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`XIBROM™
`(bromfenac ophthalmic solution) 0.09%
`Sterile
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`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
`• 1½H2O. The structural formula of bromfenac sodium is
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`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%.
`Inactives: 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 purified water, USP.
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`Clinical Pharmacology:
`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.
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`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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`Pharmacokinetics:
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`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 (0.09 mg) 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.
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`Clinical Trials:
`Clinical efficacy was evaluated in two randomized, double-masked, placebo-controlled U.S. trials in
`which subjects with a summed ocular inflammation score ≥3 after cataract surgery were assigned to
`XIBROM or placebo 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
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`NDA 21-664
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`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%).
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`Indications and Usage:
`XIBROM ophthalmic solution is indicated for the treatment of postoperative inflammation in patients
`who have undergone cataract extraction.
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`Contraindications:
`XIBROM ophthalmic solution is contraindicated in patients with known hypersensitivity to any
`ingredient in the formulation.
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`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.
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`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.
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`With 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.
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`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.
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`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.
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`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.
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`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.
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`NDA 21-664
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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.
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`Information for Patients:
`XIBROM ophthalmic solution should not be administered while wearing contact lenses.
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`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 µg/kg in
`60 kg person on a mg/kg/basis, assuming 100% absorbed) and 5.0 mg/kg/day (3000 times RHOD),
`respectively revealed no significant increases in tumor incidence.
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`Bromfenac did not show mutagenic potential in various mutagenicity studies, including the reverse
`mutation, chromosomal aberration, and micronucleus tests.
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`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).
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`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, 0.9 mg/kg/day in rats caused embryo-fetal lethality, increased neonatal
`mortality, and reduced postnatal growth. Pregnant rabbits treated with 7.5 mg/kg/day caused increased
`post-implantation loss.
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`There are no adequate and well-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.
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`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.
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`Nursing Mothers:
`Caution should be exercised when XIBROM ophthalmic solution is administered to a nursing woman.
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`Pediatric Use:
`Safety and efficacy in pediatric patients below the age of 18 have not been established.
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`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.
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`Adverse Reactions:
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`The most commonly reported adverse experiences reported following use of XIBROM after cataract
`surgery include: abnormal sensation in eye, conjunctival hyperemia, eye irritation (including
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`NDA 21-664
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`burning/stinging), eye pain, eye pruritus, eye redness, headache, and iritis. These events were reported
`in 2-7% of patients.
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`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).
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`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.
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`How 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:
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`NDC 67425-004-50
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`5 mL in 10 cc container
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`Storage
`Store at 15-25°C (59-77°F).
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`Rx Only
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`Manufactured for:
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`by:
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`Under license from: Senju Pharmaceutical Co., Ltd.
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`Osaka, Japan 541-0046
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`Issued Date (to be determined)
`Printed in USA
`COPYRIGHT © ISTA Pharmaceuticals, Inc. All rights reserved
`
`Bausch & Lomb Incorporated
`Tampa, FL 33637
`
`ISTA Pharmaceuticals, Inc.
`Irvine, CA 92618