Page 1 of 27
`
`Helsinn Healthcare Exhibit 2032
`Dr. Reddy's Laboratories, Ltd., et al. v. Helsinn Healthcare S.A.
`Trial PGR2016-00007
`
`

`
`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`20-007/S030
`
`20-403/S009
`
`CONTENTS
`
`Reviews /‘Tnformation Included in this NDAReview.
`
`I
`
`T X
`
`X
`
`1
`I
`
`Ammrval Letter
`Apgrovable Letter
`Labeling
`Summa£LReview
`Officer/Em lo ee List
`
`Office Director Memo
`
`Cross Disci n line Team Leader Review
`
`Medical Review s
`
`Chemistr Review s
`
`Environmental Assessment
`
`Pharmacolo Review s
`Statistical Review s
`
`Microbiolo Revifls)_
`Clinical Pharmac(fl_ogy/Biopharmaceutics Review s
`Risk Assessment and Risk Mitigation Reviewgs}
`Prorieta Name Review s
`
`Administrative/Correspondence Documentgs)
`
`A
`
`X
`
`Page 2 of 27
`
`Page 2 of 27
`
`

`
`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICATION NUMBER:
`
`20-007/S030
`
`20-403/S009
`
`APPROVAL LETTER
`
`Page 3 of 27
`
`Page 3 of 27
`
`

`
` »
`
`‘
`
`_—- __e1axo Wellcome,Inc.
`_ Attention: CraigA.Metz, Ph.D.
`' Director, RegulatoryAfi‘airs
`. Five-MooreDrive
`'—
`9. “
`. P.O. Box~1339s
`-~-- 1.‘¢$eafch$ria*ng1€Pa:k,Nc.27_7o9e
`
`-
`
`_
`
`_
`
`‘
`
`-
`
`'
`
`f _'—r
`
`.
`
`._
`
`._:
`
`-
`‘
`. I 9.
`p_
`
`'
`
`'
`
`.-
`
`_
`
`.
`"
`
`.
`
`,
`
`.
`
`_
`
`..
`
`_’
`.
`
`-
`
`V
`
`k
`
`V
`
`-Til
`
`_
`
`_
`
`-e
`
`,
`
`V
`-.
`*
`APR 1'1 M” ..
`_
`'
`
`. —"”
`
`_
`
`A
`
`_
`
`.
`
`p
`
`.
`
`"5"
`
`-
`
`'
`-_ ,'
`V
`-9."
`‘i
`153- ;.%7.f’
`‘f:..
`I
`Metz: it
`October 13, 19:99, receiiiedi
`__ Tilileaserefertgyour supplemental new drug_appHcatidns-
`1 4;" ,. ——.
`- October 14,fl_1999, submitted under section.505fb).ofFede1al Foo£1_,"‘Drug:'andCosn_ietic Act
`for Zofi'a1i(o_ndansetron)lnjec_tion and Z_ofi’an Injection Premixed, respeEfiyely_. 4
`
`_'Q_.__,
`"
`
`7'
`
`“
`
`.
`
`.
`'
`
`A
`
`—~.
`
`_’
`
`'l‘hese '.'C_hanges Being Effected-" supplemental ne\Ld'r"ug applicatigris provide fgrgevision ofthe l
`package insert to include 1) addition ofseveral‘ new adveise reactions in the‘Observe_d_Duringe-
`_. ClinicaFPractice subsection ofthe
`REA,C'«L'lON_S_ section and 2) revisions to the
`"OVERDOSAGE section to provideiconsistency in wording betweenthe oral[and injeetable _
`p1‘odu'ct,pac1<—ageinser__ts.' _ V
`I,"
`p._
`_
`A
`b
`_
`_
`' *4’
`.We‘hai)e ccifipletecithereviewo-ti‘these supp1emei3:tal:applicafions and have-concluded that
`adequate information has been presented"to 3demonsu'ate thatthedmg products are safe and
`effe’ctive.for use as recommended in the subrnitted final printed labeling (package insert
`‘.m§ubmittedOct_ober 13",-’199—9)i. Accordingly, these supplcjnentalapplications are approved -
`A--.~efi‘ectE?in the date ofthis letter? .j._ *
`-
`-
`all of ivord “chil__ci1_'en” to
`
`. At.the“ neitt printingh’ofthe*pa'c1cage1nsert,‘_,
`‘T _‘.‘pediat1fic patientsf" in accordance witH21 CFR 20l.57(f)(9). The Divisionmaybe informed of
`A» this revision in the subsequerg
`- M
`'-t
`-t
`-
`‘
`-
`
`A
`
`I
`
`~
`
`‘
`
`. Ifa letter communicating important information about product G.e., a "Dear Health
`Care Practitioner"1etter) is issued to physicians'and’other"s"responsible for patient__care, we T” ’
`request that you submit a copy ofthe letter to
`NDA and a copy_tg_1_;he_following address: :
`.
`
`—
`'
`
`~
`
`_"
`
`_
`
`V
`
`'
`
`-
`
`_
`
`'
`
`~ A" MEDWATCH:I-IF-2
`-
`‘FDA
`"
`-
`-
`-
`.
`5600FishersLan
`_.
`"
`.~
`Roc1cville;’MD 20857"
`__
`—~
`'
`"T.’_~
`-
`‘
`'AWe" youthat you n1ust_compl‘y-vi’/ith the foran‘appr_o_ved NDA set‘forth, M ‘
`
`_V
`
`'
`
`'
`
`I
`
`l
`
`__
`
`'
`
`ii
`
`_____
`'3
`--
`
`'
`
`‘
`
`4...-
`—
`
`fl.
`
`__
`
`,
`
`i
`
`'
`
`_
`
`'
`
`"—_a _
`
`Page 4 of 27
`
`Page 4 of 27
`
`

`
`
`
`;:..;_:._ ‘T NDA 20-007/s—63o ._
`I‘
`. NDA20-403/S-009»
`. 1>age:=.f
`
`‘“
`
`_
`
`‘ .
`
`"
`
`‘T
`
`.
`
`__
`
`-
`
`v_ j
`-'
`
`.
`
`'
`
`'
`
`'-
`
`}
`
`_
`
`_
`
`~
`
`T
`
`_
`
`_‘
`".under21TCi=R3~14.sg_§g§T§14.s1-;-v
`._ Ifyou hgge any Mélodi McNeil, Regulatory Health Project’Mafiager., 5:
`(301) 321-7319.
`T
`‘
`~
`-
`'-
`—
`.
`..__
`.
`.
`Einéércly,
`
`ré
`
`‘A
`
`>
`
`,
`
`%
`41"
`_'_
`_._.-f;h__ _
`_ ~_
`.
`
`»
`%
`+ -—" “ ’
`.
`._
`.
`
`_
`
`._
`
`_
`
`M
`
`-
`
`V. _
`
`~
`
`v
`
`'_
`
`-
`
`_‘
`_.
`~
`*—»§ '
`
`,
`
`'
`
`.
`
`V
`
`»
`,
`‘
`
`‘
`
`_
`
`.
