Omidria

6 ADVERSE REACTIONS The most common reported adverse reactions (≥2%) are eye irritation, posterior capsule opacification, increased intraocular pressure, and anterior chamber inflammation. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Rayner Surgical Inc. at 1-877-0MIDRIA or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to the rates in the clinical studies of another drug and may not reflect the rates observed in practice. Table 1 shows frequently reported ocular adverse reactions with an incidence of ≥ 2% of adult patients as seen in the combined clinical trial results from three randomized, placebo-controlled studies [see Clinical Studies ( 14 )] . Table 1: Ocular Adverse Reactions Reported by ≥ 2% of Adult Patients MedDRA Preferred Term Placebo (N=462) Omidria (N=459) n (%) n (%) Ocular Events Anterior Chamber Inflammation 102 (22%) 111 (24%) Intraocular Pressure Increased 15 (3%) 20 (4%) Posterior Capsule Opacification 16 (4%) 18 (4%) Eye Irritation 6 (1%) 9 (2%) Foreign Body Sensation in Eyes 11 (2%) 8 (2%) In a safety study that enrolled 72 pediatric patients up to 3 years old, no overall difference in safety was observed between pediatric and adult patients.

4 CONTRAINDICATIONS Omidria is contraindicated in patients with a known hypersensitivity to any of its ingredients. Hypersensitivity to any component of this product ( 4 )

11 DESCRIPTION Omidria is a sterile aqueous solution, containing the α 1 -adrenergic receptor agonist phenylephrine HCl and the nonsteroidal anti-inflammatory ketorolac tromethamine, for addition to ocular irrigating solution. The descriptions and structural formulae are: Phenylephrine Hydrochloride Drug Substance: Common Name: phenylephrine hydrochloride Chemical Name: (-)- m -Hydroxy-α-[(methylamino)methyl]benzyl alcohol hydrochloride Molecular Formula: C 9 H 13 NO 2 · HCl Molecular Weight: 203.67 g/mole Figure 1: Chemical Structure for Phenylephrine HCl Ketorolac Tromethamine Drug Substance: Common Name: ketorolac tromethamine Chemical Name: (±)-5-Benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid : 2-amino-2-(hydroxymethyl)-1,3-propanediol (1:1) Molecular Formula: C 15 H 13 NO 3 · C 4 H 11 NO 3 Molecular Weight: 376.40 g/mole Figure 2: Chemical Structure for Ketorolac Tromethamine Omidria is a clear, colorless to slightly yellow, sterile solution concentrate with a pH of approximately 6.3. Each vial of Omidria contains: Actives: phenylephrine hydrochloride 12.4 mg/mL equivalent to 10.16 mg/mL of phenylephrine and ketorolac tromethamine 4.24 mg/mL equivalent to 2.88 mg/mL of ketorolac. Inactives: citric acid monohydrate; sodium citrate dihydrate; water for injection; may include sodium hydroxide and/or hydrochloric acid for pH adjustment. Figure 1 Figure 2

2 DOSAGE AND ADMINISTRATION Omidria must be diluted prior to intraocular use. For administration to patients undergoing cataract surgery or intraocular lens replacement, 4 mL of Omidria is diluted in 500 mL of ocular irrigating solution. Irrigation solution is to be used as needed for the surgical procedure for a single patient. The storage period for the diluted product is not more than 4 hours at room temperature or 24 hours under refrigerated conditions. Do not use if the solution is cloudy or if it contains particulate matter. Each vial of OMIDRIA must be diluted prior to use for administration to a single patient undergoing cataract surgery or intraocular lens replacement. Dilute 4 mL of OMIDRIA in 500 mL of ocular irrigating solution. Irrigation solution is to be used as needed for the surgical procedure. ( 2 )

1 INDICATIONS AND USAGE Omidria ® is added to an ocular irrigating solution used during cataract surgery or intraocular lens replacement and is indicated for maintaining pupil size by preventing intraoperative miosis and reducing postoperative ocular pain. OMIDRIA is an alpha 1-adrenergic receptor agonist and nonselective cyclooxygenase inhibitor indicated for: Maintaining pupil size by preventing intraoperative miosis ( 1 ) Reducing postoperative pain ( 1 ) OMIDRIA is added to an ocular irrigating solution used during cataract surgery or intraocular lens replacement.

