PDR®
`55
`2001
`
`EDITION
`
`PHYSCANS'
`DESK
`REFERENCE®
`
`!Hinlor VIce President, Dlrec1ory Services: Paul Walsh
`
`lllu Pretlldent, Sales and Marketlnf&l Dikran N. Barsamian
`National Sales Manacer, Custom Sales: Anthony Sorce
`hftlor Account MllluiCW-tFrank Karxowsl<y
`Account M~:
`Marion Gray, RPh
`Lawrence C. Keary
`Suzanne E. Yarrow, RN
`National Sales MliiiiiCer, Medical Econornlcll Trade Sales:
`Bill Gaffney
`Senior Bullnese Manacer: Mark S. Ritchin
`Financial Analyst: Wayne M. Soltis
`VI« Prellclent, CUnlcal CommunlclltloM and
`New Bus'- De~elopment. Mukesh Mehta, RPh
`New Bus'- Dewelopment Manacer: Jeffrey D. Dubin
`Manacer, DrvC lnfomurtlon s.ntces: Thomas Aemlng, RPh
`Ofllllnformatlon Spec:la .. ta: Maria Deutsch, MS. PharmD, CDE;
`Chr1stlne Wyble, PharmD
`~dltllf, Dlrec1ory S.~lcee: David W. Sitton
`l'f<IIMt Manager: Edward P. Connor
`
`s.nlor Aaeoclate Editor: Lori Murray
`Aul•tant Editor: Gwroned L. Kelly
`OlrectOf of l.farec:t Markedna; Mlcnael Bennett
`Dlrec1 Mall Mancer. Lorraine M. Loening
`Senior MarketlrC Anatywt: Dina A. Maeder
`Dlrec10f of PnMiuctlon: Came Williams
`Data Manacer. Jeffrey D. Schaefer
`Procluctlon Manager: Amy Brooks
`Production Coordlnatora: Glanna Caradonna, Dee Ann OeRuvo,
`Melissa Katz
`Index Supe~l8or: Johanna M. Mazur
`lnde.x Editor: Shannon Reilly
`Art "-late: Joan K. Akertlnd
`o~ 1mac1nc s~ Shawn w. Cahill
`DICJtallmiiCinc Coordinator: Frank J. McElroy, Ill
`f>tutnnaceutlcal Coordinator: Mary Kaadan
`Electronic Publlahln& Despr: Uvlo Udlna
`FulfiUrnent Manaeera: Louis J. Bolclk, Stephanie DeNardl
`
`M EDICAL ECONOMICS ~ 0 2001 and pubished by Medical Economica Company, Inc. at Montvale, NJ 07645-1742. All rights reseNed. None ol
`1he conte111 ol INs ptbllcallon may be reproduced. s10Aid in a r9IJ1eval system. resold, 111Cis1Jibu!ed, or transmitted in any fonn or
`· --
`- - - • - -- - --
`by any.._,. (eleclronlc. rnecllanical, pllolooopying. recording, or OlllenNise} withoul U>e po1or written pennlssloo ol U>e publisher.
`PHYSICIANS' DESK REFERENCE". POA", Pockel POA". The POA" Family Guide to Presctiplion Drugs", The POA" Fatnly
`OudiiO WQmen's Health and Preecription Drugs-, and The PDA" Family Guide to Nutrition and Health" ara regisle<ad 1radamatlca used hefain under llcenw. POR for
`()phlh"*'lio Medicines"'. POA lor Nonprescrlpdon Drugs and Olelary SlJ!)plements"'. POR Companion Guide"', POR Pharmacopoeia'" Pockel Edition, PDA" for Hertel
`Modicl.-'"· POR tor Nutritional Supplements"'. POA" MediCal Dictionary"', POA" Nurw's Drug Handbook"'. POA" Nurse's Dictionary"'. The PDA" FamMy Guide
`Encyclo!*tkl ol Medical Care' " · The PDA" Family Guide to Natural Medicines and Healing Therapies'" · The PDA" Family Guide to Common Ailr'neflts"'. The PDA" Family
`Guide to OwNtiol-C<lun1M Drugs' " . and PDA" Electronic Llb<aoy'" are trademart<s used herein under license.
`0111-. of~ ~ Compeny: President and Chief ExiiCUtil!e Officer: Curtis B. Allen; Vice President, New Media: L Suzanne BeDell; Vice Presidenr, Corporate Human
`RR$0Uro<~~ Pn""'"' M. U.lash; Chief Rnancial Officer. Cllristop/lef' Cettdl; VICe President and Controller. Bany Gray; Vice Presldenl. RNnce: Donna Santarpla; Senior l'1ce President.
`OllfiCtory Sc!Mces: PIIUI Watfilt; Senior Vice President. Operations: John R. W81e
`
`ISBN:1~2
`
`Dr. Reddy’s Laboratories, Ltd., et al.
`v.
`Helsinn Healthcare S.A., et al.
`U.S. Patent No. 9,(cid:20)(cid:26)(cid:22),(cid:28)(cid:23)(cid:21)
`Reddy Exhibit 1009
`
`Exh. 1009
`
`

`
`~AODUCT INFORMATION
`
`PtWP•r.tion for Adminiflratlon:
`I. Su•pend conuuner from oyelet support.
`2. Remove proleetor from outlet port BL bottom of ronudner.
`3. Attach udminitilnolion ""' · Refer "' oompl•te directtOI\1
`Qccompnn)'1og &t!t.
`COMPATtniLI'l'Y ANl> STABILITY
`lntnmusculw: \\<Den oonslJl.uted a.s d1~ wtlh Ste.nle
`Wnter for l'IJ'!C(oOn, suaperunoM of ZTNACEP for IM OI\Jec·
`t1on maintain eatisfac.t(lry potency fo-r 24 houn at room ~m ·
`perature 11nd for 48 hours unde r l'efrigorntion (5"C).