`
`W
`
`._
`
`_
`
`--
`
`A— '
`
`,
`
`_
`
`H
`%4\'\100
`‘—<
`‘
`’
`
`I
`
`I
`
`.#u
`
`.
`
`’_
`
`"'
`
`.
`
`.
`
`‘
`‘ Li1ia‘T§Iiirico_,_~M;D.
`--
`v_~
`Director
`T_
`DivisiotI‘of_Gastrointes'tiné1Land Coa,gt_1lationDrugi 3-7
`'-Producf§*
`_
` _ _...
`,_
`____
`.
`Ofice of Drug Evaluation III-.-‘——
`’-
`Cent¢1_'_for,Dmg Ev_z_1_}uatio1Land 1}_§seafrcl1~- 1-‘
`pj
`:'..
`
`~ ..
`.-
`
`,
`
`-——-
`~
`
`“
`
`.
`_ +
`
`93
`
`-»
`
`V
`
`'"'
`
`'
`
`"
`
`-~
`
`I
`
`-'_
`
`-~-*
`
`'
`
`
`
`-
`
`_
`V -- ‘
`
`
`
`T
`
`%
`
`»
`
`i
`
`‘
`
`*-’-’-
`
`.
`
`.
`
`V
`
`«
`zArch'ivANDAs 2o—oo7,2o-403.
`TI-IFI_)-18_()'/Div.Fi1cs , H _.-«
`‘
`I .I-IFD-L80/M.McNc'i1.:
`—‘
`.5 .
`I~IF-2/,MedWatch.(With1.abelin.‘A;) “-
`HFD-002"/ORM (with labeling)‘
`-
`I'IFD-103/ADIEK (with.1_abelingl_
`..
`’.'IIFD-40/DDMAC(wiflI1ab¢,1_ifi8)«.
`HFI-20/Pgess Ombe
`laibeling) " “‘ "
`A
`‘
`HF]j.400/OP]3I(A_A(YVith_1aEe17ing)‘
`.
`1
`.__I*iF_I)’-613/OGI').(wi;t_111abeling)-
`%
`~ ——~—
`.
`I-IF'D-095'/DDMS3IM"I‘(wi.thTlabel1'1'1"g‘:)"'
`.. "“ "‘:“"~
`HED.-"820/DNDC”Division Dirggtor, \- '
`"‘DISTR1CT0FFICEf
`;
`» f1% %
`V g -~
`‘
`— 1AJy::n_n;/AbpriI‘10;'—2iV)0O ‘
`I
`’
`"
`-V
`Ini_t_ialed by: LTalarico 4/1o/oo_ _
`;_ 7
`%____."'iH_
`.____
`fina1?Apxill1,2000
`J
`-‘
`filenaxrblg-..;_ c:\;nydocuments\cso\n\2O007604-_ap.dAoc-_ —~:;
`_7_.e_§,_gPRo:zALT(,A.1_2;)
`_
`.4
`--
`-
`‘
`U
`
`_
`
`-
`__
`
`V
`
`-
`
`_.
`
`"
`
`‘
`
`.
`
`-:
`
`x
`
`.
`
`§
`-4- .4
`T
`7f
`
`J
`
`A—_.—
`
`_T
`"
`
`~~:AL
`
`_
`
`A
`
`W 7.
`
`»-.—
`
`"
`
`—.
`
`‘
`
`_%
`
`..,
`
`-
`
`.._
`
`S—-~
`
`._ —.
`
`—-—
`
`..—. ...
`
`—~._
`
`AA—~
`
`Page 5 of 27
`
`Page 5 of 27
`
`

`
`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`20-007/S030 7
`
`20-403/S009
`
`LABELING
`
`Page 6 of 27
`
`Page 6 of 27
`
`

`
`_
`
`~
`
`2'
`
`‘I >
`
`L‘ 0
`
`IIEINAVL PRlN7TEl.'")iLA7B_VE__l:l.NG H
`"
`ZOERANO (ondansetror”Iydr6_g;hloride) Injection Premiieci
`.
`V_
`' Packagé-Insert
`
`_ __
`
`
`
`._...——
`
`; ~
`
`.._‘
`
`-§
`
`-
`
`em:
`
`_;_.
`
`5
`
`,
`
`v Page 7 of 27
`
`Page 7 of 27
`
`

`
`U W - p=IxF“'3-‘J, ."°!35°!“I.
`@ --
`--
`'(=i>.n.°iIi=>°Ii=5Ii
`
`”
`
`'
`
`.
`
`.
`
`4' uonasuapuo)
`
`li0i.lVWUD3Ni.l9i'l00Ud =
`
`.
`
`.
`
`,
`.
`izo
`(ondansetron
`U
`hydrochloride)
`Injection Premixed
`
`"PiiuuucriurbnMAnou
`”
`U
`
`V
`
`—a
`
`-
`
`A
`
`"
`
`
`
`
`
`' 5-HT3 receptor type. Chemically it is (2) 1. 2. 3% 9-tetrairydro-9—methyi—
`-one. monuhydrochioridg: dihydrate. It has the iollowing structural formula:
`
`CH,
`
`7
`
`'
`
`I. "
`
`' "K
`’
`.
`H
`‘lift-wnitepowderthatissoiubieinwaterand nonnalsaiiné
`(l.V.) or lntqmuuular (l.M.) Adminlstminn: Each 1rnL ofaqueous solution in the 2-mL single-dose vial
`tnejiydrochiondiuiihydrate; 9.0 mg oi sodium cmoridef USP. and 0.5;ingot citric acid mnnohydrate. USP - _’'-‘= V-
`
`itrata dihydrate. USP as buffers in Water tor iniaction. USE"
`"
`>-
`-"
`_
`‘
`solution in the 20—mL muitidose vial comains‘2 mg oi ondansetron as the iiydrochioridia'6ihydmte' 8.3 mg of sodium
`A
`‘
`-, _.
`-
`A
`citric acid monohydrate, USP and 9.25 mo of sodium?-irate dihydraie, USP as butters; and 12 mg of methyiparaben,
`_
`‘-
`-
`.
`"
`_-__. .
`‘
`'
`’
`.
`,
`'_
`'
`NFand0.15mg oipropylparaben, NFaspreservatives iiwaterforInjection. USP.
`‘
`.
`—
`—-
`' -"
`. .
`-
`ZOFRAN injection is a clear. cuteness.nonpywgenic. sterileseiution. The pH at the injection solution is 3.3 to 4.0.
`‘
`I ~ '--*
`'
`garlic. Premium! snliitiiin iorlnuavonnusMininhtratloninSinpls-Dost. FlullllePlastic coiitainorr
`- "
`~
`'
`
`
`
`.
`
`
`
`
`‘____.n»,.
`
`-
`
`_
`
`..
`
`.
`
`'
`
`.
`,
`
`,_
`
`-
`
`s
`
`-
`
`_,
`
`-_
`
`.
`
`'
`
`‘
`owover. cytoto‘iic chernotherapyappears tube associ-‘
`'
`‘
`‘
`_
`,
`'
`datedwithreleaseofsemtqninfromthg_e__nierqchrpma1fincellsatthesmall intestine.Inhumans.urinary5—HlAA(5-hydroxyintioieaceticacid) f ’
`'
`- ' .
