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					     Best-Corrected Visual Acuity Following
    Treatment With Twice-Daily, Preservative-
        Free Ketorolac 0.45% in Patients
          Undergoing 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.
1
                                  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.

2
    • Study design
                                        METHODS
        – 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
                     Anterior Chamber Cell        Anterior Chamber Flare
                     Cell Count   Score          Flare         Score
                     0              0            None            0                  SOIS = 0
                     1-5          +0.5           Faint          +1
                     6-15          +1            Moderate       +2
                     16-25         +2            Marked         +3
                     26-50         +3            Intense        +4
                     > 50          +4
    • 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
3     chi-square, Fisher exact test, or Wilcoxon test.
      RESULTS: Percentage of Patients With ≥ 3-Line
         Improvement in BCVA From Baselinea
            Percentage of Patients With ≥ + 3-Line    Ketorolac 0.45% (n = 301 to 315)
             Improvement in BCVA from Baseline
                                                                                                                              a Screening      day.
                                                      Vehicle (n = 116 to 155)                                                bP  = .003.
                                                                                                                         c
                                                                                                                  60.5        c P = .002.
                                                                                          b
                                                                                   54.4
                                                                 50.3

                                                     37.1
                                                                 41.1                                              44.0
                                                          38.1                     39.1




                                                      1          3                7                                      14
                                                                     Days After Cataract Surgery
     • 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
4   Note:(P = .139)
          Ketorolac 0.45% is FDA-approved for control of inflammation and pain after cataract surgery. Improving visual acuity is an off-label use.
                                  RESULTS: Postcataract Inflammation
                                                                       SOIS = 0 During Study
         Percentage of Patients With SOIS = 0
                                                                                                                 aP < .001.
                                                      Ketorolac 0.45% (n = 318)
                                                                                                                 bn = 317 for
                                                      Vehicle (n = 155)
                                                                                                                 the ketorolac
                                                                                                 52.5
                                                                                                        a        group.



                                                                                     a
                                                                              32.1


                                                                                                  26.5
                                                         13.2
                                                4.7                           16.8
                                                                11.0
                                                       5.8

                                                  1b         3                  7                           14
                                                                   Days After Cataract Surgery

    • 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.
5
                                                   RESULTS: Postcataract Pain
                                                         Pain Score = 0 on Day 1
                                                                             72.4a
             Percentage of Patients With No Pain
                                                                                          aP   < .001.




                                                          39.7




                                                         Vehicle        Ketorolac 0.45%
                                                        (n = 156)          (n = 322)

    • A significantly higher percentage of patients treated with ketorolac 0.45% than
      those treated with vehicle had no pain 24 hours after surgery.

6
       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).




7
    RESULTS: Adverse Events With Incidence of ≥ 5%
                                                     Vehicle           Ketorolac 0.45%           P
        Adverse Event
                                                    (n = 163)             (n = 330)            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)            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
8           burning,” or “eyes stinging.
    RESULTS: Treatment-Related Adverse Events
             With Incidence of ≥ 1%
                                                      Vehicle    Ketorolac 0.45%     P
       Adverse Event
                                                     (n = 163)      (n = 330)      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
      AC = anterior chamber; NS = not significant.
      • 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%
9       over the course of study, and were not considered related to treatment.
                                  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
10     improved tolerability and a less frequent dosing regimen.
                             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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                                     REFERENCES
     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.




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