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`)Glrom - FDAprescribirI_;irfu'maim, sideetbctsmduses
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`Xibrom
`
`Generic Name: bromfenac sodium
`
`Dosage Form: ophthalmic solution
`
`Visit the Official Site
`PAZEOT“ (olopatadine hydrochloride ophthalmic solution) 0.7%
`CO
`
`>
`
`FDX
`
`Overview
`
`Side Effects
`
`Dosage
`
`Interactions
`
`""”"'"““"”‘°°'“’”'°"°”'°'“"""'
`
`Page 1 of 16
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`SENJU EXHIBIT 2190 ‘"6
`
`LUPIN V. SENJU
`IPR2015-01100
`
`

`
`1002/2015
`
`)Gbrom — FDA prescribing infumaiion, sideelfecls aid uses
`
`Professional
`
`More v
`
`Xibrom T” (bromfenac ophthalmic solution) 0.09%
`
`Sterile
`
`Xibrom Description
`
`Xibrom (bromfenac ophthalmic solution) 0.09% is
`
`a sterile, topical, nonsteroidal anti—inflammatory
`drug (NSAID) for ophthalmic use. Each mL of
`Xibrom contains 1.035 mg bromfenac sodium
`(equivalent to 0.9 mg bromfenac free acid).
`
`Bromfenac sodium is designated chemically as
`
`sodium 2—amino—3—(4—bromobenzoyl)
`phenylacetate sesquihydrate, with an empirical
`formula of C15H11BrNNaO3 - 1‘/2H2O. The
`structural formula of bromfenac sodium is:
`
`Visit the Official sit§ X
`
`PAZEOTM (olopatadine
`hYd'°°“'°'_'de ophfihalmm
`5°|Ut'°n) 0-7 /"
`. 0
`
`
`
`e~©‘c*Q
`
`Ha"
`
`cH,co,m -11/2!-I20
`
`Bromfenac sodium is a yellow to orange
`crystalline powder. The molecular weight of
`
`bromfenac sodium is 383.17. Xibrom ophthalmic
`solution is supplied as a sterile aqueous 0.09%
`solution, with a pH of 8.3. The osmolality of
`Xibrom ophthalmic solution is approximately 300
`
`mOsmol/kg. Each mL of Xibrom ophthalmic
`solution contains: Active: bromfenac sodium
`
`hydrate 0.1035%. lnactives: benzalkonium
`chloride (0.05 mg/mL), boric acid, disodium
`
`edetate (0.2 mg/mL), polysorbate 80 (1.5 mg/mL),
`povidone (20 mg/mL), sodium borate, sodium
`sulfite anhydrous (2 mg/mL), sodium hydroxide to
`
`adjust the pH, and water for injection, USP.
`
`lI1p1Iwww.<h1gs.c<m/prdxibrorn.lIInl
`
`Page 2 of 16
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`Slideshow: Easy On The Eye - 8
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`Tips for Maintaining Good Eyesight
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`)Gtrom - FDAprescribirx_;infu'maim, sideetiectsmduses
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`CLINICAL PHARMACOLOGY
`
`inhibiting cyclooxygenase 1 and 2.
`
`Mechanism of Action:
`
`Bromfenac is a nonsteroidal anti-inflammatory
`drug (NSAID) that has anti-inflammatory activity.
`The mechanism of its action is thought to be due
`to its ability to block prostaglandin synthesis by
`
`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.
`
`Pharmacokinetics:
`
`The plasma concentration of bromfenac following ocular administration of 0.09% Xibrom
`(bromfenac ophthalmic solution) in humans is unknown. Based on the maximum proposed
`dose of one drop to each eye (0.09mg) and PK information from other routes of administration,
`the systemic concentration of bromfenac is estimated to be below the limit of quantification (50
`ng/mL) at steady-state in humans.
`
`Clinical Trials:
`
`Clinical efficacy was evaluated in two randomized, double—masked, vehicle—control|ed U.S.
