DESCRIPTION SECTION.

11 DESCRIPTION. BromSite (bromfenac ophthalmic solution) 0.075% is sterile aqueous, topical NSAID, formulated in DuraSite(R) for ophthalmic use. 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 C15H11BrNNaO3o 1/2 H2O. The structural formula for bromfenac sodium sesquihydrate is:Bromfenac sodium is bright orange to yellow powder. The molecular weight of bromfenac sodium sesquihydrate is 383.17. BromSite is greenish-yellow to dark yellow viscous liquid with an osmolality of approximately 290 mOsmol/kg. Active: Each mL contains bromfenac sodium sesquihydrate 0.81 mg, which is equivalent to bromfenac free acid 0.76 mg. Preservative: benzalkonium chloride 0.005% Inactives: boric acid, sodium borate, citric acid anhydrous, sodium citrate dihydrate, poloxamer 407, polycarbophil, sodium chloride, edetate disodium dihydrate, sodium hydroxide (to adjust pH to 8.3), and water for injection (USP).. spl-bromsite-str.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious adverse reactions are described elsewhere in the labeling:Slow or Delayed Healing [see Warnings and Precautions (5.1)]Potential for Cross-Sensitivity [see Warnings and Precautions (5.2)]Increased Bleeding Time of Ocular Tissue [see Warnings and Precautions (5.3)]Keratitis and Corneal Reactions[see Warnings and Precautions (5.4)]Contact Lens Wear [see Warnings and Precautions (5.5)]. Slow or Delayed Healing [see Warnings and Precautions (5.1)]. Potential for Cross-Sensitivity [see Warnings and Precautions (5.2)]. Increased Bleeding Time of Ocular Tissue [see Warnings and Precautions (5.3)]. Keratitis and Corneal Reactions[see Warnings and Precautions (5.4)]. Contact Lens Wear [see Warnings and Precautions (5.5)]. The most commonly reported adverse reactions in 1-8% of patients were: anterior chamber inflammation, headache, vitreous floaters, iritis, eye pain and ocular hypertension. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-406-7984 (toll free), or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .. 6.1 Clinical Trial Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 in 1-8% of patients were: anterior chamber inflammation, headache, vitreous floaters, iritis, eye pain and ocular hypertension.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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 (129 times unilateral daily dose assuming 100% absorbed, on mg/m2 basis) and mg/kg/day (540 times unilateral daily dose on mg/m2 basis), respectively revealed no significant increases in tumor incidence. Bromfenac did not show mutagenic potential in various mutagenicity studies, including the bacterial 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 (195 and 65 times unilateral daily dose, respectively, on mg/m2 basis).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Bromfenac is 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 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. Following bilateral topical ocular twice-daily dosing of Bromfenac 0.075% ophthalmic solution, the plasma concentrations of bromfenac ranged from below the limit of quantification (LOQ 0.20 ng/mL) to 2.42 ng/mL at 30 to 60 minutes post-dose.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Ocular Inflammation and Pain. Clinical efficacy was evaluated in multi-centered, randomized, double-masked, parallel group, placebo-controlled US trials in which subjects requiring cataract surgery were assigned to receive BromSite or vehicle. Patients undergoing cataract surgery self-administered BromSite or vehicle twice daily, beginning day prior to surgery, continuing the day of surgery and for 14 days after surgery. Clearance of ocular inflammation was assessed on Days 1, 8, 15, and 29 using slit lamp biomicroscopy. The primary efficacy endpoint was the proportion of subjects with anterior chamber cell (ACC) grade at Day 15. The secondary efficacy endpoint was the proportion of subjects who were pain free after cataract surgery as assessed using Visual Analog Scale.Proportion of Subjects with Cleared Ocular Inflammation, ACC Grade Visit BromSite Vehicle Treatment Difference (95% CI) Study Day 54/168 (32.1%) 7/85 (8.2%) 23.9% (14.7%, 33.1%) Day 15 96/168 (57.1%) 16/85 (18.8%) 38.3% (27.1%, 49.5%) Study Day 40/168 (23.8%) 8/85 (9.4%) 4.4% (5.5%, 23.3%) Day 15 64/168 (38.1%) 19/85 (22.4%) 5.7% (4.2%, 27.3%) Proportion of Subjects who were Pain Free Study Day 129/168 (76.8%) 41/85 (48.2%) 28.6% (16.2%, 40.9%) Study Day 138/168 (82.1%) 53/85 (62.4%) 19.8% (8.0%, 31.6%).