`’n may stimulate the vagai afferents
`_
`’
`_
`I
`.throughthe 5-HT; receptors and initiatetheyomiting reflex _
`.
`.
`
`_> T -V-_—~
`
`'
`
`' 7
`
`
`
`
`_
`
`I
`
`_
`
`_
`
`_
`
`
`_'
`
`_
`” __
`
`'
`‘
`compounu from the urine The prime
`'
`‘
`,
`'
`»
`recovered as the parent
`_
`.
`_
`mgfollowedbygIucuroniaanLsu|1ateconiugation.__1
`In normal voiunteersmtefoilowing mean phannacokineti
`lewinra singii: 0.15-mu/kg I.V. dose.
`=
`.
`.
`‘
`'
`.. Janioi:Pnaunaidizinancsinuormaivaiiinisiax-~
`"
`Plasma Clearance L/it/kg)
`
`'
`
`'
`
`'
`
`'
`
`'
`
`'
`
`'
`
`.__
`
`'
`r-—'“‘
`
`.
`
`‘
`
`_
`
`—
`
`-
`
`.
`
`~—
`
`_
`
`I
`'pauiauicpatiuTrs(ranoe,2.5toaiiours)incompaiison
`nan-rare
`'
`'
`j
`_
`'
`-
`witiiaduits(Ianae,3to35iiours).
`’
`innorrnalvoIunteers(19to39yaarsoid.n-23).tnepaakpiasrnaizoricentratianwaszfitno/mLtoiiowindasingIe32-niydoscadmiir_S
`istmdasa15-mlnutul.\LintusiorLTiiemaaneiiniinationhait-iitew$4.1|'iours.Systemic_exposurnto32mu otondarisatronwasnot
`mmr§ormmmmsmusmydwmmmrhodm1nmhmAUCwhumm&rwdmufl3BwmsmmMmamuflmauwm
`
`>'
`
`V.
`
`.. _.f T‘.
`_,—
`
`
`
`exposure
`155i95%cl136.1ao]aniI161[959sci137.190)ng-hInil.iorl.iAaridIJA.orosuis._iaspoctivw
`423[95%Ci'33.8.54;4lrinImLa1umhannnuivn...a.........-......«............----
`
`wasuauwaiuitwithvaitissoi
`pdiphsiriacorieentratxoiisweru
`
`~
`
`‘
`
`.
`A Page
`
`‘
`
`-W‘
`of 27
`
`Page 8 of 27
`
`

`
`-v-new-up-II-Iv}
`stxryuaoz
`3 rtouvwuoarruonooua
`..
`
`‘
`
`"
`
`"
`
`.
`
`-
`UOJl3SIflZp|l0)
`""eNV}I.:IOZ
`_'_‘
`—~ “M V
`
`V
`-
`’
`
`A
`
`V
`
`"
`
`’
`
`eeonucrtnronnerrou-—-0 -
`
`.___V_
`
`
`
`.
`
`-*
`
`—
`
`'
`
`-W"
`
`_ (ondansetmn
`(ondansction
`hydroEhlotid_e).V
`.}§«v.irod1Ioride)
`'_
`‘
`'
`Injection
`'
`“‘
`__
`»
`Injection"
`DES-t:ll'n0il:iheactivoingr§_dieminZOFltANlrijectlonandZDFRANlnjectionkremixedisondansetrenhydrochloride(Hcl).theracemir:
`_ _fonn of ondan@_a_nd a selective blocking agent ofthe serotonin 5-HT, receptor type. chemically it is (z) 1, 2. 3. 9-tetrahydro-9-rnethyl-.
`~ 3‘l(2‘mfltWHH-ifllilifllol-1-Ytlrrlfllllyll-4H-cartraaoljgijone. monohydrochlgritie. dihyclrate. it has the following structuraflormula;
`.
`
`~
`’
`
`-
`
`‘
`
`_.
`
`-,
`
`-
`
`'
`V.
`_ g _‘
`L'_-'
`..
`'
`
`._
`
`.
`
`-
`
`,
`
`A_
`
`'
`
`V
`
`.
`
`_
`
`_'
`
`-2
`
`V
`
`_
`
`I.
`
`.-
`
`-
`
`‘
`
`‘
`
`
`;
`~ ‘"7’
`
`' 7"
`
`-
`
`V "”?'- _‘~~Vi#
`-A
`,
`.
`V..-'..—
`V
`-‘ -
`
`.
`
`”’
`
`
`
`
`
`.
`
`
`
`.
`
`,.
`~
`
`V
`' C
`
`_
`'
`
`-
`
`'
`
`.
`'
`
`'
`
`'
`
`'
`
`V
`
`L
`'
`
`V
`
`_
`
`It
`
`__1
`
`_
`
`.
`
`’
`
`‘i
`
`T
`
`The empiricalionnula is C.gH,9N3D-Hcl-2H20,' representing a molecular weight of 365.9. V
`" Vondansetron Hcl isa white to off-white powder that is soluble in water and nonnal saline.
`Sterile lnlectlonftlr Intravenous (l.lI.) or lniranmcular (l.M.) Mmlnlstralionz Each~1—mL of aqueous solution in the Z.-‘mL sing|e—tlose vial
`# contains 2 mg of ondansetronas the hydrochloride-dihydrate; 9.0 mg ol sodium cliloride. USP; and 0.5 mg of citric acid monohyorate. USP
`and 0.25 mg of sodium citrate dil1ydrate,.USi’..as_outfers in Water for injection, USP.
`.
`_
`.
`Each 1 mL of aqueous solution inth_e_20-mt; multidose vial contaiosz mg of ondansetron as the hydrochloride dihydrate: 8.3 mg of sodium ._"" ’
`cntonea.+rse+o.5mgorcifiéacidmononyarate. USP'and0.25 mgofsodiumcitratedlhydrate. USPasbullers:and 1.2 mgofmethylparaben,
`'
`NF and 0.15 mg of propylparaben, NF as preservativesin Water for Injection. USE.
`.
`.
`ZOFRAN lnlectlon is a clear.colt_t_rVless. nonpiyrogenic‘. sterile solution. The pH otthe injection solution is 3.3 to 4.0.‘
`. Sterile. Premixed soifitlon for intravenousAdministration in Single-Dose". Flexible Plastic container: Each 50 mL contains ondansetion
`32 mg (as the hydrochloride dihydrate): dextrose 2500 mg;~and citricacid 26 mg and sodium citrate 11.5 mg as butters in Water for lnjec-
`tion..l.lSP.ltcontainsno preservatives. The osmclarity of this solution is 270 mosm/I. (approx). and the pH is 3.0 to 4.0..
`-
`
`-
`;7— -
`
`..
`
`-
`s
`»
`-
`.
`’ _
`.
