OMS302 (phenylephrine and ketorolac injection) 1%/0.3% to maintain intraoperative pupil size and to prevent postoperative ocular pain in cataract surgery with intraocular lens replacement

Abstract

Cataract surgery with intraocular lens replacement is among the most commonly performed surgical procedures worldwide. Various pharmacologic agents are administered topically before and/or after, and a few are delivered intracamerally during, surgery to achieve mydriasis and to treat postoperative pain and inflammation. OMS302 (Omidria™ [phenylephrine and ketorolac injection] 1%/0.3%), a proprietary drug containing phenylephrine and ketorolac, was developed for use during cataract surgery to maintain intraoperative pupil size by preventing miosis and reduce early postoperative ocular pain. Containing no preservatives or bisulfites, OMS302 is formulated in a single-dose, single-patient use vial. Added to a standard 500 ml container of irrigation solution used during the procedure, OMS302 is infused into the anterior chamber with direct action on the iris and other ocular tissues. As the only US FDA-approved drug that is indicated both to prevent miosis and reduce postoperative pain associated with cataract surgery, OMS302 provides a new treatment option for ophthalmic surgeons.

Keywords:

• bisulfites
• cataract
• intraocular lens replacement
• ketolorac
• miosis
• mydriasis
• Omidria™
• phenylephrine
• preservatives

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Erratum

Cataracts are the leading cause of vision impairment and blindness worldwide. The prevalence of cataracts increases yearly, with 1.6 million individuals estimated to be blind due to this condition by 2020 in the USA alone [1]. Surgery is a highly effective treatment for this condition, making cataract removal with intraocular lens (IOL) replacement among the most commonly performed surgical procedures in the USA [2,3]. Since the introduction of cataract surgery, many advancements in operating technology and technique have been made. Consequently, routine uncomplicated cataract surgical procedures are clearly one of medicine’s brightest accomplishments.

A prerequisite for safe cataract surgery is an adequately dilated pupil [4–6]. Mydriasis is typically obtained by agents that either disrupt the parasympathetic activity of the iris (i.e., anticholinergics, such as tropicamide and cyclopentolate) or stimulate its sympathetic activity (i.e., sympathomimetics, such as phenylephrine), or a combination of both types of agents. Miosis, on the other hand, involves stimulation of the parasympathetic activity of the iris or disruption of its sympathetic activity [7]. Intraoperative trauma from the surgical procedure also induces pupillary constriction via the intraocular release of prostaglandins [8,9]. Various methods of drug delivery have been studied to obtain rapid and adequate mydriasis for cataract surgery with IOL replacement, including drops, depots and mechanical devices, with the common goal of obtaining maximal dilation of the pupil. However, preoperative administration of topical mydriatic agents does not yield consistent results, often neither maximally nor rapidly dilating the pupil. Furthermore, sympathomimetic agents have been reported to contribute unwanted effects, such as increased risk of cardiovascular side effects [10,11]. Furthermore, preoperative administration of mydriatics does not preclude intraoperative miosis that occurs via release of prostaglandins resulting from surgically induced trauma [8,9,12], and that is associated with greater risk of surgical complications [7,13,14].

Given these limitations, administration of intraoperative mydriatic agents intracamerally during surgery has become more common [10,15,16]. Although reported to be effective in maintaining mydriasis during cataract surgery, intracameral mydriatics – like preoperative mydriatics – only dilate the pupil and have no inhibitory effect on prostaglandin-mediated miosis. In addition, many combination preparations require pharmacy compounding, which, unbeknown to the surgeon, may introduce impurities or affect the potency and/or reduce the quality of the agents to be administered. Therefore, the use of these agents can put a patient at risk for unwanted postoperative safety events, such as mixture errors, toxic anterior segment syndrome or intraocular infections [17,18].

Postoperative pain following cataract surgery also remains a concern even with modern advances in surgical technique. A prospective clinical study with the primary objective to evaluate pain following cataract surgery with phacoemulsification reported that 34% of patients experience some degree of pain following the procedure [19]. Some surgeons use topical NSAIDs to treat secondary inflammatory pain associated with the surgical incision [20,21].

As described, mydriatic drugs and drugs to manage inflammation and pain have been the mainstay of the ophthalmic surgeon’s armamentarium. Although newer corticosteroids and NSAIDs have been introduced in recent years, the acceptance and use of these agents are not consistent across surgeons. This review describes a new drug containing two active agents, OMS302 (Omidria™ [phenylephrine and ketorolac injection] 1%/0.3%), approved by the US FDA for intracameral administration during contemporary cataract surgery to address two common issues associated with these procedures: intraoperative miosis and postoperative ocular pain. The availability of such a product may be beneficial in standardizing pharmacological methods of maintaining intraoperative mydriasis and in preemptively reducing postoperative ocular pain.

OMS302 (phenylephrine 1% & ketorolac 0.3%)

A new drug product containing 1% weight/volume (w/v) phenylephrine hydrochloride (phenylephrine) and 0.3% w/v ketorolac tromethamine (ketorolac), OMS302 (Omidria Omeros Corporation, Seattle, WA), was approved by the FDA in May 2014 for use during cataract surgery or IOL replacement, representing approximately 4 million procedures annually in the USA [Omeros Corporation, Data on File], to maintain pupil size by preventing intraoperative miosis and reduce postoperative pain. The active ingredients in OMS302, phenylephrine and ketorolac, have each been used in ophthalmic settings for many years. However, OMS302 is a drug product that contains these two agents, each with a well-established efficacy and safety profile, in a single drug product delivered into the eye at the time of surgery. Phenylephrine, as an α1-selective adrenergic agonist, was selected for its mydriatic effects; ketorolac, as an NSAID, was included for its ability to prevent miosis and inhibit pain.

