Ketorolac vs. Bromfenac: A Review of Seven Prospective Randomized Studies Comparing PGE2 Inhibition & Aqueous Penetration Frank A. Bucci, Jr., MD Bucci Laser Vision Institute Wilkes Barre, Pa The author of this poster has received a research grant from Allergan, Inc.

Penetration • PGE2 • Peak Dosing • On Label Acular LS vs. Xibrom Penetration • PGE2 • Peak Dosing • On Label (Acular LS 0.4%) p > .001 Ketorolac 772.5 ng/ml Bromfenac (Xibrom 0.09%) 39.5 ng/ml n = 30 (QID x 3 days preop) q 10 min x 4 90 min pre op n = 32 (BID x 3 days preop) Acular LS ~20X vs. Xibrom q 10 min x 4 90 min pre op Penetration • Peak dosing mean PGE2 • Peak dosing 277.3 250.8 772.5 p>.001 pg/ml ng/ml 39.5 Xibrom Acular LS Xibrom n=30 n=32 Bucci – ARVO 2007 n=28 n=28

* Acular LS vs. Xibrom * Ketorolac “Trough - Single dose” • Penetration • PGE 2 mean Penetration (Acular LS 0.4%) 130.5 ng/ml (21.1X) 6 hrs post single dose p = .004 n = 28 Bromfenac (Xibrom 0.09%) 6.2 ng/ml 12 hrs post single dose Acular LS ~ 20X vs. Xibrom n = 28 PGE2 Penetration 263.7 130.5 204.2 * * p = .004 * ng/ml * p = .020 pg/ml Acular LS Xibrom Acular LS n = 28 n = 28 Xibrom n = 28 n = 28 J Cat Refract Surg - 2008

Acular LS vs. Xibrom Acular LS PGE2 • QID x 2 days pre op “Trough dosing - 2 day run up’’ (on label) Acular LS • QID x 2 days pre op • sample 6 hrs after last dose DOS Xibrom • BID x 2 days pre op • sample 12 hrs after last dose DOS Penetration PGE2 386.24 83.6 pg/ml 285.6 ng/ml 9.1 X (p < .001) * * p=.006 9.2 Acular LS QID Xibrom BID Acular LS QID Xibrom BID n = 30 n = 31 n = 30 n = 31 Advance Therapy - 2009

ACUVAIL • Distinguishing Characteristics 1. Reduction in pH to 6.8 • more un-ionized drop available for absorption 2. Increased drug concentration to 0.45% • vs. 0.4% Acular LS 3. Addition of CMC • improves comfort • protects ocular surface • prolongs drug retention 4. No BAK, EDTA or Octoxynal

ACUVAIL vs. Xibrom vs. Nevanac Methods Peak Dosing • randomized • 122 eyes • on label • double-masked 3 Groups Peak dosing (on label) drug concentration ACUVAIL BID 1 day pre op 1 gtt. am DOS 4 gtts. q15 min 1 hr prior to sx. Xibrom BID 1 gtt. am DOS 4 gtts. q15 min Nevanac TID Aqueous Sample PGE 2 levels • aqueous penetration • prostaglandin inhibition (PGE2)

Aqueous Penetration • Peak dosing (on label ) ACUVAIL vs. Xibrom vs. Nevanac Aqueous Penetration • Peak dosing (on label ) 688.8 54% 447.1 5X 10X 140.3 67.6

PGE 2 Inhibition • Peak dosing (on label) ACUVAIL vs. Xibrom vs. Nevanac PGE 2 Inhibition • Peak dosing (on label) ACUVAIL 224.8 ± 164.9 pg/ml (n = 42) Xibrom 288.7 ± 226.1 pg/ml t (n = 41) Nevanac 320.4 ± 205.6 pg/ml * (n = 38) t p < 0.10 * p < 0.05

ACUVAIL vs. Xibrom vs. Nevanac PGE2 320.4 288.7 224.8 pg/ml * p=0.025 (vs Nev) * ACUVAIL Xibrom Nevanac (n=42) (n=41) (n=38) PGE 2 Inhibition • Peak dosing (on label) ACUVAIL vs. Nevanac (p = 0.025) * Xibrom vs. Nevanac (p = 0.516) ACUVAIL vs. Xibrom (p = 0.10) t

ACUVAIL vs. Xibrom • Trough Dosing • randomized • single dose • double-masked • 120 eyes • on label Trough - Single dose model • no days pre op dosing • no immediate pre op dosing ACUVAIL (q 12 hr) one dose 12 hrs prior to sample Xibrom (q 24 hr) one dose 24 hrs prior to sample

ACUVAIL vs. Xibrom Trough • Single Dose • PGE2 pg/ml n = 53 n = 53

ACUVAIL • Conclusions 1. Peak Penetration ACUVAIL > Xibrom ACUVAIL > Nevanac 2. Peak PGE2 Xibrom > Nevanac ACUVAIL >t Xibrom 3. Trough PGE2 ACUVAIL (q12) > Xibrom (q 24) * * * *