`CUNICAL PHARMACOLOGY:
`Pherrner:ettyrramlt:s:__Ondansetron iVsa.selective 5-HT; receptor antagonist. While ondansetron's mechanism of action has not been fully
`characterized. it is not_a'dopamine—receptorantagonist. Serotonin receptors of the 5-HT, type are present both periphelalb/.on vagal nerve‘
`terminals and cemrally in the chemoreceptor trigger zone of the area postrema. it is not certain whether onda'nsetron's antiemetic action in
`ated with release of serotonin from ttreenterochrpnraffin cells olthe small intestin_e:ln humans. urinary 5_-l-llAA (5:hydroxyindoleaeetic acid)
`
`_
`_’ ”’_
`'
`
`_
`
`' ’
`
`‘-
`
`A
`
`»
`
`'
`
`-
`2-
`
`' .
`- _ ‘
`
`-
`
`.
`
`'
`
`,
`-
`
`,. _
`1 ;‘
`
`»-
`
`‘ ;
`
`”
`
`V
`
`.
`
`‘
`
`‘
`
`1
`
`'
`
`‘
`
`‘
`
`'
`
`<
`
`_
`
`~
`..vagotomy and greater splanchnic nerve section, or pretreatment witha serotonin 5-HT, receptor antagonist
`In nonnal volunteers, single l.\I. doses of0.15 mg"/kg ofondansetroli t'ia1‘no effect on esophageal motility. gastric motility, loweresopha-
`geal sphincter pressure. orsmall intestinal transit time. in anotltecstudy in.six normal male volunteers. a 16-mgflse infused over 5 minutes.
`showed no effect of the drug oncardiac output, hearrrate. stm.ke_volum'e. blood pressure. or electrocardiogram (ECG). Multiday adminis-V
`tratlon ofondansetron hasVheen shown to slow colonic transit In n_orrnal volunteers. Ondansetron has no effect onplasma prolactin
`
`1 '
`
`»
`
`W
`
`I -
`
`_
`
`_
`
`-
`
`-
`
`A
`
`—
`-
`
`~
`
`V
`
`‘
`"
`
`.
`
`.
`'
`
`___,
`'
`
`‘ '
`
`'
`
`'
`
`'
`
`_
`
`r“.
`
`
`
`Onclansetron does not alter the respiratory depressant effects produced by affentanil
`_
`~
`“by atracurlum. Interactions with general or local anesthetics have not been studied.
`‘ Pliannecokinetlce: Qndansetron is extensively rrtetabolized_iri hti’ri1‘a'iis';with approitirrrately 5% of a radiolabeled d
`
`
`
` Elimination Half-life (ll), .
`
`
`
`
`
`ild-to-moderate liver impair-'
`rth Increases in the mean apparent vhfime of distribution of less than twofold. as
`compared to normals. The mean hail—lile of 3.6 hours in normals increased to 92 hours in patients with mild-to-moderate hepatic impair-
`ment and-was _pr_olong_ed to 20.6 hours inpatients with severevhepatic insufficiency.
`V
`.
`V
`. A reductron.in_t_:learance and increase in elimination half-life are seen in patients over 75 years old. in clinical trials with patients with -
`cancer. there was neither a difference in,safety nor efficacy between-patients over 65 years of age and those under 65 years of age; there
`was an insttfficiem number of patientsrover 75 years‘of age to permit conclusions in that age-group. No adjustment in dosage-is recom-
`mended rn the elderty..
`-
`..
`' -»
`.
`
`
`
`
`
`
`
`
`
`
`
`'-
`.‘ '
`
`-
`
`
`
`
`
`
`
`
`
`
`
`
`fl
`pediatric patients (see CLINICAL TRIALS: Pediatricsm
`In a study of 21 -pedliflic Ditienis (aged 3 to 12 yrs) who were undergoing surgery requiring anesthesia for a duration of 45 minutes-
`to 2 hours. a single l.V. dose of ondansetron. 2 mg (3 to 7years)’or4 mg (8 to 12 years). was administered immediately prior to ‘anesthesia
`induction. Mean weight-nonnalized clearance and volume of distribution values in these pediatric surgical patients were similar to those
`previously reported foryoung adultssMean term‘
`hall-lifewas slightly reduced in pediatric Mients (range. gs to 3hours)_in comparison’
`with adults (range. 3 to 3.5 hours).
`‘
`_
`V
`in normal volumeers (19;to 30 years old;n = 23). the peak plasma concenhation was 264 ng/mL following a single 32-mg dose admin-
`istered as a 15-minute l.V. infusion. The mean elimination half-lite was 4.1 hours. systemic exposure to 32_mg of ondansetron was not.
`.
`A
`proportional to dose as measured by oornnanng dose-nonnalmd AUG wines to an 81mg dose. This is consistent with a small decrease in
`-
`»
`-
`systemic clearance with tncreaslnd plasma concentrations.
`.
`_
`_
`-t
`
`Astudywas perfonnedrn normalvolunteers(n;'56)toevaluamdnnhamaooldnedcsofasutgled-mgdoseadmmlsteredasas-ndnum~
`inlusien compared to a single intramuscular injection. Systemic exposure as measured by mean AUG was equivalent. with values of
`
`155 [9556 or 136. 180] and 151 195% CVl137.19o]ng-n/mL for l.v. and LM. omups. respectively. Mean D933 Plasma coneentrationsvrere
`429 [9593 cl 3:18, 54.4] ng/mL at to minutes after l.lI. infusion and 31.9 [9596 cl 26.3. 38.6] ng/mL at 41.mrnutesafterl.M.
`The
`
`
`meanelimrnation''
`rrarr-trrewasnotatrecwdbyrouteoradinlriisoattorr
`_
`—
`--
`‘
`
`_V
`
`_
`
`7.
`
`
`
`Page 9 of 27
`
`

`
` Z0l=HAN°:.(Thdansetron hydrochloride) Injection A
`
`
`
`.
`
`.
`
`_.
`
`A ZOFBAN° (ondansetron hydrochloride) Injection Premixed
`- —Elasnra pmtein binding of ondansetron as measured in vitro was 70% to 76%-. with binding constant over the plrannacologic concentra-
`tion range (10th 500 nglmt). Circulating drug also distributes intc erythrocytes.
`_
`0 Pfisitiviflymphoblast transfonnation test to ondansetron has been reported. which suggests immunologic sensitivity to ondansetron.
`cuurmmms:
`'
`..
`__.
`-
`,
`Chorhottrenprlnduced Nausea and Vomiting: In a double-blind study of threediftererrt dosing regimens of ZOFRAN injection, 0.015 mt}/kl-J.
`0.15 mil/kit. and 0.30 mu/kn, each given three times during the courseot cancer chemotherapy, the 0.1ErmgIlrg dosing regimen was more
`effective than the 0.015-my/lip dosifigregimen. The 0.30-ma/kg dosing reuimehwas not shown to be more'eflective than the (L15-mg/kg
`dosing regimen.
`'
`.
`'
`’
`'
`cleplnlln-Baudcnemomenpnln a double-blind study-irr28 patients. ZOFRAN injection (three 0.15mg/lro doses) was signifntlymore
`we thahlplacebo in preventing nausea and vomiting induced by cispIatr'n—based chemotherapy. Treatment responsewas as follows:
`ram": 2: Prevention or crfémoiiiaiapy-Induced Nausea and germ in Single-Bay clsplalin Therapy‘
`
`Number of patients _
`4- '
`treatment response
`
`
`.
