`
`4
`
`
`
`
`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. (0)
`
`
`---------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. (0)
`
`------DOSAGE FORMS AND STRENGTHS----­
`Topical ophthalmic solution: bromfenac 0.07% (0)
`
`
`
`____________________________________________________________________________________________
`
`
`
`
`FULL PRESCRIBING INFORMATION:
`12 CLINICAL PHARMACOLOGY
`
`
`CONTENTS*
`12.1 Mechanism of Action
`
`
`12.3
`Pharmacokinetics
`
`
`1
`INDICATIONS AND USAGE
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`
`2
`DOSAGE AND ADMINISTRATION
`
`Carcinogenesis, Mutagenesis,
`13.1
`
`
`Recommended Dosing
`2.1
`
`
`Impairment of Fertility
`
`
`
`
`2.2
`Use with Other Topical Ophthalmic
`
`
`14 CLINICAL STUDIES
`
`Medications
`
`
`Ocular Inflammation and Pain
`14.1
`
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`16 HOW SUPPLIED/STORAGE AND
`
`
`CONTRAINDICATIONS
`4
`
`HANDLING
`
`
`5 WARNINGS AND PRECAUTIONS
`
`17 PATIENT COUNSELING
`
`
`
`5.1
`Sulfite Allergic Reactions
`
`INFORMATION
`
`
`
`5.2
`Slow or Delayed Healing
`
`
`
`Slowed or Delayed Healing
`17.1
`
`
`5.3
`Potential for Cross-Sensitivity
`
`
`17.2
`Sterility of Dropper Tip
`
`
`5.4
`Increased Bleeding Time
`
`
`17.3
`Concomitant Use of Contact
`
`
`5.5
`Keratitis and Corneal Reactions
`
`Lenses
`
`
`5.6
`Contact Lens Wear
`
`
`Concomitant Topical Ocular
`
`ADVERSE REACTIONS
`
`Therapy
`
`
`Clinical Trial Experience
`6.1
`
`USE IN SPECIFIC POPULATIONS
`
`
`8.1
`Pregnancy
`
`
`8.3
`Nursing Mothers
`
`
`8.4
`Pediatric Use
`
`
`8.5
`Geriatric Use
`
`
`11 DESCRIPTION
`___________________________________________________________________________________________
`
`
`
`--------------CONTRAINDICATIONS----------------
`None (4)
`
`-------WARNINGS AND PRECAUTIONS--------
`• Sulfite Allergic Reactions (0)
`
`
`
`• Slow or Delayed Healing (0)
`
`
`
`• Potential for cross-sensitivity (0)
`
`
`•
`
`Increase bleeding of ocular tissues (0)
`
`• Corneal effects including keratitis (0)
`
`
`
`• Contact Lens Wear (0)
`
`
`
`-------------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. (0).
`
`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
`
`
`17.4
`
`
`
`
`
`
`*Sections or subsections omitted from the full
`
`prescribing information are not listed.
`
`
`
`
`
`6
`
`
`8
`
`
`
`Reference ID: 3288918
`
`
`
`LUPIN EX 1049
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`Page 1 of 6
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`5
`
`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
`
`
`5 WARNINGS AND PRECAUTIONS
`
`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), 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 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
`
`
`
`Reference ID: 3288918
`
`
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`Page 2 of 6
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`6
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`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.
`
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`
`
`
`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
`
`
`
`Reference ID: 3288918
`
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`
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`(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:
`
`
`
`7
`
`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
`
`
`
`Reference ID: 3288918
`
`
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`Page 4 of 6
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`8
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`
`
`
`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 0.07%
`
`Vehicle
`
`Difference (%)
`(Asymptotic 95% CI)
`
`Study 1
`
`
`At Day 8
`
`27/112 (24.1%)
`
`
`7/108 (6.5%)
`
`17.6 (8.4, 26.8)
`
`
`
`At Day 15
`
`51/112 (45.5%)
`
`14/108 (13.0%)
`
`
`32.5 (21.4, 43.8)
`
`Study 2
`
`
`At Day 8
`
`33/110 (30.0%)
`
`14/110 (12.7%)
`
`
`
`17.3 (6.7, 27.9)
`
`
`
`At Day 15
`
`50/110 (45.5%)
`
`30/110 (27.3%)
`
`
`
`18.2 (5.7, 30.7)
`
`Proportion of Subjects who Were Pain Free
`
`
`
`
`Study
`
`
`Visit
`
`Bromfenac 0.07%
`
`Vehicle
`
`Difference (%)
`(Asymptotic 95% CI)
`
`Study 1
`
`Study 2
`
`
`At Day 1
`
`At Day 1
`
`
`91/112 (81.3%)
`
`47/108 (43.5%)
`
`
`37.7 (25.9, 49.6)
`
`84/110 (76.4%)
`
`61/110 (55.5%)
`
`20.9 (8.7, 33.1)
`
`
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`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
`
`
`
`Reference ID: 3288918
`
`
`
`Page 5 of 6
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`
`9
`
`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
`
`
`
`
`Reference ID: 3288918
`
`
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`Page 6 of 6
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