10 OVERDOSAGE Systemic overdosage of phenylephrine may cause a rise in blood pressure. It may also cause headache, anxiety, nausea, vomiting, and ventricular arrhythmias. Supportive care is recommended.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The two active pharmaceutical ingredients (API) in Omidria, phenylephrine and ketorolac, act to maintain pupil size by preventing intraoperative miosis, and reducing postoperative pain. Phenylephrine is an α 1 -adrenergic receptor agonist and, in the eye, acts as a mydriatic agent by contracting the radial muscle of the iris. Ketorolac is a nonsteroidal anti-inflammatory that inhibits both cyclooxygenase enzymes (COX-1 and COX-2), resulting in a decrease in tissue concentrations of prostaglandins to reduce pain due to surgical trauma. Ketorolac, by inhibiting prostaglandin synthesis secondary to ocular surgical insult or direct mechanical stimulation of the iris, also prevents surgically induced miosis. 12.3 Pharmacokinetics In a pharmacokinetic study evaluating Omidria, systemic exposure to both phenylephrine and ketorolac was low or undetectable. A single-dose of Omidria as part of the irrigation solution was administered in 14 patients during lens replacement surgery. The volume of irrigation solution used during surgery ranged between 150 mL to 300 mL (median 212.5 mL). Detectable phenylephrine plasma concentrations were observed in one of 14 patients (range 1.2 to 1.4 ng/mL) during the first 2 hours after the initiation of Omidria administration. The observed phenylephrine plasma concentrations could not be distinguished from the preoperative administration of phenylephrine 2.5% ophthalmic solution prior to exposure to Omidria. Ketorolac plasma concentrations were detected in 10 of 14 patients (range 1.0 to 4.2 ng/mL) during the first 8 hours after the initiation of Omidria administration. The maximum ketorolac concentration was 15 ng/mL at 24 hours after the initiation of Omidria administration, which may have been due to application of postoperative ketorolac ophthalmic solution.

12.1 Mechanism of Action The two active pharmaceutical ingredients (API) in Omidria, phenylephrine and ketorolac, act to maintain pupil size by preventing intraoperative miosis, and reducing postoperative pain. Phenylephrine is an α 1 -adrenergic receptor agonist and, in the eye, acts as a mydriatic agent by contracting the radial muscle of the iris. Ketorolac is a nonsteroidal anti-inflammatory that inhibits both cyclooxygenase enzymes (COX-1 and COX-2), resulting in a decrease in tissue concentrations of prostaglandins to reduce pain due to surgical trauma. Ketorolac, by inhibiting prostaglandin synthesis secondary to ocular surgical insult or direct mechanical stimulation of the iris, also prevents surgically induced miosis.

12.3 Pharmacokinetics In a pharmacokinetic study evaluating Omidria, systemic exposure to both phenylephrine and ketorolac was low or undetectable. A single-dose of Omidria as part of the irrigation solution was administered in 14 patients during lens replacement surgery. The volume of irrigation solution used during surgery ranged between 150 mL to 300 mL (median 212.5 mL). Detectable phenylephrine plasma concentrations were observed in one of 14 patients (range 1.2 to 1.4 ng/mL) during the first 2 hours after the initiation of Omidria administration. The observed phenylephrine plasma concentrations could not be distinguished from the preoperative administration of phenylephrine 2.5% ophthalmic solution prior to exposure to Omidria. Ketorolac plasma concentrations were detected in 10 of 14 patients (range 1.0 to 4.2 ng/mL) during the first 8 hours after the initiation of Omidria administration. The maximum ketorolac concentration was 15 ng/mL at 24 hours after the initiation of Omidria administration, which may have been due to application of postoperative ketorolac ophthalmic solution.

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3 DOSAGE FORMS AND STRENGTHS Omidria is an intraocular solution containing 10.16 mg/mL (1% w/v) of phenylephrine and 2.88 mg/mL (0.3% w/v) of ketorolac for use in a single patient. Intraocular solution containing phenylephrine 10.16 mg/mL (1%) and ketorolac 2.88 mg/mL (0.3%) for use in a single patient. ( 3 )

Omidria phenylephrine and ketorolac TRISODIUM CITRATE DIHYDRATE WATER CITRIC ACID MONOHYDRATE PHENYLEPHRINE PHENYLEPHRINE KETOROLAC KETOROLAC

NDA205388

Omidria

phenylephrine and ketorolac

82604-600

HUMAN PRESCRIPTION DRUG

INTRAOCULAR

PRINCIPAL DISPLAY PANEL NDC 82604-600-04 OMIDRIA ® (phenylephrine and ketorolac intraocular solution) 1% / 0.3% For Intraocular use. Must Be Diluted. Single-Patient vial Sterile 4 mL Quantity: 4 Rx Only NDC 82604-600-00 OMIDRIA ® (phenylephrine and ketorolac intraocular solution) 1% / 0.3% For Intraocular use. Must Be Diluted. Single-Patient vial Sterile 4 mL Quantity: 1 Rx Only omi00-0003-05 omi00-0003-06

