597

ARTICLE

Intracameral ketorolac and phenylephrine

effect on intraoperative pupil diameter
and postoperative pain in cataract surgery
Eric D. Donnenfeld, MD, J. Steven Whitaker, MD, JD, Mitchell A. Jackson, MD, John Wittpenn, MD

Purpose: To evaluate the study drug OMS302 (Omidria [phenyl- 0.7 G 0.1 for the study drug versus vehicle and ketorolac, respec-
ephrine and ketorolac injection 1.0%/0.3%]) compared with a tively; P < .0001 each). Ocular pain assessed using the Visual
balanced salt solution (vehicle), ketorolac, and phenylephrine on Analog Scale was significantly reduced for the study drug
pupil diameter during cataract surgery and early postoperative compared with the vehicle or phenylephrine (least-squares mean
ocular pain. difference 4.6 G 2.2 and P Z .042 and 5.9 G 2.2 and
P Z .009, respectively). Significantly fewer patients treated with
Setting: Twenty-three centers in the United States. the study drug (3 [6.1%]) had an intraoperative pupil diameter small-
er than 6.0 mm compared with those treated with the vehicle
Design: Randomized clinical trial. (25 [47.2%]; P < .0001), ketorolac (18 [34.6%]; P Z .0004), or
phenylephrine (11 [22.4%]; P Z .0216).
Methods: Patients were randomized (1:1:1:1) to receive vehicle,
phenylephrine, ketorolac, or the study drug containing phenyleph- Conclusions: The study drug was safe and efficacious in main-
rine and ketorolac administered intracamerally during surgery. Intra- taining mydriasis and reducing postoperative ocular pain. Both ke-
operative pupil diameter was determined each minute by video torolac and phenylephrine contributed to the therapeutic effects,
capture. Postoperative ocular pain was evaluated for up to 12 hours. with the combination showing superiority to either agent alone in
maintaining an intraoperative pupil diameter of 6.0 mm or larger.
Results: The study evaluated 223 patients. The study drug was J Cataract Refract Surg 2017; 43:597–605 Q 2017 ASCRS and ESCRS
significantly better than the vehicle and ketorolac in maintaining Published by Elsevier Inc. This is an open access article under the CC
mydriasis (least-squares mean differences 0.9 G 0.1 [SEM] and BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

A
dequate pupil dilation and maintenance of dilation Preoperative use of nonsteroidal antiinflammatory drugs
are necessary for safe and efficient cataract surgery. (NSAIDs) has been shown to prevent intraoperative
Guzek et al.1 have shown that inadequate mydri- miosis.4 When administered preoperatively, multiple daily
asis or intraoperative miosis is associated with numerous dosing of these topical agents is typically required; however,
complications such as vitreous loss and zonular breaks patient compliance can be a problem.5,6 It has been shown
during cataract surgery, with the risk for each complica- that even with good patient compliance, topical drops are
tion increasing by almost 50% for each millimeter decrease washed out of the aqueous during surgery,A which can sub-
in pupil diameter. In a second study,2 the risk for posterior stantially limit their effectiveness.
capsule rupture and/or vitreous loss is almost twice as The drug product OMS302 (Omidria [phenylephrine
great in small pupils as in large pupils during cataract pro- and ketorolac injection 1.0%/0.3%]) is approved for use in
cedures. A third study3 found that the decreased posterior the United States and contains both phenylephrine (an
chamber visualization caused by intraoperative miosis a1-adrenergic receptor agonist) and ketorolac (a nonselec-
resulted in an increased likelihood of posterior capsular tive cyclooxygenase [COX]-1/COX-2 inhibitor). It is
rupture, iris chafing, and retained lens material. preservative-free and bisulfite-free. The drug is intended

Submitted: September 30, 2016 | Final revision submitted: February 4, 2017 | Accepted: February 24, 2017
From Ophthalmic Consultants of Long Island (Donnenfeld), Rockville Center, and Ophthalmic Consultants of Long Island (Wittpenn), East Setauket, New York, Omeros
Corp. (Whitaker), Seattle, Washington, and Jacksoneye (Jackson), Lake Villa, Illinois, USA.
Supported by Omeros Corp., Seattle, Washington, USA. The sponsor participated in the design of the study, conducting the study, data collection, data management,
data analysis, interpretation of the data, and the preparation, review, and approval of the manuscript. Manuscript writing and editing support was provided by 12 Point
LLC and funded by Omeros Corp.
Presented at the annual meeting of the American Academy of Ophthalmology, Orlando, Florida, USA, October 2011.
Corresponding author: J. Steven Whitaker, MD, JD, 201 Elliott Avenue West, Seattle, Washington 98119, USA. E-mail: [email protected].
Q 2017 ASCRS and ESCRS Published by Elsevier Inc. This is an open ac- 0886-3350/$ - see frontmatter
cess article under the CC BY-NC-ND license (http://creativecommons.org/ http://dx.doi.org/10.1016/j.jcrs.2017.02.030
licenses/by-nc-nd/4.0/).
598 INTRACAMERAL KETOROLAC AND PHENYLEPHRINE

