NDA 21-664/ S-019
`Page 1
`
`HIGHLIGHTS OF PRESCRIBING INFORM ATION
`These highlights do not include all the
`information needed to use Xibrom (bromfenac
`ophthalmic solution) 0.09% safely and effectively.
`See full prescribing information for Xibrom.
`
`XIBROM (bromfenac ophthalmic solution) 0.09%
`Initial U.S. Approval: 1997
`
`------------INDICATIONS AND USAGE---------
`Xibrom is a nonsteroidal anti-inflammatory drug
`(NSAID) indicated for the treatment of
`postoperative inflammation and reduction of ocular
`pain in patients who have undergone cataract
`extraction (1).
`
`---------DOSAGE AND ADMINISTRATION---
`One drop should be applied to the affected eye two
`times daily beginning 24 hours after cataract
`surgery and continuing through the first 2 weeks of
`the postoperative period (2.1).
`
`----------CONTRAINDICATIONS----------
`None (4).
`
`-------WARNINGS AND PRECAUTIONS-----
` Sulfite Allergic Reactions (5.1)
`
` Slow or Delayed Healing (5.2)
`
` Potential for cross-sensitivity (5.3)
`
`Increase bleeding of ocular tissues (5.4)
`
`
` Corneal effects including keratitis (5.5)
`
` Contact Lens W ear (5.6)
`
`-------------ADVERSE REACTIONS-------------
`The most commonly reported adverse reactions in 2
`to 7% of patients were abnormal sensation in eye,
`conjunctival hyperemia and eye irritation (including
`burning/stinging) (6.1).
`
`To report SUSPECTED ADVERSE REACTIONS,
`contact IST A Pharmaceuticals, Inc. at 1-877-788-
`2020, or FDA at 1-800-FDA-1088 or
`
`www.fda.gov/medwatch.
`
`See 17 for PATIENT COUNSELING INFORM ATION
`Revised: XX/2013
`
`------DOSAGE FORMS AND STRENGTHS--
`Topical ophthalmic solution: bromfenac 0.09%
`(3)
`____________________________________________________________________________
`FULL PRESCRIBING INFORM ATION:
`
`8.4 Pediatric Use
`CONTENTS*
`
`8.5 Geriatric Use
`1
`INDICATIONS AND USAGE
`
`11 DESCRIPTION
`2 DOSAGE AND ADMINISTRATION
`
`12 CLINICAL PHARM ACOLOGY
`2.1 Recommended Dosing
`12.1 Mechanism of Action
`2.2 Use with Other Topical Ophthalmic Medications
`12.3 Pharmacokinetics
`3 DOSAGE FORMS AND STRENGTHS
`13 NONCLINICAL TOXICOLOGY
`4 CONTRAINDICATIONS
`13.1 Carcinogenesis, Mutagenesis,
`5 WARNINGS AND PRECAUTIONS
`Impairment of Fertility
`14 CLINICAL STUDIES
`5.1 Sulfite Allergic Reactions
`5.2 Slow or Delayed Healing
`14.1 Ocular Inflammation and Pain
`16 HOW SUPPLIED/STORAGE AND HANDLING
`5.3 Potential for Cross-Sensitivity
`17 PATIENT COUNSELING INFORM ATION
`5.4 Increased Bleeding Time
`5.5 Keratitis and Corneal Reactions
`17.1 Slowed or Delayed Healing
`5.6 Contact Lens W ear
`17.2 Sterility of Dropper Tip
`6 ADVERSE REACTIONS
`17.3 Concomitant Use of Contact Lenses
`6.1 Clinical Trial Experience
`17.4 Concomitant Topical Ocular Therapy
`6.2 Post-Marketing Experience
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.3 Nursing Mothers
`
`*Sections or subsections omitted from the full
`prescribing information are not listed.
`
`__________________________________________________________________________________
`
`Reference ID: 3439375
`
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`SENJU EXHIBIT 2026
`INNOPHARMA v. SENJU
`IPR2015-00903
`
`

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`NDA 21-664/ S-019
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`
`FULL PRESCRIBING INFORMATION
`1
`INDICATIONS AND USAGE
`Xibrom (bromfenac ophthalmic solution) 0.09% is indicated for the treatment of
`postoperative inflammation and reduction of ocular pain in patients who have
`undergone cataract surgery.
