`(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:
`
`C19H24N2O6
`
`Mol Wt 376.40
`
`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 pH.
`
`ACULAR LS® 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® ophthalmic solution is approximately 290 mOsml/kg.
`
`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® 0.4% or its vehicle QID for up to 4 days. Significant differences favored
`ACULAR LS® for the reduction of ocular pain and burning/stinging following photorefractive keratectomy
`surgery.
`
`Page 1 of 4
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`SENJU EXHIBIT 2240
`LUPIN v. SENJU
`IPR2015-01097
`
`
`
`Results from clinical studies indicate that ketorolac tromethamine has no significant effect upon intraocular
`pressure.
`
`The safety and effectiveness of ACULAR LS® in post-cataract surgery patients has not been established.
`
`INDICATIONS AND USAGE
`
`ACULAR LS® ophthalmic solution is indicated for the reduction of ocular pain and burning/stinging following
`corneal refractive surgery.
`
`CONTRAINDICATIONS
`
`ACULAR LS® 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), 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® ophthalmic solution be used with caution in patients with known
`bleeding tendencies or who are receiving other medications, which may prolong bleeding time.
`
`Page 2 of 4
`
`
`
`Information for Patients: ACULAR LS® ophthalmic solution should not be administered while wearing
`contact lenses.
`
`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® 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® 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.
`
`ADVERSE REACTIONS
`
`The most frequently reported adverse reactions for ACULAR LS® ophthalmic solution occurring in
`approximately 1 to 5% of the overall study population were conjunctival hyperemia, corneal infiltrates,
`headache, ocular edema and ocular pain.
`
`Page 3 of 4
`
`
`
`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).
`
`DOSAGE AND ADMINISTRATION
`
`The recommended dose of ACULAR LS® 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).
`Rx only
`
`Revised: 11/2011
`
`© 2011 Allergan, Inc., Irvine, CA 92612, U.S.A.
` marks owned by Allergan, Inc.
`U.S. Patent 8,008,338
`Made in the U.S.A.
`
`71654US14C
`
`Page 4 of 4