17 PATIENT COUNSELING INFORMATION Inform patients that they may experience sensitivity to light. Rayner Surgical Inc. Suite 102, 14335 NE 24 Street Bellevue, WA 98007 © Rayner 2023 Patented product; see www.rayner.com/patents for further details. OMIDRIA®and the OMIDRIA® Logo are registered trademarks of Rayner Surgical Inc. 640069

14 CLINICAL STUDIES Studies in Adults The efficacy and safety of Omidria were evaluated in two Phase 3, randomized, multicenter, double-masked, placebo-controlled clinical trials in 808 adult patients undergoing cataract surgery or intraocular lens replacement. Patients were randomized to either Omidria or placebo. Patients were treated with preoperative topical mydriatic and anesthetic agents. Pupil diameter was measured throughout the surgical procedure. Postoperative pain was evaluated by self-administered 0-100 mm visual analog scales (VAS). Mydriasis was maintained in the Omidria-treated groups while the placebo-treated groups experienced progressive constriction. Figure 3: Intraoperative Pupil Diameter (mm) Change-from-Baseline At the end of cortical clean-up, 23% of placebo-treated patients and 4% of Omidria-treated patients had a pupil diameter less than 6 mm (p < 0.01). Pain during the initial 10-12 hours postoperatively was statistically significantly less in the Omidria-treated groups than in the placebo-treated groups. Figure 4: Postoperative Mean Visual Analog Scale (VAS) Scores for Pain During the 10-12 hours postoperatively, 26% of Omidria-treated patients reported no pain (VAS = 0 at all timepoints) while 17% of placebo-treated patients reported no pain (p < 0.01). Figure 3 Figure 4 Study in Pediatric Patients The safety of Omidria was evaluated in a single, randomized, multicenter, double-masked, active-controlled clinical study in 72 pediatric patients up to 3 years old undergoing cataract surgery with or without intraocular lens replacement. Patients were randomized to either Omidria or phenylephrine. Patients were treated with preoperative topical mydriatic and anesthetic agents. As in the adult studies, mydriasis was maintained in the Omidria-treated group. No overall differences in safety were observed between pediatric and adult patients.

8.5 Geriatric Use No overall differences in safety or effectiveness have been observed between elderly and adult patients.

8.4 Pediatric Use The safety and effectiveness of Omidria have been established in the pediatric population from neonates to adolescents (birth to younger than 17 years). Use of Omidria in this population is supported by evidence from adequate and well-controlled studies of Omidria in adults with additional data from a single active-controlled safety study in pediatric patients up to 3 years old [see Clinical Studies ( 14 )] . No overall differences in safety were observed between pediatric and adult patients.

