EDITION
`
`2001
`
`PHYSICANS'
`DESK
`REFERENCE®
`
`Senior VIce President, Dlrectoty Servlcea: Paul Walsh
`
`\lice Prealdent, Sales and Marketlnc; Dikran N. Barsamian
`Nftlonal SaiH Manacer, Custom Salea: Anthony Sorce
`~ Account MM-cv.l Fran~ Karl<owsJ<y
`-'"-M_..,.,.:
`Marion Gray, Rl'tl
`Lawrence C. Keary
`Suzanne E. Yarrow, RN
`National Sales Men-cer, Medical Economic• Trede SaiH:
`Bill Gaffney
`Senior Bull.-. Manacer: Marl< S. Ritchin
`Flnanclal Analyat: Wayne M. Soltis
`\lice President, Clnlul Communications and
`Hew Bualneaa Develo~ Mukesh Mehta, Rl'tl
`Hew BusiMU o.v.lopment M..,.._r: Jeffrey D. Dubin
`
`"''"•I••· DruCinformatlon ServlcH: Thomas Aeming, RPh
`0ruc Information SpeclaMats: Maria Deutsch, MS. PharmD, CDE;
`Christine Wyble, PharmD
`f41tor. DlrectOfY Servlcee: David W. Sitton
`~ Manaeer: Edward P. Connor
`
`Senior Aaeoclate Editor. Lori Murray
`Aulatant Editor. Gwynned L. Kelly
`OINCtor of ~ ~.nne; MK:nael a ennen
`Direct Mell M~~M~er: Lorraine M. Loening
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`Director of Production: Carrie Williams
`Data Manecer: Jeffrey D. Schaefer
`Production M..,.._r: Amy Brooks
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`Melissa Katz
`Index 5uperiMor: Johanna M. Mazur
`Index Editor: Shannon Reilly
`Art Aaaoclate: Joan K. Aker1lnd
`DfCIUI lmaclnc Supervleor: Shawn W. Cahill
`DIC)tallmat~Jnc Coordinator. Frank J. McElroy, Ill
`Pharm.ceutlcal Coordinator: Mary Kaadan
`Electtonlc PubllshlnC Deelener: Uvio Udina
`FUlfilment M_..,.,.: Louis J. Bolclk, Stephanie DeNardi
`
`MEDICAL ECONOMICS Copyrls1lt 0 2001 ano plllllished by Me<llaJ Eoonomic:s ~. Inc. at Monlvale. NJ 07646-t742. I>J rights r_,.,, None of
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`'Tt40M50N HI!Al.n«:ARII!
`PHYSICIANS' DESK REFERENCE*, PDR*, Pocket PDR*. The POR* Family Guide 10 Prescription Drugs", The PDR* Family
`Ouidol 10 W0010n's Health and Prescription 01\¢, and The PDR* Family Guida to Nutrition and HeaM-are registered tradamarl<s used herein undar license. POA for
`Ophlhein'IIC Medltinea"'. PDA for Nonprescriplfon Druge and Dietary Supplemenla"'· PDA Companion Guide"'. PDA Pharmacopoeia 1M Pocket Edition. PDR* for He<bal
`Modiclnoto"'· POR let Nutr1tlonal Supplementa"". PDR* Medical Dictionary"'. PDR* Nurse's Drug Handbook"', PDR* Nui'M'8 Dictionary"'. The PDR" Family Guide
`E~ Cl Medical Care"'. The PDR* Family Guide to Natural Medicines and Healing Therapies"'. The POR* Famoly Guide to Common Ailmanla'". The PDR" Family
`Guide 10 <MoNI..,.Count.,. D"'1j5"'. ano POR* Electronic Ulrary"' are trademarl<s used herein under lioense.
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`Ofllcwa of-~ c_ , Presid«Jt 1llld Chid E.xecu1We Offlc«: Cunis B. Allen; Vice P>esident, New~: L SUzanne BeDell; Vice PreskJM!. Corpoolte Human
`
`Resccne~: Pamol8 M. lldaSh; Chief Financial Offlc«: CMstophef candi; Yoce PreskJen! 1llld Conrtollet: Barry Gray; lllce Presi<let>t. Rnance: DoMa Solntarpla; s.nior lllce President,
`Oo...aOtY Semen : P'dUI Wul.n; 5etJio, y.., President. Opetatiot>s: JoiV> R. ware
`
`ISBN: 1·56363-33().2
`
`Dr. Reddy’s Laboratories, Ltd., et al.
`v.
`Helsinn Healthcare S.A., et al.
`U.S. Patent No. 8,729,094
`Reddy Exhibit 1015
`
`Exh. 1015
`
`

`
`'AODUCT INFORMATION
`p,._,.,.,ion for Admln;.uation:
`1. Suspend oontainer from oyalfJI. support..
`2. Remove prol.e<:tor from outlet port. at bottom of container.
`3. Att.ach AdmirustntJoo !M!t. Refer to complete di.rection•
`ttcc:Ompo.n)1ng ~t.
`COMPATIBILITY ,\NO STABILITY
`lntramus~ular: \Vhcn w ostituted c.s dirocwd W1th Stenle
`\Vatt!r for l.njec.tion, su'ipensionA of ZINACEP for IM injec·
`bon ma_intam sausfoctory potency for 24 hourt at rooro tem.
`pemtun'!J and for 48 hO\Jrs Uit<kir refrigerat ion ($•C).
`After the periods mentioned al>Qo.ou any um.tst:d &us pension~
`should be d\scartlt>d.
`fntravenous: When the 750-n~g. 1 54 g, and 7.5•g pharmacy
`bulk vi&Js are constituted u din.octed with Stenle Water for
`InJection, the solutJOM of ZlNACEF for fV admtrm;.tration
`mainwin aat.isfactory potency ror 24 houra at room tt!rnper·
`a. lure ancJ for 48 houl"8 (750-mg (lnd 1.5-g \"ial&' or for 7 day11.
