Ketorolac Tromethamine

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: • Delayed Healing [ see Warnings and Precautions (5.1) ] • Cross-Sensitivity or Hypersensitivity [ see Warnings and Precautions (5.2) ] • Increased Bleeding Time [ see Warnings and Precautions (5.3) ] • Corneal Effects [ see Warnings and Precautions (5.4) ] The most common adverse reactions occurring in 1 to 5% of patients included conjunctival hyperemia, corneal infiltrates, headache, ocular edema and ocular pain. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most frequently reported adverse reactions for ketorolac tromethamine ophthalmic solution occurring in approximately 1 to 5% of the overall study population were conjunctival hyperemia, corneal infiltrates, headache, ocular edema, and ocular pain. The most frequent adverse reactions reported with the use of ketorolac tromethamine ophthalmic solutions have been transient stinging and burning on instillation. These reactions were reported by up to 40% of patients participating in clinical trials. Other adverse reactions occurring approximately in 1 to 10% of the time during treatment with other ketorolac tromethamine ophthalmic solutions included allergic reactions (including eye swelling, eyelid edema, and hyperemia), corneal edema, iritis, ocular inflammation, ocular irritation, superficial keratitis, and superficial ocular infections. Other adverse reactions reported rarely with the use of ketorolac tromethamine ophthalmic solutions included: corneal ulcer, eye dryness, and visual disturbance (blurry vision). 6.2 Postmarketing Experience The following adverse reactions have been identified during postmarketing use of ketorolac tromethamine ophthalmic solutions in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The reactions, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to topical ketorolac tromethamine ophthalmic solutions or a combination of these factors, include bronchospasm or exacerbation of asthma, corneal erosion, corneal perforation, corneal thinning and corneal melt, and epithelial breakdown [ see Warnings and Precautions (5.2, 5.4) ] .

4 CONTRAINDICATIONS Ketorolac tromethamine ophthalmic solution is contraindicated in patients with previously demonstrated hypersensitivity to any of the ingredients in the formulation [ see Adverse Reactions (6.1) ] . Hypersensitivity to any component of this product. (4)

11 DESCRIPTION Ketorolac tromethamine ophthalmic solution 0.4% is a member of the pyrrolo-pyrrole group of nonsteroidal anti-inflammatory drugs (NSAIDs) for ophthalmic use. Its chemical name is (±)-5-Benzoyl-2,3-dihydro-1 H -pyrrolizine-1-carboxylic acid, compound with 2-amino-2-(hydroxymethyl)-1,3-propanediol (1:1), and its molecular weight is 376.40. Its molecular formula is C 19 H 24 N 2 O 6 and it has the following structure: Ketorolac tromethamine ophthalmic solution is supplied as a sterile, isotonic, clear colorless to slightly yellow aqueous 0.4% solution, with a pH of approximately 7.4. Ketorolac tromethamine ophthalmic solution contains a racemic mixture of R-(+) and S-(-)- ketorolac tromethamine. Ketorolac tromethamine may exist in three crystal forms. All forms are equally soluble in water. The pKa of ketorolac is 3.5. This white or almost white crystalline powder, melt between 165°C and 170°C, with decomposition. The osmolality of ketorolac tromethamine ophthalmic solution is 290 mOsmol/kg. Each mL of ketorolac tromethamine ophthalmic solution contains: Active: ketorolac tromethamine USP 0.4%. Preservative: benzalkonium chloride 0.006%. Inactives: edetate disodium 0.015%; octoxynol 40; water for injection; sodium chloride; and hydrochloric acid and/or sodium hydroxide to adjust pH. Ketorolac Tromethamine Chemical Structure

2 DOSAGE AND ADMINISTRATION One drop of ketorolac tromethamine ophthalmic solution should be applied in the operated eye 4 times per day as needed for pain and burning/stinging for up to 4 days following corneal refractive surgery. (2.1) 2.1 Recommended Dosing The recommended dose of ketorolac tromethamine ophthalmic solution is one drop four times a day in the operated eye as needed for pain and burning/stinging for up to 4 days following corneal refractive surgery. 2.2 Use With Other Topical Ophthalmic Medications Ketorolac tromethamine ophthalmic solution has been safely administered in conjunction with other topical ophthalmic medications such as alpha-agonists, antibiotics, beta-blockers, carbonic anhydrase inhibitors, cycloplegics, and mydriatics. Drops should be administered at least 5 minutes apart.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Ketorolac tromethamine is a nonsteroidal anti-inflammatory drug which, when administered systemically, has demonstrated analgesic, anti-inflammatory, and anti-pyretic activity. The mechanism of its action is thought to be due to its ability to inhibit prostaglandin biosynthesis. 12.3 Pharmacokinetics One drop of 0.5% ketorolac tromethamine ophthalmic solution was instilled into one eye and one drop of vehicle into the other eye TID in 26 healthy subjects. Five of 26 subjects had detectable concentrations of ketorolac in their plasma (range 11 to 23 ng/mL) at day 10 during topical ocular treatment. Two drops of 0.5% ketorolac tromethamine ophthalmic solution instilled into the eyes of patients 12 hours and 1 hour prior to cataract extraction achieved a mean ketorolac concentration of 95 ng/mL in the aqueous humor of 8 of 9 eyes tested (range 40 to 170 ng/mL).

