HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information
`needed to use PROLENSA™ (bromfenac ophthalmic
`solution) 0.07% safely and effectively. See full prescribing
`information for PROLENSA™ ophthalmic solution.
`
`PROLENSA™ (bromfenac ophthalmic solution) 0.07%
`Initial U.S. Approval: 1997
`
`-----------------INDICATIONS AND USAGE ----------------
`PROLENSA 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 surgery. (1)
`------------ DOSAGE AND ADMINISTRATION ------------
`Instill one drop into the affected eye once daily beginning
`1 day prior to surgery, continued on the day of surgery, and
`through the first 14 days post-surgery. (2.1)
`-----------DOSAGE FORMS AND STRENGTHS ----------
`Topical ophthalmic solution: bromfenac 0.07% (3)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
` 2.1 Recommended Dosing
` 2.2 Use with Other Topical Ophthalmic
`
`Medications
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
` 5.1
`Sulfite Allergic Reactions
` 5.2
`Slow or Delayed Healing
` 5.3 Potential for Cross-Sensitivity
` 5.4
`Increased Bleeding Time
` 5.5 Keratitis and Corneal Reactions
` 5.6 Contact Lens Wear
`6 ADVERSE REACTIONS
` 6.1 Clinical Trial Experience
`8 USE IN SPECIFIC POPULATIONS
` 8.1 Pregnancy
` 8.3 Nursing Mothers
`FULL PRESCRIBING INFORMATION
`1
`INDICATIONS AND USAGE
`PROLENSA™ (bromfenac ophthalmic solution) 0.07% is
`indicated for the treatment of postoperative inflammation
`and reduction of ocular pain in patients who have
`undergone cataract surgery.
`2
`DOSAGE AND ADMINISTRATION
`2.1
`Recommended Dosing
`One drop of PROLENSA ophthalmic solution should be
`applied to the affected eye 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
`PROLENSA 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.
`3
`DOSAGE FORMS AND STRENGTHS
`Topical ophthalmic solution: bromfenac 0.07%
`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 seen more frequently in
`asthmatic than in non-asthmatic people.
`5.2
`Slow or Delayed Healing
`All topical nonsteroidal anti-inflammatory drugs (NSAIDs),
`including bromfenac, 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,
`including bromfenac. Therefore, caution should be used
`when treating individuals who have previously exhibited
`sensitivities to these drugs.
`5.4
`Increased Bleeding Time
`With some NSAIDs, including bromfenac, there exists the
`potential for increased bleeding time due to interference
`with platelet aggregation. There have been reports that
`
`-------------------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 Wear (5.6)
`------------------- ADVERSE REACTIONS ------------------
`The most commonly reported adverse reactions in 3 to 8%
`of patients were anterior chamber inflammation, foreign
`body sensation, eye pain, photophobia, and vision blurred.
`(6.1).
`
`To report SUSPECTED ADVERSE REACTIONS, contact
`Bausch & Lomb Incorporated at 1-800-323-0000, or FDA
`at 1-800-FDA-1088 or www.fda.gov/medwatch.
`See 17 for PATIENT COUNSELING INFORMATION
`
`Revised: 4/2013
`
` 8.4 Pediatric Use
` 8.5 Geriatric Use
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
` 12.1 Mechanism of Action
` 12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
` 13.1 Carcinogenesis, Mutagenesis, Impairment
`
`of Fertility
`14 CLINICAL STUDIES
` 14.1 Ocular Inflammation and Pain
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
` 17.1 Slowed or Delayed Healing
` 17.2 Sterility of Dropper Tip
` 17.3 Concomitant Use of Contact Lenses
` 17.4 Concomitant Topical Ocular Therapy
`*Sections or subsections omitted from the full prescribing
`information are not listed.
`ocularly applied NSAIDs may cause increased bleeding of
`ocular tissues (including hyphemas) in conjunction with
`ocular surgery.
`It is recommended that PROLENSA 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, including bromfenac,
`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
`PROLENSA should not be instilled while wearing
`contact lenses. Remove contact lenses prior to instillation
`of PROLENSA. The preservative in PROLENSA,
`benzalkonium chloride may be absorbed by soft contact
`lenses. Lenses may be reinserted after 10 minutes following
`administration of PROLENSA.
`6
`ADVERSE REACTIONS
`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 following
`use of PROLENSA following cataract surgery include:
`anterior chamber inflammation, foreign body sensation, eye
`pain, photophobia, and vision blurred. These reactions were
`reported in 3 to 8% of patients.
`
`Page 1 of 2
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`SENJU EXHIBIT 2012
`METRICS v. SENJU
`IPR2014-01043
`
`

`

`USE IN SPECIFIC POPULATIONS
`8
`Pregnancy
`8.1
`Treatment of rats at oral doses 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 treatment-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.
`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.
`Because of the known effects of prostaglandin biosynthesis-
`inhibiting drugs on the fetal cardiovascular system (closure
`of ductus arteriosus), the use of PROLENSA™ ophthalmic
`solution during late pregnancy should be avoided.
`8.3
`Nursing Mothers
`Caution should be exercised when PROLENSA ophthalmic
`solution is administered to a nursing woman.
