epub ahead of print)

Smith S (Clin Ophthalmol 2010) reported the use of

topical difluprednate 0.05% BID employed for 16 days

in patients undergoing cataract surgery, started one

day postoperatively

Found to be highly effective in the management of

ocular inflammation and in relieving pain, and was well

tolerated

Smith S, Lorenz D, Peace J, McLeod K, Crockett RS, VogelR: Difluprednate ophthalmic emulsion 0.05% (Durezol)

administered two times daily for managing ocular inflammation and pain following cataract surgery. Clin

Ophthalmol 2010;4:983-91

Efficacious and safe in the treatment of postoperative

inflammation and pain (non-settling gel)

Reports by Fong (Clin Ophthalmol 2012) and Rajpal (J

Cataract Refract Surg 2013) of using loteprednol gel

QID in multi-center studies, documenting efficacy in

patients undergoing cataract surgery

A report by Bannale (J Clin Diagn Res 2012) noted

comparable efficacy between loteprednol etabonate

0.5% solution and topical flurbiprofen

Fong R, Leitritz M, Siou-Mermet R, Erb T: Loteprednol etabonate gel 0.5% for postoperative pain and inflammation

after cataract surgery: resuls of a multicenter trial. Clin Ophthalmol 2012;6:1113-24

Rajpal RK, Roel L, Siou-Mermet R, Erb T: Efficacy and safety of loteprednol etabonate 0.5% gel in the treatment of

ocular inflammation and pain after cataract surgery. J Cataract Refract Surg 2013;39:158-67

67

Porela-Tiihonen (J Cataract Refract Surg 2013)

performed a meta-analysis on postoperative pain after

cataract surgery (105 articles and 21 studies)

Generally there is minimal pain, and recovery is

uneventful

When there is significant discomfort, there is no

conclusive data regarding the treatment of choice

Porela-Tiihonen S, Kaarniranta K,Kokki H: Postoperative pain aflter cataract surgery. J Cataract Refract Surg

201333;39:789-98

Patients with epiretinal membranes, vascular

occlusive disease, and preoperative

prostaglandin usage, have a higher risk of

postoperative CME following cataract surgery

Henderson (J Cat Refract Surg 2007) reported

that the treatment of these types of patients

with a postoperative NSAID and a

corticosteroid for three months lessened the

risk of developing CME

Henderson BA, Kim JY, Ament CS, Ferrufino-Ponce ZK, Grabowska A, Cremers SL: Clinical pseudophakic cystoid

macular edema. Risk factors for development and duration after treatment. J Cataract Refract Surg 2007;33:1550-

1558

Endo (Acta Ophthalmol 2010) reported the use

of bromfenac in 62 patients undergoing

cataract surgery in patients with diabetes

Bromfenac successfully lessened the rate of

anterior chamber inflammation and

suppressed the development of retinal

thickening (OCT) compared to topical

corticosteroid

Endo N, Kato S, Haruyama K, Shoji M, Kitano S; Efficacy of bromfenac sodium ophthalmic solution in preventing

cystoid macular oedema after cataract surgery in patients with diabetes. Acta Ophthalmol 2010;88:896-900

Singh R (Clin Ophthalmol 2012) noted that

nepafenac 0.1% employed daily for 90 days

postoperatively in diabetic patients compared

to vehicle, reduced the incidence of CME

(3.2% versus 16.7%) based on OCT central

subfield macular thickness measurements

Singh R, Alpern L, Jaffe GJ, Lehmann RP, Lim J, Reiser HJ, Sall K, Waiters T, Sager D,: Evaluation of nepafenac in

prevention of macular edema following cataract surgery in atients with diabetic retinopathy. Clin Ophthalmol

2012;6:1259-69

Elsawy (Clin Ophthalmol 2013) reported a

comparative trial of prophylactic postoperative

use of ketorolac 0.4% QID versus topical

dexamethasone 0.1% QID in diabetic patients

undergoing cataract surgery

Ketorolac had a lessened rate of CME (2.2%)

compared to the corticosteroid group (11.6%)

as measured by OCT

Elsawy MF, Badawi N, Khairy HA: Prophylactic postoperative ketorolac improves outcomes in diabetic patinets

assigned for cataract surgery. Clin Ophthalolol 2013;7:1245-9

Hariprasad (J Ocul Pharmacol Ther 2007, and

Clin Ophthalmol 2009) treated six patients with

CME with nepafenac 0.1% suspension for three

to four weeks

• Visual acuity improved in three cases, and there was

a reduction in retinal thickness as measured by OCT

as well

Hariprasad SM, Callanan D, Gainey S, et al; Cystoid and diabetic macular edema treated with nepafenac 0.1% J

