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Best-Corrected Visual Acuity Following Best-Corrected Visual Acuity Following Treatment With Twice-Daily, Preservative-Treatment With Twice-Daily, Preservative-

Free Ketorolac 0.45% in Patients Free Ketorolac 0.45% in Patients Undergoing Cataract SurgeryUndergoing Cataract Surgery

Eric Donnenfeld, MD1; Louis D. Nichamin, MD2; David R. Hardten, MD3; Michael B. Raizman, MD4; William Trattler, MD5; Rajesh K. Rajpal, MD6; Rhett M. Schiffman, MD, MS, MHSA7

1Ophthalmic Consultants of Long Island, Rockville Centre, NY; 2Laurel Eye Clinic, Brookville, PA; 3Minnesota Eye Consultants, Minneapolis, MN; 4Ophthalmic Consultants of Boston, Boston, MA; 5Center For Excellence in Eye Care, Miami, FL; 6Cornea Consultants, McLean, VA; 7Allergan 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.

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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.

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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 CellCell Count Score

0 01-5 +0.56-15 +116-25 +226-50 +3> 50 +4

Anterior Chamber FlareFlare Score

None 0Faint +1Moderate +2Marked +3Intense +4

SOIS = 0

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RESULTS: Percentage of Patients With ≥ 3-Line Improvement in BCVA From Baselinea

Per

cent

age

of P

atie

nts

With

≥ +

3-L

ine

Impr

ovem

ent i

n B

CV

A fr

om B

asel

ine

Days After Cataract Surgery

Ketorolac 0.45% (n = 301 to 315) Vehicle (n = 116 to 155)

54.4b

60.5c

44.039.138.1 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)

1 3 7 14

Note: Ketorolac 0.45% is FDA-approved for control of inflammation and pain after cataract surgery. Improving visual acuity is an off-label use.

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RESULTS: Postcataract Inflammation

Per

cent

age

of P

atie

nts

With

SO

IS =

0

Days After Cataract Surgery

Ketorolac 0.45% (n = 318)Vehicle (n = 155)

5.8

13.2

32.1a

52.5a

4.711.0

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

1b 3 7 14

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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)

72.4a

39.7

a P < .001.P

erce

ntag

e of

Pat

ient

s W

ith N

o P

ain

Pain Score = 0 on Day 1

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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).

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RESULTS: Adverse Events With Incidence of ≥ 5%

Adverse EventVehicle

(n = 163)Ketorolac 0.45%

(n = 330)P

value

All, n (%) 79 (48.5) 116 (35.2) .004

Increased IOP 3 (1.8) 19 (5.8) .048

Anterior chamber cell 10 (6.1) 17 (5.2) NS

Conjunctival hyperemia 23 (14.1) 15 (4.5) < .001

Eye pain 25 (15.3) 14 (4.2) < .001

Photophobia 16 (9.8) 3 (0.9) < .001

Iritis 12 (7.4) 14 (4.2) NS

Corneal edema 10 (6.1) 11 (3.3) NS

Foreign-body sensation 9 (5.5) 11 (3.3) NSIOP = 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.

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RESULTS: Treatment-Related Adverse Events With Incidence of ≥ 1%

Adverse EventVehicle

(n = 163)Ketorolac 0.45%

(n = 330)P

value

All, n (%) 23 (14.1) 19 (5.8) .002

Burning and stinging 0 (0.0) 5 (1.5) NS

Anterior chamber cell 3 (1.8) 4 (1.2) NS

Conjunctival hyperemia 5 (3.1) 1 (0.3) .017

AC inflammation 4 (2.5) 1 (0.3) .043

Iritis 4 (2.5) 1 (0.3) .043

Anterior chamber flare 3 (1.8) 0 (0.0) .036

Uveitis 3 (1.8) 0 (0.0) .036

Corneal edema 2 (1.2) 0 (0.0) NS

Corneal striae 2 (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.

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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.

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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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REFERENCESREFERENCES

1. Price MO, Price FW. Efficacy of topical ketorolac tromethamine 0.4% for control of pain or discomfort associated with cataract surgery. Curr Med Res Opin. 2004;20(12):2015-2019.

2. O'Brien TP. Emerging guidelines for use of NSAID therapy to optimize cataract surgery patient care [published correction appears in Curr Med Res Opin. 2005;21(9):1431-1432]. Curr Med Res Opin. 2005;21(7):1131-1137.

3. Acuvail® [package insert]. Irvine, CA: Allergan, Inc.; 2009.

4. Data on file, Allergan, Inc.

5. Rich WJ, Radtke ND, Cohan BE. Early ocular hypertension after cataract extraction. Br J Ophthalmol. 1974;58(8):725-731.

6. Donnenfeld ED, Perry HD, Wittpenn JR, Solomon R, Nattis A, Chou T. Preoperative ketorolac tromethamine 0.4% in phacoemulsification outcomes: pharmacokinetic-response curve. J Cataract Refract Surg. 2006;32(9):1474-1482.

7. 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(9):1203-1208.

8. Acular LS® [package insert]. Irvine, CA: Allergan, Inc.; 2003.

9. Acular® [package insert]. Irvine, CA: Allergan, Inc.; 1997.