This is the question you should be able to answer at the conclusion is…

Leo Semes, OD, FAAO UAB Optometry How will this information help me when I see my next patient? OptoWest Newport Beach California Optometric Association 2016

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Contact Allergy / Dermas Treatment with Contact Allergy / Dermas Treatment with Oral Steroids Oral Steroids 78 AA/F with suspected Alphagan allergy Prednisone 5 mg PO qid X 7 d – good results

♦ Topical hydrocortisone (1%) failed

♦ Final diagnosis: nickel allergy

Oral Steroids – Side Effects 60 mg oral prednisone (35 D) — Skin effects — Thinning and bruising may occur during OD application with dose-response effect Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy: A systematic review and meta- analysis. Arch Int Med 1999 159(9): 941-55.

— Elevated BP

— PSC cataract OS

— Elevated IOP (?) Tham CCY, et al. Am J Ophthalmol 2004;137:198–201.

1 10 mg oral prednisone (28 D) (same 9 yo f) Prostaglandins — Ubiquitous OD — Initiate and modulate cell & tissue responses — Platelet aggregation — Renin release — INFLAMMATION — Synthesized on demand OS — Not stored — Short half-life

Tham CCY, et al. Am J Ophthalmol 2004;137:198–201. 8

Mechanism of NSAID Action A video is worth a thousand words http://www.youtube.com/watch?v=8v1H2N-9Hf4 Inhibition of Prostaglandin synthesis* — Arachadonic acid pathway — Leukotriene arm (steroids) — Cycloxygenase I and II (COX-II) / NSAIDS

* Mechanisms may overlap

14 15

NSAID Inhibition of Prostaglandin synthesis* General Features (Oral) — Cycloxygenase I and II (COX-II) — — COX-I Metabolized rapidly (30 min to 2 hrs) — inhibit thromboxane production & — Generally rapid effect [anti-inflammatory, — thus platelet aggregation pain relief, fever reduction] (leads to blood thinning) — Peak plasma levels: 4-6 hrs following — Selective COX-II isoenzymes, (do NOT interfere with dosing platelet aggregation) — may adversely affect hemostatic balance & — Metabolized in the kidneys — favor thrombosis but may be less disruptive to mucosal membranes

* Mechanisms may overlap 16 17

2 Oral NSAID Properes NSAID Actions (the 3 As) — Anti-inflammatory — Act to reduce inflammation — Anti-pyretic (requires higher dosage than for analgesia) — Analgesic — Widely used for arthritis pain management (chronic) — Also offer analgesia 1.4 million regular users (USA)

— Mechanism of action is inhibition of COX-1 and COX-2 enzymes — Most are anti-pyretic — Aspirin is the prototype

18 19

Precautions/Warnings Every silver lining has a cloud … Precautions/Warnings — Elderly: renal clearance is reduced; resulting in GI Toxicity w/ chronic TX higher plasma levels — Ulceration — Renally impaired: same scenario — Bleeding; can also aggravate pre-existing disorders [⇓ pl. clearance] (diverticulosis) — Hepatically impaired: no significant difference — Perforation from above 2 examples* (cyclooxygenase is Prevalence: needed for renal blood flow) 1- 2% (3-6 mo); 2- 4% @ 1 yr

*Use minimum dosage [⇑ unbound %] may be asymptomatic

20 21

Continuum of NSAID-related upper GI injury Precautions/Warnings — Peripheral edema (2% prevalence) — Caution: — fluid retention — hypertension — heart failure L May interfere with ß-blockers & ACE inhibitors

22 23

3 Precautions/Warnings Precautions/Warnings — Stevens-Johnson syndrome — Hypersensitivity reactions Caution: — asthma → — rashes and urticaria — photosensitivity — Stevens-Johnson syndrome… X 12 years

24 25

Drug interactions - Precautions/Warnings ophthalmic — Drug interactions — Brimonidine (Alphagan) — Aspirin (⇑ unbound %) — May be ineffective with the concomitant — Warfarin (may ⇓ platelet formation) administration of indomethacin (25 mg. QID) — Gingko biloba !!! — Antacids (no interference, ex., Pepcid) — Diuretics (reduced K+, Cl-excretion) — Not so for latanaprost (Xalatan) — Digoxin Sponsel WE, et al. Am J Ophthalmol. 2002; 133: 11-18.