`€7.5--g ph.o.rma("y bulk \'i..o.J) under refrigeration 16~C). ~1ore
`dilute soluuons, such u 750 m~ or 1.5 g pluJ tOO mL of
`Sterile Wawr for lnje<:t.ion1 5'l> Oex:trotle lrU«t•on. or- 0.~
`Sodium Chlonde I nj(."(;tion. aJso mom lain SAtufact.ory po-
`tency for 24 b!l\JfH flt. room t.enll)eflltUC'C (llld ror 7 days Ufl~
`der refrigeration.
`These &oiULIOlll m3J' l)e further d1luted to COncentration."- O(
`~t:Ween l and 30 mw'mL in thfl following soluUOI.\.5 and will
`lose not more tha.n 10% ucth1ty for 24 hours nt roorn tem·
`pcmtu~ or for at leU.til. 7 days undflr refii;gerotion: 0.9% So-
`dium Chloride Jl\}ecbon: 1J6 M Sodlw.n Lnetot.e h'\jecUon:
`Ringer'• Injection, USP; Loctaled !lingo•'• lrtiection, USP;
`5~ O.Xtroe<! and 0 ~Sodium Chlonde J~on: ~':to 0..•·
`trose lnJ<ctlon; 5\{ De~ttrose and 0.45% Sodium Chloride ln.
`jection: 5% DextroBC u.nd 0.225~ Sodiu.m Chlorid~ lujeetion;
`10% Dextrose Injection: and 10% Invert Sugnr in Water for
`lQject.eon.
`Uouaed tolutionA ahould be di!c:arded after the orne perioda
`mentioned aboYe.
`ZINACEF has also ~n found compatibl~ for 2<4 hours ot.
`room tcmp(!raturc when admixed in lV infwion with hepa·
`rin (10 and 50 Uln:aL) 1n O.s<l.Sodiutn Ch loride lnje<.-tion and
`Pnt.ouium Chloride t 10 and 40 mP...q/L) in 0 K Sodium
`Chloride Injection. Sndium Bieftrbono.te lnjKLII'm. USP it
`not recommended ror the dilution o(ZJNACF.P.
`TIH) 750-mg and l.5·g ZJNACEP A.J)D.Vant.uge viaJs, when
`dHutt'<l in 50 or tOO mL of 5% 0<!-xtrose lnj(_'(;t.ion, 0.9% So-
`dium Chloride Injection, or 0.45CJ, Sodium Chloride lnj@C·
`tion, may be stored (or up to 24 hours at room Lemperatu"'
`or for 7 days under refrigeration.
`Froun Stability: CoMtitute the 750-mg, 1.5·rc. or 7.5·g viol
`as dire<:t.ed for JV Ddministr Bt.ion in Tilhlo 2. Immediately
`wlthdr:~~w the total contents or the 750-mg or 1.5-g vial or 8
`or 16 tnL from the 7.~ bulk vi•l and add to a Baxu-r
`rontaming 50 or 100 mL of0.911-
`\llAI>'LE.X® MINl·BAG
`Sodium Chloride fnjection or 6% Dextrose lnjedion And
`frocte. ~'rozen solutions flN stable Ct)r 6 monlhll whim stonl(l
`at - 20'C. Fro7..en MOlutions 8hnuld be thawed ftt room t.em.
`per•ture and not refrozen. Do not force thaw by immenion
`m w•ttr baW or by microwave 1rradiab0n. 'lnawed ~lu·
`h OrHI mav be StOrOO Tor up to l4 nou.rs a1 nN•O te1:0~itit\...IC
`or for 7 d~y'$ in a t(!frigarator.
`No1e: Parenterftl drug prodttctl 9houJd be inspected \rliiU·
`1lly for partirulat.e mt~tter 3nd discoloration ~fore admin·
`ast.raUon whenever solution and container pennit.
`A$ wit.h ot.her cepholospOrins, ZlNACfr.:F powder a.s well aa
`solut.itms nnd suaptnsions tend t.o d a rken, depending 011
`storl).gO conditionN. without odvertely tdfoctlng produc:t po~
`Ieney,
`Oirectlons fM Olspensing: PhMm.cy Bulle P~••g• --N4t
`fo~ Olr«t 'rrtu.lon: The pharmacy bulk padcn.ge i$ for u~~e
`in a pht•rmacy admixture !lervite only under a. laminar flow
`hood. Entry int o tha vlal must be made with n sterile t rans.
`(er tet or other Mtcrile dispeMing device, and dle contents
`dispen.sed in allquota using aseptic t.echnique. The use of 8y·
`ringe and needle ia not recommended as it may e;.u.se leak·
`ago (see DOSAGE AND AOMINll>"''Ri\TION). AFTER INl·
`TIAL WJTHDRI\WAL USE ENTIRE CONTf; NTS OF VIAL
`PROMPTLY. ANY UNUSED PORTION MUST BE DIS·
`CARDED WITHIN 2.4 HOURS.
`HOW SUPPLIED
`ZlNACEF in the dry ~tate should be stored between 15• and
`JO'C 159' ond 86'F) ond prowcted from light. ZINACEF is o
`dry, whit.e to off~whiU! powder 8upplied in viti I& and infusion
`pocka .. followt:
`NDC 0173-0352·31 750-ml( Viol tTray of251
`NDC 0173.0354·35 L5·1f' Viol (Tray of25)
`NDC 0 173.()353·32 750·mg• lnfu•ion P ack I Tray of 101
`NDC 0173.()356-32 l.5·.g' lnfutlon Poclt (Tray of 10)
`NDC 0173-0401}.00 7.5-g* Phannocy Bulk Padtage tTray of
`6)
`NDC 0173·0436·00 750·mg ADD.Vontoge Vial tTtay of 251
`NDC 0 173-0437·00 L6·g ADO. Vantage Viol (Tray of ! OJ
`fThe above ADD-Vantll.ge viaJB .ore to be used only with Ab·
`botl ADO~ Vantage d1luent containers.)
