............... compmpytunoug ..............._........
`tlypersestsittvitytoarry oi theiryedients in Itelormrlaoctoother
`it5AiDS.(-ii
`-—-~~~~~~~~~-wwkitittiifisitili Pitiuiilltlis~~~~~~~~--
`lnrreased bleedlngtine dueioiaterference with thrornhoryte
`awegatior (5.1)
`Deiayedheallng (51)
`Corneal elfects 1ncludngireratitis(5.3)
`----————————-ADVERSE rrnrnorrs-——~---——-~
`Mostcommonadvene reactions (5 to 10%) are rqasular opacity,
`decreased visual aruity, foreign body sensation, itrreased ‘mtraoruiar
`pressure,and stirty sensation (M)
`loreport 5il5PE(iEDAi7lIEiiSEil£K710iiS,rontartAicon
`ldroratories,inr.at1-800-7574195 or Flihat
`1-WFM-1wBu
`See17ioePAT1Hii(0iiiiSEUii6liiFOIMilli0ii
`lieviserl: 02/2014
`
`iitGiit.iGii‘i5 iii‘ Pitlstltilliifi Itiitiitllimoil
`these hightidrts do nottndude all the Irrfonnation needed to
`use Il.Eiiii0' (rrepaienarophthahnir suspension), 0.3% saieiy
`and cflectively. See hrilpresrrling intocntationfor |lElr‘il0
`ilepaferraropltitaltrtir suspension), 0.3%.
`|LEVii0' (nepafenar ophthalrnirsusprnslon), 0.396, topil
`ophthalmic
`IIIH ll.S.ilnrmal: 2005
`-----~-—-- rttmunorts Am truce--—~—-—--~---—
`I.E1Iit0' (nepalenaroptrlrdmlrsusperrsion),0.396 is anoesreroiriai,
`antiirflarnnratoryprodrug Indratedforthetreatmentolpaiearrd
`irlisnvnarion assoriatedwih ratarartsurgery ii).
`------«----— DOSAEAND liitililsmiititt----~-—~~-~~
`One dop otILEVltiJ'(nepalertarophtha|mir suspesrsion),tJ.39isltorld
`lteappiled to the afiertedeyeone-time-dai|yheg'nning 1 dayprior to
`catarart surgery, rontinrredorttlte day of surgery and throudt the fest
`lweeks of the postoperative periodktadditlortal chop should be
`adninlstered 30 to 120 minutes priurto sugery.(2)
`~~~~~~~--— DOSAGE F0lit5Atl)5lltilGlil5-----~---
`Sterle ophthalmtrsuspension 0.3% 1.7 mL in a
`rirnlhottieand 3 ml inat ml bottle. iii
`Flll PIIESCIIBINEINFORMATION: (0liTINTS""
`1
`iillil(ltTi0liSitiIJliSiiGE
`2
`oosnornrmoraarrsrrtrtnorr
`
` 8
`
`ii$ElilSPE(|F|CPOWlA1|Ml5
`8.1 Pregnancy
`8.} NursingMothers
`&4 Pediatrirlise
`8.5 GeriatrirUse
`liESOtlmiiii
`<llttiut.PiiMtiMt1iI.odt
`17.1 ilechanismoiirlion
`12.! Phamarothetirs
`iioitalllultolitiiltifit
`13.1 (arrinogerreslr. hirltagenesis, lmpaimtent oi
`iertiliy
`I4 <I.1iiiul5TUIitES
`so rtowstrrrueo/sroruartttn itdliillitc
`17 errrntrrotntsutrtortronurrrotr
`17.1 Sioworbeiayedilealing
`17.2 Avoidingtontanlnationoithe Product
`17] Contartlenswear
`17.4 Irrterosrrentoruiartundiions
`17.5 (oncondtarrtiopird Ocularlherapy
`17.6 Shielllelllielore Use
`"Sertiorrsor suhsertioesomitted from thefel prescrlhhghiotmatiottate
`notlsted
`
`Flill PRISOIIIING Ilfilifllliil
`5.2
`Delayed leaihp
`iopiai nonsteroidal anti-lnharnraatorydws iliSilDsl hritrdinq llEVil0‘
`I
`IIIICATIONSIIIDUSAGE
`(nepaienar ophthaknk suspension). 0.3%. may siovror delay healing Ioplul
`lEVii0' lrrepalenar optrtitainirsrrspernrlrrtimiils indicated for the
`rortiussteroidsarealso iraown toslowordelay healing. Concomitant Iseof
`treatment oipah and irllamrnation associated with catarartstlrgery.
