DansetAmpoule

Qualitative & Quantitative Composition:Each 1 ml of aqueous solution contains 2 mgondansetron as hydrochloride dihydrate.Pharmaceutical Form:Aclear, colourless, sterile solution for injection orinfusion.Clinical Particulars:Indications: DANSET injection is indicated for themanagement of nausea and vomiting induced bycytotoxic chemotherapy and radiotherapy. DANSET isalso indicated for the prevention and treatment of post-operative nausea and vomiting.

_ Dosage&Admlnlstration:_ DANSET is available for parenteral use.___ Chemotherapy & Radiotherapy Induced Nausea &_ Vomiting (CINV and RINV): The emetogenic potential_ of cancer treatment varies according to the doses and_ combinations of chemotherapy and radiotherapy___ regimens used. The selection of dose regimen should--- be determined by the severity of the emetogenic--- challenge.

Populations:-AdultsEmetogenlc Chemotherapy & RadiotherapyThe recommended intravenous (IV) or intramuscular(1M) dose of DANSET is 8 mg administered as a slowinjection immediately before treatment.Highly Emetogenic Chemotherapy •. g. hlgh-dol.clsplatln DANSET can be given by IV, 1MAdministration. DANSET may be administered as asingle 8 mg IV or 1M dose immediately beforchemotherapy. Doses of greater than 8 mg up to t 6 mgof DANSET may only be given by IV Infusion diluted In50 to 100 ml of saline or other compatible Infusion fluid(see Instructions for Use and Handling) and Infu dover not less than 15 minutes. A single dose gr 01 rthan 16 mg should not be given. (see Warning andPrecautions) For management of highly emelogonlcchemotherapy, a dose of 8 mg of DANSET may beadministered by slow IV in not less than 30 soconds, or1M injeclion immediately before chemolherapy,followed by two further IV or 1Mdoses of 8 mg 2 to 4hours apart, or by a constant infusion of 1 mglh for up to24 hours. The efficacy of DANSET In highly emotogonlcchemotherapy may be enhanced by the addition of asingle IV dose of dexamethasone sodium phosphate 20mg, administered prior to chemotherapy.

-CINV in Children and Adolescents (aged 6 monthsto 17 years) The dose for CINV can be calculatedbased on body surface area (BSA) or weight. Inpaediatric clinical studies, DANSET was given by IVinfusion diluted in 25 to 50 ml of saline or othercompatible infusion fluid (see Instructions for Use andHandling) and infused over not less than 15 minutes.Dosing by BSA DAN SET should be administeredimmediately before chemotherapy as a single IV doseof 5mgl m2. The IV dose must not exceed 8 mg.Table 1. BSA-based dosing for CINV (aged 6monthsto 17 years)

BSA Day 1 -<0.6 rn' -z 5mglm'IV

~ 0.6 m' to ~ 1.2 rn' 5mglm'IV> 1.2m2 5 mgl m' IV or 8 mg IV

DOSing by body weightDANSET should be aornirustereo immediately beforechemotherapy asa single IV dose of 0.15 mglkg. The IVdose must not exceed 8 mg. On Day 1, two further IVdoses may be given in 4-hourly intervals.Table 2. Weight-ba.ed dosing for,CINV (aged 6months to 17 y.ar.)

~

Odywelght

10 kg

> 10 kg

-Eld rlyDAN SET is well tolerated by IlIIlIl 1110"VI I 05 yl IS andno alterations of dos 9 ,dOllnu h qUI Il(,Y Of route ofdmlnistration are required.-Renal ImpairmentNo alteration of daily dosage or frequency of dOllnl, 01route of administration are required.-Hepatic ImpairmentCI arance of ondansetron is significantly redu t II 11111s rum half-life significantly prolonged in subJ tt~ will,moderate or severe impairment of hepatic functlon Insuch patients a total daily dose of 8mg IV should IIOt bexceeded and th refore.-Patients with Poor Sparteine 1 Debrlloquln.MetabolismThe elimination holf IIfo of ondansetron is not all rod Insubjects classlfl d a poor metabolisers of sp rt Inand debrisoquln Consequently in such p ti nlsrepeat dosing will glv drug exposure levels no dill r ntfrom those of Ih 9 n ral population. No alterotion ofdaily dosage or" qu ncy of dosing are requiredPost-Operative Nau,.a & Vomiting (PONV)-PONV in AdultaForpreventlon fp top ratlve nausea and vomiting,

