ACULAR- ketorolac tromethamine solution/ drops
For Healthcare Providers >

1. Patient Information
2. Revised: 6/2012document Id:

Patient Information ⮝

17.1 Slow or Delayed Healing

Patients should be informed of the possibility that slow or delayed healing may occur while using nonsteroidal anti-inflammatory drugs (NSAIDs).

17.2 Avoiding Contamination of the Product

Patients should be instructed 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.

Also, to avoid the potential for cross-contamination, the patient should be advised to use one bottle for each eye following bilateral ocular surgery. The use of the same bottle of topical eye drops for both eyes following bilateral ocular surgery is not recommended.

17.3 Contact Lens Wear

Patients should be advised thatACULARsolution should not be administered while wearing contact lenses.

17.4 Intercurrent Ocular Conditions

Patients should be advised 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 ofACULAR.

17.5 Concomitant Topical Ocular Therapy

Patients should be advised that if more than one topical ophthalmic medication is being used, the medicines should be administered at least 5 minutes apart.

2012 Allergan, Inc., Irvine, CA 92612, U.S.A.

ACULARis manufactured and distributed by Allergan, Inc. under license from its developer, Roche Palo Alto LLC, Palo Alto, CA, U.S.A.

marks owned by Allergan, Inc.

Made in the U.S.A.

72379US10

ALLERGAN

NDC 0023-2181-05

ACULAR

(ketorolac

tromethamine

ophthalmic

solution)

0.5%

sterileRx only

5 mL

ACULAR ketorolac tromethamine solution/ drops

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0023-2181 Route of Administration OPHTHALMIC

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Ketorolac Tromethamine(UNII: 4EVE5946BQ) (Ketorolac - UNII:YZI5105V0L) Ketorolac Tromethamine 5 mg in 1 mL

Inactive Ingredients Ingredient Name Strength benzalkonium chloride(UNII: F5UM2KM3W7) edetate disodium(UNII: 7FLD91C86K) octoxynol-40(UNII: 9T1C662FKS) water(UNII: 059QF0KO0R) sodium chloride(UNII: 451W47IQ8X) hydrochloric acid(UNII: QTT17582CB) sodium hydroxide(UNII: 55X04QC32I)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0023-2181-05 1 in 1 CARTON 12/01/1992 1 5 mL in 1 BOTTLE, DROPPER; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA019700 12/01/1992

Labeler -Allergan, Inc. (144796497)

Establishment
Name	Address	ID/FEI	Business Operations
Allergan Sales, LLC		362898611	MANUFACTURE(0023-2181)

Revised: 6/2012document Id: ⮝

2df33f5e-153b-43fe-b56f-30059957354934391-3Set id: c94644d3-7b64-4f3d-a0c7-12c77466a0fcVersion: 7Effective Time: 20120618Allergan, Inc.

1. Description
2. Clinical Pharmacology
3. Indications And Usage
4. Contraindications
5. Warnings
6. Precautions
7. Adverse Reactions
8. Dosage And Administration
9. How Supplied
10. Highlights Of Prescribing Information
11. Indications And Usage
12. Dosage And Administration
13. Dosage Forms And Strengths
14. Contraindications
15. Warnings And Precautions
16. Adverse Reactions
17. 1 Indications And Usage
18. 2 Dosage And Administration
19. 3 Dosage Forms And Strengths
20. 4 Contraindications
21. 5 Warnings And Precautions
22. 6 Adverse Reactions
23. 8 Use In Specific Populations
24. 11 Description
25. 12 Clinical Pharmacology
26. 13 Nonclinical Toxicology
27. 14 Clinical Studies
28. 16 How Supplied/storage And Handling

Description  ⮝

ACULAR (ketorolac tromethamine ophthalmic solution) 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:

ACULAR ophthalmic solution is supplied as a sterile isotonic aqueous 0.5% solution, with a pH of 7.4. ACULAR 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 376.40. The osmolality of ACULAR ophthalmic solution is 290 mOsml/kg.

Each mL of ACULAR ophthalmic solution contains: Active: ketorolac tromethamine 0.5%. Preservative: benzalkonium chloride 0.01%. Inactives: edetate disodium 0.1%; octoxynol 40; purified water; sodium chloride; and hydrochloric acid and/or sodium hydroxide to adjust pH.