`toplral NSAIDs and topical steroids may hrrease the potential for healng
`I
`DOSAGE Alli) MNIIIIISTIATIOI
`prohlernr.
`5.!
`(orneaiflierts
`2.1
`Iecommenled ilosllg
`Use oi toplral itSAiDs mayresult It kerat'nis.|nsomesusreptr1r|e patients
`one drop oil1EVflD' irrqralerrar optrltaimtr suspension], tijststoutdhe
`rorttintred use oi topic! itSrilDs
`result In epithelial irreirdown, corneal
`apples] to the allcried eye rrrreilrrretialyieglrtrena 1 day prior to
`tirhrrmrorneai erosion, rorneal I reratlonorrorned perlorationlhese
`ratacart stmyery, rontirsted on the day oistrguy an through Ire fest}
`events mayhesight threaterinp Patients with evidenre oirornealeptthellai
`ween oftttepostrperatrre pa1oci.Arr adtiittonaitirop slnuid he
`atlministertti so to 110 nhmes priottosiruery.
`hreaidown should Inrnedlately dlsrontioueuse oitopkal liSAll)s trdudirg
`lEVii0'(nepalenar opi1tltalmicsusperrsloni.i1!9iand shortidberloseiy
`1.1
`lisewlhfilherloplui tipirthalrlir
`morrrtoredtor romeaileaittr.
`Medications
`Postrrartetirrg etrperlenre wlthtopiral iiSAI)s suggests ihatpatlents with
`lEVit0‘ (nepaionac ophthalmic suspension), 0196 may he adniristered h
`complicated oruiar surgeries, rorneat deeervation. corneal epithelial deierts
`ronlunrtton with othertopiral ophthainrir medications surh as
`dialretesmellltus, oclarslriace diseases (e.g.dryeye syndrome),
`beta-hioriers, carbonic anhydrase Inhhlors. alpha-agonitts, cydoptegirs.
`rteurrratoid arthritis, orrepeatoruiarsurgeries withinashortperiod oi tlrne
`ltd mydrtatirs
`may he at Irrreased rtsiior roneal adverseeventswhlrhmay iecornesight
`tfrnore than onetoptral ophthahrlrrneclratiorttshektg used. the
`threatenhplopirai ilSAlJsshou|d ireused with rautionln these patients.
`medicines must beadmhlstered atieast5 minutes apart
`Postnartetlrg errperlenre vrithtopiai iiSAI)s also suggeststlat use more
`3
`DOSAGE FORMS AIDSTREIGTIIS
`than 1 day prior tostrgery or use beyond iidays post-surgerymay increase
`Sterle ophthalltir suspension 03%
`patient risk and severity of corneal adverse events.
`1.7tIlina4ml|tottle
`5.4
`Contact lens Wear
`lnllaainlhottle
`|LlVlt0' (nepafenar ophthinir suspension), 03% should not be
`administered vrhlie using contact lenses
`t
`(0lTiiAill|ii(lT|ti|l5
`6
`AWIRSE turrrorrs
`lEVitiJ' lnepafenar opht|aiIrirsurperrsion),0.3ttslsrnntraIrdirated in
`patterns with previously demonstrated hypersensitility toany oithe
`Berauseciilkai studiesuerondurted under wideiy varying ronrltlons
`hgredlentsln the formula orto other NSAlDs
`adverse reaction ratesohsesved irstlreciiriral sturiesofa rhrgrannot be
`5
`WARNINGS MID PIKMJIIJIIS
`clrert
`romparedto themes It the cfrrtiraistuctles olanother dmg and may
`not re ert the ratesoirsenred Ir prartire.
`5.1
`Increased Ieedtng The
`6.1
`Serirrusand Otherwise lnportant
`With some nonsteroidal anti-inllarnrnatory dugsindtrding lM0'
`Adverse leartiens
`(nepaienac ophthairrk suspension), 03%, there esdststhe potential for
`lheiolirrrring adversereartionsare disrussed in greater detal in other
`hcreasedhleeclng tlrne dueto hterlesenre with throlrhoryte
`sertlonsol laheln
`agyepation.1herettave been reports thatorulartyappiied nonsterotdai
`-
`lnrreasedillee nqlime lWornitgsarrdPrerorrtiorrs 5.ll
`anti-tniiatnrnatory tugsrnay rouse Itrreased bleeding oiornlartisues
`- Delayed iieall
`:rrrunrtgmarnmrrrronss.2)
`flndudno hyphernal ioronlunctiott with oeularsugery.
