NDA 19-700/S-019
`NDA 20-811/S-003
`Page 4
`
`
`
`
`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-l-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 376.41. 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; sodium chloride; hydrochloric acid and/or sodium hydroxide to adjust the
`pH; and purified water.
`
`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.
`
`
`
`
`
`ACULAR
`(ketorolac tromethamine ophthalmic solution)
`0.5%
`Sterile
`
`DESCRIPTION
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`ALLERGAN
`
`
`
`
`
`
`
`SENJU EXHIBIT 2060
`LUPIN v SENJU
`IPR2015-01105
`
`PAGE 1 OF 11
`
`

`
`NDA 19-700/S-019
`NDA 20-811/S-003
`Page 5
`
`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.
`
`
`
`
`
`
`PAGE 2 OF 11
`
`

`
`NDA 19-700/S-019
`NDA 20-811/S-003
`Page 6
`
`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
`
`
`
`
`
`PAGE 3 OF 11
`
`

`
`NDA 19-700/S-019
`NDA 20-811/S-003
`Page 7
`
`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 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 events reported rarely with the use of ketorolac tromethamine ophthalmic
`solutions included: corneal infiltrates, corneal ulcer, eye dryness, headaches, and visual
`disturbance (blurry vision).
`
`
`
`
`
`
`PAGE 4 OF 11
`
`

`
`NDA 19-700/S-019
`NDA 20-811/S-003
`Page 8
`
`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:
`
`
`3 mL in 6 mL bottle NDC 0023-2181-03
`5 mL in 10 mL bottle NDC 0023-2181-05
`10 ml in 10 mL bottle NDC 0023-2181-10
`
`
`Store at room temperature 15°C -30°C (59°F- 86°F) with protection from light.
`
`Rx only
`
`U.S. Patent Nos.: 4,454,151; 5,110.493; and 5,414,011
`
`2001 Allergan, Irvine, CA 92612, U.S.A.
`
`ACULAR (a registered trademark of SYNTEX (U.S.A.) Inc.) is manufactured and
`distributed by ALLERGAN under license from its developer, SYNTEX (U.S.A.) Inc.,
`Palo Alto, California, U.S.A.
`
`Revised January 2002
`
`Formulation Number: 08344X
`
`
`
`
`
`PAGE 5 OF 11
`
`

`
`NDA 19-700/S-019
`NDA 20-811/S-003
`Page 9
`
`
`
`
`
`
`
`
`
`
`
`
`ALLERGAN
`
`
`
`
`ACULAR® PF
`
`
`
`
`
`(ketorolac tromethamine ophthalmic solution) 0.5%
`Preservative-Free
`Sterile
`
`
`
`
`
`DESCRIPTION
`
`ACULAR® PF (ketorolac tromethamine ophthalmic solution) Preservative-Free 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® PF 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 ACULAR® PF is 290
`mOsmol/kg.
`
`Each ml of ACULAR® PF contains: Active ingredient: ketorolac tromethamine 0.5%. Inactives:
`sodium chloride; hydrochloric acid and/or sodium hydroxide to adjust the pH to 7.4; and purified
`water.
`
`
`
`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.
`
`One drop (0.05 mL) of ketorolac tromethamine (preserved) 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.
`
`
`
`In two double-masked, multi-centered, parallel-group studies, 340 patients who had undergone
`incisional refractive surgery received ACULAR PF or its vehicle QID for up to 3 days. Significant
`
`
`
`
`PAGE 6 OF 11
`
`

`
`NDA 19-700/S-019
`NDA 20-811/S-003
`Page 10
`
`
`differences favored ACULAR PF for the treatment of ocular pain and photophobia.
`Results from clinical studies indicate that ketorolac tromethamine has no significant effect upon
`intraocular pressure.
`
`
`
`INDICATIONS AND USAGE
`
`ACULAR PF ophthalmic solution is indicated for the reduction of ocular pain and photophobia
`following incisional refractive surgery.
`
`CONTRAINDICATIONS
`
`
`ACULAR® PF 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.
`
`Post marketing 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.
`
`
`
`
`
`
`PAGE 7 OF 11
`
`

`
`NDA 19-700/S-019
`NDA 20-811/S-003
`Page 11
`
`
`
`It is recommended that ACULAR® PF 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® PF should not be administered while wearing contact lenses.
`
`The solution from one individual single-use vial is to be used immediately after opening for
`administration to one or both eyes, and the remaining contents should be discarded immediately after
`administration. To avoid contamination, do not touch tip of unit-dose vial to eye or any other surface.
`
`Carcinogenesis, Mutagenesis, and 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® PF 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® PF ophthalmic solution
`during late pregnancy should be avoided.
`
`Nursing Mothers: Caution should be exercised when ACULAR® PF 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.
`
`
`
`
`
`PAGE 8 OF 11
`
`

`
`NDA 19-700/S-019
`NDA 20-811/S-003
`Page 12
`
`
`
`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
`approximately 20% 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
`include: corneal infiltrates, corneal ulcer, eye dryness, headaches, and visual disturbance (blurry
`vision).
`
`Clinical Practice: The following events have been identified during postmarketing use of topical
`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® PF is one drop (0.25 mg) four times a day in the operated eye
`as needed for pain and photophobia for up to 3 days after incisional refractive surgery.
`
`
`
`
`HOW SUPPLIED
`
`ACULAR® PF (ketorolac tromethamine ophthalmic solution) 0.5% Preservative-Free is available as a
`sterile solution supplied in single-use vials as follows:
`
`
`ACULAR® PF 12 Single-Use Vials 0.4 mL each
`NDC 0023-9055-04
`
`Store ACULAR® PF between 15°C - 30°C (59°F - 86°F) with protection from light.
`Rx only
`
`U.S. Patent Nos.: 4,454,151; 5,110,493; and 5,414,011.
`
`©2001 Allergan, Irvine, CA 92612, U.S.A
`
`
`
`ACULAR® is a registered trademark of SYNTEX (U.S.A.) Inc. ACULAR® PF is manufactured and
`distributed by ALLERGAN under license from its developer, SYNTEX (U.S.A.) Inc., Palo Alto,
`California, U.S.A.
`
`
`
`
`
`PAGE 9 OF 11
`
`

`
`NDA 19-700/S-019
`NDA 20-811/S-003
`Page 13
`
`
`
`Revised January 2002
`
`8718X
`
`
`
`
`
`PAGE 10 OF 11
`
`

`
`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
` /s/
`---------------------
`Wiley Chambers
`2/8/02 01:42:18 PM
`
`PAGE 11 OF 11