to be administered continuously as part of the routine irri- drug or device trial within the 30 days before surgery; history of
gation solution during cataract surgery to maintain mydri- intraocular non-laser surgery in the study eye within the 3 months
before surgery or intraocular laser surgery in the study eye within
asis and to decrease postoperative ocular pain. Unlike
30 days before surgery; need for other ocular surgery at the time
topical administration of mydriatic agents and NSAIDs of the cataract extraction; and presence of any condition that would
before and/or after surgery, OMS302 directly delivers con- put the patient at risk or confound the interpretation of the study
stant concentrations of phenylephrine and ketorolac into data.
the anterior chamber to target tissues and to provide pre-
emptive inhibitory effects during the surgical procedure. Randomization
The purposes of this study were to evaluate the safety and Patients planning to have unilateral primary cataract surgery by
efficacy of OMS302 administered intracamerally on intra- coaxial phacoemulsification with insertion of an acrylic intraoc-
ular lens (IOL) were randomized to 1 of 4 treatment groups
operative pupil diameter during cataract surgery and on receiving medication added to 500 cc of a balanced salt solution:
the first 12 hours of postoperative ocular pain compared (1) vehicle (balanced salt solution), (2) 483 mM phenylephrine,
with vehicle, ketorolac alone, and phenylephrine alone. A (3) 89 mM ketorolac, or (4) study drug (OMS302 containing
full-factorial design allowed assessment of the contribution 483 mM phenylephrine and 89 mM ketorolac). Randomization to
of each of the active agents of OMS302 (phenylephrine and treatment groups (1:1:1:1 with block randomization) was stratified
by the Lens Opacities Classification System II (LOCS II) grade.7
ketorolac) to ensure that both contributed to the therapeu-
tic effect.
Screening Evaluations
Screening evaluations were performed within 28 days of the
PATIENTS AND METHODS planned surgery (day 0). For 3 days before surgery, patients
Study Design were instructed to use the topical antibiotic moxifloxacin 0.5%
This randomized double-masked vehicle-controlled parallel multi- (Vigamox) in the surgical eye 4 times a day, and patients again
center phase 2 study was performed at 23 study sites throughout were administered the topical antibiotic preoperatively on the
the U.S. (ClinicalTrials.gov identifier, NCT01193127B). All pa- day of surgery (day 0).
tients provided written informed consent after being informed of Before cataract surgery, pupillary function was assessed via a
the purpose of the study and the associated risks and benefits. swinging-flashlight test and preoperative topical anesthetics (lido-
The study adhered to the tenets of the Declaration of Helsinki caine or tetracaine) were applied to the operative eye for each
and the U.S. Health Insurance Portability and Accountability Act study patient according to the manufacturer’s instructions. For
and was approved by each site’s institutional review board or inde- mydriasis, approximately 30 minutes, 15 minutes, and 5 minutes
pendent ethics committee. before surgery, 1 drop of phenylephrine 2.5% (Mydfrin 2.5%) fol-
lowed by 1 drop of tropicamide 1.0% (Mydriacyl 1.0%) were
Inclusion and Exclusion Criteria instilled in each study patient’s operative eye (ie, 3 separate admin-
istrations within 60 minutes before surgery). For standardization,
The study included patients who met the following criteria:
opioids and systemic and topical NSAIDs were prohibited preop-
18 years or older, corrected distance visual acuity (CDVA) of
eratively. Short-acting hypnotic medications were permitted.
20/400 or better in the non-study eye, intraocular pressure
(IOP) 5 to 22 mm Hg in the study eye, and scheduled to have uni-
lateral primary cataract surgery under topical anesthesia with a co- Surgical Technique
axial phacoemulsification device and insertion of an acrylic IOL. Each surgical procedure was recorded by video photography
Exclusion criteria included hypersensitivity to phenylephrine, through the operating microscope. A scale measurement for
to any NSAID or aspirin, or to tetracaine, lidocaine, or any fluoro- each video recording was made by placing a ruler with millimeter
quinolone; presence of clinically significant medical conditions; divisions on both the infraorbital area and temporal side of the eye
presence of connective tissue disorder (eg, lupus, rheumatoid as close as possible to the plane of the iris and recorded in place for
arthritis, fibromyalgia); systolic blood pressure 150 mm Hg or 5 seconds. This was done at surgical baseline (immediately before
higher or 90 mm Hg or lower or diastolic blood pressure 105 mm Hg surgical incision creation). A masked central reader performed the
or higher or 40 mm Hg or lower; persistent or chronic cough; use of pupil size measurements at baseline, at 1-minute intervals during
phenylephrine (other than for the screening ophthalmological the procedure, and at the end of the surgical procedure (wound
examination) or NSAIDs within 7 days before surgery; use of closure).
anticoagulants or antiplatelet agents (including aspirin at doses The surgeon’s standard surgical technique for a clear corneal
O81 mg/day) within 14 days before surgery; use of topical, incision was used; all patients received topical anesthesia. Once
inhaled, or oral corticosteroids within 14 days of surgery or depot the procedure had started, the surgeon could use any pharmaco-
corticosteroids within 45 days of surgery; use of monoamine oxidase logic or mechanical means to manage a pupil that failed to main-
inhibitors (MAOIs) within 21 days before the day of surgery; use of tain an adequate size. Test irrigation solutions were used at all
ocular mast cell stabilizers within 7 days of surgery; repeated use of times during the surgery. The initial and primary ophthalmic vis-
pilocarpine in the study eye within 6 months before surgery; cosurgical device (OVD) was Duovisc (sodium hyaluronate 3.0%–
history of use of an a-1-adrenergic antagonist; anticipation of need chondroitin sulfate 4.0% with sodium hyaluronate 1.0%). The
for other topical ocular medications in either eye during the trial surgeon proceeded with the operation using his or her usual tech-
except prophylactic antibiotics; topical lid care; glaucoma medica- nique for capsulorhexis, removal of the cataract, and insertion of
tions or nonprescription tear-replacement solutions; presence of an acrylic IOL. Hydrodissection was performed with 3 mL of
narrow-angle glaucoma, unstable glaucoma, or glaucoma being test irrigation solution drawn into a syringe. At the end of the pro-
treated with prostaglandins or prostaglandin analogs in either cedure, the surgeon used 1 mL of test irrigation solution in a sy-
eye; pseudoexfoliation syndrome in either eye; history of iritis or ringe for filling the anterior chamber. For standardization, the
iris damage in the study eye; uncontrolled chronic ocular disease femtosecond laser was not used during any procedure.
in either eye; active corneal pathology or scarring in either eye Patients were given acetaminophen and instructed to call their
(except superficial punctate keratopathy in the non-study eye); ex- surgeon if they required additional analgesia. Patients were in-
traocular or intraocular inflammation in either eye; active bacterial structed to use topical moxifloxacin 0.5% in the surgical eye 3 times
and/or viral infection in either eye; participation in investigational postoperatively during day 0 and 4 times a day for the initial

