NDA 021664/S-013
`Page 4
`
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`Topical ophthalmic solution: bromfenac 0.09% (3)
`
`These highlights do not include all the information
`
`
`needed to use Bromday (bromfenac ophthalmic
`
`-------WARNINGS AND PRECAUTIONS-----
`solution) 0.09% safely and effectively. See full
`
`
`• Sulfite Allergic Reactions (5.1)
`
`
`
`prescribing information for Bromday.
`
`• Slow or Delayed Healing (5.2)
`
`
`
`• Potential for cross-sensitivity (5.3)
`
`
`
`
`Bromday (bromfenac ophthalmic solution) 0.09%
`•
`Increase bleeding of ocular tissues (5.4)
`
`
`
`Initial U.S. Approval: 1997
`• Corneal effects including keratitis (5.5)
`
`
`
`• Contact Lens Wear (5.6)
`
`
`------------INDICATIONS AND USAGE---------
`
`Bromday is a nonsteroidal anti-inflammatory drug
`
`
`-------------ADVERSE REACTIONS-------------
`(NSAID) indicated for the treatment of postoperative
`
`The most commonly reported adverse reactions in 2-
`inflammation and reduction of ocular pain in patients
`
`7% of patients were abnormal sensation in eye,
`
`
`who have undergone cataract extraction (1).
`
`conjunctival hyperemia and eye irritation (including
`
`burning/stinging) (6.1).
`
`---------DOSAGE AND ADMINISTRATION---
`
`Instill one drop into the affected eye(s) once daily
`
`To report SUSPECTED ADVERSE REACTIONS,
`beginning 1 day prior to surgery, continued on the day
`
`contact ISTA Pharmaceuticals, Inc. at 1-877-788-2020,
`
`
`of surgery and through the first 14 days post-surgery
`
`
`or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`(2.1).
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION
`
`
`------DOSAGE FORMS AND STRENGTHS--
`Revised: 9/2010
`____________________________________________________________________________________________________
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`8.4 Pediatric Use
`INDICATIONS AND USAGE
`1
`
`8.5 Geriatric Use
`
`DOSAGE AND ADMINISTRATION
`2
`
`11
`DESCRIPTION
`2.1 Recommended Dosing
`
`
`
`12
`CLINICAL PHARMACOLOGY
`2.2 Use with Other Topical Ophthalmic Medications
`
`
`
`
`12.1 Mechanism of Action
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`12.3 Pharmacokinetics
`
`CONTRAINDICATIONS
`4
`
`
`
`NONCLINICAL TOXICOLOGY
`13
`WARNINGS AND PRECAUTIONS
`5
`
`
`
`13.1 Carcinogenesis, Mutagenesis and
`5.1 Sulfite Allergic Reactions
`
`
`Impairment of Fertility
`
`5.2 Slow or Delayed Healing
`
`
`CLINICAL STUDIES
`
`5.3 Potential for Cross-Sensitivity
`
`14.1 Ocular Inflammation and Pain
`
`5.4 Increased Bleeding Time
`
`HOW SUPPLIED/STORAGE AND HANDLING
`5.5 Keratitis and Corneal Reactions
`
`PATIENT COUNSELING INFORMATION
`
`
`5.6 Contact Lens Wear
`17.1 Slowed or Delayed Healing
`ADVERSE REACTIONS
`17.2 Sterility of Dropper Tip
`6.1 Clinical Trial Experience
`
`
`17.3 Concomitant Use of Contact Lenses
`6.2 Post-Marketing Experience
`
`
`
`
`
`17.4 Concomitant Topical Ocular Therapy
`
`USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`
`*Sections or subsections omitted from the full prescribing
`
`8.3 Nursing Mothers
`
`information are not listed.
`__________________________________________________________________________________________________
`
`
`14
`
`
`16
`
`17
`
`
`
`
`
`
`6
`
`
`8
`
`
`
`FULL PRESCRIBING INFORMATION
`
`
`
`
`4
`
`
`
`
`
`LUPIN EX 1009
`
`Page 1 of 5
`
`

`
`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.
`
`
`
`
`
`
`Potential for Cross-Sensitivity
`5.3
`
`
`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.
`
`
`
`Increased Bleeding Time
` 5.4
`
`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.
`
`It is recommended that Bromday 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.
`
`
`
`NDA 021664/S-013
`Page 5
`
`
`
`1
`
`
`
` INDICATIONS AND USAGE
`
`
` Bromday (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
` For the treatment of postoperative
`
`
`inflammation in patients who have
`
` undergone cataract extraction, one drop of
`
` Bromday ophthalmic solution should be
`
` applied to the affected eye(s) once daily
`
` beginning 1 day prior to cataract surgery,
`
`continued on the day of surgery, and
`
` through the first 14 days of the
`postoperative period.
`
`
`
`
`
` 2.2 Use with Other Topical Ophthalmic
`Medications
`
`Bromday 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
`Sulfite Allergic Reactions
`5.1
`
`
` 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
`
`
`
`
`
`
`
`
`
`
`
`5
`
`Page 2 of 5
`
`