OMS302 is added to the commonly used 500-ml container of irrigation fluid delivered intracamerally during cataract surgery, directly bathing intraocular tissues with its active agents locally throughout the procedure. OMS302, when added to the irrigation solution, provides final concentrations of 480 μM phenylephrine and 89 μM ketorolac, which correspond to approximate concentrations of 0.01% (w/v) and 0.0034% (w/v), respectively. Although 500 ml of irrigation solution contains 49 mg phenylephrine and 17 mg ketorolac, the systemic exposure is limited to that absorbed from the anterior chamber. Most of the active pharmaceutical ingredients transit through the anterior chamber with irrigation and are removed as effluent (see results of clinical pharmacokinetics substudy).

OMS302 pharmacology

The pharmacologic properties of OMS302 reflect those of its active ingredients, the α1-adrenergic agonist phenylephrine and the nonselective COX inhibitor ketorolac. Phenylephrine was initially introduced into clinical use over 50 years ago and ketorolac (Toradol^®) was first approved in the USA as an injectable NSAID in 1989 and subsequently marketed for ophthalmic use in 1992 [22–24], and there is extensive nonclinical and clinical experience using each of these agents. OMS302 is the first and only FDA-approved drug product containing both of these agents and is designed to be used clinically as an admixture with irrigation solution during cataract surgery.

Phenylephrine is an α1-selective adrenergic agonist. The principal use of phenylephrine in ophthalmology is as a topically administered mydriatic agent, and it is commonly used prior to cataract surgery [25]. The iris dilator muscle contains α1-receptors that mediate contraction, causing dilation of the pupil without cycloplegia [26,27]. In vitro, phenylephrine causes constriction of human blood vessels at concentrations of 1–10 μM [28,29]. When administered systemically, phenylephrine produces vasoconstriction but does not increase the heart rate or force of contraction [30]. Phenylephrine can cause reflex bradycardia secondary to vasoconstriction and increased blood pressure caused by its vasoconstrictor properties [31]. At therapeutic doses during ophthalmic use, phenylephrine produces little, if any, CNS stimulation.

Ketorolac is an NSAID of the pyrrolo-pyrrole class. Ketorolac is a racemic mixture of -S and -R enantiomeric forms, and its pharmacologic activity is associated with the (S)-form. Ketorolac inhibits the COX enzymes COX-1 and COX-2, with IC₅₀ values for prostaglandin and thromboxane synthesis of 10–100 nM in cellular preparations and modest selectivity for COX-1 [32–34]. The systemic and ocular pharmacologies of ketorolac, and NSAIDs in general, largely reflect their ability to inhibit the synthesis of prostaglandins, prostacyclins and thromboxanes. Ketorolac is an effective analgesic and has been used to treat moderate-to-severe pain [35]. Topical ocular NSAIDs, including ketorolac, have multiple clinical uses associated with cataract surgery. Keates first introduced the NSAID Ocufen for inhibition of miosis during cataract surgery in 1984 [36]. Topical NSAIDs used to treat postoperative pain and discomfort include ketorolac (Acular^®, Acuvail^®), bromfenac (Xibrom™, Bromday^® and Prolensa™), nepafenac (Nevanac^® and Ilevro™) and diclofenac (Voltaren^®) [37,38]. NSAIDs have also been used to treat postoperative cystoid macular edema, although this use is not FDA approved [39,40].

The primary organs of toxicity for ketorolac and other NSAIDs are the gastrointestinal tract and the kidneys, with gastrointestinal bleeding and impaired renal function occurring at high doses. With sustained use, these agents also inhibit platelet function and increase bleeding time. Direct injection of ketorolac into the vitreous humor appears nontoxic at doses up to 3 mg but causes retinal degenerative changes at 6 mg [41].

Nonclinical pharmacology studies of OMS302 were designed to support the distinct pharmacology of phenylephrine and ketorolac and their complementary modes of action. Given the extensive background literature on the pharmacology of the individual active agents, the pharmacology studies focused on the effects of phenylephrine and ketorolac, used either individually or in combination, during cataract surgery with IOL insertion in the African green monkey animal model.

In pharmacology and toxicology studies of OMS302, phenylephrine was administered (either alone or in combination with ketorolac), at concentrations ranging from 3 to 7200 μM to African green monkeys undergoing phacoemulsification. At concentrations greater than or equal to 10 μM, phenylephrine induced rapid pupil dilation and maintained mydriasis adequate to facilitate phacoemulsification and lens replacement. Collectively, the nonclinical studies performed with phenylephrine demonstrate that delivery of phenylephrine to the anterior chamber elicits rapid mydriasis that is adequate in extent and duration for cataract surgery, consistent with the abundant literature and long clinical experience with phenylephrine-containing eye drops for the induction of mydriasis.

In one pharmacologic study, the delivery of phenylephrine via irrigation during cataract surgery with IOL implantation resulted in a concentration-dependent mydriasis that was adequate in both degree and duration for the completion of the procedure [Omeros Corporation, Data on File]. Furthermore, at phenylephrine concentrations of 10, 30 and 90 μM, mean pupil diameters exceeded those in the control group, which received two drops of 1% tropicamide solution prior to surgery. In a second pharmacologic study, phenylephrine was administered via irrigation during cataract surgery with phacoemulsification at a concentration of 90 μM [Omeros Corporation, Data on File]. This treatment elicited mydriasis to a diameter of 6.0 to 6.5 mm within approximately 60 s and achieved and sustained a mean pupil diameter of 8–9 mm. This mean pupil diameter was significantly greater than the mean diameter observed in the tropicamide control group (≈7 mm). In a third pharmacologic study, phenylephrine was administered via anterior chamber injection of 150 μl of solution at phenylephrine concentrations of 90, 268 and 1165 μM [Omeros Corporation, Data on File]. There was no control group in this study. Mydriasis to a mean diameter of 6–7 mm was observed in all groups within 60 s. Mydriasis was dose dependent, with increased mydriasis observed at phenylephrine concentrations above 90 μM, suggesting the utility of higher phenylephrine concentrations.