`. "
`0 Emetic episodes
`
`-
`.1-2 Ematic episodes
`-
`'
`
`
`as Emetic episodes
`“ '
`.
`--
`*
`
`More than 5 emetic episcdeslrescued‘
`
`_ Median number of emeticepisodes
`
`. Median timetdfirst érfretic episodeth)
`
`Median nauseascores (o-1oo)_§.
`‘“'
`
`I
`
`
`
`
`A
`
`’_"' 7
`
`'
`
`A
`'
`
`~._-
`
`‘-
`
`
`
`
`
`
`
`
`
`
`
`
`
`‘
`
`
`
`'
`
`7 ~
`
`--
`
`‘
`
`-
`
`-
`_
`_
`'
`-
`..
`‘
`.
`‘Efficacy based-on“aIIpat_iemstreated'1analysis.
`.
`*Median undefined since at least 50% of the patients-were rescued or had more than five emetic episodes.
`‘ "Wisual analog scale assessment of nausea:'0.= no nausea. 100 = nausea as bad as it can be.
`. ‘Visual analog scale assessment otsatisfactinn: q__=, not at allsatistied, 100 = totally satisfied.
`, Ondanselron was"'compar‘éd with metocloprarnide in a single—blind trr‘ah‘n 307 patientsreceiving cisplatin 2100 mg/m2 with or without
`other chemliiitmneutic agents. Patients received the first dose of ondansetron or metocloprarhide 30 minutes before cisplatin. Two addi-
`tional ondansetron doses wereadrninistered 4 and 8 houilater. or five additional rnetoclopramide doses were administered 2. 4. 7. 10, and
`’ 13 hours later. Cisplatin was administered over a period or 3 hours or less. Episodes of vomiting and retching were tabulated.mrer the period
`of 24 hours alter cisplatln. The results of this study are summarized belonn=-
`..
`Table3: Prevention at some lndueedby cisplatirr(2100 mg/m'=)'srngie-ouy Therapy‘ I __,_
`
`
`‘
`Z_0l-’HAN injection
`Metoclopramide‘
`
`
`
`
`0.15_ mg/kg x 3
`2 mg/kg x 6
`Dose
`,
`'—
`._
`
`
`Number of-patients in_V@r:y population " _
`"136
`138 ‘
`‘ Treatmem response»
`.
`.
`.
`_'
`-
`y
`_
`'
`
`
`0 Emetic episodes,
`54 (-10%)
`41 (30%)
`
`
`i
`-
`1'2 Emetic episodes
`34 (25%), —
`30 (22%)
`
`
`—
`. ~-
`.
`= -~3-5 Emetir: episodes
`_ _19(14_°/.)
`1e(13%)
`
`
`,
`More than 5 emetic episodes/rescu
`—29.(21%)
`49 (36°/»)_
`
`
`- comparispnof-treatinents with respect to ‘
`,
`_
`-
`
`
`.0083
`.0 Emelicepisodes’
`,
`_
`54/136
`41/138
`
`
`0.009 —
`_‘ _
`- More than.5 emetic episodes/rescued
`29/136
`. 49/138
`'
`0.005
`' Median number oremetic episodes
`1
`2
`
`
`20.5
`.
`’
`4.3
`<0.001
`7g
`Median time to first aneiic‘episode (h)
`
`
`
`Global satisfaction with control of nausea and vomiting (0400)?
`B5’ .77 V —-
`63
`0.001
`"Acute dystfinic reactions
`,_ "
`0
`' -
`-— -
`a
`— ‘0.005
`_
`v
`
`
`
`
`Alrathisia
`’
`0-—
`10
`0.002
`s,_' ‘In §ddition4ofcisplatirT,68% of patients‘
`other chemotherapeutic ag—erTt§. including cyclcphosphamide, etoposide. and fluorouracil.
`There was no difference _p=etween treatments in the types of chemotherapy that would account for differences in response.
`' Tvisual analog scale assessment 0 = nntatall satisfied.—100 = totally satisfied.
`Forty-one of the ondansetron patients were over 65 yéar‘s"ot age. The complete response rate (lero erneticepisodes) was 41% in this group
`compared with’-10% in those 65 years old or younger.
`.
`._
`'
`In a
`randomized, double-blind, parallel-group. multicenter studs? ‘single -32-mg dose of ondansetron was compared with three
`0.15-mollto doses inpatientsroceiving cisplatln doses 01 either 50 to 70 mg/ml or 2100 mglm’. Patients received the first ondansetron
`.
`dose 30 minutes belore cispiatin. Two additional ondansetron doses were administered 4 and 8 hours later to the group receiving three
`0.15-ma/kg dosesfln bath strata, sighiticantty fewer. patientson the single 32-mg dose than ttrosereceivino the three-dose regimen failed?" ‘
`Table 4: Prevention of lthernottroreyy-induced Mao and Ernesis In Single"-Don 11rIrIpy A
`
`.
`
`>
`.
`~~—~ M
`
`-
`
`'
`
`_
`
`,
`
`_
`
`'
`
`-
`
`_
`
`,
`
`‘
`
`'
`
`V
`
`-
`
`'
`
`.
`
`__
`
`’
`
`_
`
`.
`
`.l? ._
`'7“
`
`’
`
`. _.
`
`“
`-7 .-
`"
`
`
`
`'
`
`.
`
`_
`
`‘
`
`_
`
`,
`
`.
`
`'
`
`I
`"' "
`
`-~ ‘
`‘
`
`'
`
`_
`
`;
`
`'
`
`~
`
`
`
`. Page 10 of 27
`
`(la)-
`__ A.
`
`‘nigh-oou:rm_rann(;1oomwni=)‘.
`Number arfiienis
`Treatmentresponse
`__.
`0 Emetic episodes
`'
`1-2Emeticepisodes
`More than 5 emetic episodeslrescued
`3-5 Emetir: episodes
`
`Median time tofirstemetic episode (ll)
`Median nauseascores 0100)‘
`Medlumjlon eisplotln (50-Tltmu/in’)
`Number of patients
`Treatment response
`0 Emetic episodes
`1-2Emeticepisodes_
`3-5 Emetic episodes
`Modlan time to tirst orneti:
`Median nausea scores (0-1ll1)" ‘
`~ " ‘trim.-slain-.I.m.....r......_..__._:\
`
`_
`
`'
`
`-
`
`’
`
`"
`
`(
`
`)
`
`'
`
`-
`
`.,
`
`'
`
`) ‘
`)
`
`'
`
`'
`
`i
`
`(
`
`g
`
`'
`
`'
`
`>
`
`-
`
`.
`
`-
`
`_
`
`..
`
`)
`
`‘
`
`"
`
`-
`
`-
`
`.
`
`.
`
`'
`
`‘
`~_
`
`i
`
`_.
`.
`
`-
`
`I
`
`’
`
`)
`
`*
`
`_
`
`~
`
`1
`:_ '-
`: '.
`'
`
`‘
`_
`'_ ~3-
`
`
`3
`
`-I
`f’
`
`_
`
`,
`
`_
`
`-
`-'—’
`
`’
`
`.
`
`g
`
`'
`
`..
`
`.