`
`
`bromfenac ophthalmic solution 0.09% or a
`combination of these factors, include corneal
`
`
`
`
`erosion, corneal perforation, corneal thinning,
`and epithelial breakdown. [see Warnings and
`
`
`Precautions (5)]
`
`
`
`8
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`
`Teratogenic Effects: Pregnancy
`
`Category C. Reproduction studies
`performed in rats at oral doses up to 0.9
`mg/kg/day (1300 times the recommended
`human ophthalmic dose [RHOD]) and in
`rabbits at oral doses up to 7.5 mg/kg/day
`
`
`
`(11,000 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.
`
`
`
`
`
`
`
`
`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.
`
`
`Nonteratogenic Effects:
` Because of the known effects of prostaglandin
`
` biosynthesis-inhibiting drugs on the fetal
`
`cardiovascular system (closure of ductus
`arteriosus), the use of Bromday ophthalmic
`
`
`solution during late pregnancy should be
`avoided.
`
`
`
`8.3 Nursing Mothers
`Caution should be exercised when Bromday is
`administered to a nursing woman.
`
`
`
`8.4
`
`Pediatric Use
`
`NDA 021664/S-013
`Page 6
`
`
`
`
`
`
` 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
`
`Bromday should not be administered while
`wearing contact lenses
`
`
`
`
`
`
`6
`ADVERSE REACTIONS
`
` 6.1 Clinical Trial Experience
` The most commonly reported adverse
`
`
` experiences 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 events
`
`
`were reported in 2-7% of patients.
`
`
`6.2
`Post-Marketing Experience
`
`
`The following events 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 events, which
`
`have been chosen for inclusion due to either
`
`
`their seriousness, frequency of reporting,
`possible causal connection to topical
`
`
`
`
`
`6
`
`Page 3 of 5
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`

`
`
`
`
`
`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.
`
`NDA 021664/S-013
`Page 7
`
`
`
`
` 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 Bromday differ in patients 65 years
`of age and older compared to younger adult
`patients.
`
`
`
`11
`
`
`
`
`
`
`
`
`
`DESCRIPTION
`Bromday (bromfenac ophthalmic solution)
`
`0.09% is a sterile, topical, nonsteroidal
`
`anti-inflammatory drug (NSAID) for
`
`
`ophthalmic use. Each mL of Bromday
`
` 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
`structure for bromfenac sodium is:
`
`
`
`
`Bromfenac sodium is a yellow to orange
`
`
`crystalline powder. The molecular weight of
`
`bromfenac sodium is 383.17. Bromday
`ophthalmic solution is supplied as a sterile
`aqueous 0.09% solution, with a pH of 8.3. The
`
`osmolality of Bromday ophthalmic solution is
`approximately 300 mOsmol/kg.
`
`
`Each mL of Bromday ophthalmic solution
`
`contains:
`
`Active: bromfenac sodium hydrate 0.1035%
`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.
`
`
`
`
`12.3 Pharmacokinetics
`The plasma concentration of bromfenac
`following ocular administration of 0.09%
`Bromday (bromfenac ophthalmic solution)
`
`in humans is unknown. Based on the
`maximum proposed dose of one drop to
`
`
`
`the eye (0.045 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.
`
`
`
`
`
`13
`NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis and
`
`
`Impairment of Fertility
`Long-term carcinogenicity studies in rats and
`mice given oral doses of bromfenac up to 0.6
`
`mg/kg/day (900 times the recommended
`human ophthalmic dose [RHOD] of 1.67
`
`mcg/kg in 60 kg person on a mg/kg/basis,
`
`assuming 100% absorbed) and 5 mg/kg/day
`
`(7500 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.
`
`
`
`
`7
`
`Page 4 of 5
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`

`
`NDA 021664/S-013
`Page 8
`
`
`
`
`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 (1300 and 450 times RHOD,
`
`respectively).
`
`
`
`
`
`
` CLINICAL STUDIES
`14
`
` 14.1 Ocular inflammation and pain
`
`
`
` following cataract surgery
` Clinical efficacy was evaluated in three
`
`randomized, double-masked, placebo-
`controlled trials in which subjects requiring
`
` cataract surgery were assigned to Bromday
`or placebo. Patients were dosed with one
`
` drop per eye starting the day before
`surgery and continuing for 14 days. The
`primary endpoint was clearing of ocular
`
`
` inflammation by day 15. An additional
`
` efficacy endpoint was the number of
` patients who were pain free on day 1 after
`
`
` cataract surgery.
`
`In 2 of the 3 studies, Bromday ophthalmic
`solution had statistically significant higher
`
` incidence of completely clearing
`inflammation (46-47% vs. 25-29%) and
`
`
` also had a statistically significant higher
`incidence of subjects that were pain free at
`day 1 post cataract surgery (83-89% vs.
`
` 51-71%).
`
`
`
`
`STORAGE
`
`Store at 15º – 25ºC (59º – 77ºF).
`
`
`
`
`PATIENT COUNSELING
`17
`INFORMATION
`17.1 Slowed or Delayed Healing
`
` Patients should be advised of the possibility
`
`
` that slow or delayed healing may occur while
`
` using NSAIDs.
`
` 17.2 Sterility of Dropper Tip
`
`
` Patients should be advised to not touch
`
` dropper tip to any surface, as this may
`
` contaminate the contents.
`
` 17.3 Concomitant Use of Contact Lenses
`
`
`
` Contact lenses should not be worn during the
`
` use of this product.
`
` 17.4 Concomitant Topical Ocular Therapy
`
`If more than one topical ophthalmic
`medication is being used, the medicines
`should be administered at least 5 minutes
`apart
`
`
`
`
`
`
` Rx Only
`
`©ISTA Pharmaceuticals®, Inc.
`
`
`Manufactured for: ISTA Pharmaceuticals, Inc.
`
`Irvine, CA 92618
`
`
`
`
`By: Bausch & Lomb Incorporated
`
`Tampa, FL 33637
`
`
`16
` HOW SUPPLIED/STORAGE AND
`HANDLING
`
` Bromday (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:
`1.7 mL in 7.5 mL container (NDC 67425-999-
`17)
`
`
`
`
`
`Under license from:
`
`Senju Pharmaceuticals Co., Ltd.
`
`Osaka, Japan 541-0046
`
`
`
`
`® and ™ marks owned by ISTA Pharmaceuticals,
`Inc.
`
`
`
`
`
`
`
`
`8
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`Page 5 of 5