In a good laboratory practices toxicology study, phenylephrine was administered via an initial anterior chamber injection of 150 μl followed by irrigation during cataract surgery [Omeros Corporation, Data on File]. Monkeys were administered either balanced salt solution (BSS) or phenylephrine/ketorolac in BSS at low (720 μM phenylephrine/90 μM ketorolac), mid (2160 μM phenylephrine/270 μM ketorolac) or high (7200 μM phenylephrine/900 μM ketorolac) doses. Rapid dose-dependent mydriasis to approximately 7 mm was observed in all groups within 60 s of the initial injection, and further dilation to 8–9 mm occurred 60 s after the start of irrigation.

A nonclinical study of ketorolac administered via irrigation during cataract surgery in the same African green monkey animal model also demonstrated reduced postoperative inflammatory changes (anterior chamber flare), consistent with the established benefit of ketorolac on ocular inflammation [24,42,43].

The no-observed-adverse-effect-level established in the good laboratory practices toxicity study was 7200 μM phenylephrine and 900 μM ketorolac, which is well above the concentrations found in the OMS302 admixture (483 μM phenylephrine and 89 μM ketorolac) with irrigation solution [Omeros Corporation, Data on File].

Data from the nonclinical pharmacology studies of OMS302 demonstrate that mydriasis adequate for cataract surgery can be obtained with lower concentrations of phenylephrine delivered by irrigation than with tropicamide 1% alone and possibly other currently used topical ophthalmic solutions and confirmed the effect of ketorolac in reducing postoperative ocular inflammation. The administration of OMS302 or its individual active ingredients to African green monkeys was not associated with ocular or systemic toxicity at exposures 6.2-fold (phenylephrine) and 4.2-fold (ketorolac) multiples of the maximum anticipated clinical exposure.

OMS302 clinical experience

A total of four clinical studies were performed during the clinical development of OMS302. These studies included one Phase I/II exploratory study designed to evaluate safety and potential efficacy endpoints for future studies, one Phase II full-factorial study designed to evaluate the separate contributions of phenylephrine and ketorolac to the proposed indication, and two confirmatory Phase III safety and efficacy studies, one of which included a pharmacokinetics substudy.

The first clinical study evaluating OMS302 was a Phase I/II randomized, vehicle-controlled, double-masked, parallel, three-arm study of phenylephrine and a preliminary combination of phenylephrine with ketorolac in subjects undergoing cataract extraction and lens replacement [Omeros Corporation, Data on File]. This exploratory study evaluated the safety and potential clinical benefits of the phenylephrine/ketorolac combination, as well as determined clinical endpoints, for further assessment in follow-up studies. A total of 60 subjects randomized in a 1:1:1 fashion to BSS vehicle, phenylephrine diluted in BSS or phenylephrine/ketorolac combination diluted in BSS were evaluated. The study demonstrated that the combination of phenylephrine and ketorolac was superior to BSS vehicle in maintenance of mydriasis. Mean pupil diameter progressively decreased in the vehicle group throughout the procedure, whereas the phenylephrine alone and phenylephrine/ketorolac combination groups did not demonstrate pupil constriction. The difference between BSS vehicle group compared with the phenylephrine/ketorolac combination group in mean (standard error) area under the curve change from baseline in pupil diameter was 0.7 (0.2) mm (95% CI: 0.3–1.2; p = 0.0018). No treatment effect was observed on the pain endpoint with a ketorolac concentration of 60 μM.

Three subsequent clinical studies of OMS302 provide the data for the evaluation of the efficacy of the final formulation of OMS302 [44–47]; [Omeros Corporation, Data on File]. The population included in each of the clinical studies consisted of adult (18 years of age or greater) subjects who were undergoing phacoemulsification for cataract surgery or refractive lens exchange and had intraocular pressure within normal range (5–22 mmHg). Ultrasonic phacoemulsification is the procedure of choice throughout most of the world [48–52].

Criteria for exclusion from these studies included baseline conditions that may have affected subject safety and/or could have affected the primary efficacy measures and complicated interpretation of the results. Key exclusion criteria included the following: concurrent clinically significant systemic disease; connective tissue disease; abnormal baseline blood pressure; narrow angle/unstable glaucoma or treatment with prostaglandins; history of iritis or trauma with iris damage; pseudoexfoliation syndrome; uncontrolled chronic eye disease; active corneal pathology or scarring; recent surgery in the study eye; use of preoperative phenylephrine, NSAIDs, corticosteroids or ocular mast stabilizers; use of monoamine oxidase inhibitors within a week of surgery; use of monoamine oxidase inhibitors within 3 weeks of surgery; use of depot corticosteroids within a month of surgery; use of pilocarpine within 6 months of surgery; and any prior use of α1-adrenergic antagonists. Preoperative use of cyclosporine was also an exclusion criterion for Phase III Study 2. For each study, subjects underwent unilateral IOL replacement and only one eye (i.e., the operative eye) per subject was included in the efficacy analyses.

In the Phase II and Phase III studies performed, subjects did not receive preoperative NSAIDs to avoid confounding the interpretation of the study results given that ketorolac is an NSAID. Also, subject compliance can vary considerably and not all patients undergoing cataract surgery or refractive lens exchange are treated with preoperative NSAIDs clinically. Furthermore, the ketorolac concentration in OMS302 when diluted in irrigation solution is higher than reported ketorolac anterior chamber concentrations following topical use. Therefore, prohibition of preoperative NSAID treatment was not expected to impact the treatment effect of OMS302 but was specified in the protocol to assure standardization and thereby preclude complicating factors. Each subject did receive standard preoperative treatments, including Vigamox^® antibiotic regimen, lidocaine or tetracaine local topical anesthesia, and topical phenylephrine 2.5% plus tropicamide 1% mydriatic agents. For purposes of standardization, no other intracameral agents (e.g., lidocaine, epinephrine and antibiotics) were used during surgery.

Each of these three studies was randomized, double-masked and controlled. The Phase II study included OMS302 and three controls: phenylephrine at the same concentration as in OMS302, ketorolac at the same concentration as in OMS302 and vehicle (BSS). The phenylephrine and ketorolac treatment groups were included to demonstrate the effect of phenylephrine on pupil diameter and of ketorolac on postoperative pain. The vehicle group provided a negative control that was comparable with a placebo control. To maintain masking, the bottles of irrigation solution were prepared by an unmasked pharmacist or designee who was not otherwise involved in the study and an unmasked pharmacy clinical research associate monitored the pharmacy. All other study personnel remained masked throughout the study. The two Phase III studies were placebo-controlled. Because not all studies included phenylephrine and ketorolac treatment groups, the comparison of efficacy results across studies was focused on OMS302 compared with the negative control group (i.e., vehicle or placebo).

