NDA 21-862
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`NEVANAC™
`(nepafenac ophthalmic suspension) 0.1%
`
`DESCRIPTION
`NEVANAC™ (nepafenac ophthalmic suspension) 0.1% is a sterile, topical, nonsteroidal
`anti-inflammatory (NSAID) prodrug for ophthalmic use. Each mL of NEVANACTM 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.
`NEVANACTM
` ophthalmic suspension is supplied as a sterile, aqueous 0.1% suspension with a pH
`approximately of 7.4. The osmolality of NEVANACTM
` ophthalmic suspension is approximately 305
`mOsmol/kg. Each mL of NEVANACTM
` contains: Active: nepafenac 0.1% Inactives: mannitol,
`carbomer 974P, sodium chloride, tyloxapol, edentate 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
`
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`LUPIN EX 1031
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`NDA 21-862
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`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 NEVANACTM
` , 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 NEVANACTM
` 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.
`
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`NDA 21-862
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`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 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™ 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: NEVANACTM 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.
`
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`NDA 21-862
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`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 LOGO]®
`
`Manufactured by:
`Alcon Laboratories, Inc.
`Fort Worth, TX 76134 USA
`
`U.S. Patent No: 5,475,034
`
`©2005 Alcon, Inc.
`
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