FULL PRESCRIBING INFORMATION:
`CONTENTS*
`
` 1
`
` INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosing
`2.2 Use With Other Topical Ophthalmic
` Medications
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Delayed Healing
`5.2 Cross-Sensitivity or Hypersensitivity
`5.3 Increased Bleeding Time
`5.4 Corneal Effects
`5.5 Contact Lens Wear
`6 ADVERSE REACTIONS
`6.1 Clinical Studies Experience
`6.2 Postmarketing Experience
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.3 Nursing Mothers
`
`
`
`
`HIGHLIGHTS OF PRESCRIBING
`INFORMATION
`
`These highlights do not include all the information
`needed to use ACUVAIL® safely and effectively. See
`full prescribing information for ACUVAIL®.
`
`ACUVAIL® (ketorolac tromethamine ophthalmic
`solution) 0.45%
`Initial U.S. Approval: 1991
`
`________INDICATIONS AND USAGE________
`ACUVAIL® ophthalmic solution is a nonsteroidal, anti-
`inflammatory indicated for the treatment of pain and
`inflammation following cataract surgery. (1)
`
`____DOSAGE AND ADMINISTRATION_____
`One drop of ACUVAIL® should be applied by the
`patient to the affected eye twice daily beginning 1 day
`prior to cataract surgery, and continued through the first
`2 weeks of the postoperative period. (2.1)
`____DOSAGE FORMS AND STRENGTHS____
`ACUVAIL® ophthalmic solution containing 4.5 mg/mL
`ketorolac tromethamine in a single-use vial. (3)
`__________________________________________________________________________________________
`
`
`
`__________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__________
`Most common adverse reactions occurring in 1-6% of
`patients were increased intraocular pressure,
`conjunctival hemorrhage, and vision blurred. (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: 12/2014
`
`
`
`
`8.4 Pediatric Use
`8.5 Geriatric Use
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
` 13.1 Carcinogenesis, Mutagenesis,
` Impairment of Fertility
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND
` HANDLING
`17 PATIENT COUNSELING INFORMATION
`17.1 Slow or Delayed Healing
`17.2 Avoiding Contamination of the Product
`17.3 Contact Lens Wear
`17.4
`Intercurrent Ocular Conditions
`17.5 Concomitant Topical Ocular Therapy
`
`
`*Sections or subsections omitted from the full
`prescribing information are not listed.
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`Page 1 of 6
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`SENJU EXHIBIT 2183
`LUPIN v. SENJU
`IPR2015-01100
`
`

`
`
`__________________________________________________________________________________________
`FULL PRESCRIBING INFORMATION
`
` 1
`
`INDICATIONS AND USAGE
`
`ACUVAIL® ophthalmic solution is indicated for the treatment of pain and inflammation following cataract
`surgery.
`
` 2
`
` DOSAGE AND ADMINISTRATION
`2.1 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.
`
`
`2.2 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.
`
` 3
`
` 4
`
` DOSAGE FORMS AND STRENGTHS
`4.5 mg/mL ketorolac tromethamine solution (0.45%) in a single-use vial.
`
` CONTRAINDICATIONS
`ACUVAIL® 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 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.
`
`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 ACUVAIL® 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.
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`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
`ACUVAIL® 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 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.
`
`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, exacerbation of asthma, corneal
`erosion, corneal perforation, corneal thinning and corneal melt, epithelial breakdown [see Warnings and
`Precautions (5.2, 5.4)] and ulcerative keratitis.
`
` 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
`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.
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`8.3 Nursing Mothers
`Because many drugs are excreted in human milk, caution should be exercised when ACUVAIL® is
`administered to a nursing woman.
`
`8.4 Pediatric Use
`Safety and effectiveness in pediatric patients 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
`ACUVAIL® (ketorolac tromethamine ophthalmic solution) 0.45% 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 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.
`
`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 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).
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`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 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.
`
`14 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) versus 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.
`
`16 HOW SUPPLIED/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 15o-30 C (59o-86 F). Store the vials in the pouch, protected from light. Fold pouch ends
`closed.
`
`17 PATIENT COUNSELING 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 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.
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`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.
`
`17.3 Contact Lens Wear
`Patients should be advised that ACUVAIL® solution 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 of
`ACUVAIL®.
`
`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.
`
` ©
`
` 2014 Allergan, Inc., Irvine, CA 92612, U.S.A.
` marks owned by Allergan, Inc.
`Patented. See: www.allergan.com/products/patent_notices
`Made in the U.S.A.
`
`
`
`72555US12
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