Two principle efficacy endpoints were evaluated in each of these clinical studies: change in pupil diameter over time from surgical baseline (immediately prior to surgical incision) to the end of the surgical procedure (wound closure) as determined by video recordings of the procedure (primary endpoints for all three studies) and postoperative ocular pain as measured by the Visual Analog Scale (VAS) after surgery (primary endpoint for the Phase II study and one of the Phase III studies and secondary endpoint for the other Phase III study).

The efficacy evaluations in each study that contributed to the claimed indication were completed between the start of the procedure and the initial 10–12 h postoperatively. Subjects were followed postoperatively for at least 14 days.

The efficacy endpoints were collected in the same fashion for all three studies. Pupil diameter was measured just prior to initial incision, at 1 min intervals during the surgical procedure, at the end of cortical clean-up (except in the Phase II study), and immediately following the incision closure. Measurement was based on still images (which included a reference standard) obtained from video capture of the surgical procedure and was carried out by a single masked reader in each study using Image J^®, a validated software application. Early postoperative ocular pain VAS scores were collected at the same time points (2, 4, 6, 8 and 10–12 h) after surgery in all of the studies.

Analyses of the primary endpoints were also similar for the three studies. All randomized subjects who received study treatment and had data for the respective endpoint(s) were included in the respective analyses. The primary and key secondary analyses did not use any imputation method for missing data. As a sensitivity analysis, a multiple imputation method was used to impute missing values.

Multiplicity adjustments for the primary analyses of the primary endpoints and key secondary endpoints were prespecified in each of these three studies.

A total of 921 subjects were included in the Phase II and III studies, 462 subjects who received control (vehicle or placebo) and 459 subjects who received OMS302 (Table 1). The demographics of enrolled subjects are comparable with the demographics of the general population of patients receiving cataract surgery or refractive lens exchange generally. All subjects underwent phacoemulsification.

Table 1. Demographic and subject characteristics.

	Phase II study		Phase III study #1		Phase III study #2
	Vehicle (n = 57)	OMS302 (n = 56)	Vehicle (n = 201)	OMS302 (n = 201)	Vehicle (n = 204)	OMS302 (n = 202)
Age (year)
n	57	56	201	201	204	202
Mean (std)	69 (9.6)	66 (11.2)	69 (9.9)	68 (9.6)	68 (10.6)	69 (9.2)
Median	69.0	68.0	69.0	69.0	69.0	70.0
Min, Max	44, 89	23, 86	39, 89	31, 88	26, 90	39, 87
Gender, n (%)
Male	24 (42.1%)	19 (33.9%)	90 (44.8%)	82 (40.8%)	78 (38.2%)	85 (42.1%)
Female	33 (57.19)	37 (65.1%)	111 (55.2%)	119 (59.2%)	126 (61.8%)	117 (57.9%)
Ethnicity, n (%)
Hispanic or Latino	6 (10.5%)	3 (5.4%)	18 (9.0%)	30 (14.9%)	21 (10.3%)	30 (14.9%)
Not Hispanic or Latino	51 (89.5%)	53 (94.6%)	183 (91.0%)	171 (85.1%)	183 (89.7%)	172 (85.1%)
Race, n (%)
American Indian or Alaska Native	0	0	1 (0.5%)	1 (0.5%)	0	1 (0.5%)
Asian	6 (10.5%)	5 (8.9%)	19 (9.5%)	12 (6.0%)	18 (8.8%)	16 (7.9%)
Black or African American	4 (7.0%)	6 (10.7%)	26 (12.9%)	22 (10.9%)	28 (13.7%)	18 (8.9%)
Native Hawaiian or other Pacific Islander	1 (1.8%)	0	0	0	0	1 (0.5%)
White	46 (80.7%)	45 (80.4%)	155 (77.1%)	165 (82.1%)	158 (77.5%)	165 (81.7%)
Other	0	0	0	1 (0.5%)	0	1 (0.5%)
LOCS II Grade, n (%)
Low (N0, N1)	42 (73.7%)	43 (76.8%)	160 (79.6%)	155 (77.1%)	171 (83.8%)	169 (83.7%)
High (N2, N3)	15 (26.3%)	13 (23.2%)	41 (20.4%)	46 (22.9%)	33 (16.2%)	33 (16.3%)
Iris color, n (%)
Black	0	1 (1.8%)	0	0	1 (0.5%)	0
Blue	13 (23.2%)	23 (41.8%)	50 (24.9%)	59 (29.4%)	58 (28.4%)	63 (31.2%)
Brown	31 (55.4%)	23 (41.8%)	105 (52.2%)	108 (53.7%)	107 (52.5%)	106 (52.5%)
Green	1 (1.8%)	0	2 (1.0%)	1 (0.5%)	4 (2.0%)	2 (1.0%)
Grey	2 (3.6%)	2 (3.6%)	20 (10.0%)	13 (6.5%)	12 (5.9%)	13 (6.4%)
Other	9 (16.1%)	6 (10.9%)	24 (11.9%)	20 (10.0%)	21 (10.3%)	18 (8.9%)
Hazel	0	0	0	0	1 (0.5%)	0
Other eye disease, n (%)
Other eye disease, n (%)	24 (42.9%)	24 (43.6%)	110 (54.7%)	110 (54.7%)	122 (59.8%)	129 (63.9%)
Baseline BCVA (log scale)
n	54	53	198	197	197	199
Mean (Std)	0.44 (0.291)	0.37 (0.290)	0.33 (0.276)	0.29 (0.225)	0.33 (0.220)	0.35 (0.217)
Median	0.40	0.30	0.30	0.30	0.30	0.30
Min, Max	−0.10, 1.50	0.00, 1.30	−0.10, 1.60	−0.20, 1.00	−0.10, 1.60	−0.10, 1.60
Surgery received, n (%)
Refractive lens exchange	0	0	4 (2.0%)	1 (0.5%)	1 (0.5%)	1 (0.5%)
Cataract extraction and lens replacement	56 (100%)	55 (100%)	197 (98.0%)	200 (99.5%)	203 (99.5%)	201 (99.5%)