`
`'-
`
`‘
`
`_
`
`'
`
`‘
`
`
`
`Page 10 of 27
`
`

`
`~~ZOFRAN°(ondansetron hydrochloride)Jniection
`ZOERAN9(on_dansetron hydrocfrlorirle)lniection Premixed--
`Plasma protein bindingofondansetronasmeasuredin vitro was 707.in 76%,withbindinoconstantoverfhe prtannaoo'logic concetltra: “'
`tion range (10 to 500 ngImL). Circulating drug also distributes into erythrocytes.
`A positivelymphoblasttrahsfonnation testto ondanse_t_r_on_has been reported. which suggests immunologicsensitivitvto ondansetron.
`_
`.
`.
`_
`____ ,
`_.
`.
`Cllemotherepy-induced mumand Vomiting:Inadouble-blind studyofthreedifferentdosingregimensofzornm injection,o.o15 ma/ks.
`0.15 mg/kg. and 0.30 mg/kg, each given three times during the course of cancer chemotherapy, the 0.15—rng/kg dosing regimen was more
`-—effective than the 0.015-mg/kg dosingregimen. The 0.30-mg/kg dosing regimen was not shown to he more effective thanthe 0.15-mg/kg
`dosing regimen.
`CfspIatin—Basedcriemonmp;Ina double-blindshrdy,_in 23
`zornnirifiieeion (three0.15—rngIkpdoses)"wassignificarmymore
`effective than plaEbo.in.P[°L’ltlng nausea and vomiting induced bycrsplatrn-based chemotherapy. Treatment response was as follows.“
`Table 2: Prevenfloit ‘oi rirnmottterany-induced Neuseaand Ernesls in singrsoay cisprarrn Therapy‘
`.
`
`—
`»-
`ZOFRAN lniection
`'
`-
`4
`14‘
`-
`-_ Number of patients
`5-" ,
`.—
`T
`14
`
`
`
`Treatment response
`‘
`.
`-3; —
`
`
`0 (0%)
`2 (14%)
`0 Emetic episodes -----A
`
`
`0 (0%)
`8 (57%)
`1-2 Emetic episodes __
`
`
`1 (7%)
`2 (14%)
`_ 3-5 Emetfc episodes
`0.001
`13 (93%)
`g _ ,
`2 (14%)
`More than 5 emetic episodeslrescued -
`
`
`‘f'lJr;d_efined*
`_
`'
`" " 1.5
`_Median number ofemetic episodes
`
`
`0.001 .
`2.3
`~—--
`11.6 —'
`--
`--Median timeto first emetic episode (h)
`0.034
`j"
`"""‘
`59
`'- '"" V
`V -- f
`3
`Median nausea scores (0-100)§
`"
`
`
`0.009
`1015
`‘
`Global satisfaction with control'of nausea and vomiting (0-1002'. .,
`96
`—
`
`
`.'chemotherapy was high dose (100 and 120 mglmz; ZOFHAN lif)e‘r:tion n = 6, placebo n = 5) ormoderate dose (50 and-00’mgIm‘: ZOFRAN
`Injection n = B. placebo n = 9). other chemotherapeutic agentsincluded fluorouracit:doxorubicin. andcyclophosphamide. There was no ‘
`difference between treatments in thetypes ofchemotherapy ttrat would account for differences in response.
`.
`_, .
`1Etflcary based on “all patients treated” analysts.
`'
`‘
`.. -.—
`.
`‘Median undefined since at least 50% of the patients were rescued or had more than five emetic episodes? '
`H
`.
`...
`5Vlsual analog scale assessment of nausea: 0 = no naus. 100 = nausea as bad as itcan be.
`--
`--5*‘ ' ‘ " Visual analog scale assessment of satisfaction: 0,: notatall satisfied. 100 = totally satisfied.
`- Ondansetron was compared with metoclupramida in a singleeblind trial in 307 patients receiving cisplarin 2100 rngIm?wittr or without
`.
`thetchemotlierapeutfc agents; Patients received the first dose of ondansetzon ormetoclopramide 30 minutes before cispfatin. Two addi-
`tional ondansetron doses werevadministered 4 and 8 hours later. or five additional metoclupramide doses were administered 2. 4. 7. 10, and
`“ ‘13 hours later. Cisplatin was administered over a period of3 hours or-less. Episodes of vomiting and retching were tabulated over the period
`of 24 ho_urs after cisplatin. The results ofthis study aresummarized below.
`i
`-
`"
`
`Table 3: Prevention of Ernest: Induced byclsplatin (2100'mgIrn’) Single-_Day‘ Therapy; .____ ’ .
`.
`»
`.-
`.
`-
`
`
` Number of patients in efficacy population’
`‘
`.
`! ~
`Treatment response .
`.
`..
`
`
`'41 (30%)
`5'?4TU°7T.
`._ o Emetic episodes
`30 (22%)
`34 (25%)
`1-2 Emetic episodes
`
`
`18 (13%)
`19 (14%)
`.
`1
`.
`3-5 Emetic episodes’
`49 (36%)
`29 (21%)
`.
`.
`A __.
`— —
`j’ Morethan5 emetic episodeslrescyed '
`
`
`_
`‘
`—
`_
`—.
`<
`comparison oftreatmerrtswith respectto
`41/138
`- "‘ .54/13§
`0.083 -
`0Emetic episodes
`.
`
`
`' '”'
`49/136
`29/136
`' 0L9__
`More than 5 emetic.episodes/rescued
`
`
`hr 2 "
`1-
`_ ‘
`0.005
`_Median numberofemeficepisodes
`
`
`-_-V
`4.3’
`'
`20.5_
`_
`">__5t_).001
`Median timetoflrstemettcepisode (h)
`
`
`;
`__.H - 63‘
`__
`85 ,,,
`0.001
`Global satisfaction with comrol of nausea and vomiting (0-100)’
`g B"-*—.— —’
`__.
`Ig_w
`Acutedystonir: reactions
`0.005
`__
`,
`'
`.__:_
`.
`
`
`'
`'
`1rr‘-“’
`-
`_
`__.0
`" Arratmsia
`‘0.002
`_
`”
`
`
`‘In addition to cisplatin. 68% of patients-received other chemotherapeutic agents. including cyclophosphamide. etoposide. andsftuorouracil. “
`_Itrere wasrnidifference betweentreatments inthe types of chemotherapy that would account fordifferences in response.
`‘Visual analog scale assessment; 0: not at_alI satisfied. 100 = totally satisfied.
`"
`'
`.
`_ _"Forty-one of the ondansetron patients were ever 65 years rrfage. The complete responserate (zero emetic episodes) was 41% in this group
`A
`~-a- -cgmparedwith40%intlrose’65.vears oldoryoonger.
`'
`»
`..
`-
`..-__,
`'— _—
`A
`..
`‘
`In a stratified. randomized. double-blind. parallel-group. multicenterstudy. a single32-mg dose oLndanset1on wascomparedwiththrmr_
`_V__0.f5'-mg/kg dosesifpatientsreoelving cisplatin doses of either 50 to 7Qmglrn3.or_2T00‘i'ng/m3;-Patients received the first onrtansetron
`’ '“duse'30 minutes before cisplatin. Two additional ondaosetron doses were administered 4 and B hours‘la’terto~the group receirdng three
`——0.4 5-mg/kg doses. In truth strata. significantly fewer patients on the single 32-n'ifi'ose than those receiving the three-dose regimen failed. - .