`trials in which subjects with a summed ocular inflammation score 23 after cataract surgery
`were assigned to Xibrom or vehicle in a 2:1 ratio following surgery. One drop of Xibrom or
`vehicle was self—insti|led in the study eye twice a day for 14 days, beginning the day after
`surgery. The primary endpoint was reduction of ocular inflammation (to trace inflammation or
`clearing) assessed 14 days post—surgery using a slit lamp binocular microscope. In the intent-
`to-treat analyses of both studies, a significant effect of Xibrom on ocular inflammation after
`
`cataract surgery was demonstrated (62—66% vs. 40-48%). An additional efficacy endpoint was
`the time required for resolution of ocular pain in subjects who reported pain. Overall, only 20%
`of patients undergoing cataract surgery in these trials had pain on the flrst day after surgery. In
`these patients, the Xibrom group demonstrated a statistically significant difference in median
`time to resolution of ocular pain of 2 days compared to 4 days for patients receiving vehicle.
`
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`1(YDI2015
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`)Glrom - FDA uescribirg irium:-Iim, side elfects aid uses
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`If your cancer treatment includes
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`INDICATIONS AND USAGE
`
`Xibrom ophthalmic solution is indicated for the treatment of postoperative inflammation and
`reduction of ocular pain in patients who have undergone cataract extraction.
`
`CONTRAINDICATIONS
`
`Xibrom ophthalmic solution is contraindicated in patients with known hypersensitivity to any
`ingredient in the formulation.
`
`Warnings
`
`Contains sodium sulfite, a sulfite that may cause allergic-type reactions including anaphylactic
`symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people.
`The overall prevalence of sulfite sensitivity in the general population is unknown and probably
`low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.
`
`There is the potential for cross-sensitivity to acetylsalicylic acid, phenylacetic acid derivatives,
`and other NSAIDs. Therefore, caution should be used when treating individuals who have
`previously exhibited sensitivities to these drugs.
`
`With some NSAlDs, there exists the potential for increased bleeding time due to interference
`with platelet aggregation. There have been reports that ocularly applied NSA|Ds may cause
`increased bleeding of ocular tissues (including hyphemas) in conjunction with ocular surgery.
`
`Precautions
`
`General:
`
`All topical nonsteroidal anti—inflammatory drugs (NSA|Ds) may slow or delay healing. Topical
`
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`corticosteroids are also known to slow or delay healing. Concomitant use of topical NSAlDs
`
`and topical steroids may increase the potential for healing problems.
`
`Use of topical NSAlDs may result in keratitis. In some susceptible patients, continued use of
`topical NSAlDs 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
`NSAlDs and should be closely monitored for corneal health.
`
`Postmarketing experience with topical NSAlDs 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 NSAlDs should be used with caution in these patients.
`
`Postmarketing experience with topical NSAlDs 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 Xibrom 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:
`
`Xibrom ophthalmic solution should not be administered while wearing contact lenses.
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility:
`
`Long—term carcinogenicity studies in rats and mice given oral doses of bromfenac
`
`up to 0.6 mg/kg/day (360 times the recommended human ophthalmic dose [RHOD] of 1.67
`pg/kg in 60 kg person on a mg/kglbasis, assuming 100% absorbed) and 5.0 mg/kg/day (3000
`
`times RHOD), respectively revealed no significant increases in tumor incidence.
`
`Bromfenac did not show mutagenic potential in various mutagenicity studies, including the
`reverse mutation, chromosomal aberration, and micronucleus tests.
`
`Bromfenac did not impair fertility when administered orally to male and female rats at doses up
`to 0.9 mg/kg/day and 0.3 mg/kg/day, respectively (540 and 180 times RHOD, respectively).
`
`Pregnancy:
`
`Teratogenic Effects: Pregnancy Category C.
`Reproduction studies performed in rats at oral doses up to 0.9 mg/kg/day (540 times RHOD)
`
`and in rabbits at oral doses up to 7.5 mg/kg/day (4500 times RHOD) revealed no evidence of
`teratogenicity due to bromfenac. However, 0.9mg/kglday in rats caused embryo—fetal lethality,
`
`tIlp1Mww.du_;s.orxrIIprolkilranJIrnl
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`Page 5 of 16
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`)Glrun - FDA gxescrilirg irizxmaim, side effects aid uses
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`increased neonatal mortality, and reduced postnatal growth. Pregnant rabbits treated with 7.5
`mg/kg/day caused increased post—implantation loss.