`After the pot:riodl menuoned above o.ny unu~;ed suspel'\ltion.s
`1hould be diocarded.
`lntrav.nous.: When thtt 7SO.rog. 1.5-g. llnd 1.5-g pltn_rmacy
`buJk vials arc conslituu*d o,s dirt!(.-t«i with Sterile Water for
`Injection, the •olutions or ZINI\CEF for IV •dministrotion
`maintain aatiF~factory potency for 24 houra at room temper-
`ature and for 4jj houn t 750-mg ADd 1.5 ~ ''oalsl or for 7 da,y•
`t7.5-g ph<lrn08<Y bulk vuoll under rnfn~•rnbOu (6•C). More
`dilute solutoons, •uch •• 750 ong or 1.5 M plus 100 nol. of
`Sl~rile Wntor lor lnjoction, &% Oeot""'c u\ie<:t.i.on, or 0.9'!1>
`Sodium Chlor•de Injection~ also maintain M t.i!Sfacwry IJO•
`lt'nc:y for 24 hours at room ~rnperature and for 7 doys un-
`der refrigeration.
`These solutiOil8 may be further diluted to concentnlU()ft.ot or
`betWeen 1 and 30 mg/JnL •n th8 following l!Olubons and .,...ill
`los(: not more l.han 10% activity for 24 hours nt. room lcm·
`perature or for at le&J-l 7 days under rcfrigE!r&tion: 0 ~So­
`doum Chloride ln)f!Cbon: 1/6 M Sodium l.actat<~ I'IJ'!C(oon:
`Rlnger'• llliectoon. USP; l.actaled Rinl(tr'a II\iec:uon. USP:
`5\t Dextra.., nnd 0.9% &<hum Chloride 1 nj""tion; S<J. Oex·
`trMe Injection: 5% Dextrose nod 0.45% Sodium Chloride l n·
`jectinn: 5% Dextrose nod 0.225% Sodium Chloride Injection;
`10'*. Dextrolie !IIie<:iion; ond 10'*. lnv~rt Sugu in Wnter for
`tnjectjon.
`Unused 11<Jiutiono should be Wl!<~rded nllor the time periods
`mentionod above.
`ZlNACEF h•• also been found compa tible for 2~ hours ot
`room t.emperat.uTe when odm&Xed in IV infusion with bepa-
`nn ( 10 and 50 U/ruLJ on 0 94 Sodium Chloride Injection nod
`Potassium Chloride 110 a nd 40 m!!qll.) in 0 .9'J> Sodium
`Chloride Injection. Soclium Oicarbonnto lnjedion, USP is
`not reoomme l\ded for t ho dilution of ZINACEF.
`The 750-mg a l\d 1.!>-g ZINACEF Al'>D· Vantage vial., when
`do luted in 50 or 100 mL of 5'l De- Injection. 0 9'l So-
`dium Chloride Injection, or 0.45% Sodium Chloride lqj<JC·
`tion , may be stored for up to 24 hours Qt room tempernto.re
`or for 7 days under re'frigc rt•t.ion.
`Ffoun Stobltity: Constitute the 750-mg, 1.5·g, or 7.5-g vial
`os directed for IV adminOAtrali<>n in Th.ble 2. Immediately
`witlodraw the «•tal contenla of the 75().mg or 1.5-g vial or 8
`or 16 mL rrom the 7.51.bulk vial and add "' a Bnxter
`\llAFI..E.X® MINt-tiAG-r. ""'taining r.o or 100 mi.. or0.9%
`So-dium Chloride Injection or 5% Dextros<' Injection and
`freeze. Froten solutions are stable for 6 months when atored
`at - 20•c. Frmen solutions should be thawed at room t.e.m-
`perature and not refrozen. Do not force thaw by imrntl"ilon
`m water bnths or by microwave irradintion. 'Thawed solu-
`hons may be st.orOO for up LO 24 bo-urs at room t~d1Pll•••ttatJ
`or for 7 days in a refrigerator.
`Note: Parent<>r•l drug products should be inspected vi•u-
`a lly for partlCulote matter and discolorauon before admin-
`Istration whenever solution und container pennit.
`1\8 with other cepha losporin•. ZINACll:f' I>Owder •• well as
`aoJutions ond suspension& t.eod to darken. depending (Ul
`""'rage rondotio,..., without a dversely effecting product po-
`tency.
`OirectJons for 01-SfMnsing: Ph•rm•cy Bulk PltCk•g• -Not
`for Oir.a lnfuolon: The IJhormacy bulk package iB for use
`in a pbarmo.cy admixture H rvice onJy under a laminar Row
`bood. Entry onto the vial mu! l be made with a sterile l riUIS-
`(er set or otkf.r sterile disl)ftUring de\•ice, and the C"Ontents
`dispen'S«ltn aJiquota U$ing aseptic technjque. The use ohy-
`dnge and neWie is not recommended as it may c~u86 leak-
`age I see OOSAOE AND AOMINIS'I'Tv\'I'ION). AF'l'ER INI·
`TIAL WITKDRAWAL USE ENTIRE CONTENTS OF VIJ\L
`PROMPTLY. ANY UNUSED PORTION MUST BE DIS·
`CARDED WITiflN 24 ROU'RS.