`~
`(orneal lfie(t=?iiisrnhgsr1rrdPrer‘rrtriions 5.3)
`it is rerommended that llE\il0' lnepalenac ophthaintr suspension), 03%
`61
`tiruiarhdvesse leartions
`be used withrartion in patientswith inorrnh
`tendencies orwho
`Therrodt lreuuentiy reported ortlar adverse reartioas folovrhg cataract
`are receiring uthermedhtlons whtrhmay prolong eedhgtine.
`surgery were rapstdar oparly, decreased v1suaiarrtty,ioreiyn body
`sensation, Ierreased htraocular pressure, and stiriry sensation. lhese
`reartions orrurredtn approtrimatety Sto Ioitoi patients.
`
`.a_anu.-
`
`1!
`
`iterommendedboslrp
`L1
`Z2 Usewlhiitheriopira Ophthalnir
`Medications
`3
`IJOSAGEFNIMSADIJSIIIEIIGIIIS
`ah
`rortmetorrsnorrs
`5 VMiiNIii6SAilDPltE(Aimiili$
`5.1
`lncreasedlileedlnglime
`5.2 Deiayedlieailng
`5.3
`(ornea|Eiferts
`5.4 Contadlenswear
`6 ADVEIISEREICIIOIIS
`6.1 Seriousandotherwiselmportant
`Adverselieactions
`(:2 Orrtarrtdvecseiiearttors
`£3 iionoruiarhdverseiteartions
`
`Page 1 of 2
`
`LUPIN V. SENJU
`
`IPR20l5-01100
`
`SENJU EXHIBIT 2241
`
`

`
`Othetotulandeetse rutttum nttunhg at an htleenteelewmlnately
`I 11)596hl|tltd(otI]lh(l1liltdella,(t1tIttt|¢dtlll,dly¢)!,Illl mngtn
`attsthg. cellar tlttonfort.oeularlmenmla. «Ila: nall. outlet pnllttts
`photophahh, tearing and vlremdetadment.
`Sumeofthese reattlotts may be theconseqttenteot theutnttsuvgtul
`nrnteon
`6.1
`Ilononlamtvene leatttons
`lton-ettiandtntse reantons teputed etaetnddenteofl to Nleduded
`leadathemettemton ltlU$¢lN0tll|fitg,itIl!htIll|L
`I
`US! It SPECIIC Polltullolts
`8.1
`Pregnncy
`‘lenlogedc Elfutts.
`nuquheqery (: tteptodurtlon stuaes pertonned wtth eepatena:
`P
`hm tsaed tatsatmldosesuptoto utgtttglday have revealed no
`efldenee often
`enltttydtteto eepatenae despie thelndualonot
`tmtetnaltottidty.
`tthtsdose,tIean|ma| plasmaexponle to nepafent
`atdatnfenxwmppmtimte 7t1and630tlmes human
`stna
`eztmme attttetecammenled man topltat
`tlttltnlt useful at:
`ml 20nd lhlltivltds hutun plavnaeqeosuee mhhtls, tetpttlitely. It
`nu, tnalemaltylnttdma 2 ltttngllq wetensoclttedwlln d/steclat
`Ittrused pexttnphtttatlonloss. teduced fetal welfitts and gmlth, and
`rettttetlfetzl mvhal.
`Neplfenat ltaslteeruhountouossthe placental banlettntmllteteare
`noadeuttateaed welkontnlled studlesln pregnant women. lleuuse
`anlnal teproduttlnn stellesatenotalmyspredlttlveolhtunaet response,
`tLEVt10‘(nepafeett ephthalmlt susoenslonlmfit shotltlhettsedtltliny
`ten
`gegnancy onlyit thepntenttathenehtjtsthsthepotenthl rtslt to the
`Non-lentogenkilem.
`ttetaeseulthelmn elem ntptomyanln htos nthesis Ittltitinq
`dlI§$01|lMHi|(dMlUliKl|ll9[!ltm(dISllO ttrtttthmttetlomsl,
`the ttne utIlEVlt0' (neptleutop|thah1l:mpensloe),oJllldtIteg late
`ptegunq should heavotded.
`83
`Nltshgflothen
`Nepaiettactwtetetttllntlemlllollatntlttgnulttsttntlmwnwhethet
`tlisthrghmmhhummhmmmmgsmemtdtn
`|ItmutmIt.titttlotslwtIdhetmdsedwhtttl
`'[nepatene(
`opttthalItltsumeeslen).0J96lsadnieIstetedtoanusltgwoman.