`
`There are no adequate and wel|—controlled studies in pregnant women. Because animal
`reproduction studies are not always predictive of human response, this drug should be used
`during pregnancy only if the potential benefit justifies the potential risk to the fetus.
`
`Non-Teratogenic Effects:
`
`Because of the known effects of prostaglandin biosynthesis—inhibiting drugs on the fetal
`cardiovascular system (closure of ductus arteriosus), the use of Xibrom ophthalmic solution
`during late pregnancy should be avoided.
`
`Nursing Mothers:
`
`Caution should be exercised when Xibrom ophthalmic solution is administered to a nursing
`woman.
`
`Pediatric Use:
`
`Safety and efficacy in pediatric patients below the age of 18 have not been established.
`
`Geriatric Use:
`
`There is no evidence that the efficacy or safety profiles for Xibrom differ in patients 65 years of
`age and older compared to younger adult patients.
`
`Adverse Reactions
`
`The most commonly reported adverse experiences reported following use of Xibrom after
`cataract surgery include: abnormal sensation in eye, conjunctival hyperemia, eye irritation
`
`(including burning/stinging), eye pain, eye pruritus, eye redness, headache, and iritis. These
`events were reported in 2-7% of patients.
`
`Clinical Practice:
`
`The following events have been identified during postmarketing use of bromfenac ophthalmic
`solution 0.09% 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 bromfenac ophthalmic solution 0.09%, or a combination of these factors, include
`
`corneal erosion, corneal perforation, corneal thinning, and epithelial breakdown (see
`PRECAUTIONS, General: ).
`
`lIlp1Iwww.du_;s.axIIIprolkilranJIrnl
`
`6I16
`
`

`
`1002/2015
`
`)Glr(m - FDA prescribing ilftlmdim, sitb efiecls and uses
`
`‘for new prescriptions only
`
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`Xibrom Dosage and Administration
`
`For the treatment of postoperative inflammation in patients who have undergone cataract
`
`extraction, one drop of Xibrom ophthalmic solution should be applied to the affected eye(s) two
`
`times daily beginning 24 hours after cataract surgery and continuing through the first 2 weeks
`
`of the postoperative period.
`
`How is Xibrom Supplied
`
`Xibrom“ (bromfenac ophthalmic solution) 0.09% is supplied in a white LDPE plastic squeeze
`bottle with a 15 mm LDPE white dropper-tip and 15 mm polypropylene gray cap as follows:
`
`NDC 67425-004-50
`
`5 mL in 10 cc container
`
`NDC 67425-004-12
`
`2.5 mL in 7.5 cc container
`
`Storage
`
`Store at 15-25°C (59-77°F)
`
`Rx Only
`
`U.S. Patent No. 4,910,225
`
`Manufactured for: ISTA Pharmaceuticals, Inc.
`
`Irvine, CA 92618
`
`lilp1Iwww.(tu_)s.cornIpI'oIxibrorn.lIIn|
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`7/16
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`
`10/22/2015
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`)Gbran - FDA prescribing iriormdion, side eflects and uses
`
`by: Bausch & Lomb Incorporated
`
`Tampa, FL 33637
`
`Under license from: Senju Pharmaceutical Co., Ltd.
`
`Osaka, Japan 541-0046
`
`Revised November 2008
`
`Printed in USA
`
`COPYR|GHT© ISTA Pharmaceuticals, Inc. All rights reserved.
`
`PRINCIPAL DISPLAY PANEL
`
`II1p1lwww.<h1gs.cornIprolxibrorn.IIInl
`
`8I16
`
`

`
`10/22/2015
`
`Xibrom - FDA prescribing information, side effects aid uses
`
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`NDC 67425-004-12
`
`Xibrom"'(bromfenac ophthalmic solution) 0.09%
`
`Sterile 2.5 mL
`
`Rx only
`
`Twice Daily
`
`Each mL of Xibrom ophthalmic solution contains:
`
`Active: bromfenac sodium hydrate 0_1035% equivalent to 0.09% bromfenac free acid.