Ocul Pharmacol Ther 2007;23:585-90

Hariprasad SM, Akduman L, Cleve JA, Ober M, Recchia FM, Mieler WF: Treatment of cystoid macular edema

with the new-generation NSAID nepafenac 0.1%. Clin Ophthalmol 2009;3:147-54

37 year old female one year following K-Pro

surgery, VA 20/70 OD (only eye)

CME diagnosed two months postoperatively

Started on Nepafenac TID and Prednisone

acetate 1% QID OD

Returned two months later with complete

resolution of CME (VA 20/40 OD)

Was kept on the nepafanac for three months

and has remained free of CME for twelve

months

A 75 year old male developed CME two months

following drainage of hemorrhagic choroidals

Started on bromfenac daily

Marked improvement in ocular discomfort,

CME, and VA within six weeks

CME following RD repair ranges from 9

to 43% and may delay visual recovery

Angiographic CME may occur in up to 70

to 80% of eyes following PPV for ERM

and macular hole surgery

Schoenberger SD, Miller DM, Petersen MR, Foster RE, Riemann CD, Sisk RA: Nepafenac for epiretinal membrane

surgery. Ophthalmol 2011;118:1482

Kim SJ (Arch Ophthalmol 2008) reported the use

of topical ketorolac 0.4%, which was initiated

prior to PPV surgery

A small reduction in central retinal thickness

(9%), and macular volume (6%) was seen,

though was not of statistical significance

Schoenberger (Ophthalmol 2011) reported a

more rapid reduction in macular volume

following PPV for ERM Kim SJ, Lo WR, Hubbard GB 3rd, et al: Topical ketorolac in vitreoretinal surgery; a prospective, randomized, placebo

controlled, double-masked trial. Arch Ophthalmol 2008;126:1203-9

Schoenberger SD, Miller DM, Petersen MR, Foster RE, Riemann CD, Sisk RA: Nepafenac for epiretinal membrane

surgery. Ophthalmol 2011;118:1482.

A single study has shown vitreous

concentrations, following three days of topical

usage of the following NSAIDs

Ketorolac QID 2.80 ng/ml

Bromfenac daily 0.96 ng/ml

Nepafenac TID 2.00 ng/ml

Heier JS, Awh CC, Busbee BG, et al: Vitreous nonsteroidal antiflammatory drug concentrations and prostaglandin

E2 levels in vitrectomy patients treated with ketorolac 0.4%, bromfenac 0.09%, and nepafenac 0.1%. Retina 2009;

29;1310-3

Baklayan (J Ocular Pharm 2008) showed

significant penetration and measurable

amounts of 14C labeled bromfenac in all ocular

tissues including sclera, choroid, and retina

when a single 50 uL drop was applied topically

in rabbit eyes after 24 hours

Baklayan GA, Patterson HM, Song CK, Gow JA, McNamara TR: 24-hour evaluation of the ocular distribution of 14C-

labeled bromfenac following topical instillation into the eyes of New Zealand white rabbits. J Ocular Pharm 2008;

24:392-8

Waterbury (J Ocul Pharmacol Ther 2011)

reported that ketorolac better suppressed

lipopolysaccharide-induced inflammation in

rabbit eyes at trough levels in comparison to

bromfenac

Both agents were effective at peak levels

Waterbury LD, Galindo D, Villanueva L, Nguyen C, Patel M, Borbridge L, Altar M, Schiffman RM, Hollander DA:

Ocular penetration and anti-inflammatory activity of ketorolac 0.45% and bromfenac 0.09% against

lipopolysaccharide-induced inflammation. J Ocul Pharmacol Ther 2011;27:173-8

Unlu (Can J Ophthalmol 2010) reported

intraocular penetration of diclofenac and

ketorolac in patients undergoing cataract

and/or retinal detachment surgery (20

patients)

Topically applied diclofenac reached the

subretinal fluid better than ketorolac, while

ketorolac had a better penetration into the

aqueous fluid

Unlu N, Kocaoglan H, Savin F, Hazirolan D, Demircan S, Basci N, Acar MA, Demir NM, Duman S: Penetration of

topically applied diclofenac and ketorolac into the aqueous humour and subretinal fluid; randomized clinical trial.