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 INTRACAMERAL KETOROLAC AND PHENYLEPHRINE 599

7 postoperative days. The active ingredients in the study drug as process working correlation structure was used. The least-
well as other NSAIDs, anticoagulants, aspirin, monoamine oxi- squares mean differences G SEM between the study drug and
dase inhibitors (MAOIs), corticosteroids, a-1 adrenergic antago- vehicle, the study drug and ketorolac, and the study drug and
nists, ocular prostaglandin analogues, ocular mast cell stabilizers, phenylephrine are provided with 2-sided P values based on the
and pilocarpine ophthalmic medication were not permitted for repeated-measures models. The formal decision rule used for
the duration of the study unless determined by the surgeon to this study was based on all 4 primary tests being significant at
be medically necessary. the 5% 2-sided level. No adjustment for multiplicity was per-
formed for the secondary endpoints. All P values for the secondary
efficacy endpoints were descriptive and used the Cochran-Mantel-
Endpoints and Assessments
Haenszel test, adjusting for the stratification factor LOCS II grade,
The coprimary efficacy parameters included a change in pupil pairwise Wilcoxon tests, or ANOVA where applicable.
diameter during surgery and postoperative ocular pain within
12 hours after surgery. Secondary efficacy endpoints were ocular
symptoms of discomfort assessed using the Numerical Rating RESULTS
Scale (grade 0 [none] to grade 3 [severe]), use of medication for Disposition and Baseline Characteristics
postoperative pain and/or inflammation, CDVA, ocular pain 1 Of the 264 patients screened for this study, 223 were ran-
to 30 days postoperatively measured using the Visual Analog Scale
(VAS) (scale 0 to 100 mm), and ocular inflammation measured by domized at 23 study sites (Figure 1). All but 1 of the 223
the Summed Ocular Inflammation Score (SOIS). Post hoc efficacy randomized patients received study treatment. One patient
endpoints included intraoperative pupil diameter smaller than randomized to receive the study drug cancelled the cataract
6.0 mm, moderate to severe postoperative ocular pain (VAS score procedure before receiving any study treatment. Twenty
R40), and no postoperative ocular pain (VAS score 0). The anal- patients (3 vehicle group, 3 ketorolac group, 7 study drug,
ysis of the endpoint of intraoperative pupil diameter smaller than
6.0 mm was performed at the direction of the U.S. Food and Drug 7 phenylephrine group) did not have interpretable surgical
Administration given that pupils smaller than 6.0 mm in diameter videos. The reasons for noninterpretable videos included
are associated with a multiple increase in complication rates. that the ruler was not captured so pupil diameter could
Safety endpoints included adverse events, vital signs, and ophthal- not be measured, the pupil was mechanically opened, the
mologic examination parameters (including IOP). Postoperative image was too dark or blurry to be read, the DVD recording
assessments were obtained at 2, 4, 6, 8, and 10 to 12 hours (day
0) and at 1, 2, 7, 14, and 30 days. Evaluations included assessment began after the start of surgery or finished before the end of
of ocular pain, ocular discomfort, thorough ophthalmologic exam- surgery, the surgery was not recorded, and the DVD was
inations, and record of pain medication use. corrupted and could not be read postoperatively. One pa-
tient did not provide VAS scores. In addition, 2 patients as-
Statistical Analysis signed to phenylephrine received a balanced salt solution
The coprimary endpoint analyses were based on the mydriasis (vehicle) or the study drug in error. All treated patients
analysis set population, defined as all randomized patients and completed the study with the exception of 1 study drug pa-
treated patients with a baseline and at least 1 post-baseline pupil tient who withdrew consent for further participation on the
diameter measurement, and the pain analysis set population,
defined as all randomized and treated patients with at least 1 post-
sixth day before completing all follow-up assessments.
operative VAS assessment. The mydriasis analysis set and pain Overall, the demographics and baseline characteristics
analysis set populations were analyzed according to randomized were similar between treatment groups (Table 1). The ma-