Clinical Pharmacology  ⮝

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. Ketorolac tromethamine given systemically does not cause pupil constriction.

Prostaglandins have been shown in many animal models to be mediators of certain kinds of intraocular inflammation. In studies performed in animal eyes, prostaglandins have been shown to produce disruption of the blood-aqueous humor barrier, vasodilation, increased vascular permeability, leukocytosis, and increased intraocular pressure. Prostaglandins also appear to play a role in the miotic response produced during ocular surgery by constricting the iris sphincter independently of cholinergic mechanisms.

Two drops (0.1 mL) of 0.5% ACULAR ophthalmic solution instilled into the eyes of patients 12 hours and 1 hour prior to cataract extraction achieved measurable levels in 8 of 9 patients' eyes (mean ketorolac concentration 95 ng/mL aqueous humor, range 40 to 170 ng/mL). Ocular administration of ketorolac tromethamine reduces prostaglandin E2 (PGE2) levels in aqueous humor. The mean concentration of PGE2 was 80 pg/mL in the aqueous humor of eyes receiving vehicle and 28 pg/mL in the eyes receiving ACULAR 0.5% ophthalmic solution.

One drop (0.05 mL) of 0.5% ACULAR ophthalmic solution was instilled into one eye and one drop of vehicle into the other eye TID in 26 normal subjects. Only 5 of 26 subjects had a detectable amount of ketorolac in their plasma (range 10.7 to 22.5 ng/mL) at Day 10 during topical ocular treatment. When ketorolac tromethamine 10 mg is administered systemically every 6 hours, peak plasma levels at steady state are around 960 ng/mL.

Two controlled clinical studies showed that ACULAR 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 ACULAR 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.

Indications And Usage  ⮝

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

Contraindications  ⮝

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

Warnings  ⮝

There is the potential for cross-sensitivity to acetylsalicylic acid, phenylacetic acid derivatives, and other nonsteroidal anti-inflammatory agents. Therefore, caution should be used when treating individuals who have previously exhibited sensitivities to these drugs.

With some nonsteroidal anti-inflammatory drugs, 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.

Precautions  ⮝

General

All 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.

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 24 hours prior to surgery or use beyond 14 days post-surgery may increase patient risk for the occurrence and severity of corneal adverse events.

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

Information for Patients: ACULAR ophthalmic solution should not be administered while wearing contact lenses.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Ketorolac tromethamine was not carcinogenic in rats given up to 5 mg/kg/day orally for 24 months (151 times the maximum recommended human topical ophthalmic dose, on a mg/kg basis, assuming 100% absorption in humans and animals) nor in mice given 2 mg/kg/day orally for 18 months (60 times the maximum recommended human topical ophthalmic dose, on a mg/kg basis, assuming 100% absorption in humans and animals).

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 272 and 484 times the maximum recommended human topical ophthalmic dose, respectively, on a mg/kg basis, assuming 100% absorption in humans and animals.

Pregnancy

Teratogenic Effects: Pregnancy Category C. Ketorolac tromethamine, administered during organogenesis, was not teratogenic in rabbits or rats at oral doses up to 109 times and 303 times the maximum recommended human topical ophthalmic dose, respectively, on a mg/kg basis assuming 100% absorption in humans and animals. When administered to rats after Day 17 of gestation at oral doses up to 45 times the maximum recommended human topical ophthalmic dose, respectively, on a mg/kg basis, assuming 100% absorption in humans and animals, ketorolac tromethamine resulted in dystocia and increased pup mortality. There are no adequate and well-controlled studies in pregnant women. ACULAR 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 ACULAR ophthalmic solution during late pregnancy should be avoided.

Nursing Mothers

Caution should be exercised when ACULAR ophthalmic solution is administered to a nursing woman.

Pediatric Use

Safety and efficacy in pediatric patients below the age of 3 have not been established.

Geriatric Use

No overall differences in safety or effectiveness have been observed between elderly and younger patients.

Adverse Reactions  ⮝

The most frequent adverse events reported with the use of ketorolac tromethamine ophthalmic solutions have been transient stinging and burning on instillation. These events were reported by up to 40% of patients participating in clinical trials.