`ZINACEF fnn.en as a prerui:xed solution of cefurox.ime inJeC·
`tion should not be 3tored above -~.wu C. ZINACEF is sup-·
`plied frozen in 50-mL. single.<Jo8C, plastic containers as l"o1·
`Iowa:
`NDC 0173-042~.00 750-mg' Plonic Container (Carton of
`24J
`NOC 0 173·0421>·00 1.5·g' Plastic Container I Carton of 24)
`~ r:.quivnlcnt to t.-vfuroxime.
`
`REJ'l:R.t:NCE8
`1. N:ltionRI COI'il.mltleu ror Clln;cnJ l...aborat.or)' Slol"ldard9.
`Ptrformarrre Stan,/(Jrdt {o~ Atttamicrobusl Su•ceptrbdlly
`Testing. Thard lnforrnntlonal SupplemenL NCCI..S Docu~
`ment M100-S3. Vol. II, No. 17 vmanova, Pa: NCCLS,1991.
`'l. CockCTQ{\ OW. Gault MH. l.,tedrctron of ereatlnsn.c cl~ar·
`a.ncc rrom Sfil"tun creatinme. Nt>phro,~. 1976;16:31·41.
`ZlNACJ;;~ (cMuroximu ror injection):
`Glaxo Wcllcome Inc., Ro .. areh1'rinngle Par k, NC 27709
`ZJNAc•:•-. h:efuroxime oDJ«lion~
`Manufactured for Gluo \VeHcome Inc.
`llesenrch Troruogle P,.k, NC 27709
`by BnxWr Uealthcnre Cm"'(>Oration, 0(1crfic-ld. fL !lOO 15
`ZINACEF' i• a rego•IA!r<>.i trodcmark of Glruco Wellcome.
`ADD-Vanuage is a registered tradema.rk of Abboit ~bora~
`tories.
`CLINITEST is a regun ered trademnrk of Ames Oi\'iS10n,
`Miles Lobornt.orieB, lnc.
`l'ES-TAPE is 3 rcgistcrt.-d tradernurk of EH J...illy tmd Com·
`pany.
`GA.L.o\.XY ond VIAF1...EX are registered trademark:t of ftax.
`ter lnternollona.l l.nt.
`November l!I981RL·642
`S hown i11 PrtXIII(:t ldt:,ltt/icMiotJ GtJidt. JX11Jt 3 17
`
`ZOFRA~
`lz6' fran[
`(ondans.-tron hydrot:hlotlde1
`lniection
`ZOFRANe
`(ondansetTon hydrot:htoride)
`lnjktion Premixed
`
`I~
`
`OESCRII'TION
`The active m.g:redient 1n ZOFRA.i'l Injection a.Dd ZOFRAN
`Injection r•rtmin-d •• ondnn.setron hydtoc.h1oride t IICIJ, the
`racemic form of ondan.setron and a tt.elcct ive blocking agent
`<Jf the scro1onin 5·HTs rt.'Ceptur- type. ChcrnicnUy it is(.:!:) I,
`2, 3, 9·tetrohydro·9·methyl·3·1(2·met.hyi·1H·innduol·l·)'ll
`methyiHH-carbazol·4-one, monohydrochloride, dihydrate.
`'The emp•rital formula ia C 11H1g.N'.!O• HCI• 2H20, represent·
`ing a molctular weight of 36S.9.
`Ondan.&ctron HCI 1S R white to Clff·whlt.c powder thAt i8 sol-
`uble in water and ncrmal W ine.
`St aTile Infection for Intravenous II.V.f or Intramuscular
`II.MJ Admintstnl'tion: Each 1 mt. of aqueous A()lution in
`the 2-ml.. si11gle~dos.e via l contains 2 mg of ondan.setron as
`the h ydroc.hloride dihydrate; 9.0 mg of sodium chloride,
`USP; •nd 0.5 mg of citric acid monohydrote. USJ> and 0.25
`mg of sodium citrate d1hydratc, USP -.s butr~n in Water for
`Injection, USP.
`Each 1 mL. of nq\leoW solution in the '20-mL mult idose Yi.<t1
`«>ntains 2 ong of ondnnsotron •• the hydrochloride dihy·
`dn\t.e; 8.3 tng of ~ium chloride, US'P: 0.5 mg of citric acid
`monohydrate . USP and 0 25 mg of sodiutn titrate dihydrate,
`USP .. bulfers: and 1.2 mg of methylparaben, NP and 0.15
`n1g vf j)I'O'PJipar:;be-r., ~ a3 ~iTa in Wt.tt>r (.('st 1~·
`Jectlon, U::;,P.
`ZOFR.A.I'llnjection is n c:lca:r. colorleef!, non pyrogenic, sterile
`14)]ution. The pH of the i.njedion solution is 3.3 to 4.0.
`Sterile. Pr9milted Sofutfon tor Intravenous Adm lnlstration
`in Slngt .. O~•. Re• ible Pla$tic Containers: Ecaeh 50 ml
`contains ondansetron 32 mg {as tke hyd:rochiQ>ride dihy-
`drate); dextrose 2500 mg; and citric ocld 26 mg and sodium
`citrata 11 5 IJ'Ig as buffers in W;.ter for lnjection, USP. It con~
`to.i.nJ. nop~f'\·atives Theosmolarityofthis.901ution lA 270
`mOsmll lapprox.), and the pH is 3.0 to 4.0.
`The flexible plastic container is fnbricat.ed from a 11peciaUy
`formulated, nonplast.icir.ed, thermoplastic co-polyester
`<CR.3}. \Vater ca_n permeate from inside the container into
`the overwrep but not in e.mounu sufficient to affect the $(1·
`lution significantly. Solutions inside the plastic container
`nkso ean lench out eertain of the c:hemical tOm ponents in
`very smnll t1mountB bcfort the expiration period is attained.