treatment assigned. Safety analyses were based on the safety pop- jority of the total patient population were women (137/222
ulation, which was defined as all randomized patients who [61.7%]) and white (179/222 [80.6%]). The mean age of the
received study treatment, and were summarized by the actual
treatment received.
total population was 67.3 years G 10 (SD) (range 23 to
The sample size required for this study was estimated to be 92 years). Fifty-four patients (24.3%) had cataracts rated
192 patients (48 patients per treatment group). This number as LOCS II group 1 (nuclear grades 0 or 1), and 168 patients
was based on the results in an earlier unpublished study. The (75.7%) had cataracts rated as LOCS II group 2 (nuclear
assumed study parameters would provide 90% power for a 2- grades 2 or 3).
sided t test at a significance level of 0.05. To account for patients
randomized but who did not qualify for inclusion in the mydriasis
analysis set and pain analysis set populations, a total of 200 pa- Efficacy
tients were anticipated to be randomized in the study. Maintenance of Mydriasis As shown in Figure 2, the mean
The study used a full-factorial design to allow evaluation of the
individual contribution of the 2 active pharmaceutical ingredients pupil diameter change from baseline decreased throughout
(phenylephrine and ketorolac) to maintenance of mydriasis and in the surgical procedure in both the vehicle and ketorolac
prevention of postoperative ocular pain. The changes in pupil groups, but mydriasis was maintained in both the phenyl-
diameter over time and in postoperative ocular pain were summa- ephrine and study drug groups. The study drug was signif-
rized with descriptive statistics by treatment group and time point. icantly better than the vehicle and ketorolac in maintaining
Two repeated-measures analysis of variance (ANOVA) models,
1 for the change in pupil diameter from baseline and the other mydriasis or preventing miosis. The least-square mean dif-
for the change in VAS score from baseline, were used to test for ference change from baseline between the study drug and
differences in the maintenance of mydriasis and differences in vehicle was 0.9 G 0.1 mm (95% confidence interval [CI],
postoperative ocular pain, respectively. Both models included 0.6-1.1; P ! .0001). The least-square mean difference
treatment (the study drug, ketorolac, and vehicle for the pupil change from baseline between the study drug and ketorolac
diameter model and the study drug, phenylephrine, and vehicle
for the VAS score model), timepoint (as a categorical variable), was 0.7 G 0.1 mm (95% CI, 0.5-0.9; P ! .0001). An analysis
and LOCS II grade as fixed-effect covariates. A generalized esti- of mean pupil diameter changes by minute showed that the
mating equation approach with a first-order autoregressive study drug maintained mydriasis better than both ketorolac

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600 INTRACAMERAL KETOROLAC AND PHENYLEPHRINE

Figure 1. Participant flow

diagram.

and the vehicle by the fourth minute of the procedure (both in the study drug–treated patients than in patients who
P ! .001) (Table 2). received the vehicle or phenylephrine (Figure 3). The
Table 3 shows the results of post hoc sensitivity analyses least-square mean differences in postoperative VAS scores
of intraoperative pupil diameter. Intraoperative miosis, was 4.6 G 2.2 (95% CI, 8.9 to 0.2; P Z .042) between
defined as pupil diameter smaller than 6.0 mm at any the study drug group and vehicle group and 5.9 G
time during surgery from immediately before surgical inci- 2.2 (95% CI, 10.3 to 1.5; P Z .009) between the study
sion creation to wound closure, occurred in significantly drug group and phenylephrine group.
more patients treated with vehicle, ketorolac, or phenyleph- Table 4 shows the proportions of patients in each treat-
rine than patients treated with the study drug (P ! .0001, ment group who had moderate to severe ocular pain (VAS
P Z .0004, and P Z .0216, respectively). score R40 at any time) or were pain-free (VAS score 0 at
all timepoints) on the day of surgery assessed using a post
Postoperative Ocular Pain The mean VAS score for postop- hoc analysis. Compared with patients who received vehicle
erative ocular pain (2 to 12 hours after surgery) was lower or phenylephrine, numerically fewer ketorolac-treated

Table 1. Patient demographics and baseline characteristics.