`Table 4: Prevention of chernotherariy-induced Hansen and Emule in Single-Dose Therapy", .
`Ondansetron Dose
`32 mg x 1
` ' I-llgh-dose erspiatIn_(zjoo mg/in’)
`.
`-
`Number of patients
`.
`_
`100
`_
`
`
`
`Treatment response
`~
`
`
`49 (48%)
`41 (41%)
`0Emetic episodes
`--
`
`
`25 (25%) -~ -
`_ 19 (19%)
`,
`1-2 Emetic episodes
`8 (8%)
`i
`4 (4%)
`3-5 Emetic episodes
`
`
`0 009
`20 (20%)
`36 (36%)
`More than 5 emetic episodes/rescued
`
`
`
`23
`21.7
`Median time to first emetic episode (h)
`
`
`Median nausea scores (0-100 '
`28
`13
`Medium-dose clsplatin (5040 mgfm’)
`.
`
` Number of patiems I01
`
`T eatrn nt
`se
`'— '
`~
`v
`‘
`A
`-
`
`
`'osm"ette'§?.’s"o'Ii.s
`B2(61%)
`5B(73%l
`0.083
`_ z i
`1-2 Emetic episodes‘
`11 (11%)
`'4 (15%)
`
`
`7
`:‘
`-
`3-5 Emetic episodes
`6 (6%)
`3 (3%)
`"'
`
`
`More than 5 emetic episodes/rescued
`22 (22%)
`B (9%)
`0-011
`.
`
`Median time to first emetic episode (h)
`Undefined’
`Undefined
`
`
`
` Median nausea scores (0-100)‘ ~ 9 3 0-73‘) .
`
`
`‘Visualanalogsr:aleassessment0,=nonausea.100=nauseaa8b3d3§if0?flb0-
`-—
`YMedianundefirwdsinoealeast50%ofpanentsdMnothaw‘anyemenceprsodes.
`'
`opmpru’
`‘do-sa’sudcitomatrnapr.i
`dMrblfmmlauoo-mhhNhdshflyofZOFRANlnjecdon(hnee0.15-mg/kgdoseslin’
`m‘p'admmrmw?ngwmmwflmm(5mr:e1l0o:vm0mmnmwnz0mmtmmrmmmwmmmenmmumplacebo
`
`-
`_4
`
`.
`
`0.315
`
`.»
`
`-
`
`t
`
`_
`
`_]02
`
`«
`
`_
`
`,
`
`
`
`-
`
`
`
`>
`_‘_‘_
`.
`,
`.
`'
`- -'
`.
`-» ‘~_‘
`V
`'
`;
`3
`~
`—
`-
`-
`~‘
`
`.
`
`~
`
`'
`
`
`_
`’
`
`" .1. L
`
`'
`
`' ..
`
`
`
`~
`__
`
`-if 4 4-;
`. _ —
`'_
`‘
`'
`.
`;:
`-
`
`’
`'_ “
`-
`___,
`__‘ _
`-' _i
`' ‘
`_
`. '
`_
`-
`.
`
`.
`" -
`‘
`g ,
`A
`
`’
`
`‘
`
`'
`
`-
`
`_
`
`V
`-
`'
`
`.
`
`(
`
`_
`‘
`
`-
`
`'
`
`»
`
`
`
`
`'
`
`,
`
`-
`
`_
`
`.
`
`"
`
`‘
`
`g
`
`.
`
`
`
`
`
`
`
`
`
`
`I
`
`1
`_'
`‘
`'
`'
`
`
`
`
`V-r
`
`
`
`’
`
`'
`
`V
`
`.
`
`V
`‘
`
`'-
`
`.
`_
`'
`-
`
`'
`V
`
`‘
`
`,
`~
`“-
`__ ——
`
`_
`
`‘
`
`'
`
`‘
`
`.
`
`‘
`
`—
`‘
`_
`“‘
`_
`‘
`
`_
`
`'
`
`’
`
`*
`
`‘
`
`
`
`,
`
`‘
`
`_ _
`
`'“
`.
`
`__
`
`v-
`
`_
`
`'
`
`V
`
`'
`
`r
`
`'
`
`V
`
`'
`
`.
`»
`____ f
`
`,,
`
`_‘
`
`'
`
`_
`
`j
`
`'
`
`‘
`
`
`
`--
`~
`
`--
`
`~-——.
`
`4
`
`7‘
`
`’’
`
`. __._
`- H /
`,
`.
`
`»
`5
`-—ii
`(
`'
`‘ _ -
`_
`~~
`”
`
`'
`
`g
`
`_.
`r '
`'
`
`.'
`
`-
`
`-
`
`'
`
`,
`.
`:\
`
`.
`
`‘ .
`.
`‘Ky ;.
`J
`
`.
`j ‘
`_ ,g_ A.
`_
`‘
`
`- 7
`‘
`:
`
`g
`V 1;
`2 5
`
`_
`
`’
`
`A
`"
`'i
`
`‘
`
`'
`
`~
`
`L
`
`.
`
`-
`+
`
`_
`
`‘“
`
`'
`
`‘
`
`_
`
`A
`
`'
`
`-.
`
`~
`
`'1
`
`‘
`
`‘-
`
`——A
`
`_. _,
`
`_
`
`‘
`
`_f
`7
`
`.
`
`‘
`
`~
`
`-»
`
`I
`
`v .'_
`
`" -
`'
`
`-
`
`'
`
`W-
`
`_
`
`' ——
`
`-
`
`5 7
`
`“ —
`
`-
`
`
`
`' '
`
`.
`-—
`_
`
`M
`
`,
`
`'
`
`—
`
`“
`
`.
`
`7
`
`-
`
`_
`
`.
`
`_
`
`g’
`
`_
`
`_‘__
`-7
`
`1 .
`"
`
`
`
`_ _
`
`.
`‘
`r
`-~
`g "' ;_
`_
`‘
`”
`
`.
`
`‘
`
`.
`g.
`K
`_ ' '
`
`V
`
`_
`
`._ .
`
`.
`
`~
`‘
`
`.
`
`'
`'
`I
`
`_.
`
`.'
`
`_
`
`. 2
`
`_
`M
`
`‘
`
`'
`
`V
`
`_
`
`.
`
`_
`
`._
`
`-
`
`.
`
`.
`
`_
`
`'
`
`'
`
`" .
`
`-
`
`'
`
`I
`
`Page 11 of 27
`
`

`
`
`
`
`
`
`
`
`
`
`-
`
`_
`.
`
`T.
`
`'
`
`-
`
`.
`'_
`
`_
`
`.-
`
`. _.
`-
`
`-
`
`-
`
`-.
`.
`
`.
`
`.
`'
`
`_
`..
`
`,
`
`
`'
`
`
`I
`. ; '
`_..
`
`'
`
`.
`
`-
`
`-
`
`»
`
`_
`
`.
