NEVANAC

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of labeling: Increased Bleeding Time [see Warnings and Precautions (5.1)] Delayed Healing [see Warnings and Precautions (5.2)] Corneal Effects [see Warnings and Precautions (5.3)] Most common adverse reactions (5% to 10%) are capsular opacity, decreased visual acuity, foreign body sensation, increased intraocular pressure (IOP), and sticky sensation. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials 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 the rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most frequently reported ocular adverse reactions following cataract surgery were capsular opacity, decreased visual acuity, foreign body sensation, increased intraocular pressure (IOP), and sticky sensation. These reactions occurred in approximately 5% to 10% of patients. Other ocular adverse reactions occurring at an incidence of approximately 1% 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 reactions may be the consequence of the cataract surgical procedure. Non-ocular adverse reactions reported at an incidence of 1% to 4% included headache, hypertension, nausea/vomiting, and sinusitis.

4 CONTRAINDICATIONS NEVANAC 0.1% is contraindicated in patients with previously demonstrated hypersensitivity to any of the ingredients in the formula or to other non-steroidal anti-inflammatory drugs (NSAIDs). Hypersensitivity to any of the ingredients in the formula or to other non-steroidal anti-inflammatory drugs (NSAIDS).

11 DESCRIPTION NEVANAC ® 0.1% is a sterile, topical NSAID prodrug for ophthalmic use. Each mL of NEVANAC 0.1% contains 3 mg of nepafenac. Nepafenac is designated chemically as 2-amino-3-benzoylbenzeneacetamide with an empirical formula of C 15 H 14 N 2 O 2 . The structural formula of nepafenac is: Nepafenac is a yellow crystalline powder. The molecular weight of nepafenac is 254.28 g/mol. NEVANAC, 0.1% is supplied as a sterile, aqueous suspension with a pH approximately of 7.4. The osmolality of NEVANAC 0.1% is approximately 305 mOsm/kg. Each mL of NEVANAC 0.1% contains: Active: nepafenac 0.1%. Inactives: benzalkonium chloride 0.005% (preservative), carbomer 974P, edetate disodium, mannitol, purified water, USP, sodium chloride, sodium hydroxide and/or hydrochloric acid to adjust pH, and tyloxapol. The structural formula of nepafenac

2 DOSAGE AND ADMINISTRATION One drop of NEVANAC should be applied to the affected eye three times daily beginning 1 day prior to cataract surgery, continued on the day of surgery and through the first 2 weeks of the postoperative period. ( 2.1 ) 2.1 Recommended Dosing One drop of NEVANAC 0.1% should be applied to the affected eye three times daily beginning 1 day prior to cataract surgery, continued on the day of surgery and through the first 2 weeks of the postoperative period. Shake the container well prior to dosing. 2.2 Use With Other Topical Ophthalmic Medications NEVANAC 0.1% may be administered in conjunction with other topical ophthalmic medications, such as beta-blockers, carbonic anhydrase inhibitors, alpha-agonists, cycloplegics, and mydriatics. If more than one topical ophthalmic medication is being used, the medicines must be administered at least 5 minutes apart.

1 INDICATIONS AND USAGE NEVANAC ® 0.1% is indicated for the treatment of pain and inflammation associated with cataract surgery. NEVANAC is a nonsteroidal, anti-inflammatory prodrug indicated for the treatment of pain and inflammation associated with cataract surgery.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action After topical ocular dosing, nepafenac penetrates the cornea and is converted by ocular tissue hydrolases to amfenac, an NSAID. Amfenac is thought to inhibit the action of prostaglandin H 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 2 and 3 hours post dose, respectively, following bilateral topical ocular 3 times-daily dosing of nepafenac ophthalmic suspension, 0.1%. The mean steady-state C max 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 6 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.

12.1 Mechanism of Action After topical ocular dosing, nepafenac penetrates the cornea and is converted by ocular tissue hydrolases to amfenac, an NSAID. Amfenac is thought to inhibit the action of prostaglandin H 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 2 and 3 hours post dose, respectively, following bilateral topical ocular 3 times-daily dosing of nepafenac ophthalmic suspension, 0.1%. The mean steady-state C max 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 6 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.