Vehicle Ketorolac Phenylephrine Study Drug Total
Parameter (n Z 57) (n Z 55) (n Z 54) (n Z 56) (N Z 222)
Age (y)
Mean G SD 68.5 G 9.6 67.6 G 10.6 66.8 G 8.6 66.4 G 11.2 67.3 G 10
Median 69 68 67 68 68
Min, max 44.0, 89.0 43.0, 92.0 51.0, 86.0 23.0, 86.0 23.0, 92.0
Sex, n (%)
Female 33 (57.9) 34 (63.0) 33 (60.0) 37 (66.1) 137 (61.7)
Male 24 (42.1) 20 (37.0) 22 (40.0) 19 (33.9) 85 (38.3)
Race, n (%)
American Indian or Alaska native 0 1 (1.9) 0 0 1 (0.5)
Asian 6 (10.5) 5 (9.3) 7 (12.7) 5 (8.9) 23 (10.4)
Black or African American 4 (7.0) 6 (11.1) 1 (1.8) 6 (10.7) 17 (7.7)
Native Hawaiian or other Pacific Island 1 (1.8) 0 0 0 1 (0.5)
Other 0 0 1 (1.8) 0 1 (0.5)
White 46 (80.7) 42 (77.8) 46 (83.6) 45 (80.4) 179 (80.6)
Color/opalescence, n (%)
N0 1 (1.8) 1 (1.9) 0 1 (1.8) 3 (1.4)
N1 14 (24.6) 12 (22.2) 13 (23.6) 12 (21.4) 51 (23.0)
N2 22 (38.6) 26 (48.1) 29 (52.7) 24 (42.9) 101 (45.5)
N3 20 (35.1) 15 (27.8) 13 (23.6) 19 (33.9) 67 (30.2)

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 INTRACAMERAL KETOROLAC AND PHENYLEPHRINE 601

Table 2. Pupil diameter change (mm) from baseline.

Time from Start
of Surgical Incision Vehicle Ketorolac Study Drug
1 minute
Number 53 52 48
Mean G SD 0.2 G 0.4 0.2 G 0.5 0.3 G 0.6
Median 0.2 0.2 0.3
Min, max 0.5, 1.0 1.0, 1.2 1.1, 2.4
P value .4472 .2335 d
2 minutes
Number 53 52 49
Mean G SD 0.0 G 0.5 0.1 G 0.5 0.3 G 0.6
Median 0.0 0.0 0.2
Min, max 1.0, 1.0 0.9, 1.9 1.5, 1.9
P value .0139 .1035 d
3 minutes
Number 52 52 49
Figure 2. Intraoperative change in mean pupil diameter over time in Mean G SD 0.1 G 0.6 0.0 G 0.7 0.2 G 0.6
patients treated with the study drug, vehicle, phenylephrine, or ke- Median 0.0 0.1 0.1
torolac (study drug versus vehicle and study drug versus ketorolac, Min, max 1.4, 1.1 1.9, 2.1 0.9, 2.4
both P ! .0001). Seven of 203 patients (2 each per vehicle and ke- P value .0072 .0859 d
torolac groups and 3 per the study drug treatment group) had sur- 4 minutes
gery for more than 20 minutes. Number 52 52 49
Mean G SD 0.2 G 0.7 0.2 G 0.6 0.4 G 0.8
Median 0.3 0.1 0.4
Min, max 52 1.5, 1.2 1.3, 3.2
patients and study drug–treated patients reported moderate P value !.0001 !.0001 d
to severe ocular pain on the day of surgery. Also, the data 5 minutes
suggest that, compared with patients who received the Number 51 50 48
Mean G SD 0.7 G 1.0 0.5 G 0.8 0.3 G 0.6
vehicle or phenylephrine, more ketorolac-treated patients Median 0.5 0.4 0.3
and study drug–treated patients had no ocular pain through Min, max 3.1, 1.2 2.7, 2.1 0.8, 2.0
12 hours postoperatively. These comparisons were not sta- P value !.0001 .0004 d

tistically powered and did not reach statistical significance.

