Nevanac

Generic Name: nepafenac
Dosage Form: Suspension

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 C15H14N2O2. 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.

CLINICAL PHARMACOLOGY

Pharmacodynamics

Nevanac™ suspension contains nepafenac (0.1%), a nonsteroidal anti-inflammatory and analgesic prodrug. 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.

Pharmacokinetics

Drug-Drug Interaction: 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.

Gender: Data in healthy subjects indicate no clinically relevant or significant gender difference in the steady-state pharmacokinetics of amfenac following three-times-daily dosing of Nevanac™.

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 TID 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.

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, Nevanac™ ophthalmic suspension demonstrated clinical efficacy, compared to its vehicle in treating postoperative inflammation.

Patients treated with Nevanac™ 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 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™ has no significant effect upon intraocular pressure; however, changes in intraocular pressure may occur following cataract surgery.

INDICATIONS AND USAGE

Nevanac™ ophthalmic suspension is indicated for the treatment of pain and inflammation associated with cataract surgery.

CONTRAINDICATIONS

Nevanac™ ophthalmic suspension is contraindicated in patients with previously demonstrated hypersensitivity to any of the ingredients in the formulation or to other NSAIDs.

WARNINGS

There is the potential for cross-sensitivity to acetylsalicylic acid, phenylacetic acid derivatives, and other nonsteroidal anti-inflammatory agents. Therefore, caution should be used when treating individuals who have previously exhibited sensitivities to these drugs.

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.

PRECAUTIONS

General

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.

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 for occurrence and severity of corneal adverse events.

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.

Information for Patients

Nevanac™ ophthalmic suspension should not be administered while wearing contact lenses.

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).

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™ ophthalmic suspension during late pregnancy should be avoided.

Nursing Mothers

Nevanac™ ophthalmic suspension is excreted in the milk of pregnant 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.

Pediatric Use

The safety and effectiveness of Nevanac™ in pediatric patients below the age of 10 years have not been established.

Geriatric Use

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

ADVERSE REACTIONS

In controlled clinical studies, 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.

Nonocular adverse events reported at an incidence of 1 to 4% included headache, hypertension, nausea/vomiting, and sinusitis.

DOSAGE AND ADMINISTRATION

Shake well before use. One drop of Nevanac™ ophthalmic suspension 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.

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

HOW SUPPLIED

Nevanac™ (nepafenac ophthalmic suspension) is supplied in a natural, oval, low density polyethylene DROP-TAINER® dispenser with a natural low density polyethylene dispensing plug and gray polypropylene cap. Tamper evidence is provided with a shrink band around the closure and neck area of the package.

3 mL in 4 mL bottle NDC 0065-0002-03

Storage

Store at 2 - 25°C (36 - 77°F).

Rx Only

Alcon®
Manufactured by:
Alcon Laboratories, Inc.
Fort Worth, TX 76134 USA

U.S. Patent No: 5,475,034

©2005 Alcon, Inc.

9000843-0805

Nevanac (nepafenac)

PRODUCT INFO Product Code 0065-0002 Dosage Form SUSPENSION Route Of Administration OPHTHALMIC DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength nepafenac (nepafenac) Active 1 MILLIGRAM  In 1 MILLILITER mannitol Inactive   carbomer 974P Inactive   sodium chloride Inactive   tyloxapol Inactive   edetate disodium Inactive   benzalkonium chloride Inactive 0.05 MILLIGRAM  In 1 MILLILITER sodium hydroxide and/or hydrochloric acid Inactive   water Inactive

IMPRINT INFORMATION Characteristic Appearance Characteristic Appearance Color Score Shape Symbol Imprint Code Coating Size

PACKAGING # NDC Package Description Multilevel Packaging 1 0065-0002-01 1.5 MILLILITER In 1 BOTTLE, PLASTIC None 2 0065-0002-03 3 MILLILITER In 1 BOTTLE, PLASTIC None

Revised: 02/2007