`
`htlp:/lwww.<higs.comlproIxibrom.hlml
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`9/16
`
`

`
`10/22/2015
`
`Xibran - FDA prescriling irfamdion, side effects and uses
`
`lnactives: benzalkonium chloride (0.05 mg/mL), boric acid, disodium edetate (0.2 mg/mL),
`
`polysorbate 80 (1 .5mg/mL), povidone (20mg/mL), sodium borate, sodium sulfite anhydrous
`
`(2mg/mL), sodium hydroxide to adjust the pH, and water for injection, USP.
`
`This product is sterile when manufactured and should be dispensed in the original unopened
`
`container. Instruct patient on precautions to avoid contamination.
`
`For topical application in the eye.
`
`Usual adult dosage:
`
`One drop in the affected eye(s) two times daily. See accompanying prescribing information.
`
`Store at 15—25°C (59—77°F).
`
` I ibrom
`
`bromfenac sodium solution
`
`Product Infonnation
`
`Product Type
`
`HUMAN PRESCRIPTION DRUG
`LABEL
`
`Item code (source)
`
`NDC:67425-
`004
`
`Route of Administration
`
`OPHTHALMIC
`
`DEA schedule
`
`Active lngredientIActive Moiety
`Ingredient Name
`BROMFENAC SODIUM (BROMFENAC)
`
`Basis of Strength
`BROMFENAC SODIUM
`
`Strength
`1.035 mg in 1 mL
`
`Inactive Ingredients
`Ingredient Name
`BENZALKONIUM CHLORIDE
`BORIC ACID
`EDETATE DISODIUM
`POLYSORBATE 80
`POVIDONE
`SODIUM BORATE
`SODIUM HYDROXIDE
`
`SODIUM SULFITE
`ATER
`
`Packaging
`-v Item code
`1 NDC:67425-004-50
`1
`
`2NDC:67425-O04-12
`2
`
`Strengfll
`0.05 mg in 1 mL
`11 mg in 1 mL
`0.2 mg in 1 mL
`1.5 mg in 1 mL
`20 mg in 1 mL
`11 mg in1 mL
`
`2 mg in 1 mL
`
`Package Description
`1 BOTTLE, DROPPER (BOTTLE) in 1 CARTON
`5mL in1 BOTTLE, DROPPER
`
`1 BOTTLE, DROPPER (BOTTLE) in 1 CARTON
`2.5 mL in 1 BOTTLE. DROPPER
`
`Marketing Infonnation
`Marketing category Application Number or Monograph citation
`NDA
`NDA021664
`
`Marketing start Date Marketing End Date
`01/05/2005
`
`Labeler - Ista Phannaoeuticals, Inc (957212350)
`
`Establishment
`
`Name
`Ista Pharmaceuticals, Inc
`
`Establishment
`
`Name
`Bausch & Lomb Inoorporated
`
`Adttess
`
`IDIFEI
`957212350
`
`Operations
`ANALYSIS
`
`Address
`
`IDn=EI
`222207751
`
`Operations
`ANALYSIS, MANUFACTURE
`
`II1pJIwww.tiugs.cornIprolxibrun.Iiml
`
`10116
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`
`10/22/Z115
`
`Xibrom - FDA prescribing information, sideeffecis and uses
`
`Revised: 06/2009
`
`-
`
`Laslk Eye Surgery
`Over 1 Million Surgeries Performed.As LowAs $299/eye, Free Evaluation
`CO
`
`>
`
`lsta Phannaoeutils, Inc
`
`lb
`
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`- Other brands: Prolensa, Bromday
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`Xibrom - FDA prescribing information, side effects and uses
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`Related treatment guides
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`o Postoperative Ocular Inflammation
`
` DRUG STATUS
`
`Availability
`
`Prescription only
`
`Pregnancy Category
`Risk cannot be ruled out
`
`CSA Schedule
`
`Not a controlled drug
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`Approval History
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`Drug history at FDA
`
`V
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`V
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`V
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`Get Info On Financial Assistance
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`For MS Medication
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`Drug Class
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`Ophthalmic anti-inflammatory agents
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`-1:.E?T|§-Ely'EH”
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`Xibrom - FDA prescribing information, sideelfects aid uses
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