Maintenance of mydriasis & prevention of intraoperative miosis

A primary analysis for each study evaluated the difference in the change-from-baseline in pupil diameter between OMS302 and control treatment groups. Table 2 provides the results of each study using the area under the curve analyses of change-from-baseline. A total of 69 subjects with missing data due to technical difficulties with the video recordings (e.g., corrupted video files, parts of the procedure not captured in the videos and measurement rulers not captured in the videos) were excluded from the analyses. The exclusion of these subjects from the primary efficacy analyses did not impact the overall efficacy results.

Table 2. Mean area under the curve analysis of change-from-baseline in pupil diameter (mm) during surgery.

	Phase II Study		Phase III Study #1		Phase III Study #2
	Vehicle (n = 56)	OMS302 (n = 55)	Placebo (n = 201)	OMS302 (n = 201)	Placebo (n = 204)	OMS302 (n = 202)
Mean AUC^†
n	53	49	180	184	200	195
Mean (std)	−0.57 (0.672)	0.12 (0.441)	−0.51 (0.581)	0.07 (0.414)	−0.49 (0.571)	0.09 (0.430)
Median	−0.37	0.12	−0.45	0.08	−0.48	0.08
Min, max	−3.3, 0.6	−1.1, 1.4	−2.9, 2.1	−2.7, 1.3	−2.3, 1.5	−2.2, 2.3
Difference in mean AUC
CMH weighted mean difference (SE)^‡	0.69 (0.11)		0.58 (0.05)		0.59 (0.05)
95% CI	0.47, 0.91		0.47, 0.68		0.49, 0.69
p-value^§	<0.0001		<0.0001		<0.0001

^†AUC is calculated by the trapezoidal rule from the baseline to the last post-base value. Mean AUC is calculated by dividing the AUC by duration from the baseline to the last post-baseline value.

^‡CMH-weighted mean difference (OMS302 – Placebo/Vehicle) is adjusted for the randomization strata.

^§p-value is based on the generalized CMH test stratified by the randomization strata.

The Cochran–Mantel–Haenszel weighted mean differences were similar across studies (0.58–0.69 mm), and each analysis was statistically significant. The raw means and medians were also similar between respective treatment groups. In each study, the OMS302 mean area under the curve pupil diameter change-from-baseline was positive (0.07–0.12 mm), whereas the mean change-from-baseline for vehicle or placebo was negative (−0.49 to −0.57 mm), demonstrating that OMS302 maintains mydriasis, therefore, allowing for full visualization of essential anatomical structures during the surgical procedure.

Additional prespecified supportive efficacy analyses evaluating the occurrence of intraoperative miosis (intraoperative miosis was defined as 2.5 mm of pupil constriction at any time during surgery and also as absolute pupil diameter less than 6 mm at the end of cortical clean-up or at any time during the procedure) were performed for each of the studies. Results of these analyses supported that of the primary analysis of pupil diameter with a lower proportion of subjects receiving OMS302 experiencing intraoperative miosis (Table 3).

Table 3. Intraoperative six millimeter pupil diameter and mean cortical clean up pupil diameter.

	Phase II study		Phase III study #1		Phase III study #2
	Vehicle (n = 56) n (%)	OMS302 (n = 55) n (%)	Placebo (n = 201) n (%)	OMS302 (n = 201) n (%)	Placebo (n = 204) n (%)	OMS302 (n = 202) n (%)
Subjects with <6 mm at cortical cleanup/subjects with video data			41/180 (22.8%)	7/184 (3.8%)	46/200 (23.0%)	8/195 (4.1%)
p-value^†	–	–		<0.0001		<0.0001
Subjects with <6 mm at any time during surgery/subjects with video data	25/53 (47.2%)	3/49 (6.1%)	85/180 (47.2%)	19/184 (10.3%)	76/200 (38.0%)	18/195 (9.2%)
p-value^†		<0.0001		<0.0001		<0.0001
Subjects with degree of pupillary constriction ≥2.5 mm^‡	12/53 (22.6%)	2/49 (4.1%)	50/180 (27.8%)	6/201 (3.3%)	53/200 (26.5%)	2/195 (1.0%)
p-value		<0.0008^§		<0.0001^¶		<0.0001^#
Pupil diameter (mm) at cortical cleanup
n	–	–	180	184	200	195
Mean (SD)	–	–	7.1 (2.0)	8.0 (1.8)	7.5 (2.5)	8.6 (2.4)
Median	–	–	7	8	7	8
Min, max	–	–	3.8, 18.0	2.7, 17.8	3.3, 18.7	4.8, 19.2
p-value^§	–	–		<0.0001		<0.0001

^†Chi-Square test.

^‡Maximum decrease in pupil diameter during surgery.

^§t-test.

^¶Fisher’s exact test.

Reduction in early postoperative ocular pain

The difference in mean VAS pain scores during the early postoperative period was also a primary principle efficacy analysis in the Phase II and Phase III studies of OMS302. As presented in Table 4, the Cochran–Mantel–Haenszel weighted mean differences were very similar across studies (−4.58 to −5.20 mm) and each analysis was statistically significant. The raw means and medians were also very similar between respective treatment groups. The mean VAS pain score reported by the OMS302 treatment group was less than 50% of the mean VAS pain score reported by the control group in each study.

Table 4. Mean area under the curve analysis of ocular pain visual analog scale score during 12 h postoperatively.