`HOW SUI' PLIED
`ZJNACEF in the dry stole obuuld be stored between IS" and
`30"C f59" and W F) and p~ from lighL ZlNACEF i.o a
`dry, white to otT-white powder supplied in vials and infu&ton
`packs as follow&:
`NDC Oln·0352-3l 750-mg• Vial t'l'ray or 251
`NDC 0173.0354·35 La-g• Vial (Tray o£25)
`NDC 0173-0353-32 75().mR" Infusion Pack (Tnoy of 101
`NDC 0173·0351h!2 1.5·g• ln.fusion Paek (Tnoy of 101
`NDC 0173-0400.00 7.5-g ' Pharmocy Bulk Package (Tray or
`6)
`NDC 0173·0436.00 750-mg ADD-Vantage Vial ('!'ray of 251
`i'IDC 0173-0437.00 L5·r ADD-Vantage Vial (Tray of 101
`•The above ADD-Vanta~ .. vials are"' IJ<l used only with Af>.
`b<Jtt ADD-Vontoge diluent c<ontainen.t
`ZINACEF rro:r..en. as a pl'emixed solut.ion orcefuroxime injec-
`tion should not be stored ob<Jve -~o· C. ZINACEF is aup·
`plied fro..-n in 50-mL. single-<108<!, pl .. tic containers at1 fol-
`lo"A-s:
`NDC 0173·0424-00 750-mg' PlaAtic Container (Carton or
`2'11
`NDC 0173·04~5-00 1.5·R' Plost.ic Container lCarton of 24l
`J, Equival~nt. to cetUroxime.
`
`REFKIU.'NCES
`l. Notional Committee for Clinical l.aborai<Jry Stand<lrd•.
`P~rformance Standards {or Anlfmic:robJol SuJCt:ptabrilty
`Ti•l•llf!· Third lnfonnational Suppleo:nruot. NCCLS Docu·
`mentMl00-53, Vol.ll, No.17 Villanova, P•: NCCLS; 1991.
`2. Cockcrort OW. Gault MH. l'rodiction of crcntinone clCOI'·
`aneo from sen.tm creatinine. NtphroiL 1976; 16~3 1 .. 41.
`ZINACEF® (""furoxome for in)l!etoonk
`Glaxo Welloome Inc .. &search Tnangle Pnrk, NC 27709
`ZfNt\Ct;F® (cefuroxime in)ec:toonJ:
`Mnnufoctu.rcd for Gloxo We llcomu Inc.
`Hescarch Triangle Pw-k. NC 27709
`by Ouster Healthcar<! Corporation. Deerfield, IL 60015
`ZINACEF is • "'IP•tered trndemark of Gluo Wellcome.
`,\DO-Vantage is a registered trademark of Abb<Jtt Laboro ·
`to rica.
`CLINITEST i& o regialered to·odemark of Ames OivisoOO>,
`Miles I_Aiboratones, Inc.
`1'1-:S. TAPE is a ~tered tradcmurk. of Eli l.olly nod Com-
`pany.
`GALJ\li."Y and Vli\I''L&x ure regi$lered trademarks of Bax•
`tor Jnt.e.tnationnl Inc.
`November 19981RI~642
`Shown in Prod11ct ldn~ttProu.on Guid,, pagt 317
`
`ZOFRANe
`ltll' (ron I
`(ondenwtron hydrochlorldel
`lnj.aion
`ZOFRAN~
`(ondans.tYon hydrochloride)
`lnj.ction Premixed
`
`I~
`
`1$<
`
`DESCRIPTION
`Tho octive ingro.tient in ZOf'll.i\N Injection ond ZOFRAN
`lnjc'Cl ion Premixed oa ondaMetruu bydrochloridoiHCII, tho
`rnctmic form of ondonsetron and a l!<lloctive blocking a~ent
`of tho ~ero«min 5-111'• recep~<Jr type. Chemically otis (;) 1.
`2, 3, 9·tetcahydro-9-metbyl·3·1(2·methyl·IH·omidazol·l·yll
`me thyii-4H-carbo•ol·4-onc, moMhych ochloride, dihydrnto.
`'l11c empirical formula is C18H1wN30 • HCI•2H10, repreS(Int-
`ing 4 molecular weigbi or 365.9.
`Ondonaetron HCios a white IAl off-white powder that. i.o JOI·
`uble m wateT and normal s.aJine.
`Sterile fnjection for Intravenous (I.V. ) or lntramuscul1r
`(I . .M.) Adminittr•tlon: Each J mi.. of aqueous Rolution in
`the 2·mL single-.dosc vial cont.alns 2 mg of ondansetron ns
`the hydrochloride dihydrato; 9.0 mg of •odium chloride,
`USP: and 0.5 mg of citric acid monohydrate. USP and 0 25
`mg of sodium citrate diliydrnlo, USP a.s buffers in Wa ter (or
`Injection, USP.
`Eoch I mL of Aqueous soluf..ion in the 20-ml .. muJtidose viol
`oontAins 2 mg of ondanse<ron os the hydrochloride dihy·
`draw: 8.3 mg or oodium chloride. L'SP; 0.5 mg of <itnc acid
`monohydrate, USP and 0.25 mg of !Odium cit.rate dihydrotc.
`USP a• butfcro; nnd 1.2 mg of rncthylparnben . NF and 0. 15
`l"ut; uf proTJ:t1tmr;,befl, NF ns prest..~iVft in Wate-r f& ln~
`J'!CtiOn, OSP.
`ZOf'RAN lnjertion is a clear. coloriMS, non pyrogenic, sterile
`IIOIUtion. The pH or the irljection solution io 3.3 to 4.0.
`Sterile, Premi••d Solution fof lntravenoua Admlnistr•tion
`in Slngi•Oose. Flex_ible Pfettlc Contein• rs: Eo.ch 50 m l.
`eontains ondausetron 32 mg (M t he hydrochloride dihy.
