5.1 Elevated Blood Pressure

Systemic exposure to phenylephrine can cause elevations in blood pressure.

5.2 Cross-Sensitivity or Hypersensitivity

There is the potential for cross-sensitivity to acetylsalicylic acid, phenylacetic acid derivatives, and other non-steroidal anti- inflammatory drugs (NSAIDs). There have been reports of bronchospasm or exacerbation of asthma associated with the use of ketorolac in patien ts who either have a known hypersensitivity to aspirin/NSAIDs or a past medical history of asthma. Therefore, use Omidria with caution in individuals who have previously exhibited sensitivities to these drugs.

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)] .

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.

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.

8.2 Lactation

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.

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.

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).

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.

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