Prescription Drugs

CLINICAL PHARMACOLOGY 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. 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 three times daily 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 three times daily 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). Clinical Studies Two multicenter, randomized, double-masked, parallel group comparison studies including approximately 500 patients were conducted to evaluate the effects of ACUVAIL® on anterior chamber cell and flare, and ocular pain relief following cataract extraction with posterior chamber intraocular lens (IOL) implantation. Results of these studies indicated that patients receiving ACUVAIL® had a significantly higher incidence of clearing of anterior chamber inflammation 53% (167/318) vs. patients receiving vehicle 26% (41/155) at day 14. ACUVAIL® was also significantly superior to vehicle in resolving ocular pain. On Day 1 post cataract surgery, 72% (233/322) of patients in the ACUVAIL® group were pain free compared to 40% (62/156) of patients in the vehicle group. 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.

CLINICAL PHARMACOLOGY 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. Ketorolac tromethamine given systemically does not cause pupil constriction. Pharmacokinetics One drop (0.05 mL) of 0.5% ketorolac tromethamine 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. Clinical Studies In two double-masked, multi-centered, parallel-group studies, 313 patients who had undergone photorefractive keratectomy received ACULAR LS™ (ketorolac tromethamine ophthalmic solution) 0.4% or its vehicle QID for up to 4 days. Significant differences favored ACULAR LS™ (ketorolac tromethamine ophthalmic solution) 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.

Find Lowest Prices on ACUVAIL® (ketorolac tromethamine) Ophthalmic Solution DESCRIPTION ACUVAIL® (ketorolac tromethamine ophthalmic solution) 0.45% is a member of the pyrrolo­pyrrole 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 its molecular weight is 376.40. Its molecular formula is C19H24N2O6. Its chemical structure is: ACUVAIL® solution is supplied as a sterile isotonic aqueous 0.45% preservative-free solution, with a pH of approximately 6.8. ACUVAIL® 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 osmolality of ACUVAIL® solution is approximately 285 mOsml/kg. Each mL of ACUVAIL® ophthalmic solution contains: Active: ketorolac tromethamine 0.45%. Inactives: carboxymethylcellulose sodium; sodium chloride; sodium citrate dihydrate; and purified water with sodium hydroxide and/or hydrochloric acid to adjust pH.

Find Lowest Prices on ACULAR LS™ (ketorolac tromethamine) Ophthalmic Solution 0.4% Sterile DESCRIPTION ACULAR LS™ (ketorolac tromethamine ophthalmic solution) 0.4% is a member of the pyrrolo-pyrrole group of nonsteroidal anti-inflammatory drugs (NSAIDs) for ophthalmic use. Structural and Molecular Formula: Chemical Name: (±)-5-Benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid, compound with 2-amino-2-(hydroxymethyl)-1,3-propanediol (1:1) Contains: Active: ketorolac tromethamine 0.4%. Preservative: benzalkonium chloride 0.006%. Inactives:sodium chloride; edetate disodium 0.015%; octoxynol 40; purified water; and hydrochloric acid and/or sodium hydroxide to adjust the pH. ACULAR LS™ (ketorolac tromethamine ophthalmic solution) ophthalmic solution is supplied as a sterile isotonic aqueous 0.4% solution, with a pH of approximately 7.4. ACULAR LS™ 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 osmolality of ACULAR LS™ (ketorolac tromethamine ophthalmic solution) ophthalmic solution is approximately 290 mOsml/kg.

INDICATIONS ACUVAIL® ophthalmic solution is indicated for the treatment of pain and inflammation following cataract surgery. DOSAGE AND ADMINISTRATION Recommended Dosing Patient Dosing One drop of ACUVAIL® should be applied to the affected eye twice daily beginning 1 day prior to cataract surgery, continued on the day of surgery, and through the first 2 weeks of the postoperative period. Use With Other Topical Ophthalmic Medications ACUVAIL® ophthalmic solution may be administered in conjunction with other topical ophthalmic medications such as alpha-agonists, beta-blockers, carbonic anhydrase inhibitors, cycloplegics, and mydriatics. Drops should be administered at least 5 minutes apart. HOW SUPPLIED Dosage Forms And Strengths 4.5 mg/mL ketorolac tromethamine solution (0.45%) in a single-use vial. Storage And Handling ACUVAIL® (ketorolac tromethamine ophthalmic solution) 0.45% is available as a sterile solution supplied in clear, LDPE, single-use vials packaged in 6 foil pouches, 5 vials per pouch: 30 Single-Use Vials 0.4 mL each: NDC 0023-3507-30 Storage Store at 15°-30°C (59°-86°F). Store the vials in the pouch, protected from light. Fold pouch ends closed. Allergan, Inc., Irvine, CA 92612, U.S.A. Revised: Dec 2014.