	Phase II study		Phase III study #1		Phase III study #2
	Vehicle (n = 56)	OMS302 (n = 55)	Placebo (n = 201)	OMS302 (n = 201)	Placebo (n = 204)	OMS302 (n = 202)
Mean AUC^†
n	56	55	201	201	202	202
Mean (std)	9.58 (14.100)	4.44 (9.595)	9.22 (12.928)	4.07 (8.072)	8.91 (15.192)	4.25 (8.747)
Median	2.70	0.96	3.00	1.11	2.51	1.00
Min, max	0.0, 55.2	0.0, 56.7	0.0, 65.3	0.0, 66.9	0.0, 85.8	0.0, 58.4
Difference in mean AUC
CMH-weighted mean difference (SE)^‡	−5.13 (2.31)		−5.20 (1.08)		−4.58 (1.19)
95% CI	−9.66, −0.61		−7.31, −3.09		−6.92, −2.24
p-value^§	0.029		<0.001		<0.001

^†AUC is calculated by the trapezoidal rule from the baseline to the last post-base value. Mean AUC is calculated by dividing the AUC by duration from the baseline to the last post-baseline value.

^‡CMH-weighted mean difference (OMS302 - Placebo/Vehicle) is adjusted for the randomization strata.

^§p-value is based on the generalized CMH test stratified by the randomization strata.

AUC: Area-under-the-curve.

Additional supportive analyses of VAS were performed in each study to characterize further the effect of OMS302 on pain in the early postoperative period. Greater than 50% more subjects in the OMS302 treatment groups than in the placebo or vehicle treatment groups reported no pain at each early postoperative time point and less than half as many subjects receiving OMS302 reported moderate-to-severe pain compared with subjects receiving placebo (Table 5).

Table 5. Subjects reporting no ocular pain and moderate-to-severe ocular pain during 12 h postoperatively.

	Phase II study		Phase III study #1		Phase III study #2
	Vehicle (n = 56) n (%)	OMS302 (n = 55) n (%)	Placebo (n = 201) n (%)	OMS302 (n = 201) n (%)	Placebo (n = 204) n (%)	OMS302 (n = 202) n (%)
Subjects who were pain-free (VAS = 0) at all time points^†
p-value^‡	10/56 (17.9%)	15/55 (27.3%)	28/201 (13.9%)	48/201 (23.9%)	41/202 (20.3%)	56/202 (27.7%)
		0.2351		0.0108		0.0806
Subjects with moderate-to-severe pain (VAS ≥ 40) at any time point
p-value^‡	9/56 (16.1%)	4/55 (7.3%)	30/201 (14.9%)	13/201 (6.5%)	27/202 (13.4%)	16/202 (7.9%)
		0.1495		0.0061		0.0760

^†Subjects with missing VAS during the 12 h postoperatively are considered as not being pain-free.

^‡Chi-square test.

Clinical pharmacokinetics

A substudy to evaluate the pharmacokinetics of OMS302 was conducted as a part of one of the Phase III studies [53]. A total of 26 subjects were included: 14 subjects randomized to OMS302 and 12 subjects randomized to placebo. Blood samples for analysis of phenylephrine and ketorolac plasma concentrations were collected prior to surgery and before OMS302 administration and at several time points over 24 h postoperatively. The concentrations of phenylephrine and ketorolac were analyzed by liquid chromatography tandem mass spectrometry with validated assays that had a lower limit of quantitation of 1 ng/ml.

Plasma concentrations for phenylephrine and ketorolac were low or undetectable after OMS302 administration and were insufficient for formal pharmacokinetic analysis. One OMS302 subject had detectable phenylephrine, with the highest value of 1.7 ng/ml obtained at the pretreatment time point, presumably due to exposure to the preoperative phenylephrine 2.5% eye drops and not due to administration of the OMS302. These data demonstrate that administration of OMS302 in the intraoperative irrigation solution results in no detectable systemic exposure of phenylephrine. Ketorolac was detected in 10 of 14 subjects treated with OMS302 and 1 of 12 subjects treated with placebo. The amount of ketorolac detected in the 11 subjects ranged from 1 to 4 ng/ml, levels lower than what is reported with 0.5% ketorolac eye drops (11–23 ng/ml) [24].

Clinical safety

In the four clinical studies performed, a total of 478 subjects were treated with OMS302 (or the combination of phenylephrine and ketorolac in the Phase I/II study) and 482 subjects were treated with placebo/vehicle (control). All subjects received a single administration of OMS302 as part of standard irrigation solution used during the surgical procedure, and individual exposure was determined by the total volume of irrigation solution used during, and by the overall duration of, each procedure.

The extent of drug exposure was similar across each of the four clinical studies. A single 500-ml container of irrigation solution was used for each procedure, and the average volume of irrigation used across all studies ranged from 250 to 270 ml (overall minimum volume = 100 ml; overall maximum volume = 500 ml). The mean duration of each procedure was approximately 10 min.

A summary of commonly reported adverse events (AEs) across the studies in which phenylephrine and ketorolac were administered at the approved dosages (i.e., a total of 921 subjects who participated in the Phase II and III studies) is provided in Table 6. The most commonly reported AEs were primarily eye related and also included headache. The incidence of AEs was similar between subjects receiving OMS302 and control subjects (i.e., subjects receiving vehicle or placebo). Pooled safety data across studies showed no effects on vital signs or intraocular pressure. These safety findings are consistent with the well-known safety profiles of phenylephrine and ketorolac and the low systemic exposure of phenylephrine and ketorolac when administered in the irrigation solution during intraocular surgery.

Table 6. Common treatment-emergent adverse events with subject incidence of ≥1% in OMS302 arm in pooled placebo-controlled trial database (Safety Population).