`M Pehttlcllse
`the salety andefletttveeexs ottl£Vll0' (Iewtenat ophthaltnlt
`suspenslon),03%Inpetlattkpattentx below thezgeoflo yeashave not
`heenestablstted
`8.5
`Getllttk Use
`Nowetdltiluentetlnsaletyand elledlvenets haveheenohsetved
`between eldetlyand younget patients.
`11
`DISCIIIFIIOII
`Il£Vll0‘(
`ophthlml<sIspenslonl,0.l1t ls: stet1|e.lopltal
`nonstemlda antlhthrtttnatoty tllslllilptodngforopltthinle use. Eadt
`nl otI.lVll0‘ lnepafenu ephthahtit mpenslonl, 0.l%<oItdns3 leg at
`nepaleeat. Nepalenetlsdeslytated dtentaltyasz-anirto-L
`hentoylhenzteeeatetatnldewttlt an enpltut tonnulaotttstttqttzoz.
`The structural ionnula ofnqtalenx It:
`0 N3
`
`NH;
`
`tlepienat lsayellcw tmtallitte pwdeelhe mulectlatwetghtot
`nepateeu ts 154.21.
`lLEVlt0" tnepafenat opluhalmtc uspenston),o.t!t tssmied mstettte,
`aqueous suspension will apllanmlntelyd 611
`the osmolaItyot|LEVR0'(nepatenatuphtIah1ltsuspeIsloe),0.3%Is
`aaptulmatelylot) nttlsmlhn
`hdt ml of |l£Vll0' (nepafenat ophthalnlesttxpenslonl. tlltbtontahs:
`Attlve:ttepatena(0.J1bInattlttes:hotI(at|d,p
`negtyal, tattlolter
`974P,$oditndtlnrlde,gttItgtIn,tathoIyrItetlr1teIIlosesudlurn,edetate
`dlsotln, henzalltuntum dltotide0.m59l [|tttS¢lI31|Vt),$0tillITl
`ltydmide andlothydmthlotludd to aduxt pH and pumedwatet U117.
`11
`CIIIKII. PIIAIIMIOLUGV
`11.1 Metlalstl at lttln
`Met toolat octlat doslng. neuafenat penetrates thecomeaand Is
`convenedlr/outer tlsme hydrolasestoatnlettaca nnnstetoldal
`antl-itflammatnry thug llepalenu atdatrlenat atethwfitto lnhllit
`theattlon nfptustaglartdh1ll91ntttase(tydooxygenaae).aeenzynle
`teqliedfotptlsteglantftn pmdettloe.
`
`(
`
`ddlyduahgnlMW I qtafem
`'fil'owltgPt:‘I.a"te'ra'|““M|":ua
`n
`mee
`topla
`'
`I
`ophthlmluuspenslon). 0.116. the attentmluns ttltepdenatand
`amfemt peaked atamedtattmeotostmnnd o.7st»n, te
`ttIhntltDa1lIndDay4.Ihettteatsteady-statetnuxtu
`Itatand
`lom1fenatwete0.ll47ttl169 ngltnl. and 1.13 1 0.491 n1lnL
`tespettlvellt
`llepafnue attnncentratlmt up In 3001 nghnland amtenet at
`mncemttnes wu 1000»;/ml dld notlnhhtt tlteln vltmmetahoimt tt
`6 spedfit matter mstntu ottytotttnma P450 ((1?) tsorymee KYPW.
`(W10. CYPRUS, (YPZD1, (YPl£l,atI1(YPlM).lhete!tre, tlrtq-dtug
`htuuttnns lwotvteg CtPmedtmd metabolunottommttantty
`adtnhlsteted drugs are Inltety.
`Nth Pl 901071 941514
`
`Page 2 of 2
`
`11
`
`tlotlalttultontnlofit
`and
`It:
`Is.
`.
`|
`nogettesghngaenes
`131
`Nepatemc hasnotheen evluated Ielong-hem emleogenltltystedles.
`lnteeated dtoltosomal ahenattnnswete uhsetved lnchhese hamstet ovary
`cells exposed!» vttmtn nepateearsuspeeston ttepatenatwas nottnutagenk
`htttehnesassayotit the mouse lytnphnmafetwatd mutatlne my out
`doses upto5,000 rnglhg dld not result It anlmeaseln the fomattonot
`rntannudetted polydiotnatlt etythtocytesln ma In the muse rdannudees
`assayln the bone marrow ufmtte.
