............... comymmtunoug ..............._........
`Hypersensitlvitytoarly eltlieiryedientslrr Itelormrlaoctoother
`ltSAlD5.(-i)
`-—-~~~~~~~~~-wvmtlttllfisllllt rneceunorrs~~~~~~~~--
`lnrreased bleedlngtine dueioiaterferenre with thrornlrocyte
`awegatioa (5.1)
`Delayedheallng (51)
`Corneal elfects lncludng Ireratitis (5.3)
`----————————-ADVERSE rreaenorrs-——~---——-~
`Mostcornrnonadverse reactions (5 to 10%) are cqasular opacity,
`decreased visual acuity, foreign body sensation, irereaserl ‘nlraorular
`pressure,and stlrty sensation (M)
`lorepon SUSPECIEDAIJVEISE rrermorrs, corrtacthlcou
`ldroratorles,|nc.at1-loo-1574195 or Flthat
`1-WFM-1wBu
`$ee17iocPATlHll(0tlllSEUll6lltFOIMlll|0ll
`
`lttGlitlGt‘lS or Pttlstltlllllfi Iilfltlllllmolt
`these hlghtldris do aotlndude all the Irrfonnuion needed to
`use Il.Ellll0' (rrapaienacopithahnle suspension), 0.3% safely
`and dledlvely. See lullpresuiing inlorniationfor |lElr‘ll0
`leepaferracopltlialnrle suspuslool, 0.3%.
`|LElIli0' (nepafenae ophthalraiesuspenslorr), 0.396, topll
`ophthalmic
`IIIH l.l.S.llnrmal: 2005
`-----~-—-- Iuorunorrs Am rrsace--—~—-—--~---—
`I.ElIli0' (nepaleriacophrlrarnlcsuspenstoa),0.396 Is anoasreroirlal,
`anltirllarnnratoryprodrug Indcatedfortherrearmartolpaieanrl
`hlhnenatlon assoriaredwih ratarartsurgery ll).
`------«----— DOSAEANI) IDMIIISTMIION---——-—~~~~~
`One stop oiILEVlttJ'(rrepalenatophthalrn|c suspenslonl,0.39isliorld
`lieapplled to the afieetedeyeone-tlrne-dal|yheg'nning 1 dayprior to
`cataract surgery, conlinrredontlie day of surgery and throudt the fest
`lweeks of the postoperative periodkiaddltlonal rhop should be
`adninlstered 30 to I20 rnlnutes priurto sregery.(2)
`---------—DD$AGEF0lht$All)$lltllGlll5---~--——---
`Sterle ophthalmlrsrrsperrsion 0.39t1.7 mL in a
`irrrthottlearrdlmlinatmlbottlelil
`
`Ftll.lPllE$ClllBIilt':lllFORlMTl0ll:(0lt‘mlTS"
`8
`tl$ElltSPE(|F|CP0l’tllA1l0itS
`
`Ruisat oz/2014
`
`8-1 Pregnancy
`
`1!
`
`r
`2
`
`|llDl(ltTl0ltSltlIJllSMiE
`l>0$AGEAtlDADMllIS1llAT|0tl
`Ll
`ltecommendedoosla
`12 Usewlhlltherloplrahophthalnic
`Medications
`3 oosmflmmflnsmmmm
`4
`corimarorcarrorrs
`5 VMltllIll6SAllDPltE(AlmllllS
`5.]
`Inqgagedllleedlnglimg
`5.2 Del
`lleall
`53 gmhifmmm
`5_4 (,,,ml,,,,w,,
`s ADlIEltSElt£l(ll0llS
`6.l Seriuusandotherwiselmportant
`rmseremm
`(:2 Oeriarrtdverselteacrloas
`£3 tionocularhdverselleadiorrs
`
`" 3-[5sm°I§"‘.°°""‘<""
`12 ¢lltll(ll.PllMl|Mt1Il.l)GV
`12.1 Mechanismoihetlon
`ru Pliamamtmerles
`rroroatrrrurrorrcotosr
`l3.l §ar:il|r:ygerresls.hlrlta9ertesis,lnrpalrnlerrtol
`5'
`re currrcrltsruorrs
`rs rrowsurpuro/sroruaetirorrarrotrrrc
`'7 ffi'§gm:m“"'°"
`‘
`iii €m“.°l.5.:’..“i.“.‘.”"‘°"°“"° "°”“
`17.4 lrrleroirrenloculartorrdiiorrs
`17.5 Concondtanlloplcd Ocularlherapy
`l7.6 Shielllellllelore Use
`"seetiensorsrtliseettoasornlrredfrem thelelprescrlhhghlormationare
`notlsled
`Fllll PRISOIIIING Ilfilifllllll
`5.2
`Delayed lealhg
`lopkd nonsteroldal anti-inharrrraatorydws lllSllDsl hcludlnq llElIll0‘
`I
`IIIICATIONSIIDUSAGE
`lnepaienae oplrthaknk susperrdon). 0.3%. rnay slowor delay healing loplul
`lEVli0' lneoalenac oplrthain'rrsusperolen),0.39ilr ladlrated for the
`cortlussteroldsarealso lraown ioslowordelay healing. Concomitant rrseol
`treatment olpah and hllamrnatlon associated with catarartsurgery.
`toplral NSAIDs and topical srerolds may increase the potential for healng
`I
`DOSAGE AND MNIIIIISTIATIOI
`prnhlerm.
`5.!
`(ornealflieets
`2.1
`Ierorumerrded llesllg
`Use ol toplral ltSAlDs mayresulr It kerat'nis.|nsorIesusreptr1r|e patients
`one drop otltEVflD' lrrqialerrar optrltatmlr suspensiorrl, tljttsaouldhe
`continued rise oi topic! llSrllDs
`result In epithelial lrredrdown, corneal
`applrd to the allceled eye rrrretlrrretlalybeglnrana 1 day prior to
`tlrhrrmcorneal erosion, rorneal I ceratlonorcorned periorationlhese
`catarart srmyery, continued on the clay oistrguy in through Ire fvstl
`events rnayheright threaterin; Patients with evidence olenrnealeptthellal
`ween oftlreposrrperatrrepa1od.Arr addlttunaldrop slnuld be
`administered to to H0 mums prlottosltrgery.
`hrealdowrr should Inrnedlately dlscontlaueuse oitopkal llSAll)s hdudirg
`lEVll0'(nepalenar ophthalmic suspenslonl. aliiand shouldbeclosely
`1.1
`llsewlltfilherloplcal ophttralrlte
`monitoredior romeallealth.
`Medlcatlons
`Postraartetlrrg eirperlenee wlthtoplcal llSAI)s suggests lharpatlents with
`lEVll0‘ (nepaforrar ophthalmic suspension), 0196 may be administered h
`complicated ocular surgeries, rorneal deeervallon. corneal epithelial detects
`conjunction with othertopleal ophthalnrlr medications suzh as
`dialretesmellltus, oclarslriace diseases (e.g.dryeye syndrome),
`lteta-blockers, rarbanlc anhyrlrase Inhhlers. alpha-agonlsts, cydoplegtcs.
`rfeurrratuid arthritis, orretreatocularsuuerles wilhlnashortperiod of time
`lid mydrlatlrs
`may he at Ircreased rtstlor coneal adverseeventswhlrhmay tecarnesighl
`lfrnore than onetopical ophthahrlrrnerlrationlshektg used. the
`threaterrhgloplcal llSAlJsshou|d lreused with eautlonln these patlents.
`medicines must beadrnhlshrred at|east5 minutes apart
`Postrrrartetlrg erqrerlence withtoplal llSAI)s also ouggeststlat use more
`3
`DOSAGE FORMS AIDSTREIGTIIS
`than I day prior tosregery or use beyond lidays post-surgerymay increase
`Sterle ophthalmic suspension 03%
`patient risk and severity of corneal adverse events.
`l.7nllna4rnl|totile
`5.4
`Contact lens Wear
`inlleatnlhottle
`lLlVll0' lnepafenac ophthinle suspension), 03% should not he
`arlminlstered while using contact lenses
`t
`(0lTllAlllDl(lT|0|l$
`6
`AWIRSE rrracnorrs
`lEVlllJ' lnepafenar opht|alnicsurperrslon),0.i!6lsrnntrahdkated in
`patients with previously demonstrated hypersensltldty toany olthe
`Becauserlilkal sludlesuerondurted under widely varying conrltlons
`hgredlentsln the formula orto other NSAlDs
`adverse reaction ratesohserved lrirlieclirical sturiesoia rhrgcanmi be
`5
`WARNINGS Allll erreaunorrs
`clrerr
`romparedrotherares ii the cfrniealstudles oianother dung and may
`not re ed the ratesolrsenred In prattice.
`5.1
`Increased Ieedlag The
`6.1
`Sertrrrtsand Otherwise lnpertant
`With some norrsteroidal anti-irrllarnrnatory dugslndtrding lM0'
`Adverse leaetiens
`lneoalenac ophthahrrk suspension), 03%, there eirlststhe potential for
`lhelellrrrrlog adversereacllonsare distressed in greater delal In other
`haeasedhleerlng tlrne dueto hterlerenre with throlrliocyle
`seetlonsol laheln
`agyepattornlhere have been reports Ihatoculariyapplted nonsrerotdal
`-
`lnueasedfllee nqllrne lWornirgsandPrecorrllorrs 5.ll
`anti-lallarnrnatory tugsrnay cause Irrreased bleeding olocelartisues
`- Delayed lleall
`lllltrrilrtgsrrrrdfremrrilonsill
`flndudno hyphemal laronlunction with oeularsugery.
`~
`(ornoal lflerr;7liirrnvrgsarrdPremutionr 5.3)
`ltts recommended that llE\ll0' (aepalenac aphtlrainlt suspension), 03%
`61
`orularhleerse leatttons
`be used withcaution In patlentswitlt tnorrnh
`tendencies orwho
`Therrost frequently reported oudar adverse reartioas folowhg cataract
`arereozelring othermedhtlons whlchmay prolong
`eedhgtlare.
`surgery were rapsrdar opacly, decreased vlsual acuity, foreign body
`sensation, Increased htraocular pressure, and stlrlry sensation. these
`reactions orctrrtedln approtrinutely Sto Iottol patients.
`
`PAGE 1 OF 2
`
`LUHv$%HU
`
`IPR2015—01105
`
`SENJU EXHIBIT 2241
`
`

`

`Otheuotulandtetse ruttlum nmtruhg at an htleenteelawtunlnately
`I 10596h(|ulltd(l)tI]l|l(l1liltd!lla,(t1ll’£l|¢t1tlll,lIly£)!, Ild mngln
`autsthg. tllllll ulttonfort.otularlmeremln. «Ila: Dill. outlar pnlltus
`photoplualth, tearing and vtremdeladment.
`Sumeoltltese reattlons may be tluecouuequuenteol theutnttsutglul
`nrnteoxe
`6.1
`llermcularldveese leattlons
`llnn-ottianduntse reanlotus ueputed atanlnddenteofl to Nledudel
`leidadte,hypeulemlotu. tuIuseINoun|lttg,anlshtIlllL
`I
`US! It SPECIIC rortutanolus
`8.1
`Pregnncy
`‘lenlogedc Elfutls.
`nuquheqery (: Reptedurtlon stuaes pertomued wlulu nepalena:
`P
`hm tsand uatsatmldosesuuptolo utglltglday have revealed no
`Nd!!! often
`enltllyduleto nepalenae despie lhelnduttlonol
`tmteunaltouuidty.
`tthlsdose,tIean|ma| plasunaexponle to nepafent
`mdaunfenotwmppmulmle 7lland630tlmes human
`suna
`ezemuue attlueuecuuunmenled man uopltal
`ttalmu useful at:
`ml 208111 lblltivlles human plavnaeqlosuue mhlllls, retpttlilely. It
`nu, unalemallylnttdma 2 lllungllq weuensoclttedwlln d/steclau
`Increased pettttuplalttatlonloss. uedtuced fetal welfiuts and gmlth, and
`reuhtedfetzl mvtlal.
`Neplfenat luaslueerulmtntouosstlte placental banleutntmllteteare
`madeuutateald welleuuntnlled studlesln pregnant women. lletause
`anlnal uepuoduttlnn stellesaeenotalmyspredltllveolhtunaeu response,
`ILEVRO‘ (uepafent epluthalunlt sutsoeutslonlmfil shoululhettsedtluliny
`tug
`gegnancy umlyil tltepotenttalbenelutjtstiusthepoleuuhl rtslt to the
`llon-lentogenkilem.
`lleuaeseulthelumn elem uufpuomyanln N0! nthesis Iutluiuinq
`dngsonthe letalatdiaumhtvustemtdeslte
`tlrututttusattetlouuus),
`the um utIlEVll0' (nep:leutop|thah1l:mpensloe),oJlllduIlng late
`puegnanq should heavolded.
`83
`Nltshgldotlten
`Nepalenaclwttuetttllnllemlllollamtltugnulttsnntlmwnwhether
`tlisthuglsextetedluuhunulnllltllxausenaitgggsareetcretedln
`|l1lml11lII.(illllDI5’|fltHbEInldWMl!!ll
`'[nepatem(
`ophthalIultsua:eeslen).0J96lsadninIstetedtoanuxslugwoman.
`M Pehttlcllse
`lhe salety andeflettiveeets olll£Vll0' (Iewlenat ophtlualunlt
`suspenslon),03%Inpeulattkpatlentx below tluezgeoflo yeaushave not
`beenestatlslued
`8.5
`Gerllttk Use
`Nouuletdltiluenteslnsaletyand elledluutnets haveheenohsetved
`between eldeulyand younget patients.
`11
`Dliflllrllllll
`Il£Vll0‘(
`ophthlmlt sIspeuuulonl,0.l% ls: steu1|e.lopltal
`nuutustunlda anllhlhruutnalory tllslllllptodngforoplttluinlt use. Eadu
`nl olI.lVll0‘ lnepafenu eplutluinit mpenslonl, 0.l1l<oetduts3 leg at
`nepalenat. Nepalenetlsdeslylated dttll-Czllyisl-allillo-l~
`bentoylhemeneauetamldewltlu an enpllul lonnulaolttslluqtlzoz.
`The structural lonnutla ofnqualenx 1;:
`O
`N 3
`
`NH;
`
`llepienat lsayellcw tmtalline pumdetlle mulectlauwelglutol
`aepalenu ls 154.21.
`ILEVNO‘ tnepafenat opltllalrnuc sespension),oJ!t lssmied msteulle,
`aqueous suspension wllu apllanmlntelyul 611
`lheosumlaItyol|LEVR0'(nepalemtuphtIah1ltsuspeIslon),0.3‘llIs
`atupmulmatelylotl mtlstnllug
`hell ml of |l£Vll0' (nepafeutat ophthalnlesttxpuslonl. llltbtontahs:
`Mtlve:uuepalena(0.J1bInattluues:houI(at|d,p
`neglyal, taulloluer
`97lP,$oditndulnrlde,gutItguIn,tathotyrItetlt1telulusestdlumdetate
`dlsotln, Itenlalluunlum dulotideo.oos9t [|lttl¢lI31|VC),$0lillITl
`luydmide andlouhydmdtlotludd to aduxt pll and pemedwatet U117.
`11
`CIIIKII. PIIAIIMIOLOGV
`11.1 Meelalul 01 mln
`Met toolal oculat doslng. netualenau penetrates tltecotuueaand ls
`convenedlr/ocular tlsme hyduolasestoaunlema nntusletoldal
`antl-itflammatnry thug llepalenu atdatrlenat atelhwfillo lnhllit
`tlueatllnn uufptuslaglattdh1ll91nthase(tydooxygettaae).anenzyutle
`teqlietlfotpulsteglanufun pmdutlne.
`
`(
`
`ddlyduuahgnlMW I epalena
`'fil'owlugPt:‘I.a"te'ra'|““M|":ula
`n
`mte
`topla
`'
`I
`ophtlalmluuspeuuslou1).0J16. the ceutetutmlutus ulutepdenatand
`atuufemt peaked atamedlattlneoloslmnnd o.7sl»n, re
`tIIltntltDa1lIndDay4.lhetIleaIsleady-statetnuxlu
`Itatand
`louaItfenatwete0.ll47tlI169ngII1l.atud1.1310.49lneInL
`tespettluuellt
`llepaltmz attonceuutuatlum up In 3001 ngluuuland llllflnll at
`uvncemtlm wee 1000»;/ml dld notlnhlltt ulueln vltmunetahoituuu el
`6 spedfit matter mstntu ottytotlunmn P450 ((1?) lsorymn (WW.
`(1710. CYPRUS, (YPZD1, (YPl£l,atI1(YPlM).llteteltre, ulru;-dung
`htuutlnns lwolvltg Cmuedlmd melaboIl11to1(I1lllllll1alll9[
`admhlsteued drugs are Inluely.
`Nth Pl 901071 941514
`
`PAGE 2 OF 2
`
`Is.
`
`11
`
`tuoutcuuuuuontntousv
`cud
`tluu
`.
`|
`nogettesghngaenes
`131
`Nepalemu: hasnotheen evluated Inlong-tem emleogeuultltystedles.
`lntueated duoluosomal ahenattnnswete ulusetved lnchhese hamsteu ovary
`cells exposed!» vltmn nepalenatsuspeesleut llepatenatwas nuutunutagenk
`hthekuutesassayorn the mouse lytutphnmafetwatd mutation my Dual
`doses upto5,000 rnglhg dld not uesult It anlntteaseln the fomallonol
`rnlaonuudetted puulydiotnatlt etytlutocytesln ma In the muse rdaonutdees
`assayln the bone marrow llflnke.
