............................ (oumrlupygpnous
`Hypersensitivity to any ofthe ingredients in the formula or to other
`NSAiDS.(4)
`
`----WARNINGS AND PRECAUTIONS --
`increased bleeding time due to interference with thrombocyte
`aggregation (5.1)
`Delayed healing (5.2)
`Corneal effects including keratitis (5.3)
`.............................ADVER5E nyt('|'|(ms..........................
`Most common adverse reactions (5 to 10%) are capsular opacity,
`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-10B8or
`See 17 for PATIENTCOUNSELING INFORMATION
`Revised: 02/2014
`
`.4.-~_.
`
`_._._.Nous.
`
` 8
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not Include all the information needed to
`use |LEVRO” (nepafenac ophthalmic suspension), 0.3% safely
`and effectively. See full prescribing information for ILEVRO
`(nepafenacophthaimic suspension), 0.3%.
`ILEVRO” (nepafenac ophthalmic suspension), 0.3%, topical
`ophthalmic
`Initial U.S. Approval: 2005
`......................... mmcymous Am)
`|LEVRO* (nepafenacophthalmicsuspension), 0.3% is a nonsteroidai,
`anti-inflammatory prodrug indicated for the treatment of pain and
`inflammation associated with cataractsurgery (1).
`...................... Dospgg AND ApM|N|51'pymoN
`One drop of|LEVRO" (nepafenac ophthalmic suspension), 0.3% should
`be applied to the affected eye one-time-daily beginning 1 day prior to
`cataract surgery, continued on the day of surgery and through the first
`Zweeks ofthe postoperative period. An additional drop should be
`administered 30 to 120 minutes prior to surgery. (2)
`..................... pospgg poms AND 5'm5NGn.|5..................
`Sterile ophthalmic suspension 0.3%: 1.7 mL in a
`4mL bottle and 3 mL in a 4 mt bottle. (3)
`FULL PRESCRIBING INFORMATION: CONTENTS“
`1
`INDICATIONSAND USAGE
`2
`DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosing
`2.2 Use with Otheriopical Ophthalmic
`Medications
`DOSAGE FORMS AND STRENGTHS
`3
`CONTRAINDICATIONS
`4
`5 WARNINGSANDPRECAUTIONS
`5.1
`increased Bleeding fime
`5.2 Delayed Healing
`5.3 Cornea|Effects
`5.4 Contactienswear
`ADVERSE REACTIONS
`6.1
`Serious and Otherwise Important
`Adverse Reactions
`6.2 OcularAdverse Reactions
`6.3 Non-0cu|arAdverse Reactions
`
`6
`
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.3 NursingMothers
`8.4 PediairicUse
`8.5 GeriatricUse
`DESCRIPTION
`CLINICAL PHARMACOLOGY
`12.1 MechanismofAction
`12.3 Pharmacokinetlcs
`13 NONCLINICALTOIIICOLOGY
`13.1 Carcinogenesis, Mutagenesis, impairment of
`Fertility
`CLINICALSTUDIES
`NOW SUPPLIED/STORAGE AND HANDLING
`PATIENT COUNSELING INFORMATION
`17.1 S|oworDe|ayedHeaiing
`17.2 Avoiding Contamination ofthe Product
`17.3 Contacttenswear
`17.4 lntercurrentOcuIarConditions
`17.5 ConcomitantlopicalOcuiarlherapy
`17.6 ShakeWeII Before Use
`"Sections or subsections omitted from thefuil prescribing information are
`
`not listed
`FULL PRESCRIBING INFORMATION
`5.2
`Delayed Nealing
`Iopical nonsteroidai anti-inflammatory drugs (NSA|Ds) Including ILEVRO“
`1
`INDICATIONSAND USAGE
`(nepafenac ophthalmic suspension), 0.3%, may slow or delay healing. Topical
`iLEVRO" (nepafenac ophthalmic suspension), 0.3% is indicated for the
`corticosteroids are also known to slow ordeiay healing. Concomitant use of
`treatment of pain and inflammation associated with cataract surgery.
`topical NSAIDs and topical steroids may increase the potential for healing
`2
`DOSAGE AND ADMINISTRATION
`problems.
`5.!
`Corneal Effects
`2.1
`Recommended Dosing
`Use of topical NSAlDs may result in keratitis. in some susceptible patients,
`tine drop of tiEir'Ii0' (nepafenac opirtimimic tuspunaiuni. 0.3'é$shouid be
`continued use of topical NSAlDs may result in epithelial breakdown, corneal
`.rp|:I'1I:rJ Lu tin‘ rrllecttil rye rrtrc—lirI1t-—ilarIy Isuglnrihtg 1 day prior to
`thinning, corneal erosion, corneal ulceration or corneal perforation.These
`catlrrrctsrrrryt-ry, runtiirired on the clay of surgery anti Ilrrotigh ilre iirst2
`events may be sight threatening. Patients with evidence ofcorneal epithelial
`weeks ofthe postoperative period.itnadditionairlrapsirouid be
`adnrlnisiered 30 to ran minutes prior to surgery.
`breakdown should immediately discontinue use of topical NSA|0s including
`ILEVRO‘ (nepafenac ophthalmic suspension), 0.3%and should be closely
`2.2
`Use with OtherToplcal Ophthalmic
`monitored for corneal health.
`Medications
`Postmarketlng experience with topical NSA|Ds suggests that patients with
`|LEVRO' (nepafenac ophthalmic suspension), 0.3% maybe administered in
`complicated ocularsurgeries, corneal denervation, corneal epithelial defects,
`conjunction with other topical ophthalmic medications such as
`diabetes meiiitus, ocular surface diseases (e.g., dry eye syndrome),
`beta-blockers, carbonic anhydrase inhibitors, alpha~agonists, cyclopiegics,
`rheumatoid arthritis, or repeat ocular surgeries within a short period of time
`and mydriatics.
`may be at increased risk for corneal adverse events which may become sight
`if more than one topical ophthalmic medication is being used, the
`threateningiopical NSAiDs should be used with caution in these patients.
`medicines must be administered at leasts minutes apart.
`Postmarketlng experience with topical NSA|Ds also suggests that use more
`3
`DOSAGE FORMS AND STRENGTHS
`than 1 day prior to surgery or use beyond 14 days post-surgery may increase
`Sterile ophthalmic suspension 0.3%
`patient risk and severity of corneal adverse events.
`1.7 ml in a 4 ml bottle
`5.4
`Contact Lens Wear
`3 ml in a 4 ml bottle
`ILEVRO‘ (nepafenac ophthalmic suspension), 0.3% should not be
`administered while using contact lenses.
`4
`CONTRAINDICATIONS
`6
`ADVERSE REACTIONS
`ILEVRO‘ (nepafenac ophthalmic suspension), 0.3% is contraindicated in
`patients with previously demonstrated hypersensitivity to any of the
`Because clinical studies are conducted underwidely varying conditions,
`ingredients in the formula orto other NSAIDs.
`adverse reaction rates observed in the clinical studies ofa drug cannot be
`S
`WARNINGS AND PRECAUTIONS
`directly compared to the rates in the clinical studies ofanother drug and may
`not reflect the rates observed in practice.
`5.1
`Increased Bleeding Time
`6.1
`Serious and Otherwise Important
`With some norrsteroidal anti-inflammatory drugs including lLEVNO"
`Adverse Reactions
`(nepafenac ophthalmic suspension), 0.3%, there exists the potential for
`Thefoliowing adverse reactions are discussed in greater detail in other
`increased bleeding time due to interference with thrombocyte
`sections of labeling.
`aggregation.ihere have been reports that ocularly applied nonsteroidai
`-
`Increased Bleeding lime (Warnings andPrecautions 5.1)
`anti-Inflammatory drugs may cause increased bleeding ofocular tissues
`- Delayed Healing (WarningsandPrecauiiorrs5.2)
`(including hyphema) in conjunction with ocularsurgery.
`- Corneal Effects (Warnings andPrecautions 5.3)
`it is recommended that ILEVRO“ (nepafenac ophthalmicsuspension), 0.3%
`6.2
`0cu|arAdverseReactions
`be used with caution in patients with known bleeding tendencies orwho
`The most frequently reported ocular adverse reactions following cataract
`are receiving other medications which may prolong bleeding time.
`surgery were capsular opacity, decreased visual acuity, foreign body
`sensation, increased intraocular pressure, and sticky sensation. These
`reactions occurred in approximately 5 to 10% ofpatienis.
`
`Page 1 of 2
`
`SENJU EXHIBIT 2241
`
`LUPIN V. SENJU
`
`IPR2015-01097
`
`Page 1 of 2
`
`SENJU EXHIBIT 2241
`LUPIN v. SENJU
`IPR2015-01097
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`

`
`Otherocuiar adverse reactions occurring atan incidence ofapproximateiy
`1 to 5% included coniunctlval 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.
`6.3
`Non-0cuiarAdverseReactions
`Non-ocular adverse reactions reported atan incidence of 1 to 4% included
`heatlache,iryperlension. naoseaitomitrogami sirrrtsiils
`8
`USE IN SPECIFIC POPULATIONS
`ti.1
`Pregnancy
`Teratogenlc 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 oiteratogenlcitydue to nepafenac, despite the induction of
`maternal toxicity. At this dose, the animal plasma exposure to nepafenac
`and amfenacwas approximately 70 and 630 times human plasma
`exposure at the teconrmeniied human topical ophthaimicdose for rats
`and 20and 100 times human plaslitaeaqr-usurelrrr rabbits, respectively. in
`rats, maternally toxic doses 2 I0 Irttyflttj were associated with dysiocia,
`increased postimpiantation 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,
`ILEVRO” (nepafenac ophthalmic suspension),0.3% should be used during
`pregnancy only iithe potential benelitlustiiies the potential risk to the
`fetus.
`Non-teratogenlc Effects.
`Because ofthe known effects ofprostagiandin biosynthesis inhibiting
`drugs on the fetal cardiovascularsystem (closure of the ductus arteriosus),
`the use of ILEVRO‘ (nepafenac ophthalmlcsuspension), 0.3% during late
`pregnancy should be avoided.
`8.3
`Nursing Mothers
`Nepafenac isexcreted in the tniiiroilactating ratstt tsttot known whether
`this drug is excreted in huniuu mills. Eerausernairy drugs are excreted in
`human mllli.(titiI.ltii1SJititiItllJti£irt‘i(lSttlW'lir2t‘i|l.E‘I'llU' (nepafenac
`ophthalmlcsuspension), 0.3% is administered toa nursing woman.
`13.4
`Pediatric Use
`The safety and effectiveness of iLEVRO“ (nepafenac ophthalmic
`suspension), 0.3% in pediatric patients below the age of 10 years have not
`been established.
`0.5
`Geriatric Use
`No overall differences in safety and effectiveness have been observed
`between elderiyand younger patients.
`11
`DESCRIPTION
`|tEVRO“ (nepafenac ophthalmic suspension), 0.3% is a sterile, topical,
`nonsteroidal anti-inflammatory (NSAID) prodrug for ophthalmic use. Each
`ml of ILEVRO“ (nepafenac ophthalmlcsuspension), 0.3% contains 3 mg of
`nepafenac. Nepafenac is designated chemically as 2—amino—3-
`benzoylbenzeneacetamidewith an empirical fonnuia of C15il14N202.
`The structural formula of nepafenac is:
`0 N;
`
`NH;
`
`Nepafenac is a yellow crystalline powder.The molecular weight of
`nepafenac is 254.28.
`lLEVRO" (nepafenac ophthalmic suspension), 0.3% is supplied as a sterile,
`aqueous suspension with a pH approximately of 6.8.
`The osmolaiity of |iEVRO' (nepafenacophthalmlcsuspension), 0.3% is
`approximately 300 m0sm/kg.
`Each mi of |LEVRO" (nepafenac ophthalmlcsuspension), 0.3% contains:
`Active: nepafenac0.3% inactives: boricacid, propylene glycol, carbomer
`974P, sodium chloride, guargum, carboxymethylcellulose sodium, edetate
`disodium, benzaikonium chloride 0.005% (preservative), sodium
`hydroxide and/or hydrochloricacid to adiust pH and purified water, USP.
`12
`Cl|NlCAl PHARMACOLOGY
`12.1
`Mechanism of Action
`After topical oculardosing, nepafenac penetrates the cornea and is
`converted by ocular tissue hydrolases to amfenac, a nonsteroidal
`anti-inflammatory drug. Nepafenac and amfenacare thoughtto inhibit
`the action ofprostaglandin H synthase (cyclooxygenasei, an enzyme
`required for prostaglandin production.
`12.!
`Pharmacolcinetlcs
`Following bilateral topical ocular once-daiiydosbrg oiiLtliii0' [nepafenac
`ophthalmic suspension), 0.3%, the concentrations otuepafenac and
`amfenac peaked ata median time of0.5iioui anti 0.I5lto1n. respectively
`on both Day 1 and Day 4.The mean steady-state Cmaxfor nepafenac and
`for amfenac were 0.047 t 0.269 ng/mL and 1.13 :r 0.491 ng/mi,
`respectively.
`itepolenacotconcerurations up to 3000 ngftntand amfenac at
`concentrations up to 1000 ngirni did not inhibit the in vitro metabolism of
`Espeuific rriaticer substrates ofcyiloclsroinn P-ISO ii fl‘) isoziitnet iC't'Fl.lI.?,
`CI'I‘2t'9. CYPHT9. C't‘P2lJE. Ci‘l‘2I|. and C'i'F.'»r‘iAi].Iiserafnte,drug-drug
`hiteracijons irwoiving CYP mediated metabolism oi corrcatnitarrtiy
`administered drugs are unlikely.
`Weft PI 9|I1Ci'.l'19-D51 -I
`
`Page 2 of 2
`
`13
`13.1
`
`NONCLINICAL TOXICOLOGV
`Cardnogenesis,Mutagenesis,
`lmpalrrnentoffertility
`Nepafenac has not been evaluated in long-term carcinogenicity studies.
`increased chromosomal abenatlons 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 lymphomaforward mutation assay. Oral
`doses up to 5,000 mg/kg did not result in an increase in the formation of
`micronucleated polychromatic erythrocytes in viva in the mouse micronucleus
`assay in the bone marrow of mice.
`Nepafenac did not impair fertility when administered orally to male and
`female ratsat 3 mg/kg.
`14
`(liNi(itl STUDIES
`in two double masked, randomized clinical trials in which patients were closed
`daily beginning one day prior to cataract surgery, continued on the day of
`surgery and for the first two weeks of the postoperative period, |L[VRO'
`(nepafenacophthalmlcsuspension), 0.3% demonstrated superior clinical
`efficacy compared to its vehlde in treating postoperative pain and
`inflammation.
`Treatment effect over vehicle for resolution ofocular pain occurred as early
`as day 1 post-surgery.ireatment effect overvehlcle for resolution of
`inflammation was significantly better than vehicle in both studies at day
`7and day 14 post-surgery.
`Inflammation and Ocular Pain Resolution Results of Nepafenac
`ophthaimicsuspension, 0.3% versus Vehicle at Day 14 Post-surgery
`(Ali-Randomized Population)
`TRDIIMIII
`IliIlIlMtIDlill|0|i)1lol|
`0(IlIII'Plllt Rosotutior
`If Ramp DWI‘
`it P914009?! 14
`
`SANPQIHION,
`
`-arm Neplhras ophfhelrrtk
`oars [MI] (1)
`rrrvruuctnrroiil
`vssraewuiiil
`ueparmxapimmae
`s-new-n
`n.ssern/ml"
`VtMdItriINlllI
`ants-at . 4.-ssrn tit
`Ill n/N islhe ratio nlthoae wrthcnmplete resolution ofanlerior shambercell and Rare by the pmioperative
`daytt visit omallrandornlzed subiects
`ill Ofliereuce is Nepafenac ophihalmicsttspensionfl }%(nIil)—vehicle lhc-98% confidence interval is
`derived usingasymptotic approximation.
`16
`HOWSUPPLIED/STORAGEAND
`HANDLING
`itEiiREi‘ (nepafenac ophtltntmic suspension), 0.3% issuppiied in awhile,
`oval. low densitypo-iyethyiene DROP-TAlNER' dispenser vvitha natural low
`density patyetiryterre dispensing plug and gray polypropylene cap presumed
`iuaIrovervvra|t{i.7nti ftlinniyhiamper evidence is provided witlta shrink
`band around the closure and neck area of the package.
`1.7 ml in4 mt bottle
`NDC 0065-1750-07
`3mL|n4mLbottle
`NDC 0065—i750—14
`Storage: Store at 2 -2S"C (36 - 77'F).
`Protect from light.
`17
`PATIENT COUNSELING INFORMATION
`17.1
`Slow or Delayed iiealing
`Patients should be informed of the possibility that slow or delayed healing
`may occurwhiie using nonsteroidal anti-inflammatory drugs (NSAiDsi.
`17.2
`Avoiding Contamination ofthe Product
`Patients should be instructed to avoid allowing the tip of the dispensing
`container to contact the eye orsurrounding 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 irorn using contaminated solutions.
`Use ofthe same bottlefor both eyes is not recommended with topical eye
`drops thatare used in association with surgery.
`17.!
`Contact lens Wear
`|tEVRO" (nepafenac ophthalmic suspension), 0.3% should not be
`administered while wearing contact lens.
`17.4
`lntercunentOculartonditions
`Patients should be advised that iithey develop an intercurrent ocular
`condition (e.g., trauma, or infection) or have ocular surgery, iheyshouid
`immediately seek their physicians advice concerning the continued use of the
`muiti-dose container.
`17.5
`ConcomltantToplcaiOcularTherapy
`If more than one topical ophthalmic medication is being used, the medicines
`must be administered at ieast5 minutes apart.
`17.6
`Shaire Well Before Use
`Patients should be instructed to shake well before each use.
`
`ssmst (csss)
`seuustmi
`emit um
`]M(10|,£0%I
`
`rwlsr (mt)
`mmstms)
`um s cm)
`40% 13116.47!)
`
`
`
`3]li$Wi6lIl
`ssnsetwsi
`
`U.S. Patent Nos. 5,475,034; 6,403,609; and 7,169,767
`" airademark of Novartis
`
`Alcor?
`Att’.0N LABORATORIES, iN(.
`Fort Worth, Texas 76134 USA
`© 2014 Novartis
`
`Page 2 of 2