`8.4
`Pediatric Use
`Safety and efficacy in pediatric patients below the age of 18
`years have not been established.
`8.5
`Geriatric Use
`There is no evidence that the efficacy or safety profiles
`for Prolensa differ in patients 70 years of age and older
`compared to younger adult patients.
`11
`DESCRIPTION
`PROLENSA (bromfenac ophthalmic solution) 0.07% is
`a sterile, topical, nonsteroidal anti-inflammatory drug
`(NSAID) for ophthalmic use. Each mL of PROLENSA
`contains 0.805 mg bromfenac sodium sesquihydrate
`(equivalent to 0.7 mg bromfenac free acid). The USAN name
`for bromfenac sodium sesquihydrate is bromfenac sodium.
`Bromfenac sodium is designated chemically as sodium
`[2-amino-3-(4-bromobenzoyl) phenyl] acetate sesquihydrate,
`with an empirical formula of C15H11BrNNaO3• 1½H2O. The
`chemical structure for bromfenac sodium sesquihydrate is:
`
`Bromfenac sodium is a yellow to orange crystalline powder.
`The molecular weight of bromfenac sodium is 383.17.
`PROLENSA ophthalmic solution is supplied as a sterile
`aqueous 0.07% solution, with a pH of 7.8. The osmolality
`of PROLENSA ophthalmic solution is approximately
`300 mOsmol/kg.
`Each mL of PROLENSA ophthalmic solution contains:
`Active: Each mL contains bromfenac sodium sesquihydrate
`0.0805%, which is equivalent to bromfenac free acid 0.07%
`Preservative: benzalkonium chloride 0.005%
`Inactives: boric acid, edetate disodium, povidone, sodium
`borate, sodium sulfite, tyloxapol, 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
`(COX) 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.
`12.3 Pharmacokinetics
`The plasma concentration of bromfenac following ocular
`administration of 0.07% PROLENSA (bromfenac
`ophthalmic solution) in humans is unknown. Based on the
`maximum proposed dose of one drop to each eye (0.035 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, 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
`Bromfenac 0.07% QD for the treatment of postoperative
`inflammation and reduction of ocular pain was evaluated in
`two multi-center, randomized, double-masked, parallel-
`group and placebo (vehicle)-controlled studies. Patients
`undergoing cataract surgery self-administered bromfenac
`0.07% or vehicle once daily, beginning 1 day prior to
`surgery, continuing on the morning of surgery and for
`14 days after surgery. Complete clearance of ocular
`inflammation (0 cell and no flare) was assessed on Days 1,
`3, 8 and 15 post-surgery using slit lamp biomicroscopy. The
`pain score was self-reported. The primary efficacy endpoint
`was the proportion of subjects who had complete clearance
`of ocular inflammation by day 15. In the intent-to-treat
`analyses from both assessments, complete clearance at Day
`8 and Day 15, bromfenac 0.07% was superior to vehicle as
`shown in the following table.
`
`Proportion of Subjects with Cleared Ocular
`Inflammation (0 cells and no flare)
`Study Visit
`Bromfenac
`Vehicle
`0.07%
`
`Study
`1
`
`Study
`2
`
`7/108
`27/112
`At
`(6.5%)
`(24.1%)
`Day 8
`14/108
`51/112
`At Day
`(13.0%)
`(45.5%)
`15
`14/110
`33/110
`At
`(12.7%)
`(30.0%)
`Day 8
`30/110
`50/110
`At Day
`(27.3%)
`(45.5%)
`15
`Proportion of Subjects who Were Pain Free
`Study Visit
`Bromfenac
`Vehicle
`0.07%
`
`Study
`1
`Study
`2
`
`At
`Day 1
`At
`Day 1
`
`91/112
`(81.3%)
`84/110
`(76.4%)
`
`47/108
`(43.5%)
`61/110
`(55.5%)
`
`Difference
`(%)
`(Asympt-
`otic 95%
`CI)
`17.6 (8.4,
`26.8)
`32.5 (21.4,
`43.8)
`17.3 (6.7,
`27.9)
`18.2 (5.7,
`30.7)
`
`Difference
`(%)
`(Asympt-
`otic 95%
`CI)
`37.7 (25.9,
`49.6)
`20.9 (8.7,
`33.1)
`
`HOW SUPPLIED/STORAGE AND HANDLING
`16
`PROLENSA (bromfenac ophthalmic solution) 0.07% 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:
`•
`1.6 mL in a 7.5 mL container (NDC 24208-602-01)
`•
`3 mL in a 7.5 mL container (NDC 24208-602-03)
`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 replace bottle cap after using and to not
`touch dropper tip to any surface, as this may contaminate
`the contents.
`Advise patients that a single bottle of PROLENSA be used
`to treat only one eye.
`17.3 Concomitant Use of Contact Lenses
`Advise patients to remove contact lenses prior to instillation
`of PROLENSA. The preservative in PROLENSA,
`benzalkonium chloride, may be absorbed by soft contact
`lenses. Lenses may be reinserted after 10 minutes following
`administration of PROLENSA.
`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.
`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
`
`9306700 (Flat)
`9306800 (Folded)
`
`Page 2 of 2
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