PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

Container Label - 3mL
NDC 65145-138-01

Rx only
Ketorolac Tromethamine Ophthalmic Solution 0.5%
FOR TOPICAL OPHTHALMIC USE ONLY
Sterile 3 mL


Carton Label - 3mL
NDC 65145-138-01
Rx only
Ketorolac Tromethamine Ophthalmic Solution 0.5%
FOR TOPICAL OPHTHALMIC USE ONLY
Sterile 3 mL


Container Label - 5mL
NDC 65145-139-01
Rx only
Ketorolac Tromethamine Ophthalmic Solution 0.5%
FOR TOPICAL OPHTHALMIC USE ONLY
Sterile 5 mL


Carton Label - 5mL
NDC 65145-139-01
Rx only
Ketorolac Tromethamine Ophthalmic Solution 0.5%
FOR TOPICAL OPHTHALMIC USE ONLY
Sterile 5 mL


Container Label - 10mL
NDC 65145-140-01

Rx only
Ketorolac Tromethamine Ophthalmic Solution 0.5%
FOR TOPICAL OPHTHALMIC USE ONLY
Sterile 10 mL


Carton Label - 10mL
NDC 65145-140-01
Rx only
Ketorolac Tromethamine Ophthalmic Solution 0.5%
FOR TOPICAL OPHTHALMIC USE ONLY
Sterile 10 mL


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DESCRIPTION SECTION

11 DESCRIPTION

Ketorolac tromethamine ophthalmic solution 0.5% 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-1H pyrrolizine-1-carboxylic acid compound with 2-amino-2-(hydroxymethyl)-1,3-propanediol (1:1) and it has the following structure:


Ketorolac tromethamine ophthalmic solution is supplied as a sterile isotonic aqueous 0.5% solution, with a pH of 7.4. Ketorolac tromethamine ophthalmic solution is 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 to off-white crystalline substance discolors on prolonged exposure to light. The molecular weight of ketorolac tromethamine is 376.41. The osmolality of ketorolac tromethamine ophthalmic solution is 290 mOsmol/kg.
Each mL of ketorolac tromethamine ophthalmic solution contains: Active: ketorolac tromethamine 0.5%. Preservative: benzalkonium chloride 0.01%. Inactives: edetate disodium 0.1%; octoxynol 40; water for injection; sodium chloride; hydrochloric acid and/or sodium hydroxide to adjust the pH.

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INDICATIONS & USAGE SECTION

Highlight: Ketorolac tromethamine ophthalmic solution is a nonsteroidal, anti- inflammatory indicated for:

• The treatment of inflammation following cataract surgery. (1)
• The temporary relief of ocular itching due to seasonal allergic conjunctivitis. (1)

1 INDICATIONS AND USAGE

Ketorolac tromethamine ophthalmic solution is indicated for the temporary relief of ocular itching due to seasonal allergic conjunctivitis. Ketorolac tromethamine ophthalmic solution is also indicated for the treatment of postoperative inflammation in patients who have undergone cataract extraction.

DOSAGE FORMS & STRENGTHS SECTION

Highlight: Ophthalmic solution containing 5 mg/mL ketorolac tromethamine. (3)

• 5 mL size bottle filled with 3 mL of solution
• 10 mL size bottle filled with 5 mL of solution
• 10 mL size bottle filled with 10 mL of solution

3 DOSAGE FORMS AND STRENGTHS

5 mL size bottle filled with 3 mL of ketorolac tromethamine ophthalmic solution, 0.5% (5 mg/mL)

10 mL size bottle filled with 5 mL of ketorolac tromethamine ophthalmic solution, 0.5% (5 mg/mL)

10 mL size bottle filled with 10 mL of ketorolac tromethamine ophthalmic solution, 0.5% (5 mg/mL)

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CONTRAINDICATIONS SECTION

Highlight: Hypersensitivity to any component of this product. (4)

4 CONTRAINDICATIONS

Ketorolac tromethamine ophthalmic solution is contraindicated in patients with previously demonstrated hypersensitivity to any of the ingredients in the formulation.

WARNINGS AND PRECAUTIONS SECTION

Highlight: * Delayed healing (5.1)

• Cross-sensitivity or hypersensitivity (5.2)
• Increased bleeding time due to interference with thrombocyte aggregation (5.3)
• Corneal effects including keratitis (5.4)

5 WARNINGS AND PRECAUTIONS

5.1 Delayed Healing

Topical nonsteroidal anti-inflammatory drugs (NSAIDs) may slow or delay healing. Topical corticosteroids are also known to slow or delay healing. Concomitant use of topical NSAIDs and topical steroids may increase the potential for healing problems.