Day 1Upto3do os o(Q,15mg 9

IV ry 4 hoursUp to doans of 0 15 onglkg

v ry 4 hOWl

The recommended dose of DANSET injection is asingle dose of 4 mg by 1M or slow IV injectionadministered at the induction of anaesthesia. Fortreatment of established post-operative nausea andvomiting, a single dose of 4 mg given by 1Mor slow IVinjection is recommended.-PONV in Children and Adolescents (aged 1monthto 17 years)For prevention and treatment of PONV In paediatricpatients having surgery performed undor generalanaesthesia, DAN SET may be administered by slow IVinjection (not less than 30 seconds) at a dose of 0.1mg/kg up to a maximum of 4 mg either prior to, at or afterinduction of anaestbesia, or after surgery.-Elderly There is limited experience in the use ofDANSET in the prevention and treatment of post-operative nausea and vomitingin the elderly, however DANSET is well tolerated inpatients over 65 years receiving chemotherapy.-RanallmpairmentNo alteration of daily dosage or frequency of dosinq, orroute of administration are requlred,-Hepatic ImpairmentClearance of ondansetron is sign In ntly r du d andserum half-life significantly prolong d In .ubJoCls withmoderate or severe impair nt of h patlc function, Insuch patients a total daily do e of 8 mg IV should not beexceeded.-Patients with Poor S artelnl/OobrlloqulneMetabolismThe elimination half-life of 0 an troll I 1101 It rt d Insubjects classified as poor metaboll t, ul ,)11111I111and debrisoquine. Consequently III III II "Ith IIIrepeal dosing will give drug 'i"posurt II viti 1111I11th,,"Ifrom Ihos of the general population Nt! III. I 111111III(I lIydosog or froquoncies of dosing lire I qllill IIControlndlcatlonltl '"1 d on reports of profou~ hypot nllll11111I111lilt I1fconsclou ne81 whon onda~setron WI" IIlonto,IMII" (Iwith p morpnln hydrochl ide, con. 1I1111111tII wllh'pomorphlno Is contra Indica d. Hypo, 11Itlvity to myccmoonentot tho preparatio .Warnlngl & Precautions:Hypor onsltlvlty r actlons have b n 11I11001,I Inpotienls whO h v exhibile hyper nsltivliy to Otl, rs loctlvo HT 3.Ondansolr n prolongs the QT Int 'VIII 111 d080dep nd nt m nner (see Clinical Ph rm .oIO{IY). Inddltion, poet m rketing ca es of To,s It! d Point shove be n reported In pa tents using and nsetron.Avoid and I1l8tron In patie s wllh con nltol I ng OTsyndromOnd n tron 8h uld be ad inlstered will) suuon top ti nt who hov or may develop prolongollon of Olc,

Including patients with electrolyte abnormalities,Congestive heart failure, bradyarrhythmias or patientstaking other medicinal producls that lead to OTprolongation or electrolyte abonrmaltities.Hypokalemia and hypomagnesemia should becorrected prior to ondansetron administration. AsDANSET is known to increase large bowel transit time,patients with signs of subacute intestinal obstructionshould be monitored following administration.Interactions:There is no evidence that DANSET either induces orinhibits the metabolism of other drugs commonly eo-administered with it. Specific studies have shown thatthere are no pharmacokinetic interactions whenDANSET is administered with alcohol, temazepam,furosemide, tramadol or propofol, Ondansetron ismetabolised by multiple hepatic cytochrome P450enzymes: CYP3A4, CYP2D6 and CYPIA2.Due to the multiplicity of metabolic enzymes capable ofmetabolising ondansetron, enzyme inhibition orreduced activity of one enzyme (e.g. CYP2D6 geneticdeficiency) is normally compensated by other enzymesand should result In little or no significant change inoverall o~dansetron clearance or dose requirement.Caution should be exercised when ondansetron iscoadministered with drugs that prolong the OT intervaland/or cause electrolyte abnormalities. (see Warningsand Precautions).ApomorphineBased on reports of profound hypotension and loss ofconsciousness when ondansetron was administeredwith apomorphine hydrochloride, concomitant use withpomorphine is contraindicated.

Tramadoluata from small studies Indicate that ondonsotron mayroduce the analge Ic effect oftrBmadolPregnancy & Lactation:Pregnancy The saf ty of DAN I I for u e In humanpregnancy has not b n 81 blllh d. Evaluation ofexperimental an lm I 8ltHil I do 8 not lndlcate dlrecl orIndirect harmful II I wlllH spect to the developmentof the embryo, or 1 t"l, Ihe course of gestation andperl- and post ·nolol d v lopment. However as animaltudles are not Iwnya prodlctlve of human response,the use ofDANS r In pregnancy Is not recomm nded.LactationTests have shown IhOl ondansetron passes into the milkof lactating anlm II It Is therefore recommended Ihatmothers receiving DAN SET should not breast feedthelrbabies.Effects on Ability to Drlvo and Use Machines:In psychomotor I sting DANSET does not Impairperformance nor u e sedation. No detrlm ntaleffects on such 0 tlvlil s are predicted from the

pharmacologyofDANSET.Adverse Reactions:Adverse events are listed below by system organ classand frequeocy. Frequencies are defined as: verycommon (>tI10); common (>11100/to <1110);uncommon (>1/1000 to <11100); rare >1110,000 to<111000); and very rare <1110,000), including isolatedreports. Very common, common and uncommon eventswere generally determined from clinical trial data. Theincidence in placebo was taken into account. Rare andvery rare events were generally determined from post-marketing spontaneous data. The following frequenciesare estimated at the standard recommended doses ofDANSEr. The adverse event profiles in children andadolescents were comparable to that seen in adults.*Immune system disordersRare: Immediate hypersensitivity reactionssometimes severe, including anaphylaxis.*Nervous system disordersVery common: Headache. _Uncommon: Seizures, movement disorders _(including extrapyramidal reactions such as dystonic _reactions, oculogyric crisis and dyskinesia) have been _observed without definitive evidence of persistent _clinical sequelae. _Rare: Dizziness during rapid IV administration. _'Eyo disordersRare: Transient visual disturbances (e.g. blurred vision) ---predominantly during IV administration.Very rare: Transient blindness predominantly during IVadministration. The majority of the blindness casesreported resolved within 20 minutes. Most patients hadreceived chemotherapeutic agents, which includedclsplatin, Some cases of transient blindness werereported as cortical in origin.*Cardlac disordersUncommon: Arrhythmias, chest pain with or withoutST segment depression, bradycardia.Rare: OTc prolongation (including Torsade de Pointes).*Vascular disordersCommon: Sensation of warmth orflushing.Uncommon: Hypotension.*Respiratory, thoracic and mediastinal disordersUncommon: Hiccups.*Gastrolntestinal disordersCommon: Constipation.Local burning sensation following insertion ofsuppositories."Hepatoblliary disordersUncommon: Asymptomatic increases in liver functiontests, These events were observed commonly inPatients receiving chemotherapy with cisplatin.General disorders and administration site conditionsCommon: Local IV injection site reactions.