`However. lhe safet..)' of the plastic bll.B bt.-en confirmed by
`tests in ooirnals according to USP biological standards for
`plastic containers.
`CLINICAL PHARMACOLOGY
`Pharm•codynemies: Ondnnsetron ia a selectiv.e 5·1-lT J re·
`ceptor nntngoni$t. While ondanser.ron'a mechanism of action
`has not ~n fully char6cterized, it i• not a dopamine-recep-
`tor antagonist. SerolOrun receptor:s of the S.HT1 type are
`present both peripherally on vagal nerve ternunaJs and oen·
`trnlly in tho ch~moreceptor trigg~T zone of the !\rea post-
`rcma. It !1 not certAin whether ondan.~etron's an tlc:nwt.ic ae·
`lion in cherootherapy·induced emesi& is mediated wnlrally,
`peripher1111ly. or in both sites.. Howe\·er, t}'t.otoxic chemother-
`apy appears to be aMOt'lated with rtltase of serot.orun from
`the enterochromaffin coils of the emall inte1t1ne. In hu.
`mans, urmnry 5~HlAA (f5~hydroxyindolcncetic ncid) ucre·
`hoo increases after cispl3tin admimst.ration in parol.lel with
`the- on~l of em.E"Sis. The re-leaaed serot.ooin may abm\llate
`the vagal atfere-nts through the 5-HT:~ receptors a.nd irutiate
`the vomiting refl«.
`rn nnimnl~. t he emetic NJeponRe to cispla.tin can be pre·
`\'Cnted by pretreatment with an inhibit or of serotonin syn ·
`thesis, b1lateral ttbdommal vagOtOmy and greater splanch~
`nic oen·e w<1.-ion, or pn=tft"&tmt"nt with t1 serotorun 6-HT3
`receptor antagonist.
`In nonnnl volunteers, l ingle J.V. doe.es of 0.15 mgfkg of on·
`dansetron had no e ffe<:t on esopha,::es1 motilit y. 1,rn~tric mo·
`
`GLAXO WELLCOM E/1503
`
`t~hty. IO'i\•er t tOphageaJ !iphmctcr pre.strurc, ot small inw.&ti·
`noJ trs,nsitllme . In auuthcr' study m six normal m.sd(J vol-
`unteets, a 16-mg dose mfusc.d uver 5 minutl!$ showrd no
`effect of the dro~e on cardittc ou1put. heart ra.lc. stroke vol·
`ume. blood ptehure, or eleelrocard.iognm cECC:H. Muluday
`ndm1nistrahon of ondansetroo ha$ been t hown to •low co·
`lot\tC tran~it 1n normal volunteenc, OndantMltron has no ef·
`feet on pl~~tsmtt prulfict in conctmtrotions.
`In a gender-balanced phttrmacody·namie ~;ludy (n = 66l, on·
`dan&etron 4 mg admini.itered mt.r&veooual~ or inuai.'I\USC:U··
`larly was dyn~~m1cally s1m1lflr m the preventwn of eml'1S.l&
`ond n.suse.A \18tng the ipec:ncunnhD m«<cl of emesis. Both
`t~atm\!ntl were wt~ll t.olermed.
`Onda~lron d(}f')ft not alter the rt!lplrBt.orv depre&!Wnt. cf·
`fect.a produced by alfenta.ml or the degree or neuromuxulllr
`bloc:.bde produced by atrarunum. lnt.eractions with central
`or local :mesthe\Jt:S have not ~1:'1 stud1ed,
`Ph•rmacoklnetin: Ondamseuon is extenfth·ely metal><•·
`llu.-d lo hurnQI'UI, with CJpproximately 5% of a radiolnbclcd
`dose n!(X)verOO as the parent oompotind from lbe urine. The
`pnmary metabolic pathway is hydrm:ylaiJon on the tndole
`nng followed by glururonode or sulfule <OnJUJtlltlon.
`~\!though somo noocotljugat.od metabolite!l have pharmaco-
`log-i': activity, t hc60 are nat ftliJod ul plosmn at· concnntrn~
`1101\a likely to sigmficantly oont.ribute to th~ biologiral activ~
`11 y of ondan&etron.
`Ond3nset:ron IJ a ~uhstra.te for hu.lllM hepatic: cytochrome
`P·450 enzymco, oncluding CYPIA2, CYP'lD6, and CV'P3M.
`llccuu!:le of tho multiplicity of metabolic cnayrnes C{Lpl'lble of
`metabolizing ondansetron, inhjbition or ~~ or 01\0 t::nf.yme
`(~ ~-· GYP2D6 genetic deficiency) resulta i.n littJe change m
`owraJJ rate. of oodanset.ron elimination.
`In Mrtnal voluntee.tt;, lht following mean pbarrna.~k,tnettt
`duta have bl!~n determined followmg a single 0.15-mg/kg
`I.V. do..,.
`
`Table 1; Pt\arm• eokln.,_ks in Normal Voluntaers
`
`Pe:l!lk P1nsma.
`
`Mean
`
`Age-group
`
`19..o!O
`61·74
`'2=75
`
`II
`12
`ll
`
`102
`100
`170
`
`Concentrotioo Etiminntion CJca.ran ""
`fnglmL)
`Half·lifc (h)
`3.6
`4.7
`5.5
`
`f"lAIIUIJl
`
`(J.Jhlkgl
`
`0.381
`0.3!9
`0.262
`
`i\ rmuelion in cJear3fice and l.DC~ in elimination htltlf.
`11rt are se-en 1n patients ovtr 75 year8 of np. 1n dinieal tn·
`A Is with canaJr patients. eafety And effiwcy were similar 10
`patients O\I'Ct 65 yean of age and thoAe under 65 yel'rS of
`Pge: there wu ttn insufficient nu..r:n~r of potjenbt QVtr 75
`y~an of age to pennitconclu~Jions in cbatage.-group. No dotJ...
`age a(ljUS'lm~nt \5 recommended in the elderly.
`In pati~nu with mild·to~moderat.e hepatic i_mpairment..
`clearance i& reduced tworold and mean half-life is increnl!od
`to J 1.6 houn compared to 5.7 hours in normals. ln J)fltient.s
`with severe hepatic impairrnt!-nt lChild·P\I.gb &rore1 of 10 or
`greater). clearance is reduced twofold to threefold and ap-
`pereot volume o( distribut:tOC it i!lcretied witb a resultont
`1nc-raase il'\ h&lf~lifQ to 20 ho-u.rs and hioa va.ilabiHty ap-
`proaching l00%.In !meh pothmta, a t.otol dnily dose of8 mg
`ahould not be (!Xcooded.
`Ondansetron plasma clurance wM reduced by 41 'lt 1954, Cl
`2()'1. to 57..,.) in pe.tients with severe renal impairment (c:ro-
`otinine cleaJ"8nce < 30 mUmin). 1'hiB reduction in clearance
`i~ vnriobla a nd wos oot consistent with on increase in hnlf ..
`lifo. No reduction i.n dose or dosing frequency io these pa~
`tit'nts is warn.nted.
`ln adult cancer patients, the mean elimi.n.alion half· life was:
`4.0 hours, end there wa5 no ditfe~nce in the muhidose
`pharmacokinetics over a 4-dny period. In 11 study of 2 1 ~
`ditu.ric: cancer patients {aged 4 to 18 years} who reooived
`three I.V. dO&eA of 0.15 mglkg of ondarutetron at 4~hour in-
`tervals.. panenta older th•n 15 years ot age e-xhibited on -
`dans.etron pharmaeokinerie parsmeten 1imilar to th08e of
`adults. Pnticntl ngOO 4 to 12 years genttrally showed high~r
`clearance and somewhat lllrger volnnl(!l or distrib\ltion than
`adult&. Most pediatric patients younger 1 han 15 yeara of 1.\ge
`with cancer had a shorter (2.4 hours) ondansetroo plasma
`hplf-life than p3tienta older than 15 years of age. It iJ not
`known whether these differences tn onden.sttron plasma
`holf·hfe ma.y rct~ult in diffl'ronccs in efficacy between. adults
`•nd some young pediatric potienl5 r ... CLINICAL TRIALS:
`Pediatric Studiea).
`In a study of21 pediatric pallents (aged 3 t.o 12 yean) who
`we~ undergo1n.g surgery requiring anesthma fo-r a dura~
`t1on of 45 minutes t o 2 hou~. a single t.V. dose. of oo~
`dnnsetron, 2 nlg l3 to 7 YN\rsJ or 4 mg (8 t.o 12 years), was
`•dministued iromediou.ly prior U> ane&thesia induction.
`Mean weighL-normalized cltMaru::e and vo)utne" of d11tribu~
`tion vaJu~s ia these pedintnc surgica.l patu:mLs we-re 1im1lar
`to those previously reported for young Ddults. Mean Ulrmi·
`
`This product lnfonnation is build' on labeling in effect on Ju ne
`23. 2000. For furthlf Information, contact -..ia direct mail. phone.
`or web s.i1e. Medic•l lnform•Uon, Glaxo Wt llcome Inc., PO Bo•
`13398.. Renerch Triangle
`f'lrk.. NC 27709. Healthc:are
`Prof11ssionals (Mitdical lnformat.lon): 800·314-0089. Patjents
`(Customtf Auponse Centet): NJ88-82S-5249. Glaxo Welcome
`Corporate Web Site: www.glaJCowellc::omt.com
`
`Cont.utt 2001 ~ ~ ~ fllturt fctitione; f01 ravtalons
`
`Exh. 1015
`
`

`
`1504/GLAXO WELLCOM E
`
`Zofran lnj.-Cont.
`
`nal half~hre Wf1.8 sl1ghtly reduc~ 10 pcdjatnc: patu;mts
`trange, 2.5 w 3 hours) in eornp._'l.rlson with odol~ (runge. 3
`to 3.5 hou ,..).
`h1 nonnal voh.totoors (19 t.o 39 )'l'tW! old. n • 23), ~he peak
`plasma concentration was 264 nafmL foHowing " &utgle
`32-mg d():IW admmistered as a ll\·minute LV. infuNion. Tbe
`roetul elirolft4LM>n M.lf-li!e wu 4 l hourL Syst@m.e txpos:u.re
`to 32 mg of ondaOMtron wa11 not proportional to dote as
`measured by comparing dose--normalited AUC vntue11 lOan
`S-mg d0$0. This It~ consistent wit h D small dl!CN:Mc in sys-
`temic clearnnoo with increaRinK plu11ma conc~ntrAt.aon~.
`A !!.tudy wtt• performed i_n norrual volunteent (n • r-.G) to
`evaluate the phn.n:na.ook.inettt:t of 1 8ingiP. 4-mg doso t.adtnm-
`1.$tered u a 5-n.u.nute infus10n <:Ompared. to a stn~le l.lltn-
`muscuJar U\Je<:L1on. Systemic UpM.ure a_,. meaaured by
`mean AUC was equivalent. wnh values; c>f 156 l9f~~ CI 136.
`1801 and 161 196% Cl 137, 1001 ng• hlm!. for I.V. ond I.M.
`groups. rcepottive.ly. Mean P'(tnk plasma canccntrntions
`were 42.9195% Cl33.8. 54.41 ng/mL at 10 !1Umaie• •Iter I.V.
