GEMABIN

Main information

  • Trade name:
  • GEMABIN Pdr for Soln for Infusion 1000 Milligram
  • Dosage:
  • 1000 Milligram
  • Pharmaceutical form:
  • Pdr for Soln for Infusion
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • GEMABIN Pdr for Soln for Infusion 1000 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0711/112/002
  • Authorization date:
  • 26-10-2007
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0711/112/002

CaseNo:2059513

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

RowexLtd

Bantry,Co.Cork,Ireland

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Gemabin1000mgPowderforSolutionforInfusion

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom05/03/2009until25/10/2012.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Gemabin1000mgPowderforSolutionforInfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachvialcontains1000mggemcitabine(asgemcitabinehydrochloride).

EachmlofGemabin1000mgPowderforSolutionforInfusioncontains40mggemcitabinewhenreconstitutedin25

Excipient:

Each1000mgvialcontains17.5mg(<1mmol)sodium.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Powderforsolutionforinfusion.

Whitetoslightlyyellowishpowderorcake.

AfterreconstitutionofGemabin200mgPowderforSolutionforInfusionin5mlsterile0.9%sodiumchloridesolution

orreconstitutionofGemabin1000mgPowderforSolutionforInfusionin25mlsterile0.9%sodiumchloridesolution,

ahyperosmoticsolutionisobtainedwithapHofapproximately3.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Gemcitabineisindicatedforthetreatmentoflocallyadvancedormetastaticbladdercancerincombinationwith

cisplatin.

Gemcitabineisindicatedfortreatmentofpatientswithlocallyadvancedormetastaticadenocarcinomaofthepancreas.

Gemcitabine,incombinationwithcisplatinisindicatedasfirstlinetreatmentofpatientswithlocallyadvancedor

metastaticnon-smallcelllungcancer(NSCLC).Gemcitabinemonotherapycanbeconsideredinelderlypatientsor

thosewithperformancestatus2.

Gemcitabineisindicatedforthetreatmentofpatientswithlocallyadvancedormetastaticepithelialovariancarcinoma,

incombinationwithcarboplatin,inpatientswithrelapseddiseasefollowingarecurrence-freeintervalofatleast6

monthsafterplatinum-based,first-linetherapy.

Gemcitabine,incombinationwithpaclitaxel,isindicatedforthetreatmentofpatientswithunresectable,locally

recurrentormetastaticbreastcancerwhohaverelapsedfollowingadjuvant/neoadjuvantchemotherapy.Prior

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4.2Posologyandmethodofadministration

Gemcitabineshouldonlybeprescribedbyaphysicianqualifiedintheuseofanti-cancerchemotherapy.

Recommendedposology

Bladdercancer

Combinationuse

Therecommendeddoseforgemcitabineis1000mg/m 2

,givenby30-minuteinfusion.Thedoseshouldbegivenon

Days1,8and15ofeach28-daycycleincombinationwithcisplatin.Cisplatinisgivenatarecommendeddoseof

70mg/m 2

onDay1followinggemcitabineorday2ofeach28-daycycle.This4-weekcycleisthenrepeated.Dosage

reductionwitheachcycleorwithinacyclemaybeappliedbaseduponthegradeoftoxicityexperiencedbythepatient.

Pancreaticcancer

Therecommendeddoseofgemcitabineis1000mg/m 2

,givenby30-minuteintravenousinfusion.Thisshouldbe

repeatedonceweeklyforupto7weeksfollowedbyaweekofrest.Subsequentcyclesshouldconsistofinjectionsonce

weeklyfor3consecutiveweeksoutofevery4weeks.Dosagereductionwitheachcycleorwithinacyclemaybe

appliedbaseduponthegradeoftoxicityexperiencedbythepatient.

NonsmallCelllungcancer

Monotherapy

Therecommendeddoseofgemcitabineis1000mg/m 2

,givenby30-minuteintravenousinfusion.Thisshouldbe

repeatedonceweeklyfor3weeks,followedbya1-weekrestperiod.This4-weekcycleisthenrepeated.Dosage

reductionwitheachcycleorwithinacyclemaybeappliedbaseduponthegradeoftoxicityexperiencedbythepatient.

Combinationuse

Therecommendeddoseforgemcitabineis1250mg/m 2

bodysurfaceareagivenasa30-minuteintravenousinfusionon

Day1and8ofthetreatmentcycle(21days).Dosagereductionwitheachcycleorwithinacyclemaybeappliedbased

uponthegradeoftoxicityexperiencedbythepatient.Cisplatinhasbeenusedatdosesbetween75-100mg/m2once

every3weeks.

Breastcancer

Combinationuse

Gemcitabineincombinationwithpaclitaxelisrecommendedusingpaclitaxel(175mg/m 2

)administeredonDay1over

approximately3-hoursasanintravenousinfusion,followedbygemcitabine(1250mg/m 2

)asa30-minuteintravenous

infusiononDays1and8ofeach21-daycycle.Dosereductionwitheachcycleorwithinacyclemaybeappliedbased

uponthegradeoftoxicityexperiencedbythepatient.Patientsshouldhaveanabsolutegranulocytecountofatleast

1,500(x10 6

/l)priortoinitiationofgemcitabine+paclitaxelcombination.

Ovariancancer

Combinationuse

Gemcitabineincombinationwithcarboplatinisrecommendedusinggemcitabine1000mg/m 2

administeredonDays1

and8ofeach21-daycycleasa30-minuteintravenousinfusion.Aftergemcitabine,carboplatinwillbegivenonDay1

consistentwithatargetAreaundercurve(AUC)of4.0mg/mlmin.Dosagereductionwitheachcycleorwithinacycle

maybeappliedbaseduponthegradeoftoxicityexperiencedbythepatient.

Monitoringfortoxicityanddosemodificationduetotoxicity

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Periodicphysicalexaminationandchecksofrenalandhepaticfunctionshouldbemadetodetectnonhaematological

toxicity.Dosagereductionwitheachcycleorwithinacyclemaybeappliedbaseduponthegradeoftoxicity

experiencedbythepatient.Ingeneral,forsevere(Grade3or4)nonhaematologicaltoxicity,exceptnausea/vomiting,

therapywithgemcitabineshouldbewithheldordecreaseddependingonthejudgementofthetreatingphysician.Doses

shouldbewithhelduntiltoxicityhasresolvedintheopinionofthephysician.

Forcisplatin,carboplatin,andpaclitaxeldosageadjustmentincombinationtherapy,pleaserefertothecorresponding

SummaryofProductCharacteristics.

Dosemodificationduetohaematologicaltoxicity

Initiationofacycle

Forallindications,thepatientmustbemonitoredbeforeeachdoseforplateletandgranulocytecounts.Patientsshould

haveanabsolutegranulocytecountofatleast1,500(x10 6

/l)andplateletaccountof100,000(x10 6

/l)priortothe

initiationofacycle.

Withinacycle

Dosemodificationsofgemcitabinewithinacycleshouldbeperformedaccordingtothefollowingtables:

*Treatmentomittedwillnotbere-instatedwithinacyclebeforetheabsolutegranulocytecountreachesatleast500

(x10 6

/l)andtheplateletcountreaches50,000(x10 6

/l).

*Treatmentomittedwillnotbere-instatedwithinacycle.Treatmentwillstartonday1ofthenextcycleoncethe

absolutegranulocytecountreachesatleast1,500(x10 6

/l)andtheplateletcountreaches100,000(x10 6

/l).

*Treatmentomittedwillnotbere-instatedwithinacycle.Treatmentwillstartonday1ofthenextcycleoncethe

absolutegranulocytecountreachesatleast1,500(x10 6

/l)andtheplateletcountreaches100,000(x10 6

Dosemodificationofgemcitabinewithinacycleforbladdercancer,NSCLCand

pancreaticcancer,giveninmonotherapyorincombinationwithcisplatin

Absolutegranulocytecount

(x10 6

Plateletcount(x10 6

Percentageofstandarddoseof

Gemcitabine(%)

>1,000 and >100,000 100

500-1,000 or 50,000-100,000 75

<500 or <50,000 Omitdose*

Dosemodificationofgemcitabinewithinacycleforbreastcancer,givenincombination

withpaclitaxel

Absolutegranulocytecount

(x10 6

Plateletcount(x10 6

Percentageofstandarddoseof

Gemcitabine(%)

>1,200 and >75,000 100

1,000-<1,200 or 50,000-75,000 75

700-<1,000 and ≥50,000 50

<700 or <50,000 Omitdose*

Dosemodificationofgemcitabinewithinacycleforovariancancer,givenincombination

withcarboplatin

Absolutegranulocytecount

(x10 6

Plateletcount(x10 6

Percentageofstandarddoseof

Gemcitabine(%)

>1,500 and ≥100,000 100

1000-1,500 or 75,000-100,000 50

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Dosemodificationsduetohaematologicaltoxicityinsubsequentcycles,forallindications

Thegemcitