EDITION
`
`2001
`PHYSCANS'
`DESK
`REFERENCE®
`
`Senior Vice Prealdont, Directory S.rvlcea: Paul Walsh
`
`VIce PrHident, Sales and Mart<etlnc: Olkran N. Barsamian
`National Sales ManaCer, Cuttom Sales: Antnony Sorce
`Senior Account Man..:er: Fronk KarkOW$ky
`Account M anacera:
`M arion Gray, RPh
`Lawrence C. Keary
`Suzanne E. Yarrow, AN
`National Sates Mar>-cer, ~edlcal Economics Trede Sales:
`Bill Gaffney
`Senior Buslnua Manacer: Mark S. Ritchin
`Financial Analyst: Wayne M. Soltis
`VIce President, Clinical Communications and
`New Buolneoo O.velopment: Mukosh Mehta, RPh
`New Business OeveiOIXMnt Manacer: Jeffrey D. Dl.t>in
`Man-cer, DI'IC Information Service~: Thomas Aeming, RPh
`Drug lnfonnatlon Speclalata: Maria Deutsch, MS, PharmD, CDE;
`Cllristme Wyble, Pharmo
`Editor, Directory Sertlces: David W. Silton
`ProJect Man-cer: Edward P. Comor
`
`Senior Associate Editor: Lori Murray
`Asslst811t Editor: Gwynneo L. Kelly
`Director of Direct Marhtlnc: Michael Bennett
`Direct Mall M..,..er: Lorraine M . loening
`Senior Mart<etlnc Analyst : Dina A. Maeder
`Director of Production: Carrie Williams
`Data Manacer: Jeffrey D. Schaefer
`Produc:tlon Manacer: Amy Brooks
`Production Coordinators: Glanna Caradonna. Dee Ann OeRuvo,
`Melissa Katz
`Index Supervl110r: Johanna M . Mazur
`Index Editor: Shannon Reilly
`Art Auoc:late: Joan K. AkerUnd
`Digital lmSCinC Supervisor: Shawn W, Cahill
`Digital lmaclnc Coordinator: Frank J. McElroy. Ill
`Pl\armaceutJcal Coordinator: Mary Kaaoan
`Electronic: PubiiMIIftC O.•lener: Uvio Udina
`Fulfilment Manac ... : Louis J. Bolcik, Stephanie OeNardi
`
`MEDICAl. ECONOMICS CopyTighl 0 21101 and published by Mo<icaJ Economics Company, Inc. at Monlvale, NJ 07645-1742. AJ nghts reserved. None cl
`-----~------ - 01-. oont.,. clthts publealiorl may bo repoduoed, stor.d ina~ tyst""" -
`· ..oioW:>uood,"' trensmilled on any loon 01
`THOMSON ~ by any means (eleclrorlc:, mechanical. phc(ocopying, recording. 0< otlolwise) without lhe pnor .,.rillon pormis5lon cllhe ll'Jbl$ller.
`PHYSICIANS' DESK REFERENCE", POR", Pocket POR", The POR" Family G.- 10 Prescr1pllon Dlugs", The PDR" Family
`GuiOe to w~·s HeaNI end Praocriptoon ~>rugs", and The PDR" Farniy Guide to ~and HNfth" are registered IBdemalks used h&fetn undellicense. POR tor
`Ophthalmic Mecklnee"'. POR lor Nor'9f~ OnJgs and Dietary Supplements"', PDR Comp6nion Guido"', POR Phlrmoc:opoeia"' Pocket Edilon, PDR" lor He<tlal
`Medicines'"· P0R lor N ILrmonal ~"'· PDR" - · lktionaty"'. POR" Nvrso's Orvg ~'"· POR" Nv""''s Oochonaty' " · The POR" Family G.-»
`Encydopeda clMedcal Care"'. The PDR"Famly Guide to Natural Medicirles and Healing Thetapies"'. ll'e POR" Famly Guide to Common AlmGnts"'• The PDR" Family
`G.ad6 to <>--ltle-Coun<« Onogo'", ard POR" EloeO'onic Uboa<y'" are~ used tl<lrffi\Hlder license.
`011cets Off-.. ~ ~ l'rllsidtnr ln1 Cl>ief CXecvtM! orrur: QJrtis B. Nlen; Voce Pre$1dert, New-: l . SUzanne BeDell; V'K:e l'rllsklenl, Col))o<are Human
`Resoum!s: Pamela M. Blla$11; Cl!le( Flnanc~l Gm<er: Chris10pher caridi; Vice Preslder>! andConrroller. Bany Gray; Vlce l'rllsldenr. FlnMce: OonM Santatllla; Senio' \'lot Pre$/det(,
`D~tecrory ~: Paul WalSII; Senior VICe PreSident, Operarioll.s: .lolln R. Ware
`
`Dr. Reddy's Laboratories, Ltd .. et al.
`v.
`Helsinn Healthcare S.A., et al.