8.1 Pregnancy Risk Summary There are no available data on Omidria use in pregnant women or animals to inform any drug-associated risks. Oral administration of ketorolac to rats during late gestation produced dystocia and increased pup mortality at a dose 740-times the plasma exposure at the recommended human ophthalmic dose (RHOD). Since human systemic exposure to Omidria following a lens replacement procedure is low (see Clinical Pharmacology (12.3)], the applicability of animal findings to the risk of Omidria in humans during pregnancy is unclear. Omidria should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature closure of the ductus arteriosus in the fetus has occurred with third trimester use of oral and injectable NSAIDs. Ketorolac plasma concentrations are detectable following ocular Omidria administration [see Clinical Pharmacology (12.3)]. The use of Omidria during late pregnancy should be avoided. .Q.a1a Animal Data No well-controlled animal reproduction studies have been conducted with Omidria or phenylephrine. Ketorolac, administered during organogenesis, did not cause embryofetal abnormalities or mortalities in rabbits or rats at oral doses of 3.6 mg/kg/day and 10 mg/kg/day, respectively. These doses produced systemic exposure that is 1150 times and 4960 times the plasma exposure (based on Cma,c) at the RHOD, respectively. When administered to rats during late gestation (after Day 17 of gestation) at oral doses up to 1.5 mg/kg/day (740 times the plasma exposure at the RHOD), ketorolac produced dystocia and increased pup mortality. Risk Summary There are no available data on Omidria use in pregnant women or animals to inform any drug-associated risks. Oral administration of ketorolac to rats during late gestation produced dystocia and increased pup mortality at a dose 740-times the plasma exposure at the recommended human ophthalmic dose (RHOD). Since human systemic exposure to Omidria following a lens replacement procedure is low [ see Clinical Pharmacology ( 12.3 ) ], the applicability of animal findings to the risk of Omidria in humans during pregnancy is unclear. Omidria should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature closure of the ductus arteriosus in the fetus has occurred with third trimester use of oral and injectable NSAIDs. Ketorolac plasma concentrations are detectable following ocular Omidria administration [see Clinical Pharmacology ( 12.3 )] . The use of Omidria during late pregnancy should be avoided. Data Animal Data No well-controlled animal reproduction studies have been conducted with Omidria or phenylephrine. Ketorolac, administered during organogenesis, did not cause embryofetal abnormalities or mortalities in rabbits or rats at oral doses of 3.6 mg/kg/day and 10 mg/kg/day, respectively. These doses produced systemic exposure that is 1150 times and 4960 times the plasma exposure (based on C max ) at the RHOD, respectively. When administered to rats during late gestation (after Day 17 of gestation) at oral doses up to 1.5 mg/kg/day (740 times the plasma exposure at the RHOD) , ketorolac produced dystocia and increased pup mortality.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data on Omidria use in pregnant women or animals to inform any drug-associated risks. Oral administration of ketorolac to rats during late gestation produced dystocia and increased pup mortality at a dose 740-times the plasma exposure at the recommended human ophthalmic dose (RHOD). Since human systemic exposure to Omidria following a lens replacement procedure is low (see Clinical Pharmacology (12.3)], the applicability of animal findings to the risk of Omidria in humans during pregnancy is unclear. Omidria should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature closure of the ductus arteriosus in the fetus has occurred with third trimester use of oral and injectable NSAIDs. Ketorolac plasma concentrations are detectable following ocular Omidria administration [see Clinical Pharmacology (12.3)]. The use of Omidria during late pregnancy should be avoided. .Q.a1a Animal Data No well-controlled animal reproduction studies have been conducted with Omidria or phenylephrine. Ketorolac, administered during organogenesis, did not cause embryofetal abnormalities or mortalities in rabbits or rats at oral doses of 3.6 mg/kg/day and 10 mg/kg/day, respectively. These doses produced systemic exposure that is 1150 times and 4960 times the plasma exposure (based on Cma,c) at the RHOD, respectively. When administered to rats during late gestation (after Day 17 of gestation) at oral doses up to 1.5 mg/kg/day (740 times the plasma exposure at the RHOD), ketorolac produced dystocia and increased pup mortality. Risk Summary There are no available data on Omidria use in pregnant women or animals to inform any drug-associated risks. Oral administration of ketorolac to rats during late gestation produced dystocia and increased pup mortality at a dose 740-times the plasma exposure at the recommended human ophthalmic dose (RHOD). Since human systemic exposure to Omidria following a lens replacement procedure is low [ see Clinical Pharmacology ( 12.3 ) ], the applicability of animal findings to the risk of Omidria in humans during pregnancy is unclear. Omidria should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature closure of the ductus arteriosus in the fetus has occurred with third trimester use of oral and injectable NSAIDs. Ketorolac plasma concentrations are detectable following ocular Omidria administration [see Clinical Pharmacology ( 12.3 )] . The use of Omidria during late pregnancy should be avoided. Data Animal Data No well-controlled animal reproduction studies have been conducted with Omidria or phenylephrine. Ketorolac, administered during organogenesis, did not cause embryofetal abnormalities or mortalities in rabbits or rats at oral doses of 3.6 mg/kg/day and 10 mg/kg/day, respectively. These doses produced systemic exposure that is 1150 times and 4960 times the plasma exposure (based on C max ) at the RHOD, respectively. When administered to rats during late gestation (after Day 17 of gestation) at oral doses up to 1.5 mg/kg/day (740 times the plasma exposure at the RHOD) , ketorolac produced dystocia and increased pup mortality. 8.2 Lactation Risk Summary There are no data on the presence of Omidria in human milk, the effects on the breastfed infant, or the effects on milk production. Howerver, systemic exposure to Omidria, following a lens replacement procedure is low [see Clinical Pharmacology ( 12.3 )] . The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Omidria and any potential adverse effects on the breastfed child from Omidria. 8.4 Pediatric Use The safety and effectiveness of Omidria have been established in the pediatric population from neonates to adolescents (birth to younger than 17 years). Use of Omidria in this population is supported by evidence from adequate and well-controlled studies of Omidria in adults with additional data from a single active-controlled safety study in pediatric patients up to 3 years old [see Clinical Studies ( 14 )] . No overall differences in safety were observed between pediatric and adult patients. 8.5 Geriatric Use No overall differences in safety or effectiveness have been observed between elderly and adult patients.

16 HOW SUPPLIED/STORAGE AND HANDLING Omidria (phenylephrine and ketorolac intraocular solution) 1%/0.3% is supplied in a clear, 5-mL glass, single-patient-use vial containing 4 mL of sterile solution, for addition to ocular irrigating solution. Omidria is supplied in a multi-pack containing: 4 vials : NDC 82604-600-04 or 1 vials: NDC 82604-600-00 Storage: Store at 20˚ to 25˚C (68˚ to 77˚F). Protect from light.

Storage: Store at 20˚ to 25˚C (68˚ to 77˚F). Protect from light.