26 27

Precautions/Warnings Indications for Oral NSAIDs — Miscellaneous — Mild to Moderate Pain — Pregnancy: Generally Category B; — Rheumatoid Arthritis Lodine, Motrin, Vioxx, Voltaren [C] — OsteoArthritis — Not recommended during lactation/ — Ankylosing Spondylitis nursing — Tendinits

— NEAS for pediatric use (< 6 months) — Primary Dysmenorrhea (600 mg, qid) (Ibuprofen arginate: Castelo-Branco C,Casals G,Haya J. Efficacy and Safety of Ibuprofen Arginine in the Treatment of Primary Dysmenorrhoea. Clin Drug Invest 24(7):385-393, 2004.) 28 29

4 Oral NSAIDS (O-T-C) – Ibuprofen [“Escape,” or “rescue” drugs] Oral NSAIDS (O-T-C) - Ibuprofen Motrin, Advil, Nuprin - 200 mg. — Standard dosage: 400 mg q 4-6 h — ♦ DOSAGE (Rx): 2 tabs (400 mg) q Pediatric dosing: 10 mg/Kg q6-8 h (up to 40 mg / Kg / D; ages 6 mo. to 12 yrs.) 4-6 h

(management of adult pain) — Also available as suspension (100mg/5ml) — Ophthalmic application in Children's Elixsure IB keratitis, uveitis, eg. — Chewable tabs 50, 100 mg — Capsules 100 mg

31 32

Oral NSAIDS (O-T-C) - Ketoprofen Ketoprofen (12.5, 25, 50 mg) Orudis 12.5 mg. 12.5-25 mg may be faster than ibuprofen 200 mg Sunshine A, Olson NZ, Marrero I, Tirado S. Onset and duration of analgesia for low-dose ketoprofen in the treatment of postoperative dental pain Clin Pharmacol. 1998 Dec;38(12): 1155-64. ♦ DOSAGE: 4 caps / tabs (50 mg.) q 4-6 h But similar onset compared to ibuprofen ♦ Orudis (Ketoprofen) Capsules and Extended-release liquigel 200mg Olson NZ, Otero AM, Marrero I, Tirado S, Cooper S, Doyle G, Jayawardena S, Sunshine A. Capsules (approved 08/13/03) Onset of analgesia for liquigel ibuprofen 400 mg, acetaminophen 1000 mg, ketoprofen 25 mg, and placebo in the treatment of postoperative dental pain. Clin Pharmacol. 2001 Nov; 41(11):1238-47.

Ketoprofen: analgesic, anti-pyretic, anti- 25 -50mg may be a superior analgesic to inflammatory ketorolac 10 or 20 mg

Olmedo MV, Galvez R, Vallecillo M. Double-blind parallel comparison of multiple doses of ketorolac, ketoprofen and placebo administered orally to patients with postoperative dental pain. Pain. 2001 Feb 1;90(1-2):135-41.

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NSAIDS as alternatives to narcotic analgesics Oral NSAIDS (O-T-C) - Naproxen — may offer superior analgesia to natural — Naprosyn 220 mg. and synthetic narcotics in a variety of ♦ DOSAGE: 1-2 tabs (220-440 mg.) q 4-6 h situations [for analgesic effect; lower dosage than for anti-

Malan TP Jr, Gordon S, Hubbard R, Snabes M. The cyclooxygenase-2-specific inflammatory effect] inhibitor parecoxib sodium is as effective as 12 mg of morphine administered intramuscularly for treating pain after gynecologic laparotomy surgery. Anesth Analg. 2005 Feb;100(2):454-60. — Anaprox, Aleve 220 mg. Lovell SJ, Taira T, Rodriguez E, Wackett A, Gulla J, Singer AJ. Comparison of valdecoxib and an oxycodone-acetaminophen combination for acute ♦ DOSAGE: 2 tabs (440 mg.) initially, musculoskeletal pain in the emergency department: a randomized controlled trial. Acad Emerg Med. 2004 Dec;11(12):1278-82. then 1 tab q 4-6 h [for analgesic effect]

Brill S, Plaza M. Non-narcotic adjuvants may improve the duration and quality of analgesia after knee arthroscopy: a brief review. Can J Anaesth. 2004 Dec;51(10): 975-8.