`U.S. Patent No. 8,729,094
`Exhibit 1017
`
`

`
`PDR®
`55
`2001
`
`EDITION
`
`PHYSCANS'
`DESK
`REFERENCE®
`
`Senlor VIce PNsklont, Directory Services: Paul Walsh
`
`Senior Associate Editor: Lori Murray
`Assistant Editor: Gwynned L. Kelly
`Director ot Direct Markatlnc; Michael Bennett
`Direct Mall Manacer: Lorraine M. Loening
`Senior Marketlnt Analyst: Dina A. Maeder
`Director ol ProdiiCtlon: Carrie Williams
`Data Manaaer: Jeffrey D. Schaefer
`Production M lll'l .. er: Amy Brooks
`Production Coordinators: Glanna Caradonna, Dee Ann DeRuvo,
`Melissa Katz
`Index Supervisor: Johanns M. Mewr
`Index Editor: Shannon Reilly
`Art Associate: Joan K. Akerlind
`Digital lrnaglfiC Supel'llaor: Shawn W. Cahill
`Digital lm-elna Cootdfnator: Frank J. McElroy, Ill
`Pharmaceutical Coordinator: Mary Kaadan
`Electronic Publl&hlnt DeslCJ!er: Uvlo Udlna
`Futflllment Manacers: Louis J. Botclk, Stephanie DeNardi
`
`Vice President , S81es end Marketlnt: Dikran N. Barsam~an
`National Sales MIIII8Cer, C.tom Sales: Anthony Sorce
`Senior Account M1111.ger: Frank Ka11<owsky
`Account M anacars:
`Marion Gray, RPh
`Lawrence C. Keary
`Suzanne E. Yarrow. RN
`National Sale& M1111 .. er, ~adleal Economic& Trade Sales:
`Bill Gaffney
`Senior Buelneu Manater: Mark $. Ritchin
`Financial Analyst: Wayno M. Soltis
`VIce President, Clinical Communication& and
`New Business Development: Mukesh Mehta, RPh
`New Business Development Manqer: Jeffrey D. Dubin
`Manacer, Orut Information Services: Thomas Fleming, RPh
`Druc Information Specialists: Maria Deutsch, MS, PharrnD, CDE;
`Christine Wyble, PharmO
`Editor, Dtrec:tOf)' Sel'llcas: Oavtd W. Sitton
`f>nl:lect M-aer: Edward P. Connor
`Copyright 0 2001 and published by Medical ECOOOIJW:s Company, Inc. al Morrtvalo, loU 07&45-1742. A.lllghts reseMld. None cl
`- -----tit---- --- the eont~ cl this pub!icabc>n may be r"J)«>duced. s!on!d in a relrMMII sy3tem, resold, recis1nbuled, 0< transnWed in any 1onn 0<
`by any,.,.,. c -. mochanical, phoiOCiOP)'Ing. reco<drlg, ()( OlheMise}-
`tho- wrttcn pentll$$ion cllhe jl(.(llis:he<.
`THOM'SON HeA&.7'HCAil£
`PHYSICWI$' DESK REFERENCE", PDR". Pocket POR", The POR" Farrily G.- 10 PTa&cnpdon Drugs", The POR" Fetr'i#-1
`Guicle loW-s Health end Preoc:ripOion Drug$", and The POR" Family Guide 10 Nu11ition and HeaJltl' aro r~ lrae*narlts used -
`undo< treenoo. POR tor
`~lmic Medicines"', POR tO< ~sct(lbon DrugsandOaary~"'. POR~ Cl<M»"". POR Pharmacopoeia"' Poclrer Edllon, POR"Io<He<tlal
`_ ,_ ,,., POR lo<Nutn'Oonal ~'". POR"MedicaiOdonary"', POR" Nurse's Drug-'", POR" N.ne's Ooctionary'" , ThePOR" famtyGI<ide
`Enc:ydopecl4a ol Medical C.ro"', The PDR" Family Gui<1e to Nallnl ~ and Healing Therapie$"'· The POR" Family Guide to Common Ailmonl$'" , The POR" Fatm(
`Guide lo <Nor-ct>&-eounter [)rugs"', and POR" Eledroric: U>rary"' are trademarl<s used herein..,.,..~""·
`Olllcels o f -~ ~Y: President ana Chief &t>CVtNe Offteer. Curtis B. Allen; V'u Pm>idcnt New Meclia: L Suzonne BeDel; """' Pmsldent Corporate Human
`Resouroes: Pomela M. Blla>h: Cttittf Rrrancial Officer. Christopher catldl; \lice President and Controller: Barry Gray: \lice Pmsident Rllance: Donna 5anlalpla; SMior Vice A'Mioetl{,
`Olfi>CIOI)' St!Mces: Po~ WOisn; S..nlo< Vico PmSJdcnt, Opcmtions: John R. Ware
`
`M EDICAL ECONOM ICS
`
`ISBN: 1-56363-330-2
`
`Exh. 1017
`
`

`
`680/AVENTIS
`
`PHYSICIANS' DESK; REfERENCE®
`
`Amaryi........Cont.
`·'
`;...
`continued. Porphyria eutaneo t:a.rda. photo&ensitivity reac~
`tiorul, and allergic. vasculitis have ~n reported_ with sulfa~
`nylu.reaa.
`Ktmato121ic RH etions
`Leukopenia, agranulocywsi•, thrombocytopenia, homolytic
`anemia:, aplastic-anertUa, and ·pancytopdnia hove be:eh r.e:-
`ported with sulrooylllJ'Oa!l.
`.: :·,·
`Met• bolic A•.ct~On.
`Hepatic porphyria reactions and disulfinun-like reoctions
`hav~ Been reported with guJ.funylu-reH; _however. no cases
`havo yet been repo\'ti>d with AMARYL (glimepjride tablets}.
`Cil.teo ofhypoi>atremla have beEii reported with gllmepiride
`and' aU other sulforqlbreas', most ofl'.en iif patlet\ta w'ho are
`on other medicatioft.l or have medic:l'd' COnditions known to
`cau.._.;e byport.atremi.8 ·or increase rete~ or antidiuretic ·hor-
`mone. Tbe ayndroni.e of inappropriate antidiuretic hormorie.
`(S!ADHl ;,ecretion b .. been·ro'ported With certaUi' otlwr .W.
`foDytureas, nnd it h., been svited that th ... lllllfooylu-
`rea• may o~ent 'I& peripheral (antidJuretic) action of
`ADR and/or in_ereo.so release of ADH,
`Ott!« ReoCt~on. ,
`Cb8..ngea iJl ~nunodatiori AMtor bllll'ffld vi~ion mny occur
`with· th'O liB<> of AMA!tvt. T.bi8' ·;j thought to be due to
`changes in blood r1ucoi;e~ Aiid m87 be more prohoUnc~
`whe-n troatniOhi l.a initiated·. 'ntis eonditi<ln ·is al&b ioon in
`uni.reatad diabetic pa~ehts. ··~d may'adual\y be reduce(! by
`t~atment'. in' pln'oobo-contro'Oed t:rial8 of AMARYL, the ia~
`cideoi:e ofbluniid v)siOo .,.,. plaoobo;'o.?l'b; and AidARYL,
`0.4%:
`•
`:h.;.
`. .... :
`.. ,
`!'.
`-"·~,;. "
`;...... .
`·~~
`.•• ;·;,.t; .: ... ,_.
`oVERDOSAGE
`; .