Can J Ophthalmol 2010;45:l610-5

Comparative study performed by Kida,

expressed as the concentration of various

NSAIDs in micromoles necessary to

inhibit 50% of the COX-2 activity

Relative potency versus bromfenac • Bromfenac 1.00

• Nepafenac (Amfenac) 0.37

• Ketorolac 0.27

• Diclofenac 0.25

Kida T, Ogawa T, McNamara TR, Song CK, Gow JA: Evaluations of the human COX-2 inhibition for amfenac,

bromfenac, diclofenac, and ketorolac. ASCRS poster (unpublished data)

Diabetic retinopathy • PGE2s are oftentimes elevated in the vitreous,

suggesting a role of the prostaglandins

• Rheumatoid arthritis patients taking salicylates

had a reduced incidence of DR

• Aspirin slowed the development of

microaneurysms in the ETDRS

Schoenberger SD, Kim SJ, Sheng J, Rezaei KA, Lalezary M, Cherney E: Increased prostaglandin E2 (PGE2)

levels in proliferative diabetic retinopathy and correlation with VEGF and inflammatory cytokines. Invest

Ophthalmol Vis Sci 2012;53:5906-11

Kern TS, Miller CM, Du Y, et al: Topical administration of nepafenac inhibits diabetes-induced retinal

microvascular disease and underlying abnormalities of retinal metabolism and physiology. Diabetes

2007;56:373-9

Four studies have investigated the usage of

intravitreal NSAIDs

Maldonado (Curr Eye Res 2011) and Reis (Arq

Bras Oftolmol 2010) injected 500 to 3000 ug of

ketorolac intravitreally in 20 patients refractory

to laser treatment for DME

30% had a short-term positive visual response

(one or more lines of vision)

No changes (or slight worsening) seen on OCT

Maldonado RM, Vianna RN, Cardoso GP, de Magalhaes AV, Burnier MN JR: Intravitreal injection of

commercially available ketorolac tromethamine in eyes with diabetic macular edema refractory to laser

photocoagulation Curr Eye Res 2011;36:768-773

Age-related macular degeneration

• Inflammatory and immunological events play a

central role

• COX-2 has been shown to be a promoter of

angiogenesis

• Complement factor H

At the present time, clinical evidence is lacking

for a benefit from topical usage of NSAIDs,

when combined with either PDT or anti-VEGFs

Kim SJ, Toma HS, Barnett JM, Penn JS: Ketorolac inhibits choroidal neovascularization by suppression of retinal VEGF.

Exp Eye Res 2010; 91:537-543

Wang Y, Wang VM, Chan CC: The role of anti-inflammatory agents in age-related macular degeneration (AMD)

treatment . Eye (Lond) 2011;25:127-39.

Age-related macular degeneration

Five-year data from the Blue Mountains Eye

Study revealed no association between the use

of systemic NSAIDs, and the incidence of AMD

Wang JJ, Mitchell P, Smith W, Gillies M, Billson F, Blue Mountains Eye Study; Systemic use of anti-inflammatory

medications and age-related maculopathy: The Blue Mountains Eye Study. Opthalmic Epidemiology 2003;10:37-48

Relieving discomfort and pain after ocular surgery, laser, and trauma

Allergic conjunctivitis Corneal ulcer pain Uveitis and ocular Inflammation

• Orbital pseudotumor

• Episcleritis/scleritis

• Inflamed pinguecula and pterygia

• Viral conjunctivitis

• Dry eye patients

Treat before irreversible macular

damage occurs

The longer the duration of CME, the less

effective any therapy becomes at

restoring central visual function

Current treatment regimens for

postoperative CME generally favor a

combination of a topical NSAID with a

corticosteroid in the prevention and/or

treatment of CME

In limited comparative studies, it appears

that bromfenac may have somewhat

greater potency in comparison to the

other currently available NSAIDs, though

additional studies are truly needed