SETRON

Prescribing Information

Setron

Granisetron Hydrochloride

Ampoules

Qualitative and quantitative composition

Each 3 ml contains 3.0 mg granisetron (as the hydrochloride).

Pharmaceutical form

Anampoulecontainingasterile,clear,colourlessorslightlystraw-coloured

solutionequivalentto1mgofgranisetronper1mlofsolution.Thecontent

allows withdrawal of 3 ml.

Theinactiveingredientsintheinfusionaresodiumchlorideandwater

for injection.

Therapeutic indications

Setronisindicatedforthepreventionortreatmentofnauseaandvomiting

induced by ematogenic cancer therapy and cytostatic therapy.

Dosage and administration

Setron ampoules are for intravenous administration.

Adults

3mgSetron,whichshouldbeadministeredeitherin15mlinfusionfluid

asanintravenousbolusovernotlessthan30secondsordilutedin20to

50 ml infusion fluid and administered over five minutes.

Toprepareadoseof3mg,3mliswithdrawnfromtheampouleand

dilutedeitherto15mlwith0.9%w/vSodiumChlorideInjectionBP(for

bolusadministration)orininfusionfluidtoatotalvolumeof20to50

mlinanyofthefollowingsolutions:0.9%w/vSodiumChlorideInjection

BP;0.18%w/vSodiumChlorideand4%w/vGlucoseInjectionBP;5%

w/vGlucoseInjectionBP;Hartmann’sSolutionforInjectionBP;Sodium

LactateInjectionBP;or10%MannitolInjectionBP(forinfusion).Noother

diluents should be used.

Prevention:Inclinicaltrials,themajorityofpatientshaverequiredonly

asingledoseofSetrontocontrolnauseaandvomitingover24hours.

Uptotwoadditionaldosesof3mgSetronmaybeadministeredwithin

a24-hourperiod.Thereisclinicalexperienceinpatientsreceivingdaily

administrationforuptofiveconsecutivedaysinonecourseoftherapy.

ProphylacticadministrationofSetronshouldbecompletedpriortothe

start of cytostatic therapy.

Treatment:ThesamedoseofSetronshouldbeusedfortreatmentas

prevention.Additionaldosesshouldbeadministeredatleast10minutes

apart.

Maximumdailydosage:Uptothreedosesof3mgSetronmaybe

administeredwithina24-hourperiod.ThemaximumdoseofSetronto

be administered over 24 hours should not exceed 9 mg.

Concomitantuseofdexamethasone:TheefficacyofSetronampoules

Elderly

No special requirements apply to elderly patients.

Children

Prevention:Asingledoseof40mcg/kgbodyweight(upto3mg)should

beadministeredasanintravenousinfusion,dilutedin10to30mlinfusion

fluid(asforadults)andadministeredoverfiveminutes.Administration

should be completed prior to the start of cytostatic therapy.

Treatment:ThesamedoseofSetronasaboveshouldbeusedfortreatment

asprevention.Oneadditionaldoseof40mcg/kgbodyweight(upto3mg)

maybeadministeredwithina24-hourperiod.Thisadditionaldoseshould

be administered at least 10 minutes apart from the initial infusion.

Patients with renal or hepatic impairment

Nospecialrequirementsapplytothosepatientswithrenalorhepatic

impairment.

Contraindications

Hypersensitivity to granisetron, related substances or the excipients.

Special warnings and precautions for use

AsSetronmayreducelowerbowelmotility,patientswithsignsofsub-

acuteintestinalobstructionshouldbemonitoredfollowingadministration

of Setron.

Nospecialprecautionsarerequiredfortheelderlyorrenallyorhepatically

impaired patient.

Asforother5-HT

antagonists,casesofECGmodificationsincludingQT

prolongationhavebeenreportedwithgranisetron.TheseECGchanges

withgranisetronwereminorandgenerallynotofclinicalsignificance,

specificallywithnoevidenceofproarrhythmia.However,inpatientswith

pre-existingarrhythmiasorcardiacconductiondisorders,thismightlead

toclinicalconsequences.Therefore,cautionshouldbeexercisedinpatients

withcardiacco-morbidities,oncardio-toxicchemotherapyand/orwith

concomitant electrolyte abnormalities.

Drug interactions

Instudiesinhealthysubjects,noevidenceofanyinteractionhasbeen

indicatedbetweenSetronandcimetidineorlorazepam.Noevidenceof

drug interactions has been observed in clinical studies conducted.

Asforother5-HT

antagonists,casesofECGmodificationsincludingQT

prolongationhavebeenreportedwithgranisetron.TheseECGchanges

withgranisetronwereminorandgenerallynotofclinicalsignificance,

specificallywithnoevidenceofproarrhythmia.However,inpatients

concurrentlytreatedwithdrugsknowntoprolongQTintervaland/orare

arrhythmogenic, this may lead to clinical consequences.

Pregnancy and lactation

Whilstanimalstudieshaveshownnoteratogeniceffects,thereisno

experienceofSetroninhumanpregnancy.Therefore,Setronshouldnot

beadministeredtowomenwhoarepregnantunlesstherearecompelling

clinicalreasons.TherearenodataontheexcretionofSetroninbreastmilk.

