WM'fiMfll-II‘MJ
`4m?
`{SSH arm-cs3:
`
`Short communication
`
`Effect of oetirizine, levocetirizine, and dextrocetirizine on
`
`histamine-induced nasal response in healthy adult volunteers
`
`- Getirizine, an effective Hl—reeeptor antagonist. is a remains
`mixtureoftwommiomeutlevoeetirizine (Reunfiomor) and mm
`{5 enmtiom).
`m To investigate the phannaeologie activity of the mo enantiomers of
`oetirizine. we conducted a randomized. double-blind, lbw-way. crossover awdy
`wmtheeitemofneannmtafithSmglevocefirizinASmgdexmfime,
`and 10
`nigoetirizineandmatched placebomnhistamine-induoedchangeainthe
`Whitehall
`nasal airways of 24 healthy volunteers. Four home after a aingie
`subhetsmehalhngedby
`”"1 “m “m "n” “mm “M“
`'
`in both nostrils. Nasal
`oomtrationsmomo.25to32nigmnof'
`Wmmawedbypaasiveanteriorrhinommomryfim).aad
`channinhistaminethrssholdwereealcalatodtomherwflhtheabsolute
`numberafsnemsafisrmhrhsllenge.
`tly attenuated the histamine-
`WMIevnmth'izinemdoetififineeigniflwn
`emedian
`Momdinereaselnmalairwayrefimmbynearlymmom
`moms: Papmm’mo 129M 1.31 Papermamreapetaivelyhrthe
`maximfleummtiommdtheyconoonfimndyinereamdtheflstamine
`thmhoidbylbnrfoldmomfito 32mgml).eomparedwithplaoeba.8neeriug
`mahomwdhybothiwooefirizineandoefirizine.flm,thue
`anfihistamnficefl'hetswerenotseenudthdextroeefirizim.
`WWSM
`shamaaimilaraotifityoflwocefirizineandmdflalneon
`the inhibitionofhistalnine-induoed hereasehinasalruistanoe, indicators that
`the antihistaminio properties ofeetlrizlne are probably attributable to
`levooetil’izim.
`
`new flaw,
`on. It: Emma-1’
`'WUnWflhna-sm’wl
`H
`.
`,
`m :-
`WDIMWMHIMMM.
`Him
`
`W:mm realm
`WMMH‘ID
`
`mushroom
`momma
`
`mammals—mm
`
`
`
`'I‘herohofhistaminehasbeenweildommtedinthe
`pathophys'tology of allergic airway diseases (1—3). An
`mmmdenmdingomthehmfewdmdaof
`thepethomicrohofhistsmineinallergiedisemhas
`beenassooiatedwiththedevelomtot‘spedfioand
`highly efficacious Hl-reoeptor antagonists for sympto-
`Wordiefnfalifigicdmlasrficuhrlyseasonalwd
`perennialallerglcrhinitisaodnrtioaria(4-G).Theflg-
`receptor antagonists. generally called antihistamines,
`have broadly been classed into two categories.
`the
`first— sari second-generation antihistamines. The first-
`motion antihistamines have been associated with
`mudnermayxtemand anticholinergio side-effects.
`particularly aedationand impaired payehomotor antitr-
`itymaodarethereforenotnraehuaedeurrentlan
`contrast, dismantled-moon antihistamines,
`snohaseetirifineJoratadineJndfexofenadinethibit
`fewer sedative and antieholinregic effects and have a
`rapidwsuofaetiommafinsthemidealforsympto-
`mtiereliefoftbeallergiodiaease.
`
`Controlled trials in patients with manual and
`perennial rhinitis have demonstrated that cenrizine is
`effecfiveinattenuatingnasalmdlorocularsymptoma
`resultiasfi'omexperhnentalornsxuralalhrgznerpo-
`m(8-11).Howewr,oetirizineiaaraomatemiatareof
`two enantiomars:
`levoeetirizine (R enaniiomer} and
`democe‘tirizine(Smmflmr).Theahnoftbisetndy
`wastoinvesfiaatetheaetivityofthesetwoenantimers
`on histamine-imd changes in nasal reeisnnoe and
`sneezingio healthyvolumeera.andthenmoompare
`these effectswith those ofcetirizine and placebo.
`
`Mliwm
`
`Sultana
`Mmeiglnheahhymflerfiovoluteersmeamliedinlfi
`My.0ftm.24umem(nhemm15tmhjapdm
`m(memege29yem}wmpletedtheatudy.11wymem
`Free and head name] May on routine luau-tale.“ and
`bioehmiulhbodmtmmoffiwvdmmmoked
`
`339
`
`Apotex, Inc. (IPR2019-00400), EX. 1005, p. 001
`
`Apotex, Inc. (IPR2019-00400), Ex. 1005, p. 001
`
`