`
`.
`
`.
`
`_'_
`
`
`ZDFRANF--(ondansetmn h¥'drocl_Ilt'r-ridetlnjeotlgn 3
` -
`-.
`‘
`it
`-
`ZOFRAN°(ondansetron hydroc lo_ride)_lru'ection-PremixedV
`_
`' __
`V
`
`V
`The resultsaresumrr'ia7i?e"d"
`4
`V
`-
`-
`inprevenfing nauseaand
`
`
`
`"
`mriE Prevention atchemotherapy-Induced mum and aunt: in single-nay tiyelnpho:phamidI'l1ierIpy’
`of patients
`Treatment response
`
`0 Emetic episodes
`__
`1-2 Emetic episodes —— V-—
`_,
`.
`"
`'
`3-5Emeticepisodes
`< “"
`'
`_
`
`lyre than 5 emetic episodulrescued '
`,
`
`Median number atemetir: episodm
`-— -~ --
`
`Median time to first emetic episode (h)"
`
`.
`Median nauseascores to-rm);
`
`GIob_al'satislaction with control of nausea and vomiting (o-too)‘
`‘
`.
`'
`rapy that would account torditterences in response.
`a
`-
`_
`.
`.
`.
`ittticacy based on “allpatients.treated" anatysis.
`g
`—
`. g,
`_
`.
`sinceat least 50% ot patients did nuuiaveany emetic‘episodes. -—
`.
`-—
`__-. e ,
`§Visua| analog scaleasessmentof nausea‘ 0 = no nausea, 100 =' nausea as bad as itcan be.
`‘
`.'
`"Visual analog scale assessment ot satisfaction: 0 = not at all satisfied; 100 a: totally satisfied.
`.
`. no-Irnbnont: In uncontrolled trials. 127-patientueeeiving cisplatin (median dose..Jo0rngIm'é’)and.ondansetmn who had two or fewer
`emetic episodes were retreatedwith ondansetron and chemotneflvy. mainlycisplatin. foratotal of 269 re-treatment courses7Tn.e'rtian. 2; _
`‘range, 1 tntll). Noemeticepisodesoocurred in160 (59%). and
`emeticepisodes occurred in 217 (81%) re-treatmentcourses.
`PediatricStudios:Four operrlabei. nonoomparative (one US. three foreign) trials have been perfonned with 209 pediatric cancer patients
`aged 4 to 18years given avarietyot ctsotatirier noncisplatin regimens. Inthethreeforeigntrials. the initialZOFRAN Injection dose ranged
`'_lrom 0.04 to 0.87 mglkg to
`"
`"
`.
`.-
`'
`‘
`'
`'
`‘
`ondansetron ranging tromt to
`metic episodes on day 1. Thus.
`,
`FRAN Injection
`
`
`
`,_. .
`
`.
`'
`
`_
`
`.
`
`» ”
`
`.
`'
`
`
`
`_
`
`7-
`
`":-
`i-- ‘
`
`
`
`-
`
`_
`'.
`,
`"‘"’ A
`'
`g was well tolerated in thesepedlatric patients.
`Poflflltlmivfl llltml Ind V0ffliiifl92A_£’1Il;I[€!ln o!Post'operaIinNeueaml VorrrIllr'rg:Adult surpi
`-
`immediately before the induction ol general balanced anesthesia (barbiturategthiopental, metlrohexital
`gtentanyl: nitrous oxide; neuromuseularbloclcadez succrnylcltolino/curare and/or vecuronium oratracurium; and so
`pplemental isotlurane)
`.
`were evaluated in two double-blind US studies involving 554 patients. ZOFRAN Injection (4 mg) l.V. g;ven_over2_to 5.minutes was signiti-—
`ntty/rnoreetfectivethan placebo. Theresultsotthesestudiesare‘summari_zed beldwz‘
`-
`.
`.
`,
`—Table 8: Pmerrtton offtlfllwntlve Nausea ind Vomiting In Adult Patients.
`"
` Ondansetron 4 mg1.V.
`
` Emeticepisodeg ’ V‘ _ _ " — f __‘_-
`
`
`
`
`
`
`
`Numberotpatients
`~t36 -
`.
`_
`_
`139
`.
`' “
`Treatmentresponse over24~n postoperative period
`.~—--'
`..___ _
`.
`_
`-.
`_
`’ “
`
`
`Adi-I
`'“103'(76‘/o)
`64(46°/n)
`<0.001 '
`Ofmetitzepisodes
`'
`
`
`.
`’
`13(10%)
`..
`_
`17(12%)
`'
`_
`1Emeticepisode
`'
`
`
`
`
`
`'
`‘
`20'(T5%)
`'
`‘58(-12%)
`9 ',_n_ _— —
`Morethan'1 emetic episode//rescu
`"
`
`_
`_
`.
`.
`_
`.
`u
`Nausea assessments:
`‘
`_~e
`
`'
`'
`Number otpatients
`,
`.
`'
`-No nausea aver 24-lr postoperative period
`
`-
`‘
`i
`‘
`I
`'
`‘
`'
`72: .
`smd¥7-:;:.-
`' "‘
`"'
`’
`
`
`
`-
`.
`‘
`.
`--
`'
`"--~_P_ ..
`_ ..
`Emeticepisodes:
`'
`
`
`"
`'
`I
`——
`136
`—
`143 - g
`Jtlemberotpatients __
`, Treatrnentresponseo1e_rgt_-h postopefative period
`K
`’
`_
`
`
`' '7
`Dfimeticepisodes
`__
`‘ B5(63%)
`63(“%)
`,.
`0.002
`.
`1 Emetie episode
`~—t6(12%)
`29(2o°/.1
`—
`‘—-4
`-. _ .
`
`_;
`Morethant emetic episodwrescued
`35.(26%)— ‘
`5t (36%)
`--_--'
`.
`Nausea assessments:
`' '
`- ""“"”
`'
`Number at patients
`
`_
`--
`
`,
`
`'
`
`~
`
`'
`
`‘
`
`-
`
`'_
`
`V-—
`'
`_ _".‘~""
`
`3
`
`__
`
`_
`
`vh
`_.
`
`_'
`'
`_
`- _> .
`'
`
`'
`
`_
`
`
`
`"
`-
`
`._
`
`-
`
`_ .
`-
`
`
`
`.
`
`‘_
`
`*"
`'
`
`-.
`~
`
`_
`
`.
`
`‘
`
`-'
`
`
`
`
`A_.
`
`'
`
`,
`
`,.
`'_
`_
`-5 —'
`
`-
`
`_
`__,
`
`-_
`V
`;
`
`__
`
`-.
`
`,
`j.
`e
`»
`.
`2-s .
`~
`
`-
`. ”.
`
`'
`i.
`
`_
`
`__
`
`-
`
`It
`T _
`.
`
`
`
`°iPage1:2or27'
`
`Page 12 of 27
`
`

`
`nZ0‘FBAN°’(ondansetron hydrochloride)'Iniection
`ZOFltAN° (ondansetron hydrochloride) Injection l’remixed__
`’
`‘T’
`
`inproventingnauseaandvomiting.‘l'