`drate~ dextrose 2.500 mg: and citric acid 26 ong a nd sodium
`<itrste U .5 mg u buft'ers in \Voter for l.qjection, USP. It con·
`tn1n.1 no pre~n·otives. The OAmolarity ofthia solution i$ 210
`mOsnVL (approx.), und the pH is 3.0 t.o 4.0.
`Tho fiC'Xible plastic container is fa.bricawd from a specially
`formulat-ed, nonplasticizM, thermoplattic co·polye~at-er
`CCJU). Water can permeate from mside the container into
`the overwrap but not in asnounu sufficient to affect the eo-
`lution significantly. Solutions insicle the plastic (.(lntalner
`ftiSO can leach OUt C(lrtain o( t.he chemica l c:omponentS in
`v~J.ry smaU amounts before the ~xpiration p<!riod is attained.
`HowO\-.r. the safety of the plo~tic ba.o been confirmed by
`t .. u in animal• oeconding "' USP biolO!Pcal •umduds for
`pln.stic containcra.
`CLINICAL PHAR.MACOI..OOY
`Pharmaeodynemlc:s: Ondansetron is a ael~tive 5-HT ~ ~·
`ceptor antagonist. \Vb.ile ondansctron's mechanism of acuon
`hns not been fully charocteriZA.'d, it is not o dopomine-reup-
`tor nntogonist. Serotonin recopl<lrs of the 5·HT3 type a re
`present both peripherally on vugal nerve terminals and ccn·
`trnlly in the t hcmora-eptor t..rigge:r zone of the are.a pML-
`rcm.a. It is not cert.am whether ondan.setron'e a.ntieme-tic se-
`tioo m cbemotheropy-induced emesis is mediated centrally.
`penphe nlfly, or in both >ites. •lowever, cytOI<lxiC chemother·
`apy appears tO b& DJ:lsociated wit.h release of &er'Otonin rTom
`tho enterochromoftin cells of the small lnt.ootine. In hu·
`monv. urinary 5·KlAA t5·hydroxyindolcacolic acid) excre·
`tion increases after o.splatin admlnl3tration 1n parallel with
`the flnset of emtwis. The relenud seTOtortin may stimulate
`the vagal afferontd through tho 5-HT3 re«J>tor! tt11d initiate
`the vomiting reflex.
`In animals. the emetic ~6ponKe to ci8plat.in can be pre·
`vented by ptetl"e:atment. with an inhibitor of terotonjn syn-
`th .. is. bolateral abdonunal vagotomy nod greater splanch-
`1\IC nerve section, or pretreatment with o serotonin 5·tiT3
`m optor antagonist.
`In normal volunteers, single t.V. d...,. of0.15 mglkg of on ·
`daru;et.ron had no effect on <'tOphageal motility. gastric mo·
`
`GLAXO WELLCOME/1503
`
`tility, l(,wer esophBRt!UI 19phinctcr prcst~urc, or &ma_lllnte.sti·
`nal tronsi1 time. In another st.udy m six normal mal'l vol·
`unt.eero, a 16-mg dose mfused over 5 minu...,. i howed no
`effect of the d.ru.g on c.ordJOc our put.. hea.rt rata, rtroke vol-
`ume. blood '"''"sure, or ~lo<troeardoognun !ECQ~ Multiday
`o.dminiAtrntion of ond•1nsetron has Lcen shown to slow co-
`look •ront~iL in norntttl \10iu.ntecrtJ. Ondansetron bas no ef·
`feet on plasma prolac-t.an cooeentrauoos.
`In a gender-b81aneed phann8<0dynamic study In • 56). on·
`dansetron 4 mg t~dmin.iKLered iJJtn\Vtnously or mtrnmuscu~
`kuly woll dynamic:ally 8im.ilar in Lhe prevP.ntion of emosts
`rtnd nBUS(!il Uffing t.ho ipecacunnhD model of ome(4is. Both
`treatment.a wt":re well tolerated.
`0 ndBM4'tron d""" not alter the ,..pomlory dep...-nt ef·
`feet. produ.OO by alfentoml or tho degn,o, of neuromu•cul:tr
`blockade produced by atracurium. lnteractions witJ1 general
`OT locol t'Ultethet.ics luwc not bee n stud1cd.
`Pharmacokin etics.: Ond3o&etron i& e xt..ensivcly met.abo~
`liZA.'d in humans. woth 11ppro:rimately 511> of a rodioiAIJ<lled
`dose rt'CO\'ered as the parent compound from th.e unne. The
`primary metabolic pa thway is hydroxylation on the indole
`ting f6llowed by gJuturonide: or gulfttt4.:l conjugnt•on.
`AJthough some noooot\iugated mot.abolit.e.s have phannaw.
`logic: aetwity. these are not found an plasma at conreotta~
`lion• hkely to sign>ficantly contnbute to the boni<Jcicaloctiv·
`ity or ondanse.tron.
`Ondansctron is a substrate for human hepatic cytochrome
`P-450 entyme•. inc.ludin~ CYPli\2, CV1'206, a nd CYP3M.
`llecau;oe of the multiplicity of metabolic enzyme<~ <Apllble of
`metabolinng ondanset.ron. inhib1tion or IOSB of one enz.yme
`(e.g., CYP206 genetic detkiency) ret~ull.s in litt.lo change in
`o ... erall rntc.s of ondnnsetron elimination.
`I n ClMmoJ volunteers;, the following mean pharrnacok.inetic
`data have been dct<rmined rollowoll~ a si<Oglo 0.15-mg/kg
`J.V. dose.