`

`Walnut-i.
`
`mmfiwdpmaaayorhuahamafmfl
`They did 11111 Like my medication.
`mwmfimMmmzmMm‘flmmt
`Aflwlmflnwwfimhfomdmmtpfinrwmuudy Thu
`mdymwmdhyhcthimmmmimadthcmfimity
`howiflI-L mumdmmmmkm Wise
`UnivufindllmDJflfiam.
`
`51011111951111
`Mm arm 601.111thWW. rum—way.
`mmnndy. Eachvolmrmutered 11-1le
`schadubmmdwlmdemflsmmdmsm
`
`flwamhmmnmmmm
`mummrmmmmuxmw
`luhlmmhnhrashuiflmulfionflmmimmm
`mummmumm)mmw
`«ummmwwmmmm
`Tomiuimherhemflmofthemmdfimofm
`ommmmmwmmmm:
`mrdufindmemeARmdhmgemm
`minuifldthmughoutnflvifltnfll. 1311!:th
`m applhd w 3!] mm who bid a W nasal airway
`maf418hpflm'hflmdjdmhmuehymthu
`mmmmm
`affllmtrdnlufion.
`
`Mammarlmhmuinnudmmum
`mfimd<tm¢h§mmdomiadwmmm
`mummmhmmmmw
`fifisuimflmmwmmdhqmmhymhcmu
`mmmmmumdmnmmnm.
`Vonmmmumdtarmlmwwm
`
`mahflmmflaflwm mmfim.a.ad,al1bdngwall.flny
`mdmmpohmutoatmdthrcfiuicforkmzfisflma
`Melamine «1—14 days.
`
`mm 111 nasal resistance
`
`mmmmflbfl’flmWWW).
`upwfioulydum‘badt!415fiufiy.ufiudfidlwd_’2§flnmfsm
`MWamnhintommlrfi. mmhdmdbyfln
`“Myanmnmkurfiwuamkvdofmnm
`mmmumumupnuaihhperm’fgu
`mwmmmcmmmmd
`W{Ifl.hfllW,mflMMw-n
`mammnmmsmmmmm
`hmmfimmfirMmmuwm.m
`erdudmmfmmflmmw
`nbwquuflymdiuthefimlsfiuwmbdm
`
`Hisminemalpmominntast
`mmuus.e..s.1 2.4.3.15,md32nam1m
`
`sodium
`mahuminfilfihfil mandphandwmmwmmfw
`Maxim
`MMWWMWMWW
`ulthlfleyernehfl‘nwaiw.flsdfim.m)fla BLT}:
`“WmmmmmfimMmmmm
`thwflnvdmt-n'smmmnm. mm
`whoddxlllulhr‘lfllfihrughm
`wwwivdypm
`fur-1:11 now-fl maymm mmwmhm
`mm
`
`“111:1.Wmduff-unimmh11111411111n“MmJnqunsmmmmmvanmmmmmuu
`mmm-huwn-nmw
`Nullivwrl'mmhwm'h
`
` WWI-Uni} MW Wit-aw WW WWII Finland?
`1
`0.75
`I."
`I.”
`ll.“
`EH1
`1
`DJ!
`0.8:
`I!
`III.“
`I)”
`t
`1.12
`DH
`“3
`1.12
`m
`LL!
`1.41
`1.91
`
`um
`
`3
`
`1.11
`
`125
`
`11
`
`
`
`1.5!!
`
`2.115
`
`on
`
`mm
`
`'umlmmmmm
`Wwa-mwwummmmmwmmmmkmnmuw
`”154F430
`mam:
`“Ml :klflfi
`Mam than
`
`3110
`
`Apotex, Inc. (IPR2019-00400), EX. 1005, p. 002
`
`Apotex, Inc. (IPR2019-00400), Ex. 1005, p. 002
`
`