Preferred term	Pooled placebo (n = 462) n (%)	Pooled OMS302 (n = 459) n (%)
Any event	314 (68.0%)	288 (62.7%)
Eye pain	178 (38.5%)	139 (30.3%)
Eye inflammation	67 (14.5%)	74 (16.1%)
Anterior chamber inflammation	35 (7.6%)	37 (8.1%)
Headache	43 (9.3%)	30 (6.5%)
Intraocular pressure increased	15 (3.2%)	20 (4.4%)
Posterior capsule opacification	16 (3.5%)	18 (3.9%)
Photophobia	21 (4.5%)	16 (3.5%)
Ocular discomfort	26 (5.6%)	13 (2.8%)
Conjunctival hyperemia	13 (2.8%)	11 (2.4%)
Corneal edema	13 (2.8%)	11 (2.4%)
Inflammation	13 (2.8%)	11 (2.4%)
Pain	14 (3.0%)	10 (2.2%)
Eye irritation	6 (1.3%)	9 (2.0%)
Conjunctivitis	4 (0.9%)	8 (1.7%)
Foreign body sensation in eyes	11 (2.4%)	8 (1.7%)
Nausea	1 (0.2%)	8 (1.7%)
Back pain	3 (0.6%)	6 (1.3%)
Iritis	3 (0.6%)	5 (1.1%)
Vision blurred	17 (3.7%)	5 (1.1%)

Regulatory status

Omeros Corporation received FDA approval for OMS302 (Omidria) in May 2014, the first intracameral drug approved both to prevent intraoperative miosis and reduce postoperative ocular pain associated with cataract and IOL replacement, together representing approximately 4 million procedures annually in the USA. A marketing application has also been submitted to the EMA. OMS302 is supplied in a clear, 5 ml glass, single-patient-use vial containing 4 ml of sterile solution concentrate.

Conclusion

OMS302 is a new and recently FDA-approved drug product containing phenylephrine and ketorolac, each of which has a long history of topical use in cataract surgery and a well-established safety profile.

OMS302 helps to attain maximal dilation and maintain intraoperative mydriasis by preventing intraoperative miosis. Phenylephrine, approved as a single topical agent to dilate the pupil, is an α1-adrenergic receptor agonist and causes contraction of the radial dilator muscle of the iris. Ketorolac, a topical NSAID approved for the treatment of pain and inflammation following cataract surgery, inhibits the production of prostaglandins. Prostaglandins released as a result of intraocular surgical insult, or when the iris is directly stimulated, can cause contraction of the iris sphincter muscle leading to miosis. As the red reflex is diminished, the surgeon may experience difficulty in visualizing the lens material and the transparent lens capsule. The small pupil significantly increases the risk of complications during cataract surgery, and safely maximizing and maintaining intraoperative pupil size can decrease that risk. In studies evaluating OMS302, the effect on pupil diameter was clinically meaningful, with progressively increasing differences in pupil diameter over time between the OMS302-treated and control subjects; OMS302 substantially reduced the intraoperative incidence of pupil diameter less than 6 mm and that of pupil constriction of 2.5 mm or more compared with placebo.

OMS302 also reduces postoperative pain. This is mediated through the anti-inflammatory effect of ketorolac. The ability of OMS302 to diminish early postoperative ocular pain was clinically meaningful with approximately a 50% reduction in mean pain, 50% reduction in the incidence of moderate-to-severe pain, and 50% increase in the number of subjects reporting no pain, all compared to the placebo group. As previously noted, all subjects received topical preoperative anesthetic agents; however, for purposes of standardization, intraoperative agents commonly used in these procedures (e.g., intracameral lidocaine) were excluded.

Because OMS302 is administered as a part of the irrigation solution, intraocular tissues are exposed to a constant concentration of the active ingredients, regardless of the duration of the procedure. The effectiveness of OMS302 was not dependent on the total dose of each agent administered. Systemic exposure to each of phenylephrine and ketorolac in OMS302 was very low. All studies demonstrated that OMS302 was safe and well tolerated. No ocular or systemic safety signals were observed. The most commonly reported AEs were those seen following routine cataract surgery. Pooled safety data across studies showed no clinically significant differences for vital signs and intraocular pressure. These safety findings in the clinical studies are consistent with the well-known safety profiles of phenylephrine and ketorolac and the low systemic exposure of OMS302.

The substantial collection of efficacy and safety data for OMS302 supports a favorable benefit–risk ratio. The benefits appear clinically significant as the drug product provides better visualization and less operative risk while reducing postoperative pain. The drug product proved to be safe and well tolerated, with no additional safety concerns beyond those associated with the procedure itself. OMS302 is also preservative- and bisulfite-free and is produced under the stringent requirements of good manufacturing practices, thus minimizing patient risk of associated safety issues (e.g., mixture errors, toxic anterior segment syndrome and serious infection). Moreover, this product avoids concerns about use of compounded products and off-label use of approved intracameral mydriatic agents, as well as the frequent shortages of all of these widely used agents in contemporary cataract surgery.

The recent approval of OMS302 offers cataract surgeons, a new tool to achieve a safe and comfortable surgical procedure.

Expert commentary & five-year view

Cataract surgery is one of the most frequent surgical procedures performed worldwide and is generally considered safe and effective. Maintaining pupil diameter is critical during cataract surgery to optimize visualization, to facilitate an uncomplicated procedure and to lower the risk for intraoperative and postoperative complications. The occurrence of miosis is unpredictable and can occur even when the pupil appears to dilate well in the office. Certain conditions, such as intraoperative floppy iris syndrome associated with Flomax^® (tamsulosin) and eyes with previous inflammation, are at particular risk for suboptimal pupil dilation and intraoperative constriction of the pupil. In addition, the small pupil is associated with endothelial cell damage due to a longer procedure, iris damage from direct contact with the phacoemulsification or irrigation-and-aspiration tip, inadvertent retention of nuclear material or cortical remnants, damage to the zonules and rupture of the lens capsule.

Mydriasis is routinely obtained with preoperative topical agents, although intracameral agents, such as epinephrine, have been used for decades. More recently, several authors have reported the use of intraoperative drug combinations for pupil dilation, avoiding topical agents [15,16]. The use of topical or intracameral preservatives may compromise the endothelium and/or cause toxic anterior segment syndrome. Some ‘cocktails’ used in intraocular surgery require a need for compounding, a practice that has resulted in safety issues and, consequently, recent FDA scrutiny. Several of these agents, such as epinephrine and phenylephrine, are regularly subject to shortages. Because of the importance of maintaining pupil diameter during cataract surgery, some surgeons have tried to inject, in off-label use, topical agents directly into the anterior chamber or into the irrigation solution (e.g., epinephrine, Shugarcaine and diclofenac [Voltaren^®]). Others have tried using a pellet-like Mydriasert (Spectrum Thea Pharmaceuticals, Macclesfield Cheshire), a limbal sponge soaked in tropicamide and phenylephrine, or preoperative NSAIDs to facilitate mydriasis.