`llepalem: dld notlnpalrlutitlty when admtntsteted onlytomle and
`female mm} mgth;
`It
`attltul Sfllntts
`lntwodotthle mauled, nndnmlzed tllnkal trhls 1| wlich patlentswuedmed
`dallyheghnhg one day utter tn utat«x1sIIg¢ly.tontteuedontlteda/ of
`sunny andtotthe fust tvmweelu althepestoperaI1vepetlod,IuVRO'
`lnepafeeatoplthehtlt suspension). 0.316 demnsttated supeetnt tlltltal
`ellcaqronwedlolts vehlde Intmttng poslnpetattve pain and
`ltllulnatlen.
`treatment eflett ova velitleler tesohttlun eloularpah oautredaseerly
`aldey 1 post-uttrgergtlreztmeet effett wetvelltk fa resoltttlon of
`irttamrmtlon vmslgethmttyhettet than vetddeinboth student day
`7anddey14post-surgery.
`lnflunltetlon and Oeullmln llestthttlon Rents of Iepalenac
`ophthetntmsputslou. 0.316 rem Vehldeat Bay It Putwgery
`(All-Iadutlzed Poputatlen)
`
`SOIIOIHINI
`UIIIIUIID
`
`YKIKWW
`
`(llutmuemnuuu-m-qmntundunmn-muttmlnmrepuqqm
`dqllliumlnrlumtdtllthm
`worm tslltpatertugtnhlnttule-numnlu-nettle Iemtdtemeuentn
`aueuugquputeaguunn
`I6
`lfllistflllih/Sllllllfihlll
`HINDIING
`IEVRU‘ (neplenu nphtlaltnk uspenston). 0.3% lmpslled tn: whit.
`ml. Ivudendtypdyethfletu DROP-lAllEll' lspemv vdtln neutral hw
`lmltx
`tktmivuvtst M
`were kmmtrresmlet
`ntnmwpwmtmnmy).tm:re3'te'y..':tp«a7tauwma.nmu
`hmdateundthedonueandneckatea ofthe pztbge.
`1] mllntnlbottle
`tI)(UJ65-1750417
`Jnllndmlhuttle
`IIIOMS-ITSIHI
`Stmge: Stoteat1~lS‘( 136- 77' F].
`Ptoted tom llght
`11 mum Cotlltslltls uromttou
`17.1
`Slew otbdayedltulltg
`Patientsshoell helntomed atthermhlitythatsltm ordelayedhealng
`mayoccumtlle using nonslerotda antttnttanmatoty dtugt tttstlxl.
`17.1 Anldhg Contenbatlen oflhePm'uet
`Patients should he Instructed to avoid alowlng the tlp at the tispeexlng
`nnulnemcontxt theeye otsumundhgstmtures hemsethlstottld
`(methe thto hemtetontamhated by common hacterlaltnown towlse
`unlat mletttuns. Sethus datmge totheeyeaed subsequent lassofttslon
`maytesult from my tllillltlitaletflflhliottl.
`Use otlhe same hottlefot hotheyesls not recommended wlthtopkaleye
`mptthatateusedteassadattonvtttttsurgety.
`11.3
`(outed luulllev
`ItEVll0" (nepatemc ophthalmlt suspenstnI),0.3% should eothe
`adrnhtsteted whlle vreathg contact lens.
`17.4
`lntemnutt Oulrhndtiold
`Patlentssltould headvlsed tltattltheydevelopanltmttunutlotular
`tendlon (e.g.. ttauma, 01 Itfettiott) or have ocula sugety, lheysltolld
`Immedhteh seekthtlr phytkhnkadtke ttmmlttgthetontinued me ofthe
`mull-doxettmtahet.
`17.5
`(0I(ttIIllllTqtkJ100IllTl!ll”
`lfmue Ital nee tnptal nphthdmlt medlmlon lshehg Ited, the medidnes
`must headtnlrdsteredat leasts Iitucesapatt.
`17.6
`stake lllel Iefue Use
`Patlentsshould be Inmxted to shale wel betnreeath use.
`
`US. Patent Nos 5,l7$,034;6.l)3,609.' and 7,169,767
`"ITM!mltiof|t0Vif1is
`
`Alcorh
`MW MBOMTOIUU, |||(.
`FoItWntth,lenu76134 USA
`0 llmtlmttls