`infusion •nd 31.9 195% Cl 26.3. 38.61 ng/mL nt 41 Mll\Uiell
`after I.M. irvecuon. Tile mean ~limmatiOil balf·life wM not
`affected by route of adnuru6lmtaon.
`Plasma prot.elO binding of ondAnsetron as wea~;ured m v-n.ro
`was 70% to 76(,¥., with binding constant ot.·er the pharmaro-
`logic concontrotion range t 10 to 600 ng/mL). Circu!Ming
`drug Rlso distributeK into erythrocytes.
`A positive lymphoblast. tramtformat10n test to ond8osetron
`h.a.s been repOrt.t.od, which suggMLI unmunologic ~n&itiVlty
`to ond~tron.
`CLINICAL TRIALS
`In n dou-
`Chemot'-.,lpy~fnducad N1us•a and Vomiting:
`ble--blind study of t hree diJTc rcnt dOBing rcglnums of
`ZOFRAN Injection, 0.0 15 mg/\<g, 0.16 mg/kg, and 0.30 ro.g/
`kg. each J::'iVel\ three times during tbE. course of cancer
`(:hemother3py, the 0.15-mg/kg dc,ming regimen was more ef·
`fect.ive Wn the 0.015·mg/kg datting Tegjmen. The 0.30-
`mglkg dolmc regj.roen was no( ehown to be nwre effecti'f'e
`than tbe 0. 15--mg/kg dosing reginl@n.
`In 3 double-blmd study in
`Ci$pl6tin·B•ud Chemother•p~:
`28 patiflnts, ZOf'MN Injection (three 0.15-mKfkg doJJes)
`was signific.ttnt.ly more effective than placebo in preventing
`nausea Rnd .. ·on•lting induced by tisplatin·ba.Red chemother·
`apy. Treatment res:pon..'le-wu u follows:
`ISEe table 2 bektwl
`Ond~tron wa:t compared W1tb mt!'t.oelopratmde lD a s'in--
`gle-blind tria.l m 307 patieutB receiving cisphu.in ..e 100
`mi!/m2 with or w1thout other chemotherapeutic flRCnta. Pa-
`tients reeeivod t he J:lrst dose of ondantw.tron ot mctoclopra·
`mide 30 minuteJI before c:iaplotin. Two additional on·
`dansetron dOiH were adminiat.ered 4 and 8 hourt later, or
`fi"'e addibonal me-t.odopramide doees were adminittered 2,
`4. 7, 10. and 13 hoUH later. Ciloplalln was administered OYI!J'
`a period of 3 hou.rs or Jess. EpiiOde!!l of vomiting ond rete-b-
`ing were tabulated over the period of 24 houra al\er cis~
`platin. T ho resutts ofthis st.udy nrc summariU}d below:
`[See UtMe S 1Jt1 nt-xt page1
`In a strauficd, randomu.ed, aouble.bbnd, paraUe1·gl'Oup,
`multicenter Jludy, a single 32-mg dose of on.dansetron was
`oomparOO with lbree O.lS.mgl'kg doses m patie:nte receiving
`cisplatin d~ or either 50 to 70 mgtm2 o-r~ 100 mf(lm2 • Pa·
`tients received the firs:t ondanaetron d0!5e 30 minutca before
`cisplatin. 'IWo ndditional ondans_,Lron doses were admims·
`te-red 4 ~ud 8 hours later lO the ~:roup recei,..in~ three 0.15-
`mglk.g doses. ln both strata, signHicanUy fewer p.nticnl.$ on
`the single 32-rng dotoe than lhoM! receiving the three-dose
`regimen f••led.
`!See table 4 on ne><t page!
`Cyclopho•Ph•mide·B•Hd Ch•moth• r•py; In a double·
`bl;nd. plaotJbo-contl'OIIed study ofZOPRAN lnje<tion lth""'
`0.15·mg/'kg d08@1J) in 20 patient& reee~ving cycinpbospha·
`
`mide cr.oo to 600 mg/m2 ) ('hemotherapy, ZOFRA.N lnjeetit.m
`was algn16cantly more effective than pl~bo tn ~vf!nting
`nausea and vomiting. The results are surumanz.ed below~
`ISets table 5 on n~xt Jlali:lll
`R•··tre•tm•nt~ In unc(lntrulled r.ria1s, 127 potients receiv·
`ing chlPiotin (roedinn dose, 100 r:ng/m2) Arid ondansetron
`w·ho hod two or fewer emrbc episod~ were r&tre~led with
`ondaOHtron and chemotherapy, mo.iol)· ci!platin, for a total
`of 269 re--lre$ttnent rout'IK'I <median, 2; range. 1 lo 10). No
`emeuc episodes oceurred •n 160 {5~). a nd two o-r fev.·er
`emetac eptsodes occul'l"ed in 2 17 (81~) re--trealment couf'!le..
`Pedl•trk Studiu: Four open-label, nollcompArative (one
`t:S, l hrC.t) rore1gn) triBl!t hiiV6 lx!en pc:rfcmu:>orJ Wit.h 209 peM
`diot.rie cancer pat.1ent.s Clt(t-d 4 to 18 ycar!l given t1 vnriety of
`cisplabn or noncisplatln tc-J._rimena. In the thrt'ft foreign tri-
`al~. Lhe 1nitial ZOFRA..'l lll)e<:hon dose ri\ngcd from 0.04 to
`0.87 ~!'or. total doo<l of 2.16to 12 me Th.is ..... foJ.
`lowed by the oral adminillrauon of ondAn1etron ranging
`from •I 11> 24 mg doily for 3 di\,Ys. In the US tna.l. ZOFRAN
`Wt'll tallnunil3ter00 intravcmoo! ly (only) 1n three dol'les ofO.J5
`rHgl\g each for tt t.owl daily d01m of 7.2 to 39 mg. In thesn
`studios, 58% of the 196 evnluable fl..'-'ILienLt hod ft~ oomplet.e
`re!lpon!J@ (no emetic cpu~ode81 on day 1. TI1us, preifention of
`ernet1!lm the!M.': pediatnc pauents was essenthi1Jy the same
`as for paueol-3 older lhRn l8 yean of age. Ovtrall. ZOFRAN
`Injection WI..$ well tolerated m t.hes.e pe<i1atnc pa·tient.s.
