1. 1 Best-Corrected Visual Acuity Following Treatment With Twice-Daily, Preservative- Free Ketorolac 0.45% in Patients Undergoing Cataract Surgery Eric Donnenfeld, MD 1 ; Louis D. Nichamin, MD 2 ; David R. Hardten, MD 3 ; Michael B. Raizman, MD 4 ; William Trattler, MD 5 ; Rajesh K. Rajpal, MD 6 ; Rhett M. Schiffman, MD, MS, MHSA 7 1 Ophthalmic Consultants of Long Island, Rockville Centre, NY; 2 Laurel Eye Clinic, Brookville, PA; 3 Minnesota Eye Consultants, Minneapolis, MN; 4 Ophthalmic Consultants of Boston, Boston, MA; 5 Center For Excellence in Eye Care, Miami, FL; 6 Cornea Consultants, McLean, VA; 7 Allergan Inc., Irvine, CA Financial Disclosures This study was funded by Allergan, Inc., Irvine, CA. Drs. E Donnenfeld, LD Nichamin, DR Hardten, MB Raizman, W Trattler, and RK Rajpal are consultants to Allergan, Inc. Dr. RM Schiffman is an employee of Allergan, Inc.

2. 2 INTRODUCTION With advances in cataract surgery techniques, patients’ expectations have been elevated to anticipate excellent vision and little or no pain during and after surgery. 1 Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to alleviate ocular inflammation and pain after cataract surgery. 2 Ophthalmic ketorolac 0.45% solution (Acuvail ® ; Allergan, Inc.; Irvine, CA) is a new formulation of ketorolac that was developed to preserve the efficacy of prior formulations while enhancing tolerability coupled with a less frequent dosing regimen. 3 – –Key formulation modifications are inclusion of carboxymethylcellulose (CMC), exclusion of preservatives/surfactants/chelating agents, and a decrease in pH from 7.4 to 6.8. 4 – –The combination of CMC and lower pH results in approximately 2- to 3-fold higher ketorolac bioavailability to ocular tissues. 4 This study evaluated the efficacy and safety of twice-daily, preservative-free ketorolac 0.45% for treatment of pain and inflammation and performed an ad hoc analysis to assess recovery of visual acuity in patients undergoing cataract surgery.

3. 3 METHODS Study design – –Two randomized (2:1 ratio), multicenter, double-masked, vehicle-controlled trials. – –Primary eligibility criterion was uncomplicated, extracapsular phacoemulsification with posterior-chamber IOL implantation. – –Patients received ketorolac 0.45% BID or vehicle BID starting 1 day before surgery and continuing to 14 days after surgery. Outcomes – –Percentage of patients with ≥ + 3-line improvement in best-corrected visual acuity (BCVA) from baseline – –Percentage of patients with summed ocular inflammation score (SOIS) of 0 for anterior chamber cell and flare on day 14 – –Percentage of patients with no pain 24 hours after surgery Outcomes were evaluated on postoperative days 1, 3, 7, and 14. Data from the 2 clinical trials were pooled for the purpose of this presentation, and between-group differences were analyzed with a 2-sided Pearson chi-square, Fisher exact test, or Wilcoxon test. Anterior Chamber Cell Cell CountScore 00 1-5+0.5 6-15+1 16-25+2 26-50+3 > 50+4 Anterior Chamber Flare FlareScore None0 Faint+1 Moderate+2 Marked+3 Intense+4 SOIS = 0

4. 4 RESULTS: Percentage of Patients With ≥ 3-Line Improvement in BCVA From Baseline a Percentage of Patients With ≥ + 3-Line Improvement in BCVA from Baseline Days After Cataract Surgery Ketorolac 0.45% (n = 301 to 315) Vehicle (n = 116 to 155) 54.4 b 60.5 c 44.0 39.1 38.1 41.1 37.1 50.3 a Screening day. b P =.003. c P =.002. At baseline, the median BCVA was 20/40 in the ketorolac 0.45% group and 20/50 in the vehicle group (P =.321). A significantly higher percentage of patients treated with ketorolac 0.45% than those treated with vehicle had ≥ 3-lines of improvement from baseline at days 7 and 14. The overall incidence of corneal edema, corneal abrasion, corneal striae, corneal disorder, and macular edema was 5.2% (17/330) in the ketorolac group and 8.6% (14/163) in the vehicle group (P =.139) 13714 Note: Ketorolac 0.45% is FDA-approved for control of inflammation and pain after cataract surgery. Improving visual acuity is an off-label use.

