DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS. Sterile ophthalmic suspension: 0.1%3 mL in 4 mL bottle Sterile ophthalmic suspension: 0.1% 3)3 mL in 4 mL bottle.

GERIATRIC USE SECTION.


8.5 Geriatric Use. No overall differences in safety and effectiveness have been observed between elderly and younger patients.

HOW SUPPLIED SECTION.


16 HOW SUPPIED/STORAGE AND HANDLING. NEVANULLC(R) (nepafenac ophthalmic suspension) is supplied in natural, oval, low density polyethylene DROP-TAINER(R) dispenser with natural low density polyethylene dispensing plug and gray polypropylene cap. Tamper evidence is provided with shrink band around the closure and neck area of the package.3 mL in mL bottle NDC 54868-6302-0 Storage: Store at - 25C (36 77F).

INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE. NEVANULLC(R) ophthalmic suspension is indicated for the treatment of pain and inflammation associated with cataract surgery.. NEVANULLC(R) ophthalmic suspension is nonsteroidal, anti-inflammatory prodrug indicated for the treatment of pain and inflammation associated with cataract surgery 1).

DESCRIPTION SECTION.


11 DESCRIPTION. NEVANULLC(R) (nepafenac ophthalmic suspension) 0.1% is sterile, topical, nonsteroidal anti-inflammatory (NSAID) prodrug for ophthalmic use. Each mL of NEVANULLC(R) suspension contains mg of nepafenac. Nepafenac is designated chemically as 2-amino-3-benzoylbenzeneacetamide with an empirical formula of C15H14N2O2. The structural formula of nepafenac is:Nepafenac is yellow crystalline powder. The molecular weight of nepafenac is 254.28. NEVANULLC(R)ophthalmic suspension is supplied as sterile, aqueous 0.1% suspension with pH approximately of 7.4. The osmolality of NEVANULLC(R)ophthalmic suspension is approximately 305 mOsmol/kg. Each mL of NEVANULLC(R) contains: Active: nepafenac 0.1% Inactives: mannitol, carbomer 974P, sodium chloride, tyloxapol, edetate disodium, benzalkonium chloride 0.005% (preservative), sodium hydroxide and/or hydrochloric acid to adjust pH and purified water, USP.. image of structural formula.

ADVERSE REACTIONS SECTION.


6 ADVERSE REACTIONS. Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of drug cannot be directly compared to the rates in the clinical studies of another drug and may not reflect the rates observed in practice.. Most common adverse reactions (5 to 10%) are capsularopacity, decreased visual acuity, foreign body sensation, increased intraocular pressure, and sticky sensation. 6.1)To report SUSPECTED ADVERSE REACTIONS, contact Alcon Laboratories, Inc. at 1-800-757-9195 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Ocular Adverse Reactions. The most frequently reported ocular adverse events following cataract surgery were capsular opacity, decreased visual acuity, foreign body sensation, increased intraocular pressure, and sticky sensation. These events occurred in approximately to 10% of patients.Other ocular adverse events occurring at an incidence of approximately to 5% included conjunctival edema, corneal edema, dry eye, lid margin crusting, ocular discomfort, ocular hyperemia, ocular pain, ocular pruritus, photophobia, tearing and vitreous detachment.Some of these events may be the consequence of the cataract surgical procedure.. 6.2 Non-Ocular Adverse Reactions. Non-ocular adverse events reported at an incidence of to 4% included headache, hypertension, nausea/vomiting, and sinusitis.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Nepafenac has not been evaluated in long-term carcinogenicity studies. Increased chromosomal aberrations were observed in Chinese hamster ovary cells exposed in vitro to nepafenac suspension. Nepafenac was not mutagenic in the Ames assay or in the mouse lymphoma forward mutation assay. Oral doses up to 5,000 mg/kg did not result in an increase in the formation of micronucleated polychromatic erythrocytes in vivo in the mouse micronucleus assay in the bone marrow of mice.Nepafenac did not impair fertility when administered orally to male and female rats at mg/kg (approximately 90 and 380 times the plasma exposure to the parent drug, nepafenac, and the active metabolite, amfenac, respectively, at the recommended human topical ophthalmic dose).

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY. Enter section text here. 12.1 Mechanism of Action. After topical ocular dosing, nepafenac penetrates the cornea and is converted by ocular tissue hydrolases to amfenac, nonsteroidal anti-inflammatory drug. Amfenac is thought to inhibit the action of prostaglandin synthase (cyclooxygenase), an enzyme required for prostaglandin production.. 12.3 Pharmacokinetics. Low but quantifiable plasma concentrations of nepafenac and amfenac were observed in the majority of subjects and hours postdose, respectively, following bilateral topical ocular three-times-daily dosing of nepafenac ophthalmic suspension, 0.1%. The mean steady-state Cmax for nepafenac and for amfenac were 0.310 +- 0.104 ng/ml and 0.422 +- 0.121 ng/ml, respectively, following ocular administration.Nepafenac at concentrations up to 300 ng/mL did not inhibit the in vitro metabolism of specific marker substrates of cytochrome P450 (CYP) isozymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4). Therefore, drug-drug interactions involving CYP mediated metabolism of concomitantly administered drugs are unlikely. Drug-drug interactions mediated by protein binding are also unlikely.