`llepalem: dld notlnpalrlutillty when Idtnlnlsteted onlytomle and
`female mm} mgllu;
`ll
`allllul Slllnlts
`lntwodntultle mauled, nndomlzed tllnkal trhls 1| wlidu patlentswuedmed
`dallyheghnhg one day puler tn utmetsllgeiy. tontlnuted ontltetlq of
`sugeuy andlouthe fuust twnweelu uulthepestoperaI1vepeulod,ItlVRO'
`lnepaleeatopllhtinlt sttseenslonl. 0.316 demonstrated supeiunu tlltltal
`elllcaqronwedlolts uuehlde Inltutltug pnslnpeuatlve pain and
`lullulnatlen.
`ltealmenl eflett ova velitleler resolution oloularpaiu oauutedaseatly
`alday 1 post-uuurgetgtlreztmeet effett wetvelltk la resoluutlen of
`irllamrmtlen vmslgelhmtlyhetteu than vefldeinbolh student day
`7anddny1lpmt-surgery.
`lnflunlmlon and Oeullmln llestutttlon llestls of Iepalemu:
`opltllnlnlmspuuslou. 0.316 rem Veluldeat Bay It Putwgery
`(All-Iadutlzed Populatlen)
`
`SOIIOIHINI
`UIIIIUIID
`
`YKIKWW
`
`Ulunuuueuunuuu-m-qmnuundmema-mullml:-nynmuuqqm
`dqllliewulnrluuuhtdtllthm
`mum uslltpateruqtnrmduunumemnlu-tattle Iemumemmuemil
`eueunugapupuuxaguuuun
`I6
`lfllistflllih/Sllllllfillll
`lllllbllllfi
`IEVRU‘ (neplenuut nptutlalunlc uspenslon). 0.3% lmpslled lna whit.
`ml. lumdemltypdyelltflene DROP-lAllEll' lspemv vdtln mtural hw
`lmttt
`tkumiuuvtun M
`were kmmurresmlel
`nunmwpwnuutuumyu.tm:re3te'yu.':ep5’uauwmaunmu
`bandateundtlleulosuuteandneckatea oftlse pztlage.
`1] unllnlnlbottle
`lI)((lJ65-1750417
`Jnllndmlhuttle
`IIIOMS-ITSIHI
`Stmge: Stoteat1~lS‘( 136- 77' F].
`Plated tom llght
`17 mum couuusttuuus euromnou
`17.1
`Slew otllelayeelllulhg
`Patientssttoull helnlomed oltherumlulilythatsltm Illdelayedhealng
`mayoccumtlle using nonslerolda antlinllanmatouy duugu uutsmsu.
`17.1 Anldhg Contenbatlen oflhePm'uet
`Patients should he Instructed to avoid alowlng the up uul the tispenxlng
`nnulnertuoruuct tlteeye ousumundhgstmtures bemsethlutouuld
`(methe thto bemnetontauninted by common hacterlalunown towlse
`unlau mlettltutun. Seuhuts darmge totlteeyeaed subsequent lassoltlslon
`mayuesult lrnm my untamiuateduolutiouut
`Use ollle same botllefor hotheyesls not tecmnended wlthtopkaleye
`mptthataueusedlnassadatlonvtltltsurgety.
`17.)
`(once luulllev
`IlEVll0" (nepalemu: ophthalmlt suuupenslnI),0.3% should Iothe
`adrnhlsteted wltlle vreauhg contact lens.
`17.4
`lntemnent Oulrhndllold
`Patlentssluould headvlsed Iltatlltleydevelopanlumtuunutlotulau
`tendlon (e.g.. tuauma, ou Itfettion) or have ocuula slugety, lheysluoelul
`|mmedhlel/ seektlltlr phyuklmadtlte mtemlngthetontinued me ofthe
`mull-dunettmtahel.
`17.5
`(0I(oIIullTqlkJ10€lIllTl!ll”
`lfmue Ital one tnptal ulpilhdtlult medlutlon lshehg Ited, the medidnes
`must headunlrlsteuedat leasts Iilutesapatt.
`17.6
`Slalue lllel Ielue llle
`Patlentssluould be Inmxted to skate wel belnreeath use.
`
`US. Patent Nos 5,47$,034;6.l)3,609.' and 7,169,767
`'alndemaut of llovattis
`
`Alcor?
`MW MBOMTORKS, |||(.
`FoItVlntth,lenu76134 USA
`0 lllllllmttls
`
`