`

`mmmdmm
`‘l'lhll 1'. Writinaimmmhthmlflwww.5mmamw5mmmmmmmmmmmm
`mmawmm1mmemmmm-ammm
`
`
`WNM‘M-fim—DD
`
`“swung-an.-
`
`datum—amt:-
`
`30-
`
`uhmMn—IMH—
`
`Wmmmmwwmmmaammmmmmewmmmmd ”Nannie-en
`
`mob-mm
`Warm WePsm
`Writ- Icclt‘l'il‘ll ”all!
`With: shadow-(Elms
`mm wafifiuhficflsmfl
`Within wmbflm
`Mall «momenta
`
`MMMmimdoflmiaafiartbeimPAR
`mtfidfimSmhaafierdxbefamhnuflhepmdm
`WWNMJ.
`
`Statilt'naiaflatvsia
`Thempkahammmdhyapmahflamndeneonfl:
`buiscfaprevimamflyfdanMNeJDnth‘nhaflahmeathmud
`Mahmmtrhhufivedmulemuwhmmm
`mqtdredlodatccttlipificlmdmbiinginhimminafiuuhfldn
`mevalwithm motorist;
`Reliable
`WHEN!” tl'lalludytoaflowfwdawom
`All data were expressed as median valuea, and the overall
`mine-nae of chance in hm Whom. and seem.
`andthemherofmmmn'manymmmmmd
`wmmm.uummpmmmm
`“Wmmmmwmuwmflthe
`mkflamnmhudmmmm yam
`“[lflflflfiflfilmm
`mm: ml
`mums )onm
`mafiblenficroeompimr.fio-
`Mmmmmmotreunimmmu
`significant.
`
`Of thezavolunteers recruited mtetheamdy, reenltefor
`foursobjectawereaotinclodedintheovcralleficaey
`analysis. Oncaubjcctauifctcdfromanepisodcot'
`bmnchifieaflerviaitd-andpt‘iortoreocivingthelaat
`mutvieits. and therd'ore did not empkuthe
`catinc study protocol. The other three subjects. despite
`rhethmthattheyweefigiblghkdtoreactto
`hiemineahowingahimmhtethmhold concentration
`of >321):me ateverytreatmentvistt. mms
`mthereforeconaidexed to benot evaluable, and these
`volunteeremereplaced.
`
`Efieuofweemunmaireelstam
`
`Maaanammtofnasalah‘way resistanceuaderplaacbo
`demonstrated that this was iota-cased by histamine
`adndnhmflonina
`mannerflahlel)
`Treatment with bath cetirizine and levocetiririne
`Wmemummmmwmm
`innaaalairwayreaistameatthemaximaleomtraticn
`ofBZmymIvdlhalmoetSWcredocfimoverplacebo
`(Table 1). Bmhuefiflzineandtevocefiriatnewerefom
`to attenuate significantly the effects of histamine at
`oomfl'afimaofzsmd EIEWJWJH
`eontrastJreaanentwith dmreeetirizinedidnot show
`any significant effect on histemhe-indmed increase in
`nasalairwayreaietanceaacompuedtoplweho.
`
`Effect at treatma-a: en melamine 111mm concentration
`
`Aficrtreamentwithplacebo, Mild-(GMJanbjem
`
`demonstrated a hiataminethreshthreshold concentration of
`581mb! Treatment with oetirizine levocetmzlne
`and dextoaetiriztne decreased the number of subject:
`demonstrating a histamine threshoid concentration of
`$8 myml to 7:24 (29%), me (21%), and 13124 (54%),
`reapecfivcht. The histamine threshold concentration
`was significantly incrlascd fourfold flora a median
`vahacofflmslmlafleru'eamtwithplaccbotoa
`median value of 32mm after
`trcaunent with
`cetirizinc
`(P<0.05) or
`levocefirizinc
`(P401125)
`(Fable 2). In contrast. dmttroeefirifine was not found
`town-sigifiomtlythehistamine threshold concentra-
`tiouaecomparedtoplacebo, aathcnumberot‘aubjecta
`withathreahotdconcentrafionbetowfimymlwas 13
`outuf24. Leweetiriziaewasfoundtobeaigntfimdy
`34!
`
`Apotex, Inc. (IPR2019-00400), EX. 1005, p. 003
`
`Apotex, Inc. (IPR2019-00400), Ex. 1005, p. 003
`
`