`
`.-\g.,.«YYOP
`
`19-40
`61 -74
`;,75
`
`n
`n
`12
`ll
`
`P1aauu1
`Mean
`PNtk Plasma
`Concentration EUminat.ion Clearance
`onghnL)
`Half-life (b)
`ti.J1:v'kgl
`
`102
`106
`170
`
`3.5
`4.7
`5.5
`
`0.381
`0.319
`0.262
`
`A reduction in clearance and increa:w. in elimination bsJ(.
`life a rc RCcn in patient.a over 75 yeurs of age. In clinical tri·
`a l5 with eoncer patients. safety and efficacy were similar in
`pattent.a over 65 years of age and those under 65 yearS of
`age; there was an in.auffiaeot number or patients over 75
`Y"ars of age to permit conC-lusion• in that age--group. No dos-
`age adju~rt.ment is recommended in the elderly.
`In patients with mild·tO·modorat..c hepatic impairment..
`clearance is rt!duced twofold and mellJl holf-life i• increased
`"'11.6 hours compsrt!d IAl 6.7 hours in nonnals. In patients
`with ~evere hepatic impairment !Chold-Pugh ocore0 or 10 or
`greater), r.leoranc:e is redu<-ed twofold to thN!<Jfold a nd ap-
`pe.Nnt voJu.m.a of djstribution is incro.o.sed with. o resuJtallt
`"''"''"" ir. Ja!f-lifc to 20 ~·• and bio$va.ilability ap·
`pi'OIIching 1~. In such patient&, • total d<lily d..,. of 8 mg
`should not be exceeded.
`Onda.nsetron plasma clearance W aJ rt!du.OO by 41\ll !95% C1
`20% to 67%) in pat.ient& with severe rena) impnirme.nt (ere·
`atinine clearao~ < 30 mUmjn). 'rhis reduction in clearance
`is variBble and waa not. consistent wit.h an. increase in half·
`life. ~. rt!duction in dose or dosing frequency in these pa-
`tients ia wa rranted.
`ln adull cancer patients, the mean e liminatjon hair-life wa.s
`4.0 hours. and there was no diffon•nce in tho multido!'e
`pharmoeokinetics over o 4-day period. In a study of 21 pe-
`diatric cancer patients (aged 4 to 18 years) who received
`three I.V. dooes of0.16 mg/kg ofondanoetron at 4-hour in·
`tervals. patients olde r than 16 yeot8 of age exhibited on·
`dansetron pharmuoold nctic pammcters similar to those of
`aduiU . Patients ag-ed 4 to I 2 year• generally •howed higher
`clearance and somewhat larger volum~ of distribution than
`adulta. Most pediatnc patients younxer than 15 yean of age
`with conoor had a short~r (2.4 houre) ondansetn:m plasma
`half-life than pat.ient.s older than 15 yean of age. It is not
`known whether these ditfererH:es m ondanset;ron plas.rua
`half-life may result in differen«>> in efficacy between adults
`ond ""me young pediatric patienla (""" CI..INJCAL TRIAJ..S:
`Pediatnc Studies!.
`In • study of21 pediatric pati enu (o~ .. d 3 to 12 years! who
`were undergoing surgery requiring anesthesia for a dura·
`tion of 45 minute$ to 2 hours. a single t.V. dose of on-
`d= .. tron. 2 mg t3 to 7 years! or 4 mg (8 to 12 years), ,.. ..
`adrnini&tered immediately prior to anuthesin induction.
`Mean weight-normalized cleaTttnce and volu_me of distribu-
`tion values in these pOOiatric surgicoJ patients were similar
`to those previously reported fo-r young adults. Mean tenni·
`
`Continued on next pag•
`
`This product infOJmatlon is bu&d on labeling in effect on June
`23,2000. For further Information. cont•c:t via direct m•il, phone,
`or w.t> lito. Medio•llnfCifmation, Gloxo Wellcomo Inc.. PO Bo•
`13398, Ruearcll Trlanglo Par~. NC 21709. Hulthcaro
`Prolusionals !Medical Informa tion): 800-334-0089. Patient•
`[Cultomtr Response Cooter): 1·88S-825·5249. GI~Xo Wollwmt
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`Consult 2 001 ~ s~ end fvturt .mtionl for revisions
`
`Exh. 1009
`
`

`
`1504/GLAXO WELLCOME
`
`Zofran lnj.-cont.
`
`nal half~hfe wns ShfJbtly reduCfld in podiatric pali••nts
`tran1e. 2.5 1<> 3 hours) m c:omparison W1th adulto (nu~ge, 3
`to 3.5 hounl
`In normal ,,)un~rs ( 19 to 39)'l'M8 old, n • 23). the peak
`pla8mu conc::entrnt1on was 26-1- ng/nlL following a smgle
`32~nlg tlose administe red tas a H>·minute l.V. infusion . 'rhe
`mean t liroination htllf'·life was 4. l houl"8. Systemiccx·J>I)8u.ru
`1.0 32 mg of onda.nselroo wa.s not proportional to dose R8
`meru1ured by comparing dose·nonnaliu-d AUC \'olu"" 1<> ;>n
`S·ma: dose.. ThU 1s con.sutent with a tmall docrease in sys~
`temac dea:rn.nce wtth tn.c:reosing pla5mo COOC!C!ob'3b0ns.
`A tt.tudy was perfomled in nonnal volunteers (n • S6) to
`ovoluate the pharmacokir\etJcs of a sinK.I~ 4·mg dose adm1n·
`telered as a 5·mmuw infusion compurod to a single intru·
`muscula r injecUon. Sygtemic (!x:potit•rc O.! measure<l hy
`me•n AUC was equiv•lent. with va1Ul'6 of 156195% Cl 136.