Other adverse events occurring approximately 1% - 10% of the time during treatment with ketorolac tromethamine ophthalmic solutions included allergic reactions, corneal edema, iritis, ocular inflammation, ocular irritation, superficial keratitis, and superficial ocular infections.

Other adverse events reported rarely with the use of ketorolac tromethamine ophthalmic solutions included: corneal infiltrates, corneal ulcer, eye dryness, headaches, and visual disturbance (blurry vision).

Clinical Practice: The following events have been identified during postmarketing use of ketorolac tromethamine ophthalmic solution 0.5% in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The events, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to topical ketorolac tromethamine ophthalmic solution 0.5%, or a combination of these factors, include corneal erosion, corneal perforation, corneal thinning and epithelial breakdown (see PRECAUTIONS, General).

Dosage And Administration  ⮝

The recommended dose of ACULAR ophthalmic solution is one drop (0.25 mg) four times a day for relief of ocular itching due to seasonal allergic conjunctivitis.

For the treatment of postoperative inflammation in patients who have undergone cataract extraction, one drop of ACULAR ophthalmic solution should be applied to the affected eye(s) four times daily beginning 24 hours after cataract surgery and continuing through the first 2 weeks of the postoperative period.

ACULAR ophthalmic solution has been safely administered in conjunction with other ophthalmic medications such as antibiotics, beta blockers, carbonic anhydrase inhibitors, cycloplegics, and mydriatics.

How Supplied  ⮝

ACULAR (ketorolac tromethamine ophthalmic solution) is supplied sterile in opaque white LDPE plastic bottles with white droppers with gray high impact polystyrene (HIPS) caps as follows:

5 mL in 10 mL bottle - NDC 16590-002-05

Store at 15 C - 25 C (59 F- 77 F) with protection from light.

Rx Only

Revised: 05/2011

2011 Allergan, Inc.

Irvine, CA 92612, U.S.A.

ACULAR is manufactured and distributed by Allergan, Inc. under license from its developer, Roche Palo Alto LLC, Palo Alto, CA, U.S.A.
marks owned by Allergan, Inc.
Made in the U.S.A.

71590US13C

Relabeling and Repackaging by:
STAT Rx USA LLC
Gainesville, GA 30501

ACULAR Rx only

(ketorolac tromethamine ophthalmic solution) 0.5%

sterile 5 mL

ACULAR ketorolac tromethamine solution/ drops

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:16590-002(NDC:0023-2181) Route of Administration OPHTHALMIC

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength KETOROLAC TROMETHAMINE (UNII: 4EVE5946BQ) (KETOROLAC - UNII:YZI5105V0L) KETOROLAC TROMETHAMINE 5 mg in 1 mL

Inactive Ingredients Ingredient Name Strength BENZALKONIUM CHLORIDE (UNII: F5UM2KM3W7) EDETATE DISODIUM (UNII: 7FLD91C86K) OCTOXYNOL-40 (UNII: 9T1C662FKS) WATER (UNII: 059QF0KO0R) SODIUM CHLORIDE (UNII: 451W47IQ8X) HYDROCHLORIC ACID (UNII: QTT17582CB) SODIUM HYDROXIDE (UNII: 55X04QC32I)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:16590-002-05 1 in 1 CARTON 1 5 mL in 1 BOTTLE, DROPPER

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA019700 12/01/1992

Labeler - STAT Rx USA LLC (786036330)

Registrant - PSS World Medical Inc. (101822682)

Establishment
Name	Address	ID/FEI	Business Operations
STAT Rx USA LLC		786036330	relabel, repack

Revised: 5/2012 Document Id: 9b3dcaf1-1471-4f98-af83-2ea3fef6b3ca 34391-3 Set id: 5ba45168-ad5d-4ea9-bd85-fc2fa2b13dad Version: 4 Effective Time: 20120531 STAT Rx USA LLC

Highlights Of Prescribing Information ⮝

These highlights do not include all the information needed to use ACULAR safely and effectively. See full prescribing information for ACULAR .
ACULAR (ketorolac tromethamine ophthalmic solution) 0.5%
Initial U.S. Approval: 1991

Indications And Usage ⮝

ACULAR 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)

Dosage And Administration ⮝

One drop of ACULAR should be applied to the affected eye(s) four times a day for relief of ocular itching due to seasonal allergic conjunctivitis.