`

`Wallets].
`
`Murmanfmm
`
`"3
`
`O
`
`mum-Hm mun—m
`em
`
`WWW
`PheeboCetifiziae
`
`was
`was.
`
`wooesubjeet
`
`Figural. Ethelofueatmsntferlihwith placebo. lOmgoetirizine. 5mg levoeetiriziee.end 51115me nineties-
`inducedsneezes
`
`indomdinoressesinnsssiairwaytesistsmebyabnost
`50% we: placebo at the maximal oomtrstion of
`32 mymL Conconfltantly,
`the histamine threshold
`eminent-stint: was Maxed fourfold from 8 to
`32 mgfmi. The number ofsnoeoes induced by histamine
`nasal provocation was also significantly deeressed by
`treatment with oetiridne or levooetitizine. In contrast,
`treatment with dextroeetirizine did not show at similar
`'pmteotive’ effect as compared to placebo.
`Our findings are in accordance with the findings of
`several studies investigating the effects ofeetirisine in
`patients with seasonal and perennial allergic rhinitis.
`Fmaeerd at 8.1. have recently conducted two auction to
`investigatetheefi'eetsofttesnnentwifli 10 mgoetirizine
`on changes in themssl airway resistance et‘ssympto-
`matic seasonal allergic rhinities challenged with immeas-
`ing doubling doses ofbistamine (1?, 18). These authors
`shouted that eefirizine significantly attenuated hista—
`mine-induced hot-eases
`in nasal airway resistance
`{‘NAR) {mi}! 1.5 h after administration (17}, and that
`theeeefi‘eetswmprevsientMZdhafiertrsattnmt
`(18), when oomparedwith phoebe.
`Thisisthefirstmdytoinvesfigatethespeeifioefi'wteof
`eachenantiomrofoefifizine onlhehisumineaindueed
`nasal
`In view of the similarity of the
`antihistaminie effects obsewed foreetirizineandievooe-
`tirizineartdtheiackofanys'mnifioenteffeflsfot
`dextrocetirizineinthisstudy. itislikehrthattheefl'eets
`ofeetitizineinthemsgemeotofaflersicrhinifismdue
`to levomtirizine. Sims estiziznne is composed ofequsl
`qmdtiesofthetwoenmfiomourstndysumtsthat
`
`(P<0.05} more eifeetive than dextrooetinzine in
`increasing the histamine threehoid concentration. A
`comparison between eetirizine and levooetirizine, how-
`ever, didnot showasignifiesnt diffeteme between them
`{table 2).
`
`Eiieet sftrsetmsnt on sneezing
`
`Fig. 1 shows the am of individual u-eatment on the
`lumber of mes induced by histamine ohafienge.
`TteBiInent with either eefirizine or Jevooetiriziue ais-
`nifieantly (P4031) reduced bistamineéndwed esteem,
`but nottreatmentwithdextrocefirizinessmparud to
`placebo (93.0.10).
`
`Evshiathnnfssisty
`
`Them was no special report on health-related problems
`or discomfort (i.e., drowsiness. fatigue. and dry mouth)
`caused by study mediestioms among the volunteers.
`Onlyomsebjeetrepomdanadmsemtor
`WMWSfiyseflmmfirmt
`withievoeetirizieesndwssnotjodaedtobeadireet
`muhoftheemdydrugflomflhiswasssingk-doee
`steelmandthevoitmteersweteinterviewedtlh after
`eaohintskeofthe smdymediestiou.
`
`m I
`
`nthissmdyJemostifizineSmgandoetirizinelflmg
`appuredtobeeomrableintbeirsntihiam'‘nio
`activity. They signiEanlly ammted histamine-
`342
`
`Apotex, Inc. (IPR2019-00400), EX. 1005, p. 004
`
`Apotex, Inc. (IPR2019-00400), Ex. 1005, p. 004
`
`