5.2 Cross-Sensitivity or Hypersensitivity

There is the potential for cross-sensitivity to acetylsalicylic acid, phenylacetic acid derivatives, and other NSAIDs. There have been reports of bronchospasm or exacerbation of asthma associated with the use of ketorolac tromethamine ophthalmic solution in patients who have either a known hypersensitivity to aspirin/non-steroidal anti-inflammatory drugs or a past medical history of asthma. Therefore, caution should be used when treating individuals who have previously exhibited sensitivities to these drugs.

5.3 Increased Bleeding Time

With some NSAIDs, there exists the potential for increased bleeding time due to interference with thrombocyte aggregation. There have been reports that ocularly applied nonsteroidal anti-inflammatory drugs may cause increased bleeding of ocular tissues (including hyphemas) in conjunction with ocular surgery.

It is recommended that ketorolac tromethamine ophthalmic solution be used with caution in patients with known bleeding tendencies or who are receiving other medications, which may prolong bleeding time.

5.4 Corneal Effects

Use of topical NSAIDs may result in keratitis. In some susceptible patients, continued use of topical NSAIDs may result in epithelial breakdown, corneal thinning, corneal erosion, corneal ulceration, or corneal perforation. These events may be sight threatening. Patients with evidence of corneal epithelial breakdown should immediately discontinue use of topical NSAIDs and should be closely monitored for corneal health.
Postmarketing experience with topical NSAIDs suggests that patients with complicated ocular surgeries, corneal denervation, corneal epithelial defects, diabetes mellitus, ocular surface diseases (e.g., dry eye syndrome), rheumatoid arthritis, or repeat ocular surgeries within a short period of time may be at increased risk for corneal adverse events which may become sight threatening. Topical NSAIDs should be used with caution in these patients.
Postmarketing experience with topical NSAIDs also suggests that use more than 1 day prior to surgery or use beyond 14 days post-surgery may increase patient risk for the occurrence and severity of corneal adverse events.

5.5 Contact Lens Wear

Ketorolac tromethamine ophthalmic solution should not be administered while wearing contact lenses.

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USE IN SPECIFIC POPULATIONS SECTION

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects. Pregnancy Category C
Pregnancy Category C: Ketorolac tromethamine, administered during organogenesis, was not teratogenic in rabbits and rats at oral doses of 3.6 mg/kg/day and 10 mg/kg/day, respectively. These doses are approximately 100 times and 250 times higher respectively than the maximum recommended human topical ophthalmic daily dose of 2 mg (5 mg/mL x 0.05 mL/drop, x 4 drops x 2 eyes) to affected eyes on a mg/kg basis. Additionally, when administered to rats after Day 17 of gestation at oral doses up to 1.5 mg/kg/day (approximately 40 times the typical human topical ophthalmic daily dose), ketorolac tromethamine resulted in dystocia and increased pup mortality. There are no adequate and well-controlled studies in pregnant women. Ketorolac tromethamine ophthalmic solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic Effects: Because of the known effects of prostaglandin- inhibiting drugs on the fetal cardiovascular system (closure of the ductus arteriosus), the use of ketorolac tromethamine ophthalmic solution during late pregnancy should be avoided.

8.3 Nursing Mothers

Because many drugs are excreted in human milk, caution should be exercised when ketorolac tromethamine ophthalmic solution is administered to a nursing woman.

8.4 Pediatric Use

Safety and efficacy in pediatric patients below the age of 2 have not been established.

8.5 Geriatric Use

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

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CLINICAL STUDIES SECTION

14 CLINICAL STUDIES

Two controlled clinical studies showed that ketorolac tromethamine ophthalmic solution was significantly more effective than its vehicle in relieving ocular itching caused by seasonal allergic conjunctivitis.
Two controlled clinical studies showed that patients treated for two weeks with ketorolac tromethamine ophthalmic solution were less likely to have measurable signs of inflammation (cell and flare) than patients treated with its vehicle.
Results from clinical studies indicate that ketorolac tromethamine has no significant effect upon intraocular pressure; however, changes in intraocular pressure may occur following cataract surgery.

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NONCLINICAL TOXICOLOGY SECTION

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility

Ketorolac tromethamine was not carcinogenic in either rats given up to 5 mg/kg/day orally for 24 months or in mice given 2 mg/kg/day orally for 18 months. These doses are approximately 125 times and 50 times higher respectively than the maximum recommended human topical ophthalmic daily dose given as QID for itching to affected eyes on a mg/kg basis.
Ketorolac tromethamine was not mutagenic in vitro in the Ames assay or in forward mutation assays. Similarly, it did not result in an in vitro increase in unscheduled DNA synthesis or an in vivo increase in chromosome breakage in mice. However, ketorolac tromethamine did result in an increased incidence in chromosomal aberrations in Chinese hamster ovary cells.
Ketorolac tromethamine did not impair fertility when administered orally to male and female rats at doses up to 9 mg/kg/day and 16 mg/kg/day, respectively. These doses are respectively 225 and 400 times higher than the typical human topical ophthalmic daily dose.

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