CLINICAL STUDIES SECTION.


14 CLINICAL STUDIES. In two double-masked, randomized clinical trials in which patients were dosed three-times-daily beginning one day prior to cataract surgery, continued on the day of surgery and for the first two weeks of the postoperative period, NEVANULLC(R) ophthalmic suspension demonstrated clinical efficacy, compared to its vehicle in treating postoperative inflammation.Patients treated with NEVANULLC(R) ophthalmic suspension were less likely to have ocular pain and measurable signs of inflammation (cells and flare) in the early postoperative period through the end of treatment than those treated with its vehicle.For ocular pain in both studies significantly higher percentage of patients (approximately 80%) in the nepafenac group reported no ocular pain on the day following cataract surgery (Day 1) compared to those in the vehicle group (approximately 50%).Results from clinical studies indicated that NEVANULLC(R) has no significant effect upon intraocular pressure; however, changes in intraocular pressure may occur following cataract surgery.

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS. NEVANULLC(R) is contraindicated in patients with previously demonstrated hypersensitivity to any of the ingredients in the formula or to other NSAIDs.. Hypersensitivity to any of the ingredients in the formula or to other NSAIDS.( 4).

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION. Enter section text here. One drop of NEVANULLC(R) ophthalmic suspension should be applied to the affected eye(s) three-times-daily beginning day prior to cataract surgery, continued on the day of surgery and through the first weeks of the postoperative period. 2). 2.1 Recommended Dosing. One drop of NEVANULLC(R) should be applied to the affected eye(s) three-times-daily beginning day prior to cataract surgery, continued on the day of surgery and through the first weeks of the postoperative period.. 2.2 Use with Other Topical Ophthalmic Medications. NEVANULLC(R) may be administered in conjunction with other topical ophthalmic medications such as beta-blockers, carbonic anhydrase inhibitors, alpha-agonists, cycloplegics, and mydriatics.

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION. Enter section text here. 17.1 Slow or Delayed Healing. Patients should be informed of the possibility that slow or delayed healing may occur while using nonsteroidal anti-inflammatory drugs (NSAIDs).. 17.2 Avoiding Contamination of the Product. Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures because this could cause the tip to become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions.. 17.3 Contact Lens Wear. NEVANULLC(R) should not be administered while wearing contact lens.. 17.4 Intercurrent Ocular Conditions. Patients should be advised that if they develop an intercurrent ocular condition (e.g., trauma, or infection) or have ocular surgery, they should immediately seek their physicians advice concerning the continued use of the multi-dose container.. 17.5 Concomitant Topical Ocular Therapy. If more than one topical ophthalmic medication is being used, the medicines must be administered at least minutes apart.. 17.6 Shake Well Before Use. Patients should be advised to shake the bottle well.. U.S. Patent No; 5,475,034ALCON(R)ALCON LABORATORIES, INC.Fort Worth, Texas 76134 USA(C) 2007 Alcon, Inc.Additional barcode labeling by:Physicians Total Care, Inc.Tulsa, OK 74146.

MECHANISM OF ACTION SECTION.


12.1 Mechanism of Action. After topical ocular dosing, nepafenac penetrates the cornea and is converted by ocular tissue hydrolases to amfenac, nonsteroidal anti-inflammatory drug. Amfenac is thought to inhibit the action of prostaglandin synthase (cyclooxygenase), an enzyme required for prostaglandin production.

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY. Enter section text here. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Nepafenac has not been evaluated in long-term carcinogenicity studies. Increased chromosomal aberrations were observed in Chinese hamster ovary cells exposed in vitro to nepafenac suspension. Nepafenac was not mutagenic in the Ames assay or in the mouse lymphoma forward mutation assay. Oral doses up to 5,000 mg/kg did not result in an increase in the formation of micronucleated polychromatic erythrocytes in vivo in the mouse micronucleus assay in the bone marrow of mice.Nepafenac did not impair fertility when administered orally to male and female rats at mg/kg (approximately 90 and 380 times the plasma exposure to the parent drug, nepafenac, and the active metabolite, amfenac, respectively, at the recommended human topical ophthalmic dose).

NURSING MOTHERS SECTION.


8.3 Nursing Mothers. NEVANULLC(R) is excreted in the milk of lactating rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when NEVANULLC(R) ophthalmic suspension is administered to nursing woman.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINCIPAL DISPLAY PANEL. NEVANULLC(R) (nepafenac ophthalmic suspension)NDC 54868-6302-03 mL image of package label.