12.1 Mechanism of Action Ketorolac tromethamine is a nonsteroidal anti-inflammatory drug which, when administered systemically, has demonstrated analgesic, anti-inflammatory, and anti-pyretic activity. The mechanism of its action is thought to be due to its ability to inhibit prostaglandin biosynthesis.

12.3 Pharmacokinetics One drop of 0.5% ketorolac tromethamine ophthalmic solution was instilled into one eye and one drop of vehicle into the other eye TID in 26 healthy subjects. Five of 26 subjects had detectable concentrations of ketorolac in their plasma (range 11 to 23 ng/mL) at day 10 during topical ocular treatment. Two drops of 0.5% ketorolac tromethamine ophthalmic solution instilled into the eyes of patients 12 hours and 1 hour prior to cataract extraction achieved a mean ketorolac concentration of 95 ng/mL in the aqueous humor of 8 of 9 eyes tested (range 40 to 170 ng/mL).

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3 DOSAGE FORMS AND STRENGTHS Ophthalmic solution containing ketorolac tromethamine 0.4% (4 mg/mL). Ophthalmic solution containing ketorolac tromethamine 0.4% (4 mg/mL). ( 3 )

Ketorolac Tromethamine Ketorolac Tromethamine KETOROLAC TROMETHAMINE KETOROLAC BENZALKONIUM CHLORIDE EDETATE DISODIUM OCTOXYNOL-40 WATER SODIUM CHLORIDE HYDROCHLORIC ACID SODIUM HYDROXIDE

ANDA205191

Ketorolac Tromethamine

Ketorolac Tromethamine

65862-775

HUMAN PRESCRIPTION DRUG

OPHTHALMIC

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 0.4% - Container Label NDC 65862-775-05 Ketorolac Tromethamine Ophthalmic Solution 0.4% For Use in the Eyes Only Rx only Aurobindo PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 0.4% - Container Label

17 PATIENT COUNSELING INFORMATION Slow or Delayed Healing Inform patients of the possibility that slow or delayed healing may occur while using nonsteroidal anti-inflammatory drugs (NSAIDs). Avoiding Contamination of the Product Instruct patients to avoid allowing the tip of the bottle to contact the eye or surrounding structures because this could cause the tip to become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions. Contact Lens Wear Advise patients that ketorolac tromethamine ophthalmic solution should not be administered while wearing contact lenses. Intercurrent Ocular Conditions Advise patients that if they develop an intercurrent ocular condition (e.g., trauma or infection) or have ocular surgery, they should immediately seek their physician’s advice concerning the continued use of ketorolac tromethamine. Concomitant Topical Ocular Therapy Advise patients that if more than one topical ophthalmic medication is being used, the medicines should be administered at least 5 minutes apart. Distributed by: Aurobindo Pharma USA, Inc. 279 Princeton-Hightstown Road East Windsor, NJ 08520 Manufactured by: Eugia Pharma Specialities Limited Hyderabad - 500032 India

14 CLINICAL STUDIES In two double-masked, multi-centered, parallel-group studies, 313 patients who had undergone photorefractive keratectomy received ketorolac tromethamine ophthalmic solution 0.4% or its vehicle QID for up to 4 days. Significant differences favored ketorolac tromethamine for the reduction of ocular pain and burning/stinging following photorefractive keratectomy surgery. Results from clinical studies indicate that ketorolac tromethamine has no significant effect upon intraocular pressure. The safety and effectiveness of ketorolac tromethamine in post-cataract surgery patients has not been established.

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

8.2 Lactation Risk Summary It is not known whether ketorolac when given topically is present in human milk. Because many drugs are excreted in human milk, caution should be exercised when ketorolac tromethamine is administered to a nursing woman.

8.4 Pediatric Use Safety and effectiveness of ketorolac tromethamine in pediatric patients below the age of 3 have not been established.

8.1 Pregnancy Risk Summary There are no adequate or well-controlled studies with ketorolac tromethamine in pregnant women. No evidence of teratogenicity has been observed in rats or rabbits with ketorolac tromethamine at clinically relevant doses.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no adequate or well-controlled studies with ketorolac tromethamine in pregnant women. No evidence of teratogenicity has been observed in rats or rabbits with ketorolac tromethamine at clinically relevant doses. 8.2 Lactation Risk Summary It is not known whether ketorolac when given topically is present in human milk. Because many drugs are excreted in human milk, caution should be exercised when ketorolac tromethamine is administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness of ketorolac tromethamine in pediatric patients below the age of 3 have not been established. 8.5 Geriatric Use No overall differences in safety or effectiveness have been observed between elderly and other adult patients.

16 HOW SUPPLIED/STORAGE AND HANDLING Ketorolac tromethamine ophthalmic solution 0.4% is a clear colorless to slightly yellow solution supplied in white opaque LDPE container with LDPE nozzle and gray color HDPE cap as follows: 5 mL in 10 mL bottle NDC 65862-775-05 Storage: Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from light.