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Instill one drop of BromSite to the affected eye twice daily (morning and evening) beginning day prior to surgery, the day of surgery, and 14 days postsurgery. (2.1). 2.1 Recommended Dosing. One drop of BromSite should be applied to the affected eye twice daily (morning and evening) day prior to surgery, the day of surgery, and 14 days postsurgery.. 2.2 Use with Other Topical Ophthalmic Medications. BromSite should be administered at least minutes after instillation of other topical medications. BromSite may be administered in conjunction with other topical ophthalmic medications such as alpha-agonists, beta-blockers, carbonic anhydrase inhibitors, cycloplegics, and mydriatics.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise patients to read the FDA-approved patient labeling (INSTRUCTIONS FOR USE) Slow or Delayed Healing Advise patients of the possibility that slow or delayed healing may occur while using NSAIDs. Concomitant Topical Ocular Therapy If more than one topical ophthalmic medication is being used, advise patients to administer BromSite at least minutes after instillation of other topical medications. Concomitant Use of Contact Lenses Advise patients not to wear contact lenses during administration of BromSite. The preservative in this product, benzalkonium chloride, may be absorbed by soft contact lenses. Sterility of Dropper Tip/Product UseAdvise patients to replace the bottle cap after use and do not touch the dropper tip to any surface as this may contaminate the contents.Advise patients to thoroughly wash hands prior to using BromSite.Distributed by:Sun Pharmaceutical Industries, Inc.Cranbury, NJ 08512US Patent No. 8778999 DuraSite(R) and BromSite(TM) are trademarks of Sun Pharma Global FZEApril 2016.

INSTRUCTIONS FOR USE SECTION.

INSTRUCTIONS FOR USE. BromSitebrom fe nak (bromfenac ophthalmic solution) 0.075% Read this Instructions for Use before you start using BromSite and each time you get refill. There may be new information. This leaflet does not take the place of talking to your healthcare provider about your medical condition or treatment. Information about BromSite: Do not let the BromSite applicator tip touch your eye, fingers, or any other surfaces.If you are using BromSite with other eye (ophthalmic) medicines, you should wait at least minutes after using the other medicine to give your BromSite dose.You should not wear contact lenses while using BromSite.Put the gray cap back on the BromSite after each use.Before you use BromSite for the first time:Tear open the foil pouch using the perforated notch and remove the BromSite bottle. Throw away the foil pouch.Remove the white cap by turning it in the clockwise direction (See FIGURE A). Throw away the white cap.Hold the bottle upright. Remove the gray cap by turning it in the counterclockwise direction (See FIGURE B).Replace the gray cap on the bottle and close tightly.Follow Steps to each time you use BromSite.Step 1. Wash your hands well. Step 2. Turn the closed bottle upside down (See FIGURE C). Step 3. Flick bottle firmly time before each use to move the medicine into the tip of the bottle (See FIGURE D). Step 4. Keep the bottle upside down and remove the gray cap by turning it in the clockwise direction (See FIGURE E). Step 5. Tilt your head back. Gently squeeze the bottle to place drop into the affected eye (See FIGURE F). Replace the gray cap on the bottle and close tightly.How do store BromSiteStore BromSite at 59F to 77F (15C to 25C).Throw away the BromSite bottle after your treatment is finished.This Instructions for Use has been approved by the U.S. Food and Drug Administration. Distributed by:Sun Pharmaceutical Industries, Inc.Cranbury, NJ 08512 US Patent No.8778999 DuraSite(R) and BromSite(TM) are trademarks of Sun Pharma Global FZE Approved: 04/2016. Do not let the BromSite applicator tip touch your eye, fingers, or any other surfaces.. If you are using BromSite with other eye (ophthalmic) medicines, you should wait at least minutes after using the other medicine to give your BromSite dose.. You should not wear contact lenses while using BromSite.. Put the gray cap back on the BromSite after each use.. Tear open the foil pouch using the perforated notch and remove the BromSite bottle. Throw away the foil pouch.. Remove the white cap by turning it in the clockwise direction (See FIGURE A). Throw away the white cap.. Hold the bottle upright. Remove the gray cap by turning it in the counterclockwise direction (See FIGURE B).. Replace the gray cap on the bottle and close tightly.. Store BromSite at 59F to 77F (15C to 25C).. Throw away the BromSite bottle after your treatment is finished.. spl-bromsite-fig A. spl-bromsite-fig B. spl-bromsite-fig C. spl-bromsite-fig D. spl-bromsite-fig E. spl-bromsite-fig F.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Bromfenac is 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 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.