PEDIATRIC USE SECTION.


8.4 Pediatric Use. The safety and effectiveness of NEVANULLC(R) in pediatric patients below the age of 10 years have not been established.

PHARMACOKINETICS SECTION.


12.3 Pharmacokinetics. Low but quantifiable plasma concentrations of nepafenac and amfenac were observed in the majority of subjects and hours postdose, respectively, following bilateral topical ocular three-times-daily dosing of nepafenac ophthalmic suspension, 0.1%. The mean steady-state Cmax for nepafenac and for amfenac were 0.310 +- 0.104 ng/ml and 0.422 +- 0.121 ng/ml, respectively, following ocular administration.Nepafenac at concentrations up to 300 ng/mL did not inhibit the in vitro metabolism of specific marker substrates of cytochrome P450 (CYP) isozymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4). Therefore, drug-drug interactions involving CYP mediated metabolism of concomitantly administered drugs are unlikely. Drug-drug interactions mediated by protein binding are also unlikely.

PREGNULLNCY SECTION.


8.1 Pregnancy. Teratogenic Effects. Pregnancy Category C: Reproduction studies performed with nepafenac in rabbits and rats at oral doses up to 10 mg/kg/day have revealed no evidence of teratogenicity due to nepafenac, despite the induction of maternal toxicity. At this dose, the animal plasma exposure to nepafenac and amfenac was approximately 260 and 2400 times human plasma exposure at the recommended human topical ophthalmic dose for rats and 80 and 680 times human plasma exposure for rabbits, respectively. In rats, maternally toxic doses >= 10 mg/kg were associated with dystocia, increased postimplantation loss, reduced fetal weights and growth, and reduced fetal survival. Nepafenac has been shown to cross the placental barrier in rats. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, NEVANULLC(R) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.Non-teratogenic Effects.Because of the known effects of prostaglandin biosynthesis inhibiting drugs on the fetal cardiovascular system (closure of the ductus arteriosus), the use of NEVANULLC(R) during late pregnancy should be avoided.

SPL UNCLASSIFIED SECTION.


2.1 Recommended Dosing. One drop of NEVANULLC(R) should be applied to the affected eye(s) three-times-daily beginning day prior to cataract surgery, continued on the day of surgery and through the first weeks of the postoperative period.

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS. Enter section text here. 8.1 Pregnancy. Teratogenic Effects. Pregnancy Category C: Reproduction studies performed with nepafenac in rabbits and rats at oral doses up to 10 mg/kg/day have revealed no evidence of teratogenicity due to nepafenac, despite the induction of maternal toxicity. At this dose, the animal plasma exposure to nepafenac and amfenac was approximately 260 and 2400 times human plasma exposure at the recommended human topical ophthalmic dose for rats and 80 and 680 times human plasma exposure for rabbits, respectively. In rats, maternally toxic doses >= 10 mg/kg were associated with dystocia, increased postimplantation loss, reduced fetal weights and growth, and reduced fetal survival. Nepafenac has been shown to cross the placental barrier in rats. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, NEVANULLC(R) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.Non-teratogenic Effects.Because of the known effects of prostaglandin biosynthesis inhibiting drugs on the fetal cardiovascular system (closure of the ductus arteriosus), the use of NEVANULLC(R) during late pregnancy should be avoided.. 8.3 Nursing Mothers. NEVANULLC(R) is excreted in the milk of lactating rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when NEVANULLC(R) ophthalmic suspension is administered to nursing woman.. 8.4 Pediatric Use. The safety and effectiveness of NEVANULLC(R) in pediatric patients below the age of 10 years have not been established.. 8.5 Geriatric Use. No overall differences in safety and effectiveness have been observed between elderly and younger patients.

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS. Enter section text here. Increased bleeding time due to increased thrombocyte aggregation 5.1)Delayed healing 5.2) Corneal effects including keratitis 5.3). 5.1 Increased Bleeding Time. With some nonsteroidal anti-inflammatory drugs including NEVANULLC(R), there exists the potential for increased bleeding time due to interference with thrombocyte aggregation. There have been reports that ocularly applied nonsteroidal anti-inflammatory drugs may cause increased bleeding of ocular tissues (including hyphemas) in conjunction with ocular surgery.It is recommended that NEVANULLC(R) ophthalmic suspension be used with caution in patients with known bleeding tendencies or who are receiving other medications which may prolong bleeding time.. 5.2 Delayed Healing. Topical nonsteroidal anti-inflammatory drugs (NSAIDs) including NEVANULLC(R), 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 Corneal Effects. 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 NEVANULLC(R) and should be closely monitored for corneal health.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 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.Postmarketing experience with topical NSAIDs also suggests that use more than day prior to surgery or use beyond 14 days post surgery may increase patient risk and severity of corneal adverse events.. 5.4 Contact Lens Wear. NEVANULLC(R) should not be administered while using contact lenses.