INDICATIONS ACULAR LS™ (ketorolac tromethamine ophthalmic solution) ophthalmic solution is indicated for the reduction of ocular pain and burning/stinging following corneal refractive surgery. DOSAGE AND ADMINISTRATION The recommended dose of ACULAR LS™ (ketorolac tromethamine ophthalmic solution) 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. Ketorolac tromethamine 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 LS™ (ketorolac tromethamine ophthalmic solution) 0.4% is supplied sterile in an opaque white LDPE plastic bottle with a white dropper with a gray high impact polystyrene (HIPS) cap as follows: 5 mL in 10 mL bottle- NDC 0023-9277-05 Note: Store at 15°C - 25°C (59°F- 77°F). This product is manufactured and distributed by ALLERGAN under license from its developer, Roche Palo Alto LLC, Palo Alto, California, U.S.A. May 2003. FDA Rev date: 12/1/2008

PATIENT INFORMATION 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). Avoiding Contamination Of The Product Patients should be instructed that the solution from one individual single-use vial is to be used immediately after opening for administration to the affected eye. The remaining vial contents should be discarded. The use of the same single-use vial of topical eye drops for both eyes following bilateral ocular surgery is not recommended. In these circumstances, advise patients to use one vial for each eye immediately after opening and discard the remaining contents after use. Patients should be instructed to avoid allowing the tip of the vial to contact the eye or surrounding structures because this could cause the tip to become contaminated by common bacteria known to cause ocular infections or cause injury to the eye. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions. Store the vials in the pouch, protected from light. Fold pouch ends closed. Contact Lens Wear Patients should be advised that ACUVAIL® solution should not be administered while wearing contact lenses. 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 of ACUVAIL® . 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.

PATIENT INFORMATION ACULAR LS™ (ketorolac tromethamine ophthalmic solution) ophthalmic solution should not be administered while wearing contact lenses.

OVERDOSE No information provided. CONTRAINDICATIONS ACUVAIL® solution is contraindicated in patients with previously demonstrated hypersensitivity to any of the ingredients in the formulation.

OVERDOSE No information provided. CONTRAINDICATIONS ACULAR LS™ (ketorolac tromethamine ophthalmic solution) ophthalmic solution is contraindicated in patients with previously demonstrated hypersensitivity to any of the ingredients in the formulation.

SIDE EFFECTS 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. Clinical Studies Experience The most common adverse reactions were reported in 1-6% of patients and included increased intraocular pressure, conjunctival hyperemia and/or hemorrhage, corneal edema, ocular pain, headache, tearing and vision blurred. Some of these reactions may be the consequence of the cataract surgical procedure. 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, exacerbation of asthma, corneal erosion, corneal perforation, corneal thinning and corneal melt, epithelial breakdown [see WARNINGS AND PRECAUTIONS] and ulcerative keratitis. DRUG INTERACTIONS No information provided.

SIDE EFFECTS The most frequently reported adverse reactions for ACULAR LS™ (ketorolac tromethamine ophthalmic solution) 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 events reported with the use of ketorolac tromethamine ophthalmic solutions have been transient stinging and burning on instillation. These events were reported by 20% - 40% of patients participating in these other 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, ocular pain, superficial keratitis, and superficial ocular infections. Clinical Practice: The following events 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 events, 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 corneal erosion, corneal perforation corneal thinning and epithelial breakdown (see PRECAUTIONS, General). DRUG INTERACTIONS No information provided.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS 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. 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 either have 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. 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 ACUVAIL® ophthalmic solution be used with caution in patients with known bleeding tendencies or who are receiving other medications, which may prolong bleeding time. 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. Contact Lens Wear ACUVAIL® should not be administered while wearing contact lenses. Nonclinical Toxicology 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 900 times and 300 times higher respectively than the typical human topical ophthalmic daily dose given as twice daily to an affected eye 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 1500 and 2700 times higher than the typical human topical ophthalmic daily dose. Use In Specific Populations 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 600 times and 1700 times higher respectively than the typical human topical ophthalmic daily dose of 0.35 mg (4.5 mg/mL x 0.04 mL/drop, twice daily) to an affected eye 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 300 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. ACUVAIL® 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 ACUVAIL® solution during late pregnancy should be avoided. Nursing Mothers Because many drugs are excreted in human milk, caution should be exercised when ACUVAIL® is administered to a nursing woman. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use No overall clinical differences in safety or effectiveness have been observed between elderly and other adult patients.

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), including ketorolac tromethamine ophthalmic solution, 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 LS™ (ketorolac tromethamine ophthalmic solution) ophthalmic solution be used with caution in patients with known bleeding tendencies or who are receiving other medications, which may prolong bleeding time. Carcinogenesis, Mutagenesis, Impairment of Fertility Ketorolac tromethamine was neither carcinogenic in rats given up to 5 mg/kg/day orally for 24 months (156 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 (62.5 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 280 and 499 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 112 times and 312 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 46 times the maximum recommended human topical ophthalmic dose 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 LS™ (ketorolac tromethamine ophthalmic solution) 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 LS™ ophthalmic solution during late pregnancy should be avoided. Nursing Mothers Caution should be exercised when ACULAR LS™ (ketorolac tromethamine ophthalmic solution) ophthalmic solution is administered to a nursing woman. Pediatric Use Safety and effectiveness of ketorolac tromethamine 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.