20230419

2

3 DOSAGE FORMS AND STRENGTHS Sterile ophthalmic suspension 0.1% 3 mL in a 4 mL bottle Sterile ophthalmic suspension 0.1% 3 mL in a 4 mL bottle ( 3 )

NEVANAC nepafenac NEPAFENAC NEPAFENAC BENZALKONIUM CHLORIDE MANNITOL CARBOMER HOMOPOLYMER TYPE B (ALLYL PENTAERYTHRITOL CROSSLINKED) SODIUM CHLORIDE TYLOXAPOL EDETATE DISODIUM SODIUM HYDROXIDE HYDROCHLORIC ACID WATER

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 3 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).

13 NONCLINICAL TOXICOLOGY 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 3 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).

NDA021862

NEVANAC

nepafenac

0078-0778

HUMAN PRESCRIPTION DRUG

OPHTHALMIC

PRINCIPAL DISPLAY PANEL NDC 0078-0778-03 STERILE Nevanac ® (nepafenac ophthalmic suspension) 0.1% 3 mL NOVARTIS PRINCIPAL DISPLAY PANEL NDC 0078-0778-03 STERILE Nevanac® (nepafenac ophthalmic suspension) 0.1% 3 mL NOVARTIS

17 PATIENT COUNSELING INFORMATION Slow or Delayed Healing Advise the patient of the possibility that slow or delayed healing may occur while using NSAIDs [see Warnings and Precautions (5.2)] . Avoiding Contamination of the Product Advise the patient 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. Use of the same bottle for both eyes is not recommended with topical eye drops that are used in association with surgery. Contact Lens Wear Advise the patient that NEVANAC 0.1% should not be administered while wearing contact lens [see Warnings and Precautions (5.4)] . Intercurrent Ocular Conditions Advise the patient that if they develop an intercurrent ocular condition (e.g., trauma, or infection) or have ocular surgery, they should immediately seek their physician’s advice concerning the continued use of the multi-dose container [see Warnings and Precautions (5.1)] . Concomitant Topical Ocular Therapy If more than one topical ophthalmic medication is being used, the medicines must be administered at least 5 minutes apart [see Dosage and Administration (2.2)] . Shake Well Before Use Advise the patient to shake the container well [see Dosage and Administration (2.1)] . Distributed by: Novartis Pharmaceuticals Corporation East Hanover, NJ 07936 ©Novartis T2021-99

14 CLINICAL STUDIES In two double-masked, randomized clinical trials in which patients were dosed 3 times daily beginning 1 day prior to cataract surgery, continued on the day of surgery and for the first 2 weeks of the postoperative period, NEVANAC 0.1% demonstrated superior clinical efficacy compared to its vehicle in treating postoperative pain and inflammation. Patients treated with NEVANAC ® 0.1% 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, a 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 NEVANAC 0.1% has no significant effect upon IOP; however, changes in IOP may occur following cataract surgery.

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

8.3 Nursing Mothers Nepafenac 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 NEVANAC 0.1% ophthalmic suspension is administered to a nursing woman.

8.4 Pediatric Use The safety and effectiveness of NEVANAC 0.1% in pediatric patients below the age of 10 years have not been established.

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 greater than or equal to 10 mg/kg were associated with dystocia, increased post-implantation 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, NEVANAC 0.1% 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 NEVANAC 0.1% during late pregnancy should be avoided.

8 USE IN SPECIFIC POPULATIONS 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 greater than or equal to 10 mg/kg were associated with dystocia, increased post-implantation 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, NEVANAC 0.1% 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 NEVANAC 0.1% during late pregnancy should be avoided. 8.3 Nursing Mothers Nepafenac 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 NEVANAC 0.1% ophthalmic suspension is administered to a nursing woman. 8.4 Pediatric Use The safety and effectiveness of NEVANAC 0.1% 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.

16 HOW SUPPLIED/STORAGE AND HANDLING NEVANAC ® 0.1% is supplied in a white, oval, low density polyethylene dispenser with a natural low density polyethylene dispensing plug and gray polypropylene cap. The 1.7 mL fill is presented in an overwrap, which provides tamper evidence to the package. Tamper evidence for the 3 mL fill is provided with a shrink band around the closure and neck area of the package. 3 mL in a 4 mL bottle……………………………………………………………………………NDC 0078-0778-03 Storage: Store at 2°C to 25°C (36°F to 77°F).