`1801 and 161 195'Jo Cl 137. 190} ng• hlmL for I.V • ..nd I M
`croupt!. respectively. ~tean peak pt:uuna concentration•
`wero 42.9 195~ Cl 33.8. 54.41 nglmL ot 10 minutes after I.V.
`infusion Wld 31.9 195% Cl 26.3. 38.61 n(!lmL nt 41 mmuteo
`nft.cr LM. injection . 'rhu mean eliminlltion balf·liJe wM not
`affected by route of ndminjatmt,ion.
`l'huiOHt ptt•tein bindtng of ondansetron ~l8 •neas11red. in vitro
`was 7~ to ;&4, w1t.h binding consumt O\'Cr the pharmnco-
`1ogtc conce-ntNttlon range (10 to 500 nAfmL>. Circulating
`drug aiM di3tnbut .. into erythrocyteo.
`A posltjve lymphob1A5t t'I'3Jl5formauon te&t to ondaosetron
`has been reported, whieh suggests imn•unologic sensitiVlty
`t.o ontla~tsetron.
`CLINICAL TRIALS
`In a dou·
`Ch•motherapy~lnduud Nausea end Vomiting:
`ble·blind study of three different dooing regimeruo of
`ZOFRAN lnject1on, 0 015 mglkg, 0.15 m!lil<g. and 0.30 mg/
`kg, each given three tianes during the course of tancer
`chemotherapy, the 0.15-mg/kg dO>Jing regimen w .. more ef.
`foctive tha n th o 0 .015·mg/kg do•in~ r~gimen. The 0 .30·
`mglkg dosing regimen wns not shown t.o be more effective
`than the 0.15-mg/kl( dOI!Iing regimen.
`Clsp/flin-BitsMJ Ctt.mother.,y: In a double-blind study 1n
`28 potion!B. ZOPRAN Injection tthi"C<! O. ll>·mg/kg dooeo)
`was atgnific.antly more effective thon placebo in prevenhng
`nnu~a a.o.d vomiting 1.ndueed by cisplat.in.·based chemother-
`apy. Treatment response was as follow~:
`!See ta ble 2 beluwl
`Ondansetron wu compared with metoclopramide in a sin-
`ale-blind trial in 307 patients rec•ivlng dsplatin <> 100
`mglm1 with or w1thout other che.mot.herapeulic:: agents. Pa-
`tiento received the fint d06e of onda....,tron or metoclop.,..
`m1de 30 minutes before cisplatin. Two additional on·
`dansetron dosetJ were administered 4 ond 8 bours later, or
`five additional mctoelopramidc doses were administe red 2,
`4, 7, 10, and 13 hours la ter. Cispl&tin wn~t admin ist.ert:d over
`a period of 3 b.oura or 1068. Episod~ of vo10iting and retch·
`mg were tabula!A!d over the period of 24 hours aft.er cio·
`plotin. Tbe reoulu of thio •tudy are oummarized below:
`l!,o.. tuJ>:e s ... 0<1<'1 iA'~J
`In a strat•tled. rnndomued. O()uble·bllnd, p..<tr.lllei-group.
`multicenter study, a si.ng le 32-mg dOI!<l of ondansetron wao
`compa red wlth three 0. 15~mglkg doses in patients recelving
`tisplatin doseo of either 50 to 70 mg/m2 or ;;,; 100 mg/m2• Po·
`tiento rooeived the fint ondansetron dose 30 minutes be foro
`Cllplatin. Two additlonal ondanset.ron closes were admirus·
`tered 4 and 8 hours later 1<> the group I"'CC!iving three 0. 15-
`mg/kg doses. In both •trata, signjficantly fewer patients on
`tho •ingle 32·mg doso than those recmving Lhe throo-d06e
`regimen f.ailtod.
`!See table 4 on next pngel
`Cy~lophosph•mld•·B•••d Chemoth•r•py~· J.o a double·
`blind. placeb<H:ontrolled study of ZOf'RAN Injection I three
`0.15·mg/kg d ... o) 10 20 patienl4 'I!Celvmg <}'clophoopha·
`
`mide (~00 1<1 600 m(!lm2) chemotherapy, ZOfRAN lr\ic>ction
`was significantly more effective t.han plaCX!bo in pruv~nting
`nausea a nd vornit.iog. The results a re fi;O(lu:nanted below:
`1&.! i..•blo 5 on Mx~ page)
`R• ·trutm.m: In uncontrolled trials, 127 patienu rooeiv·
`mg cisplaun (med•an dose. 100 mglm2) and ond.an&f"tnm
`who had two or fe:wcr emenc epi.IOdH were re-treated with
`ondansetron and chemot.hernpy. mnlnly cisplutin , foro tot.al
`of 269 re·trontment courses (mc<liun, 2; range, I t.o 10). No
`e:metic episodes OC<!.urrl!d in 160 t59',), and two or rewt~r
`t;metic episodes O«urred in 217 (81%) re-treatment. OOUrJCB.
`Pftdi•tric StudiH : Four open· label, noncompari\th'P fane
`t:S. thn>e for<>1gn) trials hove been performed "'ith 209 pe.
`dtatric cancer patients agtd 4 to 18 ye-ars given a v&nety of
`cisplatm or nondsplattn rt-gimens Jn the three Corctro tri·
`ol• . the initial ZOFRAN ln)echcm dose ranged from 0.04 t.o
`0.87 mg/kg for • total do8e nf 2.16 to 12 mg. 'l'hi~ wue fol·
`lowed by tho otal f1droinlstration c)f oodans:etron rnnging
`from 4 t.o 24 m~ daily for 3 dayo. In the US trial. ZOf'R.AN
`was adn1lnts~ted intravenously (only) lD th.ree doses of 0.15
`mglkg each for a toUll daily dooe of 7 2 to 39 mg. In theee
`studies, 58% of the 196 evaluobl• patients hAd • c:omple~
`re~ponse (no emetic episodes) on day L Thus. preventlon or
`e mesis In thoM! pedititrie pu~1enta wos essentially [he Mmc
`as for patients older than 18 Y••r• of •ge. Overoll, ZOFRAN
`Injection wea well tolerated m t.lwi<e pediatnc paticnl.tl.