`Postopentive Neus .. and Vomiting: Pr•~•nrJon of Post•
`ope,•flv• N•u••• and Vomiting: Adult SUl"gJCol p8tienLa
`who reccwOO ondanset-ron immediately before tbe ind\1c:tion
`of general be.lanoed aneath~sia tbarbit-uratAl: thiopent al,
`me-thoheXJt.aJ, nr Lh.iamylAI: oplol)id: alfentan1l or fentanyl~
`nitrou.t oxide: N!'uromUM'UI&r blot:bde: sucdnyleholinelro-
`rare and/or vecuro-nium or nlracurium; end supplemental
`isofturnne) were evaluated in two double-blind US :studi~
`involving 5,54 patients. ZOFRAN lnjedion (4 mg) t.V. gh•e.n
`over 2 to 5 minute~ wa• :'4lgniticantly more utf€!ctivn than
`placebo. 'l'he result& of these 1!1h1di~!:l are §Ummo.rired below:
`rs.e l.ll.blo 6 at top of poge 15061
`The study populations in Table 6 eon.sisted muinl1 of fe-
`malt-t uodergoing lapai"C**pic procedures
`ln a plu(t.lb&-c:ontrolled .study c:ondueted in 468 ma.le!! under~
`going outpatient procedurcd, n single 4 mg t.V. ondansetron
`do~ prevented post.operotiv0 vomiting over u 24· hour study
`period in 79% of ll\alos roceiving drug compared to 63% of
`malet roooiving plact:bo (P < O.()Ol).
`Two other pla~bo-controlled studies were conducted in
`2'192 patients undergoing major abdominal or .:ynecologioll
`surgcric~11 to e"·aluat.e .a !Jingle 4~mg or 8-mg 1. V. ondansetron
`dose for prevention of po8f.()pert~ti\.·e nal.L~B an-d vomiting
`over Ll 24-hour study periOO. At the 4·mg dO!H\ge, 59% of po·
`tl(llltl rec::eiving ondanset ron versus 45% rcc:eiving placebo
`in the flret study (P <O.OOU and 41% of patienbJ reteiving
`ondan&et.ron versus 3()(1, tece.1ving placebo 1n the seoond
`study fP.O oon e:~:pe-rienced DO emetic ept.IOde.. No addi·
`tional b@ne.fit was observed in patients who received I. V. on-
`da~Uetron 8 mi: ooroporOO to patients who received l V. on·
`danset.ron 4 mg.
`P~trlo Shldi- Thrt• double-blirul. plocci>o-<.'O.'lirolled
`otl..---di~ heve been ;xrfarnt.ed tor.e tiS, !wo foreign} in 1049
`male and female patient.l (2 to l2 yean of age' undergoing
`general s oe&tbesia W1th n1trous o~de. The surgieal proce-
`dure~ included ton.stllectomy wtth or without adenoidec-
`tomy. itrnbi.!mus surgery, bcmiorrbapby, and orchidopexy.
`Patient.e we·re random1~ed to eithe·r single I.V. doses of on·
`dnnwtron W.l mglkg for pediotric patient~ weighing 40 kg
`o:r lesa, 4 mg for pedio.tric pat-ienta weighing more than 40
`kg) or placebo. Study drug was administered over at teast
`30 seconds, immediately prior to or following aneethesia U\·
`ducdon. Ondanset:ron was l.l.gillficantly mort e lf"ecbve than
`placebo in preventing nouse• •.nd Yomitinc. The results of
`t.h~.&e studi~ are summn.ritcd below:
`!See tuble 1 on page 1~061
`
`T•bl• 2: Prevention of Ch•mothenpy•fndueed Nause• • nd Emesis in Slngi•~Dey Cispletin Ther•py•
`
`Number or potient.s
`Tr-eatment retlponae
`0 Emetic epiMMies
`1- 2 Emt~Lic ap1JJOdes
`J-....5 Emetic. episodes
`More than S @mi"tic episodf'lllresc:ued
`
`Median number of emetic epil'Ode&
`
`Median time to fi.rs~ emetic opirwdc t h)
`
`ZOFRAN lf1ie<tion
`
`14
`
`2 (14%)
`8 (57%)
`2t14%)
`2114%)
`
`1.5
`
`11.6
`
`Placebo
`
`14
`
`0 (0%)
`0 (()'~)
`I (7'A>)
`13 193'1)
`
`l,;ndefinedf
`
`2.8
`
`PVruuet
`
`0001
`
`0.001
`
`.
`
`3
`
`59
`
`0.034
`
`~led.ian no.u.~n CC01'8 {0-lOOt-1
`Global satisfoction with control or
`...
`96
`nauseA rmfl vomiting IQ- IOOY'
`10.5
`0.009
`Chemothcrnpy wos h1gb do8(l UOO a nd 120 mWnl , ZOFRAN Tn,Jcctaon o = 6. pla~bo n = 51 or modernt.e dl>lWl 150 and SO
`mg/m2~ ZOfo'RA.N JnjNtion n • 8, placebo n ~ 91. Other chemotherapeutic agent-s induded fluorouTac.il, do~~:Mubicin. and
`C)""Clophosphanude. Ther-e Wftt n() dafff"rence between treatments in the types of c~M-motherapy that would :\CcOuot ((IT d1f·
`ferent-eS 1n response.
`'1 Efficacy based on •::aJJ patienl" t~ated .. analysis
`+Median undefined since nt lettit f)()ll. of the p._'ltients were rescued or hnd more than fh·e @metic- episode1.