Safety
Other Efficacy Endpoints The percentage of patients who had at least 1 adverse event
In general, there was no treatment effect for any ocular was generally similar across each treatment group (Table 5).
discomfort domain (tearing, photophobia, eye discharge, Most adverse events were mild or moderate in severity.
itching, foreign body sensation, and haziness), CDVA, A similar incidence of severe adverse events was observed
postoperative inflammation measured by SOIS, or ocular in the 4 treatment groups. Four patients in the vehicle group
pain scores at 1 day through 30 days. had severe adverse events as follows: eye inflammation
The proportion of patients in the study group using any (n Z 2), anterior chamber cell increase (n Z 1), and
postoperative ophthalmic antiinflammatory medications conjunctival hyperemia (n Z 1). One patient in the ketor-
up to 1 day after surgery, the use of which was left to the olac group had 2 severe adverse events (eye inflammation
discretion and/or routine practice of the respective sur- and eye pain). Four patients in the phenylephrine group
geon, was comparable to that observed in the phenyleph- had 5 severe adverse events as follows: photophobia
rine and ketorolac treatment groups. The proportion of (n Z 2), anterior chamber cell increase (n Z 2), and blurry
patients in each treatment group who used any postopera- vision (n Z 1). Three patients had 4 severe adverse events
tive ophthalmic antiinflammatory medication was as in the study drug group as follows: eye inflammation
follows: vehicle 32/56 (57.1%), phenylephrine 37/56 (n Z 1), headache (n Z 1), nausea (n Z 1), and vomiting
(66.1%), ketorolac 36/55 (65.5%), and study drug 36/56 (n Z 1). The only severe adverse events that were consid-
(64.3%). The number of patients in each treatment group ered at least possibly related to study treatment were photo-
who required any medication to treat ocular pain on the phobia and increased anterior chamber cells in 2 patients in
day of surgery was as follows: vehicle 25/56 (44.6%), phen- the phenylephrine treatment group. All other severe
ylephrine 27/56 (48.2%), ketorolac 10/55 (18.2%), and adverse events were considered to be unrelated or unlikely
study drug 18/56 (32.1%). to be related to the study treatment. One patient treated

Table 3. Pupil diameter during surgery.

Parameter Vehicle (n Z 53) Ketorolac (n Z 52) Phenylephrine (n Z 49) Study Drug (n Z 49)
Intraop pupil diameter !6.0 mm, n (%) 25 (47.2) 18 (34.6) 11 (22.4) 3 (6.1)
P value vs study drug !.0001 .0004 .0216 d

n Z number of patients

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602 INTRACAMERAL KETOROLAC AND PHENYLEPHRINE

and the vehicle. The study drug was statistically signifi-

cantly better than ketorolac in maintaining mydriasis and
than phenylephrine in reducing postoperative ocular pain,
showing the contribution of each of the active ingredients.
In this study, intraoperative miosis, defined as pupil
diameter smaller than 6.0 mm at any time during surgery,
occurred in significantly more patients treated with the
vehicle, ketorolac alone, or phenylephrine alone than in
those treated with the study drug. The pronounced effect
of the study drug in preventing intraoperative miosis during
surgery relative to the effects of phenylephrine alone or ke-
torolac alone was surprising. As shown in Table 2, 87.1%
fewer study drug–treated patients than vehicle-treated pa-
tients had a pupil diameter smaller than 6.0 mm at any
Figure 3. Mean VAS score for postoperative pain on the day of sur- time during surgery. In contrast, 52.5% fewer patients
gery in patients treated with the study drug intracamerally, vehicle, treated with phenylephrine alone and 26.7% fewer
phenylephrine, or ketorolac (study drug versus vehicle, P Z .042; patients treated with ketorolac alone than vehicle-treated
study drug versus phenylephrine, P Z .009) (VAS Z Visual Analog
patients had pupil diameter smaller than 6.0 mm at any
Scale).
time during surgery. The study drug OMS302 thus provided
a more-than-additive effect relative to phenylephrine alone
with phenylephrine had a treatment-emergent serious and ketorolac alone in preventing intraoperative miosis (ie,
adverse event of atypical facial neuralgia, which was consid- pupil diameter !6.0 mm at any time during surgery). That
ered unrelated to study treatment. No patients discontinued the antimiotic effect of ketorolac in maintaining intraoper-
from the study because of an adverse event, and no patient ative pupil diameter was still evident on top of the strong
had a fatal adverse event. mydriatic effect of phenylephrine was unexpected. This is
Table 6 shows the treatment-emergent adverse events notable because although mean results can mask outliers,
occurring in more than 5% of patients in at least 1 treatment this post hoc analysis showed that the study drug–treated
group. The most frequently observed adverse events, cate- patients maintained a pupil of 6.0 mm or larger throughout
gorized using standard Medical Dictionary for Regulatory the procedure more frequently than even those treated with
Activities–defined terms were eye pain, inflammation, eye phenylephrine alone. Phenylephrine is an a-1 selective
inflammation, pain, headache, and photophobia. adrenergic receptor that works in a fashion similar to that
No notable changes in vital signs (blood pressure, respi- of epinephrine, a nonselective adrenergic receptor, to dilate
ratory rate, heart rate, and temperature) were observed for the pupil. Given the similar mechanisms of action and the
any treatment group. No treatment-related findings during results above, the intracameral administration of both ke-
the ophthalmologic examination, including changes in IOP, torolac and phenylephrine in OMS302 might be expected
were observed. to provide additional benefits over epinephrine alone in
preventing miosis during cataract surgery.
DISCUSSION The number of patients who required supplemental ocular
The study drug OMS302 (Omidria [phenylephrine and ke- pain medication on the day of surgery was least in the ketor-
torolac injection 1.0%/0.3%]) added to 500 cc of a balanced olac group and less in the study drug group than in the phen-
salt solution delivered the pharmacologic actions of both ylephrine and vehicle groups. The lower mean VAS score for
phenylephrine and ketorolac when administered intracam- postoperative pain in the study drug group than in the vehicle
erally during cataract surgery. The study drug–treated and phenylephrine groups was not a result of an increased use
patients had significantly improved maintenance of mydri- of pain medication; in fact, fewer study drug–treated patients
asis compared with ketorolac-treated patients and vehicle- used postoperative pain medications. This finding is sup-
treated patients. The study drug also significantly reduced ported by other studies that found ketorolac provides effec-
postoperative ocular pain compared with phenylephrine tive pain and inflammation control after cataract surgery.8,9