`·~
`j:
`CWerdOoOg.'ohulfonyhireae, inelodlng'AMA.RYI'J, can pro-
`auce byJil>glycetnia. Mild•liypoglycem.ieoympto"!i without
`lo•o of cotUCiousir•ss"or ·neurol~e · fi!iding!s should· bO
`tt-eatad a~sivoly with· oi'Al' glo<OM,andfadjuot:.tnents irl
`drug dosage 'ar!tlloi"meal patttnls: Cloie fftonil:oring illciold
`oontinue until the pb)'lliefail la ....,r<ct that tbe· J)at!enl io
`out of danliet. ~"' b,j)og)yconile i'aiJI;tioliil with eoma,:sei>
`zurc, or ether 'DCllJ'ologicalllmpairme.nt ·oCcur infrittuedtly,
`but eonatitilte ·atc.-ditil e:rn'erg1!nc:ie!i~r&q\iirlf&g ilrillkodi&~
`hospitalii.atiott~ J£ hypoglyCemic con:ia':W'd.iugnoecd o·r WI·
`ped~--~eipatierit $hould be. gj·.;en· a rab.id in&aven6U* ifi.
`jeetioU of ooncentl'ated (50%) g]ucooe·l!olution. nm should
`be· fOilOwod' tiy ·a oontinuou¥ lhfUilioo of"o II\O're dilute.·il~l
`glucose solution at a rata that will maintain thb 'blood gJu•
`"""" at a level obove 100 m;JdL. Patient& ihbUid be cl<i<lolY
`monitOred for ti illiniinttin of Z4 to 4B boUN~ bec:auso b~
`g\yooroia roof recur .JWt lippitent clinical tecovery.
`"
`~GE ~AD~9.rj ·.
`,
`- ..
`There iA nG. bed dosage regime-n for iht! mana~.orement of di·
`abetu mellituii·wilbAMARYL or any <>!her hypog1ycemio
`apnW!r.he patient'• fasting bloocl<g!ii.,_ and HbAlc murt
`be ~ao;,iid perio<ficaUy lo·cletennine l:lle·minimwn eJI'et'
`tivo dooe for the patiant;. to detect prtnlary .failure; i.e, in:·
`adequai<! lowering of'blooli tloeooo: at the muimlim reeom.•
`mendod doie•Of1Dodieati~ and to det<!tt seeondary failuro1
`i.e., loss of adeQuate blood ~tlucose lowering response'a'ftei
`an initial period of olrectiVene.,·Giyoooylated hemoglobin
`levels •hould be performed to monitor the patient's reo-
`to tOO·ro.py.
`.
`.. ~ .. ~ ,4 _
`Short-term adminhotration of AMAJtYL maY be ·sufl'lcieiit
`. \
`diJ.r\rig p~rioda or tnmsitnt ·toes of contfof in patient& usu~
`ally controlled well on aret and exercise. '
`'
`Usual Startino ~ .. l·
`The usual starting do$0 of AMA1!YI. .. initial therapy is l- 2
`mg 00(" daily, aamin'Uwred with ljnakfast or ,the fiM roaiii
`mea). 'J'boee patien,. who may be more sensitive I<> h.i-pogly-
`ceroic drulio should be siartea at I rug, once' daily, and sl\ould
`be titratad carefullr, (See PREQ.Al,ITIQNS ~ction fur Pd·
`iietlti: a~ incTe&Hd mk.)
`.
`-.
`. ;.,..,
`~'
`No el<lld dosage relationship ruciato bet ... een Alo!ARYL arid
`the other oral hypOgly.c~n\ic i:lgt'.ntt., The maxim~ 1l\1'rting
`do•e of AMARYL should be no more tbon 2 mg.
`Failure to folio.,. an appropriate dosag<> regimon rnay pre-
`t:ipitate hypoglycemia.. Patients who do n.ot. ~dbere t.o their
`preacribecl dietary and drug .regi;nen are moro prone to e'X.•
`hi bit un.u.Lisfact.ory 1'\"sponse to therapy.
`U..,_.. Malnt• nenc• no....
`~
`The usua) maintenance dose i$ 1 to 4 mg once ruti1y. 1'he
`maximum recomm~nd~d dose is 8 mg cmoo daily. AfteT
`reaching B. do&e of 2 mg, dosage incrca~s ahou)d be mado in
`increments of no mo~· than 2 mg Qt 1- 2 week intervals
`based upon the patienfs blood glucose response. Long·tenn
`efficacy ahould 00 monitored by me.as~ment of HbAJc te:v-
`e15. fo1· example .. every 3 toG mootha.
`AMARYL-Metformin Combination Therapy > •
`lf pa.tient.s do oot roapOnd ndequate.ly to tbe maxi.m:d dooo of
`AMARYL monotherepy. adrlition of m~tformln m11y be oon·
`sidGred. Publi!hed clinical information existd for the-use of
`otbi!r •ulfonyfu.reaa ineluding gl;yhurid~. ~;lipixide, chlorpro-
`pamide, and tolbutamide in comblnt1tion with ruetformin.
`With conoomitant AMARYL and motfonnin therapy, tho do·
`•ir«< control of blood gluoo"" may be obtained by :><lju•ling
`tb.e dose of eru:h drug. Howe\'e-r, attempu.; shou.ld OO: mack! to
`identify the minimum effective ~ l)f eaeh drug to ocltieve
`this goal. 'W1th concomitant AMARYL and metformin ther-
`apy, t he ri!ik of hypoglyce-mia a..<~SI.lciated with .-\MARYL
`;herapy continue--s nnd may be increaSt.--d. Appropriate pre·
`ea.ut:i4)ns ~hould be takf-n.
`
`'
`
`,
`
`_
`
`.(
`
`,·
`
`,,
`
`,
`
`•
`
`ANZEM~e lnjecti9 n
`(an·z~mlt]
`(dolasatron m-sVIat• injection)
`
`PrHCriiMng Information at of Febnulry 1999 ·
`D'ESCRIPrlO~
`,
`ANZE:MET (dolasotr<~n m(lgylate) is a.n antinauooant and
`antiemetic agent. Chemically, doln'Jetron mesyl;;tte i~
`(2u,Ga,~,93j!}.oct.ahydro-ll-oxo-2,6-motban"'2H.quinolizin•
`8-yl·lH·indoJe-3-atrboxyJate monomethao""-'ulfona~ mono·
`
`~~:
`
`· Wa
`tion pe
`AMAR)'.L
`weeks) fo
`Iori~> half·
`:>..'dARY!.duo·to po
`• d~·- ,,, (
`..