`§Visual annloiJ scale assessm~'n~ of nausea: 0 • no nnuttea, 100 s nou8(la il.fJ bad n!! it cnn be.
`il Visual aM log scale assessment of $atisfactwn: 0 • not at all sat.iHficd. 100 ,. totally tmt illflcd.
`
`PHYSICIANS' DESK REEERENCE®
`
`Pr•ventlon of Furth« PosfOf>Mt"-iv• N•u• ., •nd-Vomifino:
`Adult .fl.lrgic:aJ pal~ntl receiving ge:Mral balanced a neslJ\6...
`•u• (barbit-urate: IJuopeotal, methohe--.&.ul. or th1sm_ylal:
`0p101d: a.l!entanil or fentanyl: rutrous mude: neuromuaculnr
`hlodtade: suct:inytcholi.nelcu.rare ~ndlor vecuroruum or aLra~
`Ct1rium; and iiupplemt!nl.tl.l iiSQflurane) who received oo pro--
`l)hylnct-ic antiemt~l.itJI Qnd who ~xperiunced nllusea find/or
`Yonut ing within 2 hou.n posthperatJ\•ely ware evaluated in
`two double-blind US l!ltudie. in\J()Ivmg 4-41 pntieuu. PB·
`ltenlf wbo expeneneed ~ epl$0de of pot!lt.Open:tti\·e nauteft
`a nd/or vomiting wert: gtven ZOFRAN II)_Jed.ion (4 m1) I V.
`uver 2to 5 minut.eta. and this wns ai~·mflcuntly more effective
`than placebo. The rt'llolt.s of th~se !llludjet~ are su.nmanted
`oolow:
`IS.. tuble 8 on po~e 15061
`~study populatiON In Table 8 eonsi!tcd mainly of women
`undergoing laparOICOptt procedurH.
`P«<i•tric Stud,.,: One double-bliruf. placebo-eontrolled.
`US .study was perlonned in 35l male and female l)uLpa·
`titlnts ~2 to 12 years of llg.l) who rec::eaved general anesthuio
`with nitrous oxide ond no prophylactic nnli(!meHcs. Surgical
`f>I'O(edores w~ro unre.str it.:led. Patient.! who e:X~ri~tlCCd
`two or more emetic. episodes within '2 hou~ following dis·
`COJ\tJnuation of mtro\15 oxide were mndomiz.ed to either 11i~
`glo I.V. doses of ondanselron <0.1 mglltg for pediatric: Ill'·
`dents weighing 40 kg or less, " mg for pediat.rit' pattentl
`we1ghing mon thRn 40 kg) or placebo admmisterod ov~r ot
`lef1~t. 30 seconds. OndMBetrtin w11s ~ll(mticanUy more etfoo.
`Live than placebo in preve.nting further CJl isodes of nftusc.n
`nnd vomiting. The result..'l of t he 8tudy nre summariu.--d he·
`low:
`IS<e table 9 at top of""'" 15011
`Rep.•t Oo.Sttg In Adults: ln pat.ienta who do not achieve
`adequate control of ~toperative nau.aea a nd vonUting fol·
`low1ng a siogle. prophylactic. preindu(tion, I.V. dose of on·
`dl~naetron 4 tng, nd.min.iatrat.jon of 11 Sl'OOnd l.V. dose of on·
`dnn8f;ltron 4 rug postope:rati"ely does not provide addltion.oJ
`oonlrol of nause• and vomiting.
`lNDICKMONS AND USAGE
`1. f>te'Yention of nou&eo • .nd vornitiO« u:socialed with initial
`and Tepeat courtel of ~metogenic c•ncer dle.mothere.py,
`meluding high-dose cisplatin. Effic.ocy of the 32-mg singJ~
`do~ beyond 24 hours in the~ IJnticnta has not 1>1:~11 N ..
`tublished.
`2. Prevention of pos:toperath•e n~usea andlor vomiting. AI
`with other antiemetic:s. roubne prophyl:uci& is not recom·
`mended tor patients in whom there 2.8 liUle expectation
`tlult nausea and/or "Vomiting will 0«'\\r J)ol!itopenttively. In
`patients whert't nnusea and/or vomiting must be avoided
`postoperati.,.ttly, ZOFRAN Injection il!l rocommended even
`where. the i.ncidenoo of po~t.ol)(!tativo nllusea and/or votn·
`iting is low. t'or P'~ti(!nts who do not. l'ec(!ive propbylo.ctit.
`ZOFRAN Jnjettion and experi@nte nausea and/or vomit·
`ing postoperatively, WFRAN lll}t'(:tloo may be given to
`prevent further e pi.od .. (..,.. CLINICAL TRIAI.Sl.
`CON'l'RAINlliCATIONS
`'ZOFRAN I.njection nnd ZOFRAN Injec.tion Premixed nrt
`t:'On\.'fa.mdic.at..ed tbr pulicuttt Kno.,.n tU ha.ve ~n.e:ns1t:rvity
`to the drug.
`WARNINGS
`~lypersens:itivity n!:action• have been rtport.ed in patients
`who have exhibited h.ypersensitivity to other ,!;elective
`fi·HT:. n:!cepU>r ant ngoni.st.s.
`1'RECAtrflONS
`Ondansetron is 1'\0t. 4 drug that stirnulatea g<l&tric or intett·
`tina) peri.st.alsi•. It abould not be used iut.ead of nasoeaatrie
`auction. The use of ondansel.nln tn pe.l-ients foUowinc eb-
`dominal surgery ot 1n patient& with e.h""motherapy-induced
`n"usea and vomiting may mask a pr()frflsive ileus andlor
`gastric distention.
`Drug lnt•r·action•: Ondanset'i"Oil d()e;l not it6E'lf appc8r to
`Induce or inhibit. tbe cytochrome P450 <lrug·metabolbing
`enz.yme system of the liver. Be