5. 5 RESULTS: Postcataract Inflammation Percentage of Patients With SOIS = 0 Days After Cataract Surgery Ketorolac 0.45% (n = 318) Vehicle (n = 155) 5.8 13.2 32.1 a 52.5 a 4.7 11.0 16.8 26.5 A significantly higher percentage of patients treated with ketorolac 0.45% than those treated with vehicle had complete clearance of inflammation at days 7 and 14. a P <.001. b n = 317 for the ketorolac group. SOIS = 0 During Study 1b1b 3714

6. 6 RESULTS: Postcataract Pain A significantly higher percentage of patients treated with ketorolac 0.45% than those treated with vehicle had no pain 24 hours after surgery. Vehicle (n = 156) Ketorolac 0.45% (n = 322) 72.4 a 39.7 a P <.001. Percentage of Patients With No Pain Pain Score = 0 on Day 1

7. 7 RESULTS: Additional Efficacy Outcomes The median time to postoperative ocular pain resolution was significantly shorter in patients treated with ketorolac 0.45% compared to those treated with vehicle (1.0 day vs 2.0 days; P <.001). A significantly higher percentage of ketorolac patients than vehicle patients completed the study without requiring additional medication for inflammation or pain (81.2% vs 57.1%; P <.001). The rate of treatment failure was significantly higher in patients treated with vehicle compared to those treated with ketorolac 0.45% on days 3 (29.3 versus 16.4; P =.001), 7 (29.6 vs 14.1; P <.001), and 14 (26.6 vs 12.7; P =.001).

8. 8 RESULTS: Adverse Events With Incidence of ≥ 5% Adverse Event Vehicle (n = 163) Ketorolac 0.45% (n = 330) P value All, n (%)79 (48.5)116 (35.2).004 Increased IOP3 (1.8)19 (5.8).048 Anterior chamber cell10 (6.1)17 (5.2)NS Conjunctival hyperemia23 (14.1)15 (4.5)<.001 Eye pain25 (15.3)14 (4.2)<.001 Photophobia16 (9.8)3 (0.9)<.001 Iritis12 (7.4)14 (4.2)NS Corneal edema10 (6.1)11 (3.3)NS Foreign-body sensation9 (5.5)11 (3.3)NS IOP = intraocular pressure; NS = not significant. The incidence of IOP elevation in the ketorolac group is consistent with the potential for cataract surgery to raise IOP in the early postoperative period. 5 The lower rate of IOP elevation in the vehicle group may reflect a higher degree of intraocular inflammation combined with an inability to manifest a more typical increase in IOP following cataract surgery. Burning/stinging was reported by 1 (0.6%) vehicle patient and 5 (1.5%) ketorolac patients. a The between-group difference was not statistically significant. a Based on composite MedDRA terms consisting of “burning sensation in eye,” “instillation-site burning,” or “eyes stinging.

9. 9 RESULTS: Treatment-Related Adverse Events With Incidence of ≥ 1% Adverse Event Vehicle (n = 163) Ketorolac 0.45% (n = 330) P value All, n (%)23 (14.1)19 (5.8).002 Burning and stinging0 (0.0)5 (1.5)NS Anterior chamber cell3 (1.8)4 (1.2)NS Conjunctival hyperemia5 (3.1)1 (0.3).017 AC inflammation4 (2.5)1 (0.3).043 Iritis4 (2.5)1 (0.3).043 Anterior chamber flare3 (1.8)0 (0.0).036 Uveitis3 (1.8)0 (0.0).036 Corneal edema2 (1.2)0 (0.0)NS Corneal striae2 (1.2)0 (0.0)NS The incidence of treatment-related IOP elevation was 0% in the vehicle group and 0.6% (2/330 patients) in the ketorolac 0.45% (P >.999). The vast majority of all cases of IOP elevation occurred on the first postoperative day, did not persist with continued use of ketorolac 0.45% over the course of study, and were not considered related to treatment. AC = anterior chamber; NS = not significant.

10. 10 DISCUSSION Excellent vision is the most important outcome of cataract surgery. In this study, a significantly higher percentage of patients treated with ketorolac 0.45% had clinically significant (≥ +3-line) improvement in BCVA from baseline. Similarly, cataract and vitreoretinal surgery patients who were treated with ketorolac 0.4% (Acular LS) had significantly better BCVA compared to those treated with vehicle. 6,7 These findings suggest that perioperative use of ketorolac may help to improve visual acuity of patients undergoing intraocular surgery. Twice-daily ketorolac 0.45% effectively treated both inflammation and pain following cataract surgery. Adverse events were generally mild to moderate in severity, transient in duration, and more prevalent in the vehicle group than in the ketorolac 0.45% group. The incidence of transient burning and stinging reported upon instillation of ketorolac 0.45% was much lower than that reported in the package inserts for ketorolac 0.4% or ketorolac 0.5% (Acular) (1.5% versus “20-40%” and “up to 40%”, respectively). 8,9 Given its effectiveness against postcataract inflammation, it appears that ketorolac 0.45% combines the efficacy of prior ketorolac formulations with improved tolerability and a less frequent dosing regimen.

11. 11 CONCLUSIONS A significantly higher percentage of patients treated with ketorolac 0.45% had clinically significant improvement in visual acuity than those treated with vehicle. Twice-daily ketorolac 0.45% was well tolerated and effectively treated pain and inflammation in patients undergoing cataract extraction.

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