`Postoperet:ive Nausea and Vomiting~ Prevention of Post·
`o~11tive N• u••• •nd Vomiting: Aduh. surg:Jcal peti.enLS
`who receavHI ondnnset:ron imme<hately before the mduct.ion
`or general balnnced anesthesia tbnrbiturat.e: lhiopt!nta.l,
`mcthohexitul, t)r thiamylal; opiqid: alfe·n tanil or fonla.nyl;
`oit.rous oxido; ncuromu5cu1M bloc.kade: suocinylcho1inP1cu~
`ra..re and/or vecur01\ium or 1\trocurium; and supplemental
`isoftt~rane) wei'@ evaluated ln two double..-bliod US 8tudies
`im-olving 554 patienl.tl. ZO~'RAN Jnjectjon (4 mg) J.V. g~ven
`over 2 to 5 minutes was s-ignifiamtly more etrecbvt than
`placebo. The ..... ulto of these atudiea an! summmzed ~~.!low:
`!Se<! tablo 6 ot IAJp of page 15061
`Tbc study povulntions in Tublo 6 consisted muinly of fA·
`n111les undergoing IQJ:>arofJt:Opic ~u·ot."t.•<htres.
`In a placeho-c:ontrolled study c:onduet.ed in 468 males under-
`going ootpanent procedures. a • mgle 4 mg J.V. ondansetron
`dose prevented postoperative vomiting over a 24~hour study
`period in 7K of males receivmg drug compared to 63% of
`males ,.,..ivlng placebo IP<O.OOI).
`Two othe r plc.cebo-controlled st.udie6 we rtl conductt"<< in
`2792 patient.s undergoing m ajor obdominal or gynt."CCioglcal
`surgeries to evaluate a si.ngle 4-mg or 8-mg J.V. ond~tnsctron
`dose for prevtlnt.ion of potitoperati\le nausea and vomiting
`over a 24·hour atudy period. At the 4·mg dosage. 59'1. of pa·
`bents receiving onda.n.set:ron verau:s 46% ~iving placebo
`in the fil'i!t study (P<O.OOIJ nnd 41% of patients receiving
`ondansetron versus 30% receivintc plnce bo in the second
`study (P; O.OOI) experienced no emetic episodca. No addi·
`tiona! benefit was observed in pat.lcnts who received t.V. on-
`d:msetron 8 mg oornpared to patient<! who f'CQ!ived LV. on·
`dansetzon 4 "'<·
`P - S.tlldlu· Th.-u dnubt.blind. p!aceboCC<>troUed
`st-..Gies ha<t born ;><rformed (one US, !'KG fure;:tnl in 1()49
`male and female patients (2 to 12 years of agel undergoing
`gene ral a nesthesia with nitrous oxide. The surgical proc;e-
`dun~.s included tonsillectomy with or without. adenoidec-
`tomy, strabiamuo surgery, herniorrhaphy. ond orthidoJl"xy.
`Patiento weA randomized to either single LV. d ... s of on·
`da.,..,ll'On (0.1 mg/kg for pediatric patiento weiKhing 40 kg
`or less, 4 mg for pediatric pattenla weighing more tb.an 40
`kg) or placebo. Study drug was administered over 31 least
`30 seconds, inum..odia tely prior to or following anesthesia m·
`duction. Ondtmactron wus signifieoot.'y more e tfcct1ve tha n
`placebo in preventing nauseu and vomiting. 'The rcsuJts of
`these studice an tumm.a.riz.ed below:
`t&.! table 7 on page 15061
`Table 2: Prev..-.tion of Che mothet-a py..Jnduc• d Nauua and EmH is in SJngl:e·Day Cispletin Therapy•
`
`Number of patienu
`Treatment-respon.&e
`OEmeticepisodes
`1-2 Emetic ep1ood ..
`3-5 Emetic episodes
`More than 5 emetic episodes/rescued
`
`Median number of emetic epis.odes
`
`Median time to fint emetic episode (h)
`
`Median na usea sooro• 1o-100J§
`
`ZOFR.AN Injection
`
`14
`
`2 U4'A>I
`8 (57%)
`2114%1
`2 (14%1
`
`u;
`
`Jl .6
`
`3
`
`Placebo
`
`14
`
`0((}<A,)
`0(~)
`I (7%)
`13 (93%)
`
`l.indefioP<I*
`
`2.8
`
`59
`
`P Valuot
`
`0.001
`
`0.001
`
`0.034
`
`Global satisfact inn with ront.rol of
`nausea 3nd vorniung cO-IOOt 1
`0.009
`10.5
`96
`• ( hemotherapy was h1gb dose 1100 nnd 120 mg!m'; ZOF RAN ln.)echon n • 6. placebo n = 51 or moder>te dO<!Ol 150 and 80
`mglm': ZOFRAN ln]«:tion n ; 8, pla<eho n = 9J. Other chemotherapeutic ·~•nta included nuorouracil, doxorubicin. and
`cycJophosphnmidc. There \O:lH> no ddTnence betweP.J\ treatm~nts in the types of chemotberopy that would account for dlf-
`fur~nces ln rcspon3e.
`+Efficacy based on '"all patients trC'nLO<l• unalys.is.
`t Median undefined since at JeJJst f)~ of the patients w~rc rese-ued or hod more than five Pmct ic: eplsodes.