Breast feeding should therefore be discontinued during therapy.

Effects on ability to drive and use machines

TherehasbeennoevidencefromhumanstudiesthatSetronhasany

adverse effect on alertness.

Undesirable effects

Setronhasbeengenerallywelltoleratedinhumanstudies.Asreported

withotherdrugsofthisclass,headacheandconstipationhavebeenthe

mostfrequentlynotedadverseevents,butthemajorityhavebeenmildto

moderateinnature.Rarecasesofhypersensitivityreaction,occasionally

severe(e.g.anaphylaxis)havebeenreported.Otherallergicreactions

includingminorskinrasheshavealsobeenreported.Inclinicaltrials,

transientincreasesinhepatictransaminases,generallywithinthenormal

range, have been seen.

Dystoniasanddyskinesiashavebeenreportedwithmedicinesinthe5-HT

antagonist class. Such events have been reported rarely with Setron.

Asforother5-HT

antagonists,casesofECGmodificationsincludingQT

prolongationhavebeenreportedwithgranisetron.TheseECGchangeswith

granisetronwereminorandgenerallynotofclinicalsignificance,specifically

withnoevidenceofproarrhythmia(seesectionsSpecialWarningsand

Precautions for Use and Drug Interactions).

Overdosage

ThereisnospecificantidoteforSetron.Inthecaseofoverdosage,

symptomatictreatmentshouldbegiven.Onepatienthasreceived30mg

ofSetronintravenously.Thepatientreportedaslightheadachebutno

other sequelae were observed.

Clinical pharmacology

Pharmacodynamic properties

Granisetronisapotentandhighlyselective5-hydroxytryptamine(5-HT

)

receptorantagonistwithanti-emeticactivity.Radioligandbindingstudies

havedemonstratedthatSetronhasnegligibleaffinityforotherreceptor

types including 5-HT and dopamine D

binding sites.

Setroniseffectiveintravenously,eitherprophylacticallyorbyintervention,in

abolishingtheretchingandvomitingevokedbyadministrationofcytostatic

drugs or by whole body X - irradiation.

Pharmacokinetic properties

Distribution

Setronisextensivelydistributed,withameanvolumeofdistributionof

approximately 3 L/kg; plasma protein binding is approximately 65%.

Biotransformation

BiotransformationpathwaysinvolveN-demethylationandaromaticring

oxidation followed by conjugation.

Elimination

Clearanceispredominantlybyhepaticmetabolism.Urinaryexcretion

ofunchangedSetronaverages12%ofdosewhilstthatofmetabolites

amountstoabout47%ofdose.Theremainderisexcretedinfaecesas

metabolites.Meanplasmahalf-lifeinpatientsisapproximatelyninehours,

Characteristics in patients

TheplasmaconcentrationofSetronisnotclearlycorrelatedwithanti-

emeticefficacy.ClinicalbenefitmaybeconferredevenwhenSetronis

not detectable in plasma.

Inelderlysubjectsaftersingleintravenousdoses,pharmacokinetic

parameterswerewithintherangefornon-elderlysubjects.Inpatientswith

severerenalfailure,dataindicatethatpharmacokineticparametersaftera

singleintravenousdosearegenerallysimilartothoseinnormalsubjects.

Inpatientswithhepaticimpairmentduetoneoplasticliverinvolvement,

totalplasmaclearanceofanintravenousdosewasapproximatelyhalved

comparedtopatientswithouthepaticinvolvement.Despitethesechanges,

no dosage adjustment is necessary.

Preclinical safety data

Datafromtwo-yearcarcinogenicitystudieshaveshownanincreasein

hepatocellularcarcinomaand/oradenomainratsandmiceofbothsexes

given50mg/kg(ratdosagereducedto25mg/kg/dayatweek59).Increases

inhepatocellularneoplasiawerealsodetectedat5mg/kginmalerats.

Inbothspecies,drug-inducedeffects(hepatocellularneoplasia)werenot

observed in the low-dose group (1 mg/kg).

Inseveralinvitroandinvivoassays,Setronwasshowntobenon-genotoxic

in mammalian cells.

Pharmaceutical precautions

Ampoulesremovedfromthepackshouldbeprotectedfromdirectsunlight.

Ideally,intravenousinfusionsofSetronshouldbepreparedatthetimeof

administration.Afterdilution(seeDosageandadministration)theshelf-

lifeis24hourswhenstoredatambienttemperatureinnormalindoor

illuminationprotectedfromdirectlight.Itmustnotbeusedafter24

hours.Asageneralprecaution,Setronshouldnotbemixedinsolution

with other drugs.

Pharmaceutical particulars

Shelf life

1, 5 x 3 ml – 3 years

Storage

Storeinacoolplace,below25°C,protectedfromdirectlight.Donot

freeze.

Perrigo Israel Pharmaceuticals Ltd., Yeruham

TheformatofthisleafletwasdeterminedbytheMinistryofHealth

and its content was checked and approved by it in January 2011.

30200811 29.4.2012