Table 4. Postoperative VAS pain score (within 12 hours after surgery).

Vehicle Ketorolac Phenylephrine Study Drug
Parameter (n Z 56) (n Z 55) (n Z 56) (n Z 55)
Moderate to severe ocular pain (VAS score R40) at any time
Number (%) 9 (16) 2 (4) 8 (14) 4 (7)
P value vs study drug .2373 d .3602 d
Pain free (VAS Z 0) at all timepoints
Number (%)* 10 (17.9) 16 (29.1) 9 (16.1) 15 (27.3)

Number Z number of patients; VAS Z Visual Analog Scale

*Post hoc not statistically powered for analysis

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 INTRACAMERAL KETOROLAC AND PHENYLEPHRINE 603

Table 5. Summary of adverse events.

Number (%)

Phenylephrine
Parameter Vehicle (n Z 57) Ketorolac (n Z 55) (n Z 54) Study Drug (n Z 56)
Patients with treatment-emergent AEs* 45 (78.9) 37 (67.3) 43 (79.6) 47 (83.9)
Patients with treatment-related AEs† 5 (8.8) 4 (7.3) 12 (22.2) 8 (14.3)
Patients with eye-related AEs 29 (50.9) 26 (47.3) 34 (63.0) 34 (60.7)
Maximum severity of treatment-emergent AE per patient
Mild 23 (40.4) 15 (27.3) 22 (40.7) 22 (39.3)
Moderate 18 (31.6) 21 (38.2) 17 (31.5) 22 (39.3)
Severe 4 (7.0) 1 (1.8) 4 (7.4) 3 (5.4)
Patients with treatment-emergent AE 0 0 1 (1.9) 0

AE Z adverse event
*Adverse event occurring or worsening after the start of study treatment
†
Adverse event that was probably or possibly related to study drug as assessed by the investigator

In this study, OMS302 was safe and well tolerated. The surgery and has been reported to provide effective and
most frequently reported adverse events, all of which safe mydriasis in some patients.C Use of Mydrane, which
commonly occur after cataract surgery, were eye pain, is injected once at the beginning of the surgical procedure,
inflammation, eye inflammation, pain, headache, and is limited to patients who have previously achieved satisfac-
photophobia. Adverse events were generally mild or mod- tory pupil dilation with topical mydriatic therapy.C Com-
erate and not considered to be related to study treatment. pounding the mixture of buffered lidocaine and
There were no systemic side effects. Overall, the safety of epinephrine, known as epi-Shugarcaine, has been shown
the study drug observed is consistent with that reported to help maintain intraoperative mydriasis.16 Epinephrine
in intracameral mydriatic studies, phenylephrine studies, alone, often used off-label, added to irrigation solution for
and ketorolac studies.5,10–12 intracameral administration might also be used. Even
Cataract surgery in the presence of intraoperative miosis with these intraoperative treatments, during surgery there
is not without risk because small pupils have been associ- still is the tendency for miosis to occur,17 and in some pro-
ated with surgical complications such as posterior capsule cedures more invasive pupil dilation (eg, use of pupil
rupture and vitreous loss.13,14 Although specific practices expansion devices) may be required.10 Unlike OMS302,
vary, preoperative topical regimens, which attempt to create Mydrane, epi-Shugarcaine, and epinephrine do not include
an open operative field during cataract surgery, include an NSAID or other antiinflammatory agent.
mydriatics to dilate the pupil, anesthetics for mydriatic ef- Additional options for treating intraoperative miosis
fect and comfort, and steroids or NSAIDs to prevent miosis include mechanical dilation (eg, with pupil expansion de-
and to reduce pain and inflammation.4,15 Intracameral vices or iris hooks)18,19 and viscodilation,13 each of which
mydriatic agents and local anesthetics are also used to dilate has limitations. Pupil expansion devices (eg, Malyugin
the pupil at the start of the procedure or during the proced- rings) and iris hooks can cause iris tears or trauma, and
ure to maintain adequate mydriasis. Mydrane, a combina- OVDs must be thoroughly removed to prevent increased
tion of tropicamide, phenylephrine, and lidocaine, has IOP.13 Ophthalmic viscosurgical devices and pharmaco-
been approved in some European countries for obtaining logic approaches typically do not give the lasting effect
mydriasis and intraocular anesthesia during cataract needed throughout the entire procedure.

