Nevanac

NEVANAC — nepafenac suspension
Physicians Total Care, Inc.

1 INDICATIONS AND USAGE

NEVANAC ^® ophthalmic suspension is indicated for the treatment of pain and inflammation associated with cataract surgery.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing

One drop of NEVANAC ^® should be applied to the affected eye(s) 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.

2.2 Use with Other Topical Ophthalmic Medications

NEVANAC ^® may be administered in conjunction with other topical ophthalmic medications such as beta-blockers, carbonic anhydrase inhibitors, alpha-agonists, cycloplegics, and mydriatics.

3 DOSAGE FORMS AND STRENGTHS

Sterile ophthalmic suspension: 0.1%

3 mL in a 4 mL bottle

4 CONTRAINDICATIONS

NEVANAC ^® is contraindicated in patients with previously demonstrated hypersensitivity to any of the ingredients in the formula or to other NSAIDs.

5 WARNINGS AND PRECAUTIONS

5.1 Increased Bleeding Time

With some nonsteroidal anti-inflammatory drugs including NEVANAC ^® , 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 NEVANAC ^® 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 NEVANAC ^® , 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 NEVANAC ^® 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 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.

Postmarketing experience with topical NSAIDs also suggests that use more than 1 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

NEVANAC ^® should not be administered while using contact lenses.

6 ADVERSE REACTIONS

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to the rates in the clinical studies of another drug and may not reflect the rates observed in practice.

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 5 to 10% of patients.

Other ocular adverse events 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 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 1 to 4% included headache, hypertension, nausea/vomiting, and sinusitis.

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 ≥ 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, NEVANAC ^® 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^® during late pregnancy should be avoided.

8.3 Nursing Mothers

NEVANAC ^® 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 ^® ophthalmic suspension is administered to a nursing woman.

8.4 Pediatric Use

The safety and effectiveness of NEVANAC ^® 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.

11 DESCRIPTION

NEVANAC ^® (nepafenac ophthalmic suspension) 0.1% is a sterile, topical, nonsteroidal anti-inflammatory (NSAID) prodrug for ophthalmic use. Each mL of NEVANAC ^® suspension contains 1 mg of nepafenac. Nepafenac is designated chemically as 2-amino-3-benzoylbenzeneacetamide with an empirical formula of C₁₅ H₁₄ N₂ O₂ . The structural formula of nepafenac is:

Nepafenac is a yellow crystalline powder. The molecular weight of nepafenac is 254.28. NEVANAC ^® ophthalmic suspension is supplied as a sterile, aqueous 0.1% suspension with a pH approximately of 7.4.

The osmolality of NEVANAC ^® ophthalmic suspension is approximately 305 mOsmol/kg.

Each mL of NEVANAC ^® 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.

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, a nonsteroidal anti-inflammatory drug. 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 postdose, respectively, following bilateral topical ocular three-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.