`

`pmfimofkvooeflrifimatadosenmegmbe
`ussfiilinthemansmentofssssamlmdpemnnial
`alkrgicrhinifishithcmtm.
`In additlnntoits
`antihistaminlc
`,
`levocetirizine at
`the single
`dose 0” mg waswsll tuisnixd by the Winnlccfa, who
`didnotsufisi fromsny siiie-dfocuinthisatndy.
`In conclusion,
`this study demolish-ants that
`
`the
`
`
`
`MWD‘W
`
`Fuxihni studiss are mquirsd to substantiate these
`findingsin patients with onguing seasonal and perennial
`allergic rhinitis
`
`mm
`Wetlnnk Marie-flukMandLéonKaufinsnanfDlCfiud
`mm, BeiniufluuwelissChi-mian Omului'UCB-Phsrms,
`fmbnnfinguthdiupufiflhbhflsfisfimflemtmm
`mfufpwpafiniu‘lefiytm. MMWW byUCB-
`Mammals. Belgium.
`
`m L
`
`13. 001m 1'. (Miami FAR, Dam MP
`8. my 11-], Emma M, Wm MD.
`Wow-anus R. Histamine and its
`memwithhistsnfim:
`Cefiridngiwnsdimmrplsnsboln
`mh:mww,flmam51‘.
`iliesom
`nithsdemntnstionof
`subjwuwiflimmisilsrgicrhinms:
`aditorthuimsattrhinitistndon:
`the threshold oil' the activity by this:
`effects situ- nontmllu! mused pollsn
`Blackwell Sdenfiflu. 19955791400.
`methodsufiliimmmommy.
`chuliwinmsiwirmsnuimm
`imamuimumdnsnlansrsy.
`Rhimlosy issui-sea—m
`unit. 1m as. lmmmol
`can Esp Aim-u immsss—sas.
`[-1. WM 1). Guam P. Assumes“ of
`1998;“1538-645.
`3. Wm MY, Sm IE. Kama MA.
`wlysudhnphmnmlommtiunm
`HWMMMMW 9.MuTmEO.WmuJM.mrrzM—D.
`Ilopii: psflsuts am will ski-gun
`Dis 1907;135:1I65-ll76.
`Osmium outdoor study ofthii
`cwmmmamd
`it. mandinlmlmlof
`efficacy. manddmfiwufwtim
`1995;11:363-373.
`mummies iii iiiiniiis Gin Esp
`Ind safety deflsizi’ne, 10mm. and
`Mary IWMSfl'I—SI.
`MWWIWMJ .l5.CLm1PAR.Cmmmsei-epmm
`mum orihinmnomn-y.
`Allergy Gin Immunol 1996;97:6[7—616.
`5. "Wm PH. M1. of
`Wm 195433359155.
`miliismnluss‘mmymdpomcy.c1in
`1i). Loam”, Whit). Mus-Hm
`Dqul.Comparsiivcstudyof
`16. Hmmwmmflm
`339M lMMIfl-fl
`WMMW
`pmmicststistiulmtimds. New
`6. SMTCGMM'A. HIM
`You-hmmmimmt.
`Winchmnicursimisln: Mina-W
`l?.¥munN.LsmmimJ.MmM.
`mmmnmmm
`mammdmslslierfii
`Eli-W “Wain“
`Whnmnhmlmmml
`etaLOms‘tof-cliasiinthnnsui
`MMYm-t: Mum! Dstkar.
`1996953543454
`antihistmisic sfl'sctoi'iisiiiifinesnd
`”95:213-195.
`ll. Mum-mu! “MM.
`bismuhpfimuwiihw
`1'. Sims FER..Non-cmliscsdwise
`WI—CZMA.
`rhinitis. may 1997;53:205-209.
`Minimise (Hi-MID?
`Comparisonoi‘smacysndnmyof
`ts. WN.WO.MM
`Wlmfixpnflersylm
`mlrhlassndsbsstinsinpmumth
`M.GumN.hum3.PmiG.
`Nstslei‘feiii areetiiisinesiidlorsnflm
`mnmmmm
`mains—m.
`iii 24 hours in pittinis with magic
`WWIWBM.
`rhinitis. Am .1 Thar imam-311.
`11.013411an MAP Kama» L.
`Wmhoidudnufl
`W! in non-specific allergic
`may. Rhinnlm 19351113542.
`
`Apotex, Inc. (IPR2019-00400), EX. 1005, p. 005
`
`Apotex, Inc. (IPR2019-00400), Ex. 1005, p. 005
`
`

`

`Apotex, Inc. (IPR2019-00400), EX. 1005, p. 006
`
`Apotex, Inc. (IPR2019-00400), Ex. 1005, p. 006
`
`