`J Visual analog scale assessment or nau~a: 0 a no nausea. 100 = nausea u bad a..s it can be
`Vioual analog scale a.o..<e.,;ment of •nt15fact1on: 0 = not ot all satisfied. 100 • totally oatislied.
`
`Information wiN be tt~pefSeded bv suppltment.t and subsaq'*" tdi1ions
`
`PHYSICIANS' DESK REFERENCE®
`
`Prevention of FurthM-Pojto,ur•tiv• NIW-,H •nd- Vomiting:
`Adult. ltUf')f,lcnl patients rcceivmg general boloncOO snesthe--
`ah~ tbntbitu.rut.e: thiopental, ml:lthohex.Jtal, or Lhiamylal~
`oproid: t\lfentaniJ or fentanyl: nltrou.s oxide; nt•uromuaeuJnr
`blockade: 8uccinylcbolin&'eutl\re a.nd/or veeurontum or at:ra-
`rurium: and w pplemental i.softurane) who reaiv~ no pro-
`phylactiC antremeti<a ond who experienced nau""a and/or
`vomtting within 2 boun poetoperatw ely were evaluated in
`two double·blind US studiefl invotvrng 441 putie.nts. Pa·
`tjenta who ~xperienood un episodo of postopornth·e ouusco
`and/or vomiting we·re given Z{)f'RAN lojection 14 rng) l.V.
`over 2 t.o & minutes. and thia Willi • ignitiCillltly mor<> effective
`thon ploe<>bo. '1110 resulto of th•se studies •re summan...U
`below:
`IS... table 8 on page 15061
`The study populations in Tobie 8 <'Onsisted moinly of women
`undergoing lnpaTOS¢npic procodu.res.
`Podiotrle Studi• s: One dO\Ible·blind, plncobo·eonl rolled .
`US study was performed in 351 male and rcmrtlc outpa ..
`tients t2 to 12 years of aKO) who receh•ed general onesthesia
`with n1trout: oxide and no propbylac:tic anuemetics. Surgical
`procedurea w~re unreslritted. Patienta who ~xperieneed
`two or nlore emetic:: episodes within 2 hour15 (olloWUlg dis·
`contmuntion of nitrous oxide were randomizN.I to either sin-
`gle I.V. doS<!& of ondamwtron W. l mg/kg fc>r pedia tric 11• ·
`tientiJ weighing 40 kg or less. 4 mg for pcdiot.ric patients
`we1ghlng more than 40 kg) or placebo 8dmjniswrod over at
`least 30 RCOOds. Onda.naetron was &lgndica.ntly more d~­
`ti\'e than pU....bo in preventing further eP>"ode• of nausea
`and vom1ting. Tbe reoulu or the study are •ummariud be-
`low:
`!See table 9 at top of pago 15071
`R-ot Do•lng In Adulto:
`In plltieot.s who do not ach ieve
`ad~uate oonlrol of postoperative nausea and vornjting fol·
`lowing • sinKie. prophylactic. preinduction, t.V. dose of on·
`dM~~etron 4 mg, administration of a !kl<Ond I.V. d- of on-
`danselron 4 mg po5tOJl"l'l\t.ively does not provide additionol
`control or nau&ea and vomibng.
`INDICATIONS AND USAGE
`1. Prevention of nausea a nd vomlti~ associo.tod with initial
`and repeat courses of cmctogeo.ic cancer chemotherapy,
`including hiKI\-<1..., cioplatin. Efficacy of the 32-mg single
`dooe beyood 24 hours in theoe patiento hu not been -
`tablisbed.
`2. Prevention of postoperative na usea and/or vomiting. As
`wlth other antiernetics. routine prophyla xis i3 not recom·
`mended for patients il\ whom Ule,., is little expectat-ion
`t.hut nausea andlor vomiting will occur )X.lfitopera.tively. l n
`potient.s wbere nsusea and/or \'Om.iting mu8l be avoided
`JlOIIIOpentively, ZOFRAN ll\ie<:Uon ie roc:ommended even
`where the incidence of po8toperative nausea and/or '\"'m·
`ittn.g ia law. fo·r patir.nta wbo do not receive prophylactic
`ZOFRAN Injection and ekperience nausea andlor vomit·
`ing P<J•toperatively, Z()f'l~ 11\iection muy be given to
`prevent further episodoo (oee CLINJCAL 'l'RlALSl.
`CONTRAINDICATIONS
`ZOFRAN Injection and ZOFRAN lnjedic>n Premixed are
`contnundJCBled for palle"Dtft k.nuown to h.:.,.., e hyp..;.~.J
`to the drug.
`WARNINGS
`Hypc~nsitivity reaction• have been reported in patients
`who ha,·e exhibited hypersensitivity to other 5ele<tive
`5·HT, receptor antagonist&.
`PRECAUTIONS
`Ondaneet-ron is not a dYug that stimulate• gaatric or intes·
`tinol peristalsis. It should not be used instead or oasogastric
`suction . The use of ondonsctron in patienUt folJowing alr
`domina) surgery or in pal.ient-8 with c.hemothera py·induoed
`nAusea and vomiting may mask a progrenive ileus and/or
`gastrit di1tentioo.
`D<ug lntO<Ktions: Ondansetron does not i~lf eppear 1<>
`induce or inhibit the cytochrome P·450 drug·mctaboli2ing
`enzyme syetem of the liver. 8ec3u.S~ ondan.sc1ron is metab-
`oli•ed by hepatie cytochrome P-450 drug·metabolizing en-
`zymes. inducers or inhibitors of these e ntymes may change
`the clearance 3IId, hence, the h•.Jf.Jife of ondanaetron.