`
`DOSAGE AND ADMINISTRATION
`2
`2.1 Recommended Dosing
`One drop of Xibrom ophthalmic solution should be applied to the affected eye two
`times daily beginning 24 hours after cataract surgery and continuing through the first
`2 weeks of the postoperative period.
`2.2 Use with Other Topical Ophthalmic Medications
`Xibrom 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.
`DOSAGE FORMS AND STRENGTHS
`Topical ophthalmic solution: bromfenac 0.09%.
`
`3
`
`4
`
`CONTRAINDICATIONS
`None.
`
`WARNINGS AND PRECAUTIONS
`5
`5.1 Sulfite Allergic Reactions
`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 non-asthmatic people.
`
`5.2 Slow or Delayed Healing
`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.
`5.3 Potential for Cross-Sensitivity
`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.
`5.4 Increased Bleeding Time
`W ith some NSAIDs, there exists the potential for increased bleeding time due to
`interference with platelet aggregation. There have been reports that ocularly applied
`NSAIDs may cause increased bleeding of ocular tissues (including hyphemas) in
`conjunction with ocular surgery.
`
`Reference ID: 3439375
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`NDA 21-664/ S-019
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`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.
`
`5.5 Keratitis and Corneal Reactions
`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.
`Post-marketing 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.
`5.6 Contact Lens Wear
`Xibrom should not be administered while wearing contact lenses. Remove contact
`lenses prior to instillation of Xibrom. The preservative in Xibrom, benzalkonium
`chloride, may be absorbed by soft contact lenses. Lenses may be reinserted after 10
`minutes following administration of Xibrom.
`
`ADVERSE REACTIONS
`6
`6.1 Clinical Trial Experience
`Because clinical trials are conducted under widely varying conditions, adverse
`reaction rates observed in the clinical trials of a drug cannot be directly compared to
`rates in the clinical trials of another drug and may not reflect the rates observed in
`clinical practice.
`
`The most commonly reported adverse reactions reported following use of bromfenac
`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 reactions were reported in 2 to 7% of patients.
`
`6.2 Post-Marketing Experience
`The following reactions have been identified during post-marketing 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
`reactions, 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
`
`Reference ID: 3439375
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`NDA 21-664/ S-019
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`perforation, corneal thinning, and epithelial breakdown [see Warnings and
`
`Precautions (5.5)].
`
`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`
`Pregnancy Category C
`
`8
`
`Risk Summary
`There are no adequate and well-controlled studies with Xibrom in pregnant women.
`No malformations were observed in reproduction studies in rats and rabbits with oral
`doses of bromfenac at exposures up to 150 times (rats) and 90 times (rabbits) the
`predicted human systemic exposure; however, both embryolethality and maternal
`toxicity were observed at the highest dose exposures. The systemic concentration of
`bromfenac is estimated to be below the limit of quantification (50 ng/mL) at steady-
`state in humans, following ocular administration [see Clinical Pharmacology (12.3)].
`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.
`
`Clinical Considerations
`Premature closure of the ductus arteriosus in the fetus has occurred with third
`trimester use of oral and injectable NSAIDs. Measurable maternal and fetal plasma
`drug levels are available with oral and injectable routes of NSAID administration.
`The maternal plasma level of Xibrom following ocular administration is unknown [see
`Clinical Pharmacology (12.3)].
`
`Animal Data
`Reproduction studies performed in rats at oral doses of bromfenac up to 0.9
`mg/kg/day (systemic exposure 90 times the systemic exposure predicted from the
`recommended human ophthalmic dose [RHOD] assuming the human systemic
`concentration is at the limit of quantification) and rabbits at oral doses up to 7.5
`mg/kg/day (150 times the predicted human systemic exposure) produced no drug-
`related malformations in reproduction studies. However, embryo-fetal lethality and
`maternal toxicity were produced in rats and rabbits at 0.9 mg/kg/day and 7.5
`mg/kg/day, respectively. In rats, bromfenac treatment caused delayed parturition at
`0.3 mg/kg/day (30 times the predicted human exposure), and caused dystocia,
`increased neonatal mortality and reduced postnatal growth at 0.9 mg/kg/day.