NONCLINICAL TOXICOLOGY SECTION.

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 (129 times unilateral daily dose assuming 100% absorbed, on mg/m2 basis) and mg/kg/day (540 times unilateral daily dose on mg/m2 basis), respectively revealed no significant increases in tumor incidence. Bromfenac did not show mutagenic potential in various mutagenicity studies, including the bacterial 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 (195 and 65 times unilateral daily dose, respectively, on mg/m2 basis).

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere are no adequate and well-controlled studies in pregnant women to inform any drug associated risks. Treatment of pregnant rats and rabbits with oral bromfenac did not produce teratogenic effects at clinically relevant doses. Clinical ConsiderationsBecause of the known effects of prostaglandin biosynthesis-inhibiting drugs on the fetal cardiovascular system (closure of ductus arteriosus), the use of BromSite during late pregnancy should be avoided.DataAnimal DataTreatment of rats with bromfenac at oral doses up to 0.9 mg/kg/day (195 times unilateral daily human ophthalmic dose on mg/m2 basis, assuming 100% absorbed) and rabbits at oral doses up to 7.5 mg/kg/day (3243 times unilateral daily dose on mg/m2 basis) produced no structural teratogenicity in reproduction studies. However, embryo-fetal lethality, neonatal mortality and reduced postnatal growth were produced in rats at 0.9 mg/kg/day, and embryo-fetal lethality was produced in rabbits at 7.5 mg/kg/day. 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThere are no adequate and well-controlled studies in pregnant women to inform any drug associated risks. Treatment of pregnant rats and rabbits with oral bromfenac did not produce teratogenic effects at clinically relevant doses. Clinical ConsiderationsBecause of the known effects of prostaglandin biosynthesis-inhibiting drugs on the fetal cardiovascular system (closure of ductus arteriosus), the use of BromSite during late pregnancy should be avoided.DataAnimal DataTreatment of rats with bromfenac at oral doses up to 0.9 mg/kg/day (195 times unilateral daily human ophthalmic dose on mg/m2 basis, assuming 100% absorbed) and rabbits at oral doses up to 7.5 mg/kg/day (3243 times unilateral daily dose on mg/m2 basis) produced no structural teratogenicity in reproduction studies. However, embryo-fetal lethality, neonatal mortality and reduced postnatal growth were produced in rats at 0.9 mg/kg/day, and embryo-fetal lethality was produced in rabbits at 7.5 mg/kg/day. 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.. 8.2 Lactation. There are no data on the presence of bromfenac in human milk, the effects on the breastfed infant, or the effects on milk production; however, systemic exposure to bromfenac from ocular administration is low [see Clinical Pharmacology (12.3)]. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for bromfenac and any potential adverse effects on the breast-fed child from bromfenac or from the underlying maternal condition.. 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 BromSite differ in patients 65 years of age and older compared to younger adult patients.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Slow or Delayed Healing (5.1)Potential for Cross-Sensitivity (5.2)Increased Bleeding Time of Ocular Tissue (5.3)Keratitis and Corneal Effects (5.4)Contact Lens Wear (5.5). Slow or Delayed Healing (5.1). Potential for Cross-Sensitivity (5.2). Increased Bleeding Time of Ocular Tissue (5.3). Keratitis and Corneal Effects (5.4). Contact Lens Wear (5.5). 5.1 Slow or Delayed Healing. All topical nonsteroidal anti-inflammatory drugs (NSAIDs), including BromSite (bromfenac ophthalmic solution) 0.075%, 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.. 5.2 Potential for Cross-Sensitivity. There is the potential for cross-sensitivity to acetylsalicylic acid, phenylacetic acid derivatives, and other NSAIDs, including BromSite (bromfenac ophthalmic solution) 0.075%. Therefore, caution should be used when treating individuals who have previously exhibited sensitivities to these drugs.. 5.3 Increased Bleeding Time of Ocular Tissue. With some NSAIDs, including BromSite (bromfenac ophthalmic solution) 0.075%, 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 BromSite be used with caution in patients with known bleeding tendencies or who are receiving other medications which may prolong bleeding time.. 5.4 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 BromSite (bromfenac ophthalmic solution) 0.075%, 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 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 postsurgery may increase patient risk for the occurrence and severity of corneal adverse events.. 5.5 Contact Lens Wear. BromSite should not be administered while wearing contact lenses. The preservative in BromSite, benzalkonium chloride, may be absorbed by soft contact lenses.