`',,\'
`ROW SUPPLn;D, ~""
`A~fARYL tobleto ""' available In the fol)ov;ip~ ~~Jlltht
`and pad<~ ,;-.
`:.~ .
`I mg (pink; ~at.faood; obi<Jog with·noo:ched oidel·ac'doublo
`biaect, ·imprinted:·with· •AttfA RYL'I on G1le • ide and- the
`Hoecbs1.1080' on both sidH of ):he bloeet.on tbe'·othtr side) .
`Bottlesofloo , ...... -, . . . .. iNDC~9-022i-lO)>·h•
`2 rna'~ !iat.,;(i.d; oblong with notched' old'~ atC!Dubla
`bi~ lm'i>rintad -'!(itli ".AMA R'\'J,;,dh bna stde arlit th~
`• ,l<ieio of the bi.s<!ct'on tlli'tither'~ide)
`Hl · ·
`, •. , . ·' . (Nile 0039~10) . ~·
`Bo.
`Unit
`0/'', · <~'06as.o2~1ll' = ·;
`i ~ {bf~. ft~t.~ •. .hlong ·l'Atb n«.hed .rules ;t'd~uble
`bise<l, im,printed w:ith • A!.JA RYL • o.n. one oi~ anjl }~
`Hoedlsl10li91Pft both~idOlJ of the bisect on the other side)·
`(mic 003ii..022:i;IO) :, :
`Boltiel,of lOo~ .. ~ · ,/. . '·
`Unit {looe Cru:toru.(lOO)
`'·
`(NpC 003~.j)2~~1).l , ·
`store: between 59 and :art (15 and. 30• C): ,., ,; · · ·
`Diapen!.e in ·.iu~ll~.bed containers With saf'~ clo.aU'IM, ··
`CoU!Ion: rederal law p;ohibito d.iapensing.without a'.pri><
`.·:-..:.:..~ ·! .·,··~t~ !':\ ,.t .. ~.x )~· ,.._.;.;
`iK:ripdoru
`.:~"fl ~ •• ,.
`-·
`·"•·i· "'
`AMARYIA\·REG 'I'M HOECHST AO· ·
`·>
`~~~$;f:'!,'·:1 ,:·3;;;',.' , ',:'·"
`
`Reduced ·seruai' glutoae yal_ueo and degranulation of U..
`paneroatlt bota'wlla ·wore-ob~JV.o¢ in beagle dogltnp;ooed
`to 320 rug glimepir!Mg/day fOJt.lZ months (approxiJDAi.U!ly
`1,000 limos the .....,mJMndod htiman d08e based on surlac>!
`area). No evidfnce of' tumor formation wu observed-in aJiy
`orr®. One. female o.nd one male, doe de>:eloped bilateral
`• ubcapsulat' cataracU; Non-GLP .studies indica).ed that
`ciimepiride ..... unlikely to exacerbate catarad formation.
`Evaluation of the ~taractogenic potential of g!imeplri<le
`io.. !e.veral di.abetie and catarac.t ratsmodels.'Was negative
`ao.d, th&re wu no Qdvone effect. of glimepirid& on, bo\1ne o:e·
`ular leM metabolism ia organ· culture.~\ ,.
`HUMAN OPHTHALMOLOGY DATA-'
`Ophtllalmie ebminatiorm were carriQd Out in ov~' 600 sub:
`1 jectl! duri~ )ong·torm studies usjng tlii methodology of
`Tay(or an.d Weet ~t~~d l.atieo et ol. No slgni1ieant dilreren~
`were seen betwooo AMARYL and glyburide in tlie numiie>
`of subjects 'Nitb clinicalljt. important ~ges in ~ua) a<'\1~
`ity, }";~«ular !~lop., or i.\1 arv; of tl\e ~~· r.iu..reJated
`•=a6( .. ...,;ne;j,
`.
`.
`.
`, . ,
`Ophthabpio cxi1mlnatioiijl, 'l'~i'e carrll!<l opt dUring lc~·
`term stu!liea using. t.he mqtbod of Cbylack et al. No signifi-
`can'bor cUnlcally mtillnirigfut difFetences Were !K!E!n between
`AblARYL and glipitld< with respe<t to c~taroct progresoion
`by su)U~~'e !-OCS n gr~ding and obj~ti,ye 1~age 3nal..V1~
`syste03:-&1. . Yl8ual ncui~ mtraoeular prc&l!~1 and a:eneral
`,1
`ophUw..h:Uie e~a.minaUc~.
`· ·
`· .
`· -
`Prescribing Information .. of October 1999
`Roe<'hst·Roua<;eJ Pbannaceutical9
`,
`Division of Hoechst Marion Roui'Ssel, Inc . . :
`. <·
`Kans.ii City, ~10 64131 US'A
`·:
`Sftown.,irr'Pto'duct l delll'i/ictJl.iOit Guis(t, page .1()(J
`
`hydrate·. It is a· higllly &pecific and ..,lective serotonu.-aub-
`type 8 (5-H'l',.J receptor• antagonist boll> in vitro and in vivo.
`!Jolasetroo mesylate has the following structural formul&:'
`. o~··.,
`·~~·~"'," ... ~~-
`. . .
`
`,,.
`
`"
`
`0
`
`'
`
`'
`
`.
`H
`'1'1\'e empirical 'fon&ula Is C,,H;.N,O, • cH,SO, H • H,t>,
`with a molecular weigltt, of 438.50. Approxim~telr 74% 9t
`dolasetron meaylate monohydrate is'do~n ~. · .. · '
`DolaHtron rnesyJa~ monohyd.~~ is~ a· wlii~ tb oW-White
`)lOWder thilf is fteely soluble tn· water .na pmpyloite glycol,
`~!~ .Oiuble in ethanol, w , •]igl>Uy sol~b!~· D;', norj"!
`ANZEM&T Jnjeetion ii a cleta;"ct\brlQI, n<mpy-ro·geruc. ilte'r-
`iJe so1titioii for inttavmous admitli&tratiOn_. E8cn~~Diinilitet
`df ANZEMET InJection ron tams 20 m; of'doli.Mtii!ii·mesyf:
`ate ana 38.2 mg minnitiil w:ith ""atiete~ bidl'er iD 'water for
`m~ion. 'The plf of the resulth,ls-.O!Uilo\\'ii 3:2 t.O 3,111 • ,.
`'~-,./·.',{:':,
`cJmcALPfLWJACOLOGY
`"
`.
`Oola .. tron m .. ylate and its actiy .. ·metabolite; hydrodolai'
`etron (MDI;·U ; l66), are seleetiw o.erotooio,.6·R'i'i recep&ol'
`1\D-tllgODi.at$., not shown .to hav& activity at other ·lmawn ~
`rotonio.~rw and with Jo,w. a8inity for dopamine ,...."'
`ton.Tha~.s.ffT;~·aielocated·o.u·then..,..e
`terminala of the v&c!ll.in the<pel'ipb017 and oentrall)' iii; the
`eb~moreceptor' ·trigger aone ot· tb&• area poiltrema. It~ ii
`thought that chemotherapeutic agents produce. na-usea. aM.
`Vomiting by nle81!ing ..,.u.nm. from the ·enbmichromdia
`cella of.thUJDa}Hnlootlne, and-that tbe nl••••choetotonili
`then'octi-6.HT, reoepton locatod'.lm Viiphflore--to
`'!J<~·-.., .. ·.;r-
`initiate the vomiting~ ···'' ·-~~ ··~ !, •· ;,..
`Acutc, U.Ul!lly:roversibkli ECG cliru>gti'(Pitand QT, prolon,
`p tion: QRS' wido.;ina'), cauoed.bx·dol..etron """'Yiali!, ba••
`b%n.cibservad in hooltliy vohmtocrB and in cootroUed clin,
`ictd triaiiS. The active metabolite~ of dolasetron may block
`sodium. channels, a property uDnJlated·to itt: ability. to block
`5-!ITa TeteptoN. QT, prolOilgatian .i• primarily dU.. .tii·QRl!
`widening,, DQ!aoetron' appears to prolong both dopolarita·
`tion and, tO a lesMr es:tent,· repolBriz.atioor time. The maani~
`tude and freqlancy .of the ECG ·chlihges incrcia.oed' with d ...
`(related to peak plasma conaonkatiOdo· of hYdrocL>Iaoetroit
`but not the partnt oompoun<!J; Th,~..EC~ jnlepi!'J proiOJl;
`I~ to b ... Jiiie withlri 6lo 8 bou~, D)ll
`gatioM
`'iilf.l\1 Pi'eeont at 24 liou:r follow' ujl. uo!U:.
`adbiini.ft_raticni hi& little o.r no etfect On
`btOtiir'PtesJfmt ' ,~<:• ·~ ·• •••
`~-· •. :,..~
`- ·. , ~·
`ih bloi.l!liy'ills(dnhfol-. tN:~!U), doia..ltiiri roeay1ateill,sj!i81e
`mtmVe.uiiUil dooes'il;jt<i 5'mg>'knrodllced lio effect ori' pQpil
`liiie' ar inoillii6jjftil elia'.l~ 'm El!lG l'racili&'l. ft.e.aiillil' fljjlll
`ncuropoychiatric tosla rcv•'aled thai dola&et:ron mes'vlate
`dlcl \ilit 'allOr' iOOciefor<il)l<ieilftatlon. 'Mi!lti@e daily~df
`dout:ron haye bad ·nll'tlrect~n eolciiue't:ransit m•humllllio.
`Dola~trim meaylale fiu'n.o< ~fft!et:olt-pi88Mit pto1ilcti'd ~
`·· ~·.-. ,~ ''l'
`. -.-;
`'1':"- ···- > .n-~--
`centt&tiOM": ".;
`--;:
`Pherm.eoklMti_ca m· H\lmllnl,."'
`IOtrav~nous d(;Jasetron rn~late is rapidly tlimina~d (t~
`<10· mlli) and co!llpletely metabolized to the ·moot Ollnkally
`::.
`~leVahtsp«ie$,:hydrodoJ~·.
`·)
`.,t.
`''
`(
`Tbe-·reduction of do18iCtron to hydrodoluet-ron is mediated
`by. a U:biquitoua en>)me; wbonyl J"eductase. Cytochrome
`P-460 (GYP)UD6 io prinfarily responoible for the · &llboe-
`quent' h:ydroxylat:ion <lf·hydmdol&.~b'Oil aiid bcth,CYPIIlli
`and ft:a~ monooxygeoase o:re l'C6jxmlible for the N-oxida;:
`tion of l!)'drodol,...t.un.
`· ·' · •
`· •
`' "'
`HydrodolMetron is e:ccre.ted in tbe urine unchahged (53.0%
`of luimini!tered intravenous dose). C>t.ller 'tirinaey metabo·
`lil<l& include bydroxylated glucuronidat and N·ol<ide.
`•
`Hydn:>dola&etnm a.pperiied" rapidly in ptastU.at with a ~
`mum corlooniration oct.uTring ap·proxitnatoly 0.6 hour· aft:w
`the end Of intravenOU$ treatment, and w~:~.s eliminated' with
`a mean baJf.Jife of 7<3 hours (%CV'~24) and an apparent
`clearance of 9.4 mUnrinlkg <'-"'CV~28) in 24 adul~. HycJro.
`dolasoti'OD ia elimintat6d ·by multiple routetl, inc:tudi:tJg renal
`exn-et.ioo And, after· ·metabolism,· mainly gluturonidatioo,.
`and hydroxylation~ H,Ydrodol ... tron ..mt>itl linear phat!
`maeok:inetles M;E!'t the intraveoous d'ose r;mge of 50 t.o 200
`mg and theY are ihdependent of infusiOn rate. Doses lower
`than 50 mg bav~not been st"llie<!· Two thirds of> the admin·
`is:tc.red clost¥ i., m;ov·ered: in the urine tmd "Ode'•third in tbe-
`r...,o. Hydrodolasetron io widoly distributad in tho bOdy
`with a mearu ap-parent. \'olilme of diatribution of 5.8 l1kg
`(%CV,25, ND24) in advlu.
`· ..
`Sixty.,ine lo 77% of. hydrodol...,tron io bound to pi'asma
`protein. In a study with 14C Iabell!<!· dolasetron, the diatri,
`bution qf radioactivity to blood celbs wa.' not exten$IV'r-. Th8
`binding of hydrodoln&etron to c..1·acid. gJYcoprotcin ·is ;)f)~
`proxinlR~ly 50%-. The pharmuook1netit8 of hydrodolasetron
`are linoor and EJimilar· in men and women.
`The pharmacokinetics of h}'tirodolasetton, jo apecia.l a:nd
`targeU!d patient populations foJJow-Intt introvenotl4. o.~
`istr.atioo of A.!"l'ZEMET lnj~tiQn, are- summarized in Thtile
`l . The p.harmoook.inetics of hydrodolaaetron are- similur iii
`adult healthy voJunb!ers Stnd in odult cancer J)fttiE!ntB reo.
`ceiving chemothero.peutie agent&. 'fhe appa_rent clearance of
`hydroddlasretron in pediatric- and adolescent pati~.nts is 1.4
`
`.!
`
`.,, ;_; '
`
`. ,
`
`Exh. 1017
`
`

`
`I?RODUCT INFORMATION
`
`..
`
`·~
`
`AVENTIS/,681
`
`',, 10 2'(34%it
`12.5 (37~)
`.. ,
`19.2 (30%)
`
`7.i>\43%}r"
`~.5 (31.'Jf>)
`1:j~~)
`,.,,
`
`'/'.
`
`:• ' ·'
`
`··' !0 •
`
`•. ~ -d
`
`were. 50% and 40%, ~~pectJ•.-ely. However; in men:. there
`was ao iJtati.stically si~ficant diff'ennco in complate •w
`sPonse between any ANZENIET do~ and ·pl'aeebo. ·
`·
`Tree
`'atfve
`·
`·
`~
`1·
`le' lind
`' in-
`trav
`lnjectio.n doaee of 12.5, 25,
`and
`10() "'11 wlth placebo !b 124 male ahd 833 fi>male patl•nt&
`who liad undergone surg-ery with genera] bahmced anatliel
`sia and pl"l"8«nted' witn ea'rlY postOJ>!trath'e Oa.useh. or Vom-
`iting requ.iri.ng o.ntiemetit trenimenf.
`·
`-;·:.~~
`ln both studi&a, the 12.5 mg intravtmout~ dOSe or AN'ZEME'P
`was stati1:1tiUl)y e'uPerior ·to placebo foi- compJete responk
`(no~-vomiti:l'lg, ·no esea.~ m~dieaticn}'. No eig:niftc-atit in-
`creaSed efficacy was seen:witli bight'l' dos6t 1'
`•
`••
`INDICATIONS AND U~G£ .,
`• .. . • ., ...
`ANZE!I1ET lnjecti<>n -i.o. indic&t<>.<! for the following'.
`,.,
`(1) tt•• pr...,ent:lon.of nau ... and vomltfnt assodatN
`. with initi.t aM r~.Mt courMe of emetogenic cancer.
`c:hemothenpy, lnducl.ng.high doM·Citplatln; ~ . t
`,
`(2) the prevention of postopel'81ive nauMe and vomit·
`lng. As with other ant)emctiet-, routine prophylaxis it
`not recommended for patients io whom there is tittle
`&:X.J)f!Ct:atio·n that n.a.u~!f-9 a.n.d/ca_r vomiting ... m c>«ur
`postop~rahvely. ln patifn.t:B where nausea and/or vorn·
`iting must be avoided postoperatively, ANZEME'F ln-
`je<.'tion is re<'Ommend~ even where the incidence ur
`postopQrative nausea andior .;:omiting is 1nl\•;
`(3) the treatm.m of postoperative nau.seil and/or vomit·
`lng.
`
`CO~YCATIO!"S.
`"
`.
`'
`ANZEMET lnj,cliOO j• «<iotraiodicated in paO.nto luiown
`tO hi.ve nypo~naJtivity tO t~ drug.
`.
`.
`"
`WARNINGS
`•• ,: :
`. .
`ANZEME'I' "can ciiuoe ECG interval change.• \PR, QT,. J!l'
`prolongatioo and QRS wid'ening). Tlie&e chang .. are related
`in.rn.ngl)itudo and frequency to blood·1eve.1s of the active me-
`t.abolit,. The~ change·a a~ sclf-liJniting with declining
`biOO<! levels. Some patients .baye interval prowilgations for
`24 hours or ionfl"T.lnlorval Jl'"!'loogation could )ead to car-
`diovascular coll$eQ'uencea, includin,g heart block or cardiac
`.
`.•
`arrhythmias. These have rarely been r~porteQ.
`A cardia(: oonducbon abnormaJi~y observed' on art ililn.~
`·
`:rdi'~i! rllythm· nionltc)_t Griterpreted as t:ompleto
`"\vaS=-rapo~ jn s 61·y~a.r~1d woman·wbo·n.....,
`g ANZ£MET for the pr<,•ent:ion of pootopem-
`tive na\•sea and vum'iting. Thi,j p·atlent was ai.YJ taking
`verapa.m.i1. A similar t:Vent .Us.c i_nt(!rpr,etcd aa~ complete
`b.crut·blotk was rcpar..ed in one ·patient. re~iving placebo.
`A 66-year,Qid DlJ1Il witb !;l~g~ JV ni)J)-H<>dgking iymphom"
`~i<!i •udd•nly 6 hours after- recoivipg 1.8 mglkg ( 119 mg)
`intravenous ANZEM.ET liliection. This patient had ot.h.!r
`potenti~tJ .{i3k fac.tors lneh+ding &-u,bS'tantiaJ expOf;ure , to
`d9•"r.>bi9. and co.nc•m~ii:ant cyclophosphamide. · ·
`PRECAUTIONS .·
`.
`_.
`General
`.
`D~latelron should be· admini.ster*<f witt~ caution in p•
`tients who have or may dewlap prolongation of tatdiec:
`
`Exh. 1017
`
`

`
`682./AVENTlS
`
`PHYSICIANS' DESK REFERENCE~
`
`Anzemet infectl'on-tont:·
`
`" •.C-
`
`NDC Number
`
`!~,
`
`,I
`
`•.
`
`1y
`
`ANZEbiE'I' I~'
`Onciall8troni· .
`1.81J119'ki•
`Gl8.11.iJetroo•
`conductiof, intorvals, partlculatty OT.,. T-• )nclude pa-
`tionto wWi 'hypoUiomla ot hypomagnesemia; J,.tl.nto tak·
`Event
`(""!56)
`(n=696)
`ing dlunti .. with potent;• for inducing oloctroi'/H abnor' --------------1--------------.,.;-..,----.,.---,.-'----
`_H_ca_d_a_ch_•--~--------l------16_9_(_24_,_31t_l _____ -+ ___ 7_3_(.2Q _ _ ._5'h_)_, _< _ ___,
`malltl'!l. p_atlents with con~ltal ~T syndfomo1 pationta
`taking onthrmythmlo dtugo "' othor dnlgt wNCh lood to
`_Di_·=_h_""-----------+--~---86-(12._,..4_%_).:..' -----+--'.:.." ·.:..' __ 2_5_(7_.0%_.:.,~-- ,.---...:..
`QT p.olongat!on, and cuinulotlwo high doN anthiKydino
`1.• (5 1~·) .
`thorapy,
`· •
`· -.
`· ·
`•
`F
`30 (4'3. a.)
`Cro~ bypenen.oUtivity i'eilctioils ha)•e been repoi1L'<l in pa.
`_•v_e_r - -- - - - -- - - - - f - - - - - - ---· -N-----'-'-' --+---,---~-- --~-·----
`G
`·
`tieot$ who received othe-t selective 5-HT 3 receptor antago·
`_F~ao_·gu_,..e'-' -----------1------2-5-:-3-;-.6-''f,..~-..;.:..' _' ......:.·'-..,.--.,.+-.,...--~-:-~--<i'-'*"_i __ ·....,.__:..,
`nil!t8.1)>e"'l rnactions have ru>t b..,n """"with dol..otron
`~;::;1:~...
`25 (3.~%>
`~/3-4'1,) ,
`_
`_
`.
`.
`H•pali< Function AbnilnnBit
`, .
`The .P9jen.tial for ~linlcally oig;,;ft<;!Ull clNg~_kttera<-
`7 {2;091\)'
`Abdominal Pain
`22 (3.2%)
`tiCHlJI J)C)OM by dol...,tron and hydrodcl ... tron appoara to ---------------11--,...---'---------+~' ~- -__ :__ .:__,...
`9 (2.§%)'
`be low for d.J\lgs commonly u44!<l in chem~1;Jlerapy or sur-
`2Q (2,g.l)
`8)'J)f'rt.ension
`' l
`gery, becau&e hyd.rodola&eiron it t.liminoted. by muH.i.ple ----------------1f------~------~-+------'--:-~-
`rout<>s. S.. PRECAUTIONS, General for infcnnation Obout
`7 (2.0%)' ,.
`Pain
`17 (2.4%)
`potential i.nt.lraction wiU.. oth..; d<UJ!l! thz;t 1\..-oJong the QT, -:--:---:-------~--11--.,...---~--------t"--~~~-:....:.~~
`interval. Blood level• of hydrodolaaetron increased .24%
`bizziness
`15' (2,2\t)·
`7 (2.0%1
`when doluet:ron was coodministered with cimetidine (non- --------------'1--""-:---~--'-''------~-+---------'-
`••lecti.ve inhibitot of cytoobrome P-4501 fo> 7 daYi •. nna deo
`Chilla/Shive!'inc
`14 (2.0%)
`· 6 (1.~)
`c-reased 2M\ ..;th coadministration cf rifampin (JXIIA'at in-
`::-:~;--:--=--::---:---:-;;-'-::c-:-,.-;;---....:.....:--'-----:'--L-..:...-"'------
`ducer of C)'t<!cbrome P-460) for J da,ya.
`• .*: Onciaii8tron 3~ mg inlnlvonous, granioeilon 3 mg in)ta'>'nou..
`,..,
`- ' ·• . ·
`, .•
`> _
`t: Inti*• evento coded ao SGQJ'- and/or SGPT-incr.&.<a (&eo also Linr aod Biliuy Syotem below)
`ANZEMET ln,jodion baa boon safaly coadmicistenJd with
`drugs used in chemotherapy and surgery. Ao wll& other
`. ··-. '~·--.:
`. ' ·stu-.. ,_.
`, ·. $_ oi~ Pootopomlv._ . ~- an. ,d VOmillr!t
`ageots which prolong ECG intervala, caution should be ex-
`Tobl• 5. - - Ev- "' 2~ from Pl-.co
`_ '
`_
`ercioed in patienli taking drugs v.•h.ich prolong EcG inte.-. ___________
`..:._--,---'-:.:...:....,.-:;--'-· ----'""'-'----""'---+'-~--"'-:..:.-'-~'--"'-..,-~
`Placebo ·
`vals, particularly Q'l' c
`ANZEMET ln,lecijon_ ·
`ln patienta taking furosomide, nifedipine, diltia.um, ACB
`12.5 ing
`·
`··
`(,._739.~:.·~--,._ ..•
`event
`(n~l5l, .... '·
`inhibitora. verapamil, glyburide. propranolol. and vari<luo
`chemotherapy IJODU, no-ol£o<t wu ohown.o~ ~clearance- ----~---------:----l-------'-·"-"---'+------'--'·'::-':7':'"'--'---'-
`• - a-·aa.~;;;- __ ,
`.· ... -~~
`orlcy'drodolaaetron."<lkilranoe-
`51-<!'0!tJ-'
`> ·~
`58 (9.4%)-
`:..' -;_•a-::::'~:::,...:.:t·:..'':.:.":..' :..··-''"''~·~~"'-'-'.:..~'·'-''"::.· _:'·:..· :..~'·=i'::.:'"-"•'+--'-'--"--~=--"'--'---=~-+---'--""-'"-'--~~'-i
`by abouc 27% wMn d·o~·
`mM
`I ..
`23 -(3.1'1>)
`34(5$.)
`~~~:==.::,::time in-~~~!: . -'~-- .,.·.,.-.,..,.·_,_:.:..' ..:"c:.· __________ l------------1---~~-~----
`~~~~d~~~~~~:t;~~&f~~- _DNW.:.. __ ,_~;_: ·:..~..:;: __ ~-----------~~+-:-----------+----~-::~-~--7
`18 (2.4'1>)
`15 (2.4%)
`21 (2.iflh
`biti!\, cycloRIJ!lsJ>Ilam!~). in row llllll'i.Ite, 1Jl9<1~. ~.: _.
`15 (2.4%)
`Pain ·
`Corclnoto.-. M~ ~ of F!rtl!!ty
`-------'-----......:'-.-,--:+-.,.-.,:.;_--_...-.-._-.....-11'-----~.......:--"'":--
`16 (2.2%)
`i2(2.0%)
`ln a. 24-monlh <ar<inogenidty study, ~ .. wu a statisli·
`Urinary l!oU!ntiop
`cally ei~t (P<O.OOl ) inc.....,.. ·jp tho incidence of com· - - - - - - - - - - - - - - : - : . ..,,-'---,-.,-- --------'---,,...--=--...-....,-.-.;...
`binod hopatocollular adonollUUI and carcinomas in male
`mice tnole<l. with 11;0 a>lP'kiP'day and obove. In tlrllo •tudJ,
`ANZEME'W ln,lection.
`(dol ... tron m .. y)Ate iq)ection)
`mice (CD-1) wen tNatocl. orally. with doluot:ron mtoylate-
`20 mgfow
`75, 150 or 300 ~day (225, 450 or 900 1Dgim1/day). For a
`50 kg porson of average height (l.<i'S m• bodyawface area),
`these dOMt· repreeent 8~4, 6.8 aad 13.5 timea the 'f"eeOm.t.
`mended tlini<al doee (66.6 mg!m•. intravenous) on a body
`0.6~mL sin:gle 1110 amJlul~
`$urface area basil. No ill.Crea9e in liver tuthon wat o1Situved.
`12.;.5 ~
`-v
`.:
`(lle>t .o.(6). .
`;u~~~m!.~~~:.e:::All~~~~ !-~
`;, -,~ ~~;-· :.,. --~-~~--
`•' .,:, ·"
`.foil mlis.Jn!.. ,,.. ·
`In a 24-month rat (S~llO;.teyl au\iii>opruciiy •til<IJ;
`oraldo~mooyllltewi.inottumorigemca•doieo·upto • -------'-'------'---------:-:.'i', ~ . ..,.~. ~-'-:...:;"-::-,~-:-:'-7,~. -;-. ~.~=-;;,,-'"-:--:-:--...-"-
`c><
`cbemotl:l, tapy are co03U.tont with those obtained in edult:a.
`Furth~;;;;;;;., ;,.,.~-~~;....b;.'brady~ 'and syn..;po
`150 mWI<IJI'day (900 miP'in2/difYi lJI\5, tilneo the :,.,..,.,.
`mended human 00.. baaed on bOdy surlace arca.i In male No otlicaey il!formatiop was oollcctod in the padiatric poat-
`have h<>en reported immedia,t<>!y <!!' eW..ly ti>llowi.atl IV ad-
`rats nnd 300 mgikg/d.,Y (1800 mg/m2£da.y; 27 times !be roc-
`••d, , ,,,
`.. ,,
`.• >
`oporatlve lwl.uoea nndyomitinc •tud;ea.
`mini8ttation.
`ODlt11ended bwnan 00..-based on tx.iy surface arc4) in fe·
`y~~ cOMtf;.fron. c:b;P.e" i8. ·;taoui:
`aoed
`..
`,. ..
`'
`'
`,.,
`Uao tft·Eidorly Patl<lnto
`· Rasb ·
`0 mat I
`at~
`D~ ·aaju5t.tnent is bot needed in patients twet 6.';. E~ ~,t~~ S
`.. · ·--)-
`male rau.
`--
`..
`--
`- ·
`Dolasetton m~ylate was not geMtoxie in the Amu test-. the
`tivene&d ln pmotntion of oau.sea and vOiniting·in e-lderly pa~
`i.tial Pain. ~ore~nire.ty;.P:~atitls. .·.~ ~. , ': . . ~ ·
`~t''
`rai tympl)oC)-te chroJ:DOs:oin.al abet:r.a& n -test, tne Chinea-e
`He.,.lng. 'r,ste and~VisiQ(l: ·Taste pervenio~, a~oorm.U ~-i-
`tie.Dtt Wii$ no ditrererit tliim in )·Oung_ei' age gr¢Jpit
`·:
`ham•tn ovary (CHOl cell (HOPRT) forivard mutation teat,
`ADVERSE REACTIONS
`·
`"' '"'
`sio'!: ~oo:ely-llnnitue,.photOj)ilobia. .
`.
`the rot oopatoeytAl UI)$Chedul..i DNA'O)-i>theo!• (UDS) IA!!.-t
`llomat~c: llBn!J};:-bqina!w'i@; epi•taxii. pmlhromb\!l
`~=jj!f~i!:?':ials. 2265 adult. p~;i~nts ·.;~'ei~ed
`time prolonged, PTl' increased, anemi.a, p,urpu.raJpe~-
`or the mou..;;e micronUeleus tctst..
`· ·
`·
`Dolaset.TOn meeylate wa.a' foUnd to have Oo eft'ed:. On f~.ity ANZEMET fnject'iQn. The overall adYerse event rate.:\9ere
`toma, thromboeytopenia.
`•
`,
`Hypersentlttvity: Rarely- aoapbylaetic teiliiod, ·{aC1aJ
`similar with l.S mg/kg ANZEMET Injection &nd'· on·
`and rt"iprodueth·e pertormance a t oral dogcs up to 100 mgl
`kg/day (600 mp2/day, 9 timef:i tb.~' reoomltt(ended h..um4tl
`edetill.l; urtlCRtiil~' .
`• '-~~
`.. , .. -~.)... ..,-
`d.an&ctron or gl;:miectron. Patient& were· receiving concur-
`;; . .,. •
`...
`rent chemotherapy, predominaot.ly high-dose (~50 mgtm2) u~ end IIH•rl s.,.t.m:· Trins-i:e'nt i\i~~s in AST
`dOM! based on body surface <lNA) in female rats and up to
`<SCJ?Tf and/or ALT"(SGPT) ? liuio have been'TeP,Ortea ilo
`cioplatin . Fallowing iS a combined li&tlng of all adverso
`400mglkg/day (2400 l!IIP'm'lday, 36 tirrnle the recommellded
`adve,..e events ·in leas Ulan 1% of adult patient& .....:eivli>~
`"''•nto n~parbld in ,.211. of patic~t~. in t!>~ ~,n!Toll"!l !m.l•
`human dO!!<! based on body