`
`8.3 Nursing Mothers
`It is not known if Xibrom is present in human milk. The systemic concentration of
`bromfenac is estimated to be below the limit of quantification (50 ng/mL) at
`steady- state in humans, following ocular administration [see Clinical
`Pharmacology (12.3)]. Based on the low level of systemic exposure, it is unlikely
`that Xibrom would be detected in human milk using available assays. Caution
`should be exercised when Xibrom ophthalmic solution is administered to a
`nursing woman.
`
`Reference ID: 3439375
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`8.4 Pediatric Use
`Safety and efficacy in pediatric patients below the age of 18 have not
`
`been established.
`
`8.5 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.
`
`11 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 sesquihydrate (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 1½H2O. The structural structure for bromfenac sodium is:
`
`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 sesquihydrate 0.1035% equivalent to 0.9 mg
`
`bromfenac free acid
`
`Preservative: benzalkonium chloride (0.05 mg/mL)
`
`Inactives: 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 pH and water for injection, USP.
`
`12 CLINICAL PHARMACOLOGY
`12.1 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 inhibiting cyclooxygenase 1 and 2.
`
`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.
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`Reference ID: 3439375
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`NDA 21664/S-019
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`12.3 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 the eye (0.09 mg) twice a day 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.
`13 NONCLINICAL TOXICOLOGY
`13.1 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 (systemic exposure 30 times the systemic exposure predicted
`from the recommended human ophthalmic dose [RHOD] assuming the human
`systemic concentration is at the limit of quantification) and 5 mg/kg/day (340 times
`the predicted human systemic exposure), 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 (systemic exposure
`90 and 30 times the predicted human exposure, respectively).
`
`14 CLINICAL STUDIES
`14.1 Ocular Inflammation and Pain
`Clinical efficacy was evaluated in two randomized, double-masked, vehicle-
`controlled U.S. trials in which subjects with a summed ocular inflammation score
`≥3 after cataract surgery were assigned to Xibrom or vehicle in a 2:1 ratio
`following surgery. One drop of Xibrom or vehicle was self-instilled 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 end point was the time required for resolution of ocular pain
`in subjects who reported pain. Overall, only 20% of the patients undergoing
`cataract surgery in these trials had pain on the first 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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`Reference ID: 3439375
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`16
`
`HOW SUPPLIED/STORAGE AND HANDLING
`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:
`2.5mL in 7.5mL container (NDC 67425-004-12)
`5mL in 10mL container (NDC 67425-004-50)
`
`STORAGE
`Store at 15º – 25ºC (59º –77ºF).
`
`17 PATIENT COUNSELING INFORMATION
`17.1 Slowed or Delayed Healing
`Advise patients of the possibility that slow or delayed healing may occur while using
`NSAIDs.
`
`17.2 Sterility of Dropper Tip
`Advise patients to not touch dropper tip to any surface, as this may contaminate
`the contents.
`
`Use of the same bottle for both eyes is not recommended with topical eye drops
`that are used in association with surgery.
`
`17.3 Concomitant Use of Contact Lenses
`Advise patients that contact lenses should not be worn during the use of this
`product. The preservative in Xibrom, benzalkonium chloride, may be absorbed
`by soft contact lenses. Lenses may be reinserted after 10 minutes following
`administration of Xibrom.
`
`17.4 Concomitant Topical Ocular Therapy
`Advise patients that if more than one topical ophthalmic medication is being
`used, the medicines should be administered at least 5 minutes apart
`
`Manufactured by: Bausch & Lomb Incorporated
`Tampa, FL 33637
`
`Under license from:
`Senju Pharmaceuticals Co.,
`Ltd. Osaka, Japan 541-0046
`®/™ are trademarks of Bausch & Lomb Incorporated or its affiliates
`© Bausch & Lomb Incorporated
`
`Reference ID: 3439375
`
`Page 7 of 7