Table 6. Treatment-emergent adverse events occurring in 5% or more of patients.

Number (%)

Event Vehicle (n Z 57) Ketorolac (n Z 55) Phenylephrine (n Z 54) Study Drug (n Z 56)
Any Event 45 (78.9) 37 (67.3) 43 (79.6) 47 (83.9)
Specific event
Eye pain 16 (28.1) 13 (23.6) 21 (38.9) 17 (30.4)
Inflammation 13 (22.8) 8 (14.5) 12 (22.2) 11 (19.6)
Eye inflammation 5 (8.8) 12 (21.8) 9 (16.7) 11 (19.6)
Pain 11 (19.3) 8 (14.5) 8 (14.8) 9 (16.1)
Headache 5 (8.8) 4 (7.3) 2 (3.7) 4 (7.1)
Photophobia 1 (1.8) 2 (3.6) 3 (5.6) 4 (7.1)
Anterior chamber cell 3 (5.3) 2 (3.6) 3 (5.6) 1 (1.8)
Ocular discomfort 5 (8.8) 1 (1.8) 1 (1.9) 1 (1.8)
Iritis 0 2 (3.6) 2 (3.7) 3 (5.4)
Increased intraocular pressure 1 (1.8) 3 (5.5) 0 1 (1.8)
Conjunctival hyperemia 3 (5.3) 0 1 (1.9) 0
Posterior capsule opacification 1 (1.8) 3 (5.5) 0 0

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604 INTRACAMERAL KETOROLAC AND PHENYLEPHRINE

Intracameral irrigation has several benefits over topical contributed to maintaining pupil size by reducing intrao-
drops or bolus injection for maintaining mydriasis. perative miosis, with OMS302 providing significantly better
A recent studyA showed that topical drops are washed out maintenance of pupil diameter than phenylephrine alone.
by irrigation solution during surgery, which might limit
their effectiveness. Intracameral irrigation of a drug-
containing solution continuously enters the eye, maintain- WHAT WAS KNOWN
ing a constant concentration of drug within the eye while  Adequate preoperative mydriasis is a requirement for safe
the surgical stimulus for miosis is occurring. The dose of and efficient cataract surgery.
an infused drug can be lower than the dose of a bolus injec-  Several agents, including NSAIDs, mydriatics, and anes-
tion or topical application, and this lower dose decreases the thetics, are administered before and during the surgical
procedure to achieve and maintain pupil dilation; however,
risk for systemic side effects, in particular with respect to
miosis can still occur.
adrenergic agonists in patients with hypertension.19 In
addition, preoperative topical mydriatics plus intracameral WHAT THIS PAPER ADDS
irrigation of a mydriatic and/or antimiotic can more effec-  The drug product OMS302, which contains the active in-
tively maintain mydriasis than topical mydriatics alone.17,20 gredients phenylephrine and ketorolac, when added to irri-
The findings in this study are limited to the population gation solution and delivered intracamerally during cataract
surgery maintained pupil size and reduced postoperative
defined by the study entry criteria. Of note, for purposes
ocular pain.
of standardization, the study excluded patients with expo-  The independent and contributory effects of phenylephrine
sure to a-blockers, including tamsulosin (a risk factor for and ketorolac were shown in this randomized double-masked
intraoperative floppy-iris syndrome), pseudoexfoliation full-factorial study of patients having cataract surgery.
syndrome, and femtosecond laser use, all populations at  The study drug OMS302 prevented intraoperative miosis
risk for intraoperative miosis. Another study limitation (defined by a pupil smaller than 6.0 mm at any time during
was that corneal endothelial cell loss was not evaluated. the procedure) better than phenylephrine alone and better
than ketorolac alone.
Also, the study was not designed to compare the effect of
OMS302 alone with that of OMS302 plus a preoperative
NSAID. Preoperative topical NSAIDs are often used to
reduce postoperative pain and inflammation. This was
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Disclosures: Dr. Donnenfeld is a consultant to and investigator for
OTHER CITED MATERIAL and holds an equity interest in Omeros Corp. Dr. Whitaker is an em-
A. Katsev DA, Katsev CC, Pinnow JM, “Intracameral Ketorolac Concentration ployee of and holds an equity interest in Omeros Corp., Dr. Jackson
After Topical Ketorolac Administration Prior to Cataract Surgery,” electronic and Dr. Wittpenn are consultants to Omeros Corp.

Volume 43 Issue 5 May 2017