For the treatment of postoperative inflammation in patients who have undergone cataract extraction, one drop of ACULAR should be applied to the affected eye four times daily beginning 24 hours after cataract surgery and continuing through the first 2 weeks of the postoperative period. (2.1)

Dosage Forms And Strengths ⮝

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

• 10 mL size bottle filled with 5 mL of solution

Contraindications ⮝

Hypersensitivity to any component of this product. (4)

Warnings And Precautions ⮝

• 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)

Adverse Reactions ⮝

The most frequent adverse reactions reported by up to 40% of patients participating in clinical trials have been transient stinging and burning on instillation. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Allergan at 1-800-433-8871 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 12/2011

1 Indications And Usage  ⮝

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

2 Dosage And Administration  ⮝

2.1 Recommended Dosing

Patient Dosing

The recommended dose of ACULAR ophthalmic solution is one drop four times a day to the affected eye(s) for relief of ocular itching due to seasonal allergic conjunctivitis.

For the treatment of postoperative inflammation in patients who have undergone cataract extraction, one drop of ACULAR ophthalmic solution should be applied to the affected eye four times daily beginning 24 hours after cataract surgery and continuing through the first 2 weeks of the postoperative period.

2.2 Use with Other Topical Ophthalmic Medications

ACULAR ophthalmic solution has been safely administered in conjunction with other ophthalmic medications such as antibiotics, alpha-agonists, beta blockers, carbonic anhydrase inhibitors, cycloplegics, and mydriatics. Drops should be administered at least 5 minutes apart.

3 Dosage Forms And Strengths  ⮝

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

4 Contraindications  ⮝

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

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 ACULAR 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

ACULAR should not be administered while wearing contact lenses.

6 Adverse Reactions  ⮝

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.

6.1 Clinical Studies Experience

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 1 to 10% of the time during treatment with ketorolac tromethamine ophthalmic solutions included allergic reactions, 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 infiltrates, corneal ulcer, eye dryness, headaches, and visual disturbance (blurry vision).

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-marketing use of ketorolac tromethamine ophthalmic solution 0.5% 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 solution 0.5% or a combination of these factors, include bronchospasm or exacerbation of asthma, corneal erosion, corneal perforation, corneal thinning, and epithelial breakdown [see Warnings and Precautions (5.2, 5.4)].

8 Use In Specific Populations  ⮝

8.1 Pregnancy

Teratogenic Effects. 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. ACULAR 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 ACULAR solution during late pregnancy should be avoided.

8.3 Nursing Mothers

Because many drugs are excreted in human milk, caution should be exercised when ACULAR 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.

11 Description  ⮝

ACULAR (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:

ACULAR ophthalmic solution is supplied as a sterile isotonic aqueous 0.5% solution, with a pH of 7.4. ACULAR 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 to off-white crystalline substance discolors on prolonged exposure to light. The molecular weight of ketorolac tromethamine is 376.41. The osmolality of ACULAR ophthalmic solution is 290 mOsmol/kg.

Each mL of ACULAR ophthalmic solution contains: Active: ketorolac tromethamine 0.5%. Preservative: benzalkonium chloride 0.01%. Inactives: edetate disodium 0.1%; octoxynol 40; purified water; sodium chloride; hydrochloric acid and/or sodium hydroxide to adjust pH.

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

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).

One drop of 0.5% ketorolac tromethamine ophthalmic solution was instilled into 1 eye and 1 drop of vehicle into the other eye TID in 26 healthy subjects. Five (5) of 26 subjects had detectable concentrations of ketorolac in their plasma (range 11 to 23 ng/mL) at Day 10 during topical ocular treatment. The range of concentrations following TID dosing of 0.5% ketorolac tromethamine ophthalmic solution are approximately 4 to 8% of the steady state mean minimum plasma concentration observed following four times daily oral administration of 10 mg ketorolac in humans (290 70 ng/mL).

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.

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.

16 How Supplied/storage And Handling  ⮝

ACULAR (ketorolac tromethamine ophthalmic solution) 0.5% is supplied sterile, in white opaque plastic LDPE bottles with white droppers, with gray high impact polystyrene (HIPS) caps as follows:

5 mL in 10 mL bottle NDC 0023-2181-05

Storage: Store at 15 -25 C (59 -77 F). Protect from light.