Alternative options for dilating the pupil include viscomydriasis, whereby a retentive cohesive ophthalmic viscosurgical device, like Healon5^®, can widen the pupil through injection onto the anterior surface of the iris near the pupillary margin [54]. The pupil is mechanically opened as the iris bows posteriorly and peripherally. Another effective approach is the pupil stretch technique presented by Luther Fry, MD [55]. By stretching the pupil border with two hooks placed 180° apart, the sphincter muscle is ruptured. Here again, injecting ophthalmic viscosurgical device will result in a widening of the pupil.

In some cases, adhesions between the pupillary border and the anterior lens capsule may prevent pupillary dilation. If the fibrovascular, ribbon-like membrane is stripped, the pupil is no longer restricted and will dilate. This technique is known as peripupillary membranectomy [56].

An assortment of devices has also been introduced that mechanically dilate the pupil. The Graether pupil expander, the Milvella Perfect Pupil, iris hooks, the Malyugin Ring and devices recently developed by Michael Colvard (US), Ehud Assia (Israel) and Suven Bhattacharjee (India) comprise a list of effective devices that can enlarge a suboptimal pupil [57–60]. Permanent structural changes in the pupil are common with these devices.

In contrast to the permanent structural damage that can occur with dilating devices, OMS302 provides reversible pharmacologic dilation. With established safety and efficacy in several controlled clinical studies, OMS302 is the first and only FDA-approved treatment to prevent intraoperative miosis and reduce postoperative pain associated with cataract surgery. It is also the first FDA-approved drug indicated to prevent intraoperative miosis since Ocufen^® ([flurbiprofen sodium ophthalmic solution, USP] 0.03%) was initially approved to inhibit miosis in 1986.

Together with its approved indication for preventing miosis, OMS302 is approved to reduce postoperative ocular pain associated with cataract surgery. Pain is an important patient concern, which may be underappreciated because of patients’ satisfaction with their improvement in vision. If the patient complains of postoperative pain, the surgeon must respond to inflammation that has already started. OMS302 was developed to act preemptively to inhibit prostaglandin release and the inflammatory cascade through delivery of ketorolac to the operative site at the time of the surgical insult, and OMS302 has been found both to prevent intraoperative miosis and reduce postoperative ocular pain. In clinical studies, patients who received OMS302 experienced less postoperative pain than patients who received placebo. This improvement in postoperative pain may also improve overall patient satisfaction.

OMS302 is a proven new treatment option to address intraoperative miosis and postoperative ocular pain. While most ophthalmic dilating drugs focus only on sympathomimesis, OMS302 has a dual mechanism of action to provide mydriasis and prevent miosis. OMS302 presents ophthalmic surgeons with an intracameral pharmacologic option that facilitates the procedure and reduces the risks associated with intraoperative miosis. Decreasing postoperative ocular pain may also have a significant impact on patient satisfaction and outcomes. Further clinical studies of OMS302 should be conducted to evaluate the effect of this treatment on these secondary outcomes.

Information resources

Grob SR, Gonzalez-Gonzalez LA, Daly MK. Management of mydriasis and pain in cataract and intraocular lens surgery: review of current medications and future directions. Clin Ophthalmol. 2014 Jul 3;8:1281-9.

Lindstrom RL, Loden JC, Walters TR, Dunn SH, Whitaker JS, Kim T, Demopulos GA, Tjia KL. Intracameral phenylephrine and ketorolac injection (OMS302) for maintenance of intraoperative pupil diameter and reduction of postoperative pain in intraocular lens replacement with phacoemulsification. Clin Ophthalmol 2014;8:1735-44.

Key issues

• OMS302 is a drug product containing 1% w/v phenylephrine and 0.3% w/v ketolorac (Omidria™; Omeros Corp) that has been approved by the FDA for use during cataract surgery and intraocular lens replacement to maintain pupil size by preventing intraoperative miosis and to reduce postoperative pain.

• OMS302 added to balanced salt solution is delivered intracamerally during cataract surgery and intraocular lens replacement, bathing intraocular tissues with its active agents throughout the procedure, to maintain mydriasis while preemptively inhibiting intraoperative miosis and postoperative pain.

• Phenylephrine is an α1-adrenergic receptor agonist that contracts the radial dilator muscle of the iris; ketorolac, an NSAID, is a nonselective COX-1/COX-2 inhibitor that decreases prostaglandin synthesis secondary to ocular surgical trauma. The inhibition of prostaglandins by ketorolac prevents surgically induced miosis and reduces postoperative ocular pain.

• Two Phase III trials demonstrated that OMS302 was statistically superior to placebo in maintaining mydriasis and preventing miosis during surgery and in reducing early postoperative ocular pain.

• Systemic exposure to both agents was low or undetectable following intraocular administration.

• The most commonly reported adverse events were primarily eye related and also included headache, as typically seen postoperatively in cataract surgery; the incidence of adverse events was similar between subjects receiving OMS302 and control subjects (i.e., subjects receiving vehicle or placebo). Pooled safety data across studies showed no effects on vital signs or intraocular pressure.

• OMS302 is preservative- and bisulfite-free and is manufactured under the stringent requirements of good manufacturing practices, thereby reducing risk of complications such as toxic anterior segment syndrome and serious infections associated with other ocular agents and preparations.

Financial & competing interests disclosure

This paper has been funded by Omeros Corporation, Seattle, WA, USA. R Osher is a paid consultant for Omeros Corporation. G Demopulos is an employee and holds equity interest in Omeros Corporation. Writing assistance was utilized in the production of this manuscript and performed by Lily Chan of 12 Point LLC and funded by Omeros Corporation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.