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5 Relative risk of UGI bleeding w/ NSAID Semes’ Anti-inflammatory Siege administration — 600 mg Ibuprofen AM — 440 mg Naprosyn mid-AM — 600 mg Ibuprofen PM — 440 mg Naprosyn qhs

37 38

Oral NSAIDS (By prescription) – Oral “NSAID” (O-T-C) – Acetaminophen Ketoprofen — Acetaminophen 325 mg. (Tylenol) Oruvail 100, 150, 200 mg Caps Orudis 25, 50, 75 mg Caps — requires 500 – 1000 mg to reach analgesic dosage; and higher for anti-inflammatory ♦ DOSAGE: effect ♦ Oruvail (sustained release) 200 mg qD ♦ Orudis 50-75 mg qid/tid [respectively] — May have more rapid onset than ibuprofen ♦ Maximum 200 / 300 mg / day Sunshine A, Olson NZ, Marrero I, Tirado S. Onset and duration of analgesia for low-dose ketoprofen in the treatment of postoperative dental pain Clin Pharmacol. 1998 Dec;38(12): 1155-64. Ketoprofen: The three A’s — Metabolized in the liver!

DOSAGE: q 4-6 h 39 40

Oral NSAIDS (Rx) – Etodolac Oral NSAIDS (Rx) – Naproxen Lodine 200, 300 mg Caps; 400, 500 mg Tabs — Naprelan 412.5, 550 mg. (equivalent to 375/500 mg) DOSAGE: DOSAGE: 1000 mg q D, then 500 - 1000 mg q D ♦ for analgesia 200 - 400 mg q 6-8 h

♦ (higher for OA, RA; anti-inflammatory effect) Has been shown in 3 studies to reduce the risk of ♦ Maximum 1000 - 1200 mg / day acute myocardial infarction (AMI) probably by blocking platelet aggregation; advantage over Lodine XL COX-II’s ♦ 400-100 mg / day • The three A’s

• The three A’s Solomon DA, et al. Arch Int med 2002; 162: 1099-1104. Watson DJ et al. Arch Int med 2002; 162: 1105-1110. Rahme E, et al. Arch Int med 2002; 162: 1111-1115.

41 42

6 NSAIDS and AMD NSAIDS and AMD, too — 2334 participants in the BMES — 551 VA patients w/AMD diagnosis (ICD-9) — 5-year FU — 5500 controls — NSAID and steroid use was measured @ baseline Patients with a prescription filled for Anti- — Results: 2.0% late, 4.9% early AMD but inflammatory meds were 81% less likely to have a disgnosis of AMD no association with NSAID/ Steroid

use Swanson MW, McGwin G Jr. Anti-inflammatory drug use and age-related macular degeneration. Optom Vis Sci. 2008 Oct;85(10):947-50.

Wang JJ, et al. Ophthalmic Epidemiol 2003; 10: 37-47. 43 44

NSAIDS and AMD, III Oral NSAIDS (Rx) – Diclofenac Conclusion: In patients with neovascular AMD Voltaren 25, 50, 75 mg Caps. manifesting persistent exudation despite monthly ♦ DOSAGE: intravitreal antivascular endothelial growth factor ♦ Voltaren 50-100 mg initially; 50 mg q 8 h anti-VEGF therapy, we could not detect a beneficial ♦ Maximum 200 mg / day effect of adding topical bromfenac (0.09%) twice daily over 2 months. — The three A’s

(n = 22 eyes with persistent submacular fluid)

Zweifel SA, et al. Retrospective review of the efficacy of topical bromfenac (0.09%) as an adjunctive therapy for patients with neovascular age-related macular degeneration. RETINA 29:1527–1531, 2009

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Oral NSAIDS (Rx) – Others Oral NSAIDS (Rx) – Others — Tramadol (Ultram) 100 mg. — Ultracet (37.5 mg. tramadol + 325 mg., DOSAGE: q 4-6 h acetaminophen) — Ketorolac tromethamine (Toradol) 10 mg. — Dosing DOSAGE: q 4-6 h (highest risk of bleeding, — 2 tabs q 4-6 hrs. ∴ not on hospital formularies) — Ibuprofen 400 mg. DOSAGE: 1-2 tabs, q 4-6 h

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7 Onofrey’s Alternative Oral Pain Meds (Rx) – Miscellaneous — 400 mg Ibuprofen — Vicoprofen (ibuprofen 200 mg, hydrocodone 7.5 mg)

+ — DOSAGE: 1-2 tabs q 4-6 h (for 10 D) — 325 mg Acetaminophen Ibuprofen: The 3 A’s Hydrocodone: centrally acting synthetic opioid — Dosing — VICODIN contains 5 mg hydrocodone and 500 mg acetaminophen

— 2 tabs q 4-6 hrs. — VICODIN-ES contains 7.5 mg hydrocodone and 750 mg acetaminophen

— VICODIN-HP contains 10 mg hydrocodone and 660 mg acetaminophen

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Indications for Topical NSAIDs — Maintenance of pupillary dilation at cataract surgery; but. . .

— Prophylaxis for pseudophakic CME

— Topical anti-inflammatory (pre- and post-op [indomethacin, 1984*] Sanders DR, Kraff M. Arch Ophthalmol 1984; 102: 1453-56.

— Intraoperative pain (PRP)

— And, and, and…

51 52

Indomethacin & CME Indomethacin & CME — Topical INDOMETHACIN FIRST AND, topical REPORTED IN 1982 AS PROPHYLAXIS indomethacin reduced Kraff M , et al. Prophylaxis of pseudophakic cystoid macular edema with topical indomethacin. Ophthalmology. 1982; 89:885-90. post-op CME better than

placebo (pre-op and 9 mo S/P)

— And, topical administration produced higher intraocular levels than oral dosing Sanders DR, et al., Aqueous penetration of oral and topical indomethacin in humans. Arch Ophthalmol. 1983 Oct;101(10):1614-6.

Kraff MC, et al. Factors affecting pseudophakic cystoid macular edema: five randomized trials. J Am Intraocul Implant Soc. 1985 Jul; 53 11(4):380-5. 54

8 Br J Ophthalmol doi:10.1136/bjophthalmol-2014-305803 Prophylaxis for Pseudophakic CME Update Comparison of ketorolac 0.4% and nepafenac 0.1% for the prevention of cystoid macular oedema after phacoemulsification: prospective placebo-controlled randomised study . Tzelikis1, P et al.(Brazil) Published Online First 10 November 2014 Conclusions Used prophylactically after uneventful cataract surgery, non-steroidal anti-inflammatory drugs

were not efficacious in preventing macular oedema

compared with placebo.

6 worldwide studies 1980-88; outcome criterion = VA piroxicam,

hydroxyethyl-rutoside, flurbiprofen Rossetti L, et.al.Ophthalmology 1998; 105: 397-405. Solomon, LD. Efficacy of topical flurbiprofen and indomethacin in preventing pseudophakic cystoid macular edema. Flurbiprofen-CME Study Group I. Cataract Refract Surg. 1995;21:73-81. 55 56

Topical indomethacin application Ocufen (0.03 % Flurbiprofen, Allergan) — Inflamed ptyergium / pinguecula — Approved indication [12/31/86] – inhibit pupillary — 50 consecutive patients evaluated dilation during cataract surgery — Signs + symptoms = Total score — Dosing: 1 gt q ½ h for the 2 hours prior to surgery — Treatment: 0.01% indomethacin or 0.01% dexamethasone phosphate (14 days)

— Results — Equally effective for Signs, Symptoms and Total — Dexamethasone had more rebound

— Contemporary alternatives. . . .

Frucht-Pery J, et al. Am J Ophthalmol 1999; 127: 148. 57 58

Ocufen (0.03 % Flurbiprofen, Allergan) Ocufen for Dry Eye? — Additional applications — Post-operative pseudophakic CME Solomon, LD. Efficacy of topical flurbiprofen and indomethacin in preventing pseudophakic cystoid macular edema. Flurbiprofen-CME Study Group I. Cataract Refract Surg. 1995;21:73-81.

ATS — *Refractive surgery - Maintenance of pupillary dilation ATS + NSAID during clear lens implantation ATS + STD*

— Dry Eye / OSD? Symptom scores

59 Avunduk AM, et al. Am J Ophthalmol 2003;136:593–602. 60

9 Ocufen for Dry Eye – NOT! But topical steroid drops [FML] are effective! Topical steroid drops for dry eye — DES is an inflammatory condition — Studies have shown efficacy for topical steroid TS+NSAID drops — 1% methylprednisone (KCS, SjÖgren) TS+NSAID — Loteprednol etabonate (âtear clearance, KCS)/ intro TS to Restasis? TS + STD

TS Yoshida T, et al. Neurol Res 1999; 21: 509-12 RB staining Marsh P, Pflugfelder S. Ophthalmology 1999; 106: 811-16. TS + STD Paiva CS, Pflugfelder SC. Rationale for anti-inflammatory therapy in dry eye syndrome. Arq Bras Oftalmol. 2008 Nov-Dec;71(6 Suppl):89-95.

Fl staining 61 62

Leo’s dirty little dry eye secrets Voltaren (diclofenac sodium 0.1%; Ciba) — Topical NSAID solution specifically for the treatment of post-cataract surgery inflammation [7/28/88]1

— Application in post refractive-surgery (PRK, LASIK) pain; 2,3 and better than diclofenac for photophobia, too3

[initial approval - prevention of pupillary constriction during cataract surgery]

1. Ginsburg AP, et.al. J Cat Refract Surg 1995; 21: 82-92. 1. Rossetti L, et.al. J Cat Refract Surg 1996; 22(S): 794-796. 2. Bower KS. Am Fam Phys 2001; 64 (7): 1-10. 2. Frangouli A, et al. J Refract Surg 1998; 14 (2 Suppl): S207-8. 2., 3. Assouline M, et al. Ophthaomic Surg Lasers 1998; 29: 365. [France] 63 64

Voltaren (diclofenac sodium 0.1%; Ciba) Voltaren (diclofenac sodium 0.1%; Ciba) — Routinely used for post incisional refractive-surgery pain Additional ophthalmic applications can be pre-medicated

— Dosing schedule (RK, PRK): — Control of intraoperative pain — 1 drop 1 hr prior to the procedure; during PRP [30-135 min before — 1 drop @ 15 min post; treatment session] — q. i . d. X 3 da. depending on healing. Weinberger D, et al., Br J Ophthalmol. 2000; 84 (2): 135-37.

— Anti-bacterial action [Salmonella — Dosage schedule (cataract surgery): typhimurium] — 1 drop beginning @ 24 hrs post-op and q. i. d. X 2 wks.) Dastidar SG, et al., Int J Antimicrobial Agents. 2000;14(3): 249-51. Controversy: What about corneal melting??? — Filamentary Keratitis in SjÖgren syndrome [1 gt. QID X 28 D] Avisar R, et al., Cornea 2000; 19(2): 145-47. 68 69

10 Contemporary working hypothesis for Controversy pseudophakic [“preservative”] CME — Does latanoprost (or any of the prostaglandin analogs) cause post-op uveitis and /or pseudophakic CME?

Miyake K, et al. J Cataract Refract Surg 2003; 29:1800–1810. 70 71

The latest! Results — Study design — Significant IOP reduction was observed in the PA — 163 eyes of 64 consecutive patients with uveitis and group elevated IOP were reviewed — And the frequency of uveitis was similar between — Controls were the eyes of patients with uveitis but the groups (p = 0.87) NOT treated with a prostaglandin analog — Of the 69 uveitis eyes with a history of CME, there — Pre-treatment IOP and uveitis was monitored was no difference between those taking a PA than those not taking one. (p=0.19) Chang JH, et al. Use of ocular hypotensive prostaglandin analogues in patients with uveitis: does their use increase anterior uveitis and cystoid macular oedema? Br J Ophthalmol. 2008; 92: 916-21. Chang JH, et al. Use of ocular hypotensive prostaglandin analogues in patients with uveitis: does their use increase anterior uveitis and cystoid macular oedema? Br J Ophthalmol. 2008; 92: 916-21. 72 73

Xibrom (bromfenac sodium solution, 0.1%) Xibrom (bromfenac sodium solution, 0.1%) — Burning and stinging on instillation 1.5% (vs. — Ista pharmaceuticals 40% for Acular; 20-40% A-LS) — Available in Japan since 2000) — No systemic absorption from topical instillation — Statistically significant suppression of ocular — Oral equivalent is Duract (50 mg dosing; 1 inflammation (vs. placebo) drop Xibrom (60 ug); potentially toxic [GI] following cataract surgery — Few AE’s in post-market surveillance (Japan) — FDA- approved March 2005 — 6 million treated patients / 13 AE’s — 4 corneal erosions — 3 corneal perforations — 0 corneal melts

78 79

11 Xibrom (bromfenac sodium solution, 0.1%) Bromday — Topical for post-op pain resolved — in 2 days vs. 5 days for placebo qD dosing

Donnenfeld E. , et al. Bromfenac Ophthalmic Solution 0.09% (Xibrom) for Postoperative Ocular Pain and Inflammation. Ophthalmology. 2009; 114;9: 1653-1662.

80 81

TM Nevanac (nepafenac ophthalmic suspension 0.1%, Alcon)– TM Nevanac (nepafenac ophthalmic suspension 0.1%, Alcon) another potential application

— The enhanced permeability of nepafenac, combined — Topical nepafenac inhibits CNV and with rapid bioactivation to amfenac by the iris/ciliary ischemia-induced retinal body and retina/choroid, make it a target specific neovascularization by decreasing NSAID for inhibiting prostaglandin formation in the production of VEGF anterior and posterior segments of the eye. — Topical nepafenac may provide an effective new treatment for ocular — FDA-Approved August 24, 2005 for treatment of pain neovascularization and inflammation associated with cataract surgery — The excellent corneal penetration of Ke TL, et al. Nepafenac, a unique nonsteroidal prodrug with potential utility in the treatment of trauma- induced ocular inflammation: II. In vitro bioactivation and permeation of external ocular barriers nepafenac certainly plays an important Inflammation. 2000 Aug;24(4):371-84. role in this effect (mouse model)

Takahashi K, et al. Topical nepafenac inhibits ocular neovascularization. 83 Invest Ophthalmol Vis Sci. 2003 Jan;44(1):409-15. 84

46 Asian Male 46 Asian Male — “blurry vision” 11/20/2012 — Previous ocular history is negative for refractive — X 3 mo OS; began only last night OD correction, injury, glaucoma, cataract, strabismus, — Began new BP med last week amblyopia, etc. — Has never had eye exam — Family medical / ocular histories negative — Central blur in OS has improved somewhat — No known allergies — + floaters X 1 yr — Began lisinopril qD X 1 wk. [ACE inhibitor] — - flashes, discharge, pain — BP 150/100

12 46 Asian Male 11/20/12 — VA 20/40- 20/400 (PHNI) — -RAPD — IOP: 14/14 — No EOM restrictions — Confrontation FTFC OD, OS — -1.50 / -2.25 -0.50 X 070 VA NI — Anterior segment unremarkable OD, OS

Note serous sub-retinal fluid and cystic macula

46 A M with CSR, RPED, HR — Initiated Nevanac bid (11/20/12) — RTC X 1 wk — Correspond with PCP

— @ 1- wk F/U (11/27/12) — BP = 138/92 — VA 20/25 , 20/40 !!! — (-1.00 / -0.75 – 0.50 X 070) Note RPE intact and serous sub-retinal fluid — Continue Nevanac bid

13 46 A M with CSR, RPED, HR 12/11/12 — Initiated Nevanac bid (11/20/12)

— @ 2- wk F/U (12/4/12) — BP = 140/92 — VA 20/20- , 20/20- !!! — (refraction unchanged; ) — Continue Nevanac bid — RTC X 1 Wk

D/C Nevanac

12/11/12 12/11/12

D/C Nevanac

12/11/12 12/11/12

14 12/11/12 12/11/12

Ilevro (nepafenac ophthalmic suspension 0.3%) — qd dosing for post- op inflammaon and pain following

cataract surgery*

* This product has been evaluated by the FDA and any other applicaon is considered to be “off-label”

110 111

Acular (Acuvail) Acular (Acuvail) — Ketorolac is the most widely prescribed topical NSAID. — Recently available in non-preserved formulation (Acuvail) –FDA-approved for reduction of pain — FDA-approved for the amelioration of post-op following cataract surgery. refractive surgery pain. — Does not prolong corneal abrasion healing and — Off-label indications include (with evidence) reduces pain. — Acute and chronic post-op CME — Seasonal allergic conjunctivitis — Inflamed pterygia — 112 113 —

15 Addional potenal applicaon of Acular Precaution topical NSAIDs — Asthma — Allergic conjunctivitis — Exacerbation of symptoms [44 F] following 1 dose; — Uveitis and other inflammatory ocular diseases required hospitalization — Uveitis — Recommendations — Orbital pseudotumor — avoid when aspirin- or NSAID-sensitive — — avoid with asthma + nasal polyps Episcleritis and scleritis — Inflamed pinquecula and pterygia Sitegna GL, et al. Ophthalmology 1996; 103: 890-92. — Viral conjunctivitis — Ocular inflammation in dry eye patients

114 115

Addional potenal applicaon of topical NSAIDs Restasis (cyclosporin 0.05% ophthalmic emulsion — Retinal and choroidal disease — Mechanisms of action — Diabetic retinopathy — Inhibition of T-cell mediated calcineurin production — Age-related macular degeneration — Ocular tumors — Which in turn inhibits upregulation of inflammatory proteins (notably IL-2)

— And may inhibit apoptosis (conjunctival epithelial cells) Kim SJ, Flach AJ, Jampol LM. Nonsteroidal anti-inflammatory drugs in ophthalmology. Surv Ophthalmol. 2010 Mar 4;55(2):108-33.

116 117

Restasis Clinical effects Restasis (cyclosporin 0.05% ophthalmic emulsion (documented off-label ) — Systemic application as an immuno-suppressant/ — Ocular rosacea – 2/3 of pts. reduced oral -modoulator antibiotic use — Limbal stem-cell grafts

— Supplementary to chemotherapy for retinoblastoma — LASIK-associated dry eye (decreased symptoms attributed to reduced inflammatory upregulation — Originally applied in solid-organ transplants (kidney, liver, lung, heart — CL intolerance – increased wearing time — NO systemic absorption from topical dosing

118 119

16 Restasis Clinical effects Restasis Clinical effects (documented off-label ) (documented off-label effects) — KCS (T-cell mediated inflammatory inhibition) — Atopic Keratoconjunctivitis – safer option than — Posterior blepharitis and MGD (anti- steroids inflammatory effects ) [therefore, of greatest benefit for steroid-resistant patients] — Improved clinical signs — Meibomian gland inclusions — Ocular Herpes Simplex (stromal) –mechanism is — Staining scores probably inhibition of T-cells and VEGF — Viscosity of gland secretions — TBT — Schirmer score — Graft-versus-Host disease — Resolution of lid teleangiectasia

120 121

Other off-label ophthalmic applications Future direcons for immunosuppression — All for extemporaneously compounded formulations — For uveitis — VKC (1, 1.25%, 2% in oil; for 2 wks – 4 months) with — Anti-TNF-α efficacy and without SEs — Cytokine receptor antibodies — Atopic keratoconjunctivitis (2% qid)) – reduced steroid — Anti-IFN- α2a (interferon) dependence — Ocular surface — Phlyctenular keratoconjunctivis (childhood rosacea) — Cyclosporine þ — SLK (Theodore) 0.5% qid — Tacrolimus (systemic dosing for corneal grafts, atopic KC) — HSK (stromal) 2% — TSPK (2%) –suppressed epithelial opacities in ¾ of pts. — Overall – lower dosing of currently approved molecues

122 123

Corcosteroids Topical ophthalmic corcosteroids I. Therapeutic applications I. Therapeutic applications A. Uveitis E. Corneal trauma B. Keratitis F. Iridocyclitis C. Episcleritis G. Prophylaxis &post- D. Iritis operative anti- inflammatory H. Allergic and seasonal conjunctivitis

124 125

17 Choices for treatment (highest potency and penetraon) Prednisolone acetate A. Prednisolone acetate 1% 3. Dosing is based on the severity of the suspension (PredForte®, inflammation (ratchet up from qid (or Allergen, and others) q4h); tapering when inflammation is 1. Potent topical anti- under control and the treatment has been inflammatory steroids > several weeks Remember to get baseline IOP and F/U IOP 2. Best penetration into the anterior chamber; has 4. PredMild is 0.125% pred acetate for milder postsurgical application inflammations Both are BAK preserved

126 127

loteprednol etabonate 0.5% (Lotemax®, B&L) loteprednol etabonate 0.5% (Lotemax®, B&L) Unique chemical formulation c. avoids complications (ester vs. ketone for other of elevated IOP in topical corticosteroids) steroid responders a. minimizes potential for adverse side effects d. reduces risk of PSC in b. allows potential for use in long-term use* chronic conditions (but probably not the best for recurrent)

128 129

Posterior Segment applicaon of Durezol topical NSAIDs (???) (difluprednate ophthalmic emulsion) 0.05% — In patients with neovascular age-related macular — FDA-approved for the degeneration manifesting persistent exudation treatment of postoperative despite monthly intravitreal anti-VEGF therapy, we inflammation and pain could not detect a beneficial effect of adding topical associated with ocular surgery bromfenac (0.09%) twice daily over 2 months.

— Implication: intraocular penetration or efficacy is different from bromfenac/nepafenac

Zweifel SA, Engelbert M, Khan S, Freund KB. Retrospective review of the efficacy of topical bromfenac (0.09%) as an adjunctive therapy for patients with neovascular age-related macular degeneration. Retina. 2009 Nov-Dec;29(10):1527-31.

130 131

18 Durezol – safety and efficacy Durezol (anterior uveis) (difluprednate ophthalmic emulsion) 0.05% (difluprednate ophthalmic emulsion) 0.05% — Difluprednate, administered 2 times — Difluprednate administered QID is daily starting 24 hours before at least as effective as prednisolone cataract -surgery, was highly administered 8x/day in resolving the effective for managing ocular inflammation and pain associated inflammation and relieving pain and with anterior uveitis. discomfort postoperatively. Foster CS, et al. Durezol — Difluprednate was well tolerated — Difluprednate provides effective (Difluprednate Ophthalmic Emulsion 0.05%) compared with Pred Forte 1% and provides a convenient twice- treatment for anterior uveitis and ophthalmic suspension in the daily option for managing treatment of endogenous anterior requires less frequent dosing than uveitis. J Ocul Pharmacol Ther. 2010 postoperative ocular inflammation. Smith S, et al., Difluprednate ophthalmic emulsion 0.05% Oct;26(5):475-83. (Durezol) administered two times daily for managing ocular prednisolone acetate. inflammation and pain following cataract surgery. Clin Ophthalmol. 2010 Sep 7;4:983-91. 132 133

Durezol (anterior uveis) Actinic (UV) - Associated Conditions (difluprednate ophthalmic emulsion) 0.05% – adnexal applications of NSAIDs — Instillation of difluprednate • Actinic damage ophthalmic emulsion 0.05% is a safe and effective treatment that • Secondary to sun-damaged skin does not require surgical • Histologically - a loss of collagen and intervention and does not produce severe side-effects. elastic tissue

(comparable to sub-Tenon injection of steroid) Nakano S, et al. Steroid eye drop treatment (difluprednate ophthalmic emulsion) is effective in reducing refractory diabetic macular edema. Graefes Arch Clin Exp Ophthalmol. 2010 Jun;248(6):805-10.

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Topical Voltaren (gel) — Solaraze (declofenac sodium 3% gel) — actinic keratosis (FDA approved 2000;

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19 The latest in prevenng intraoperave miosis and Anti-inflammatories in Ocular Allergy Treatment reducing postoperave pain in cataract surgery Steroids used to be reserved for non-responsive cases. But now many OMIDRIA is a sterile solution concentrate optometrists are using them as a first-line therapy for allergic containing 1% w/v of phenylephrine and 0.3% w/v ketorolac in a single-patient-use vial. conjunctivitis. By A.J. DeVivo, OD, and Terry Scheid, OD 1 INDICATIONS AND USAGE Omidria™ is added to an ophthalmic irrigation solution used during cataract surgery or intraocular 2/15/2013, Review of Optometry lens replacement and is indicated for maintaining pupil size by preventing intraoperative miosis and reducing postoperative ocular pain.

2 DOSAGE AND ADMINISTRATION Omidria must be diluted prior to intraocular use. For administration to patients undergoing cataract surgery or intraocular lens replacement, 4 mL of Omidria is diluted in 500 mL of ophthalmic irrigation solution. Irrigation solution is to be used as needed for the surgical procedure. The storage period for the diluted product is not more than 4 hours at room temperature or 24 hours under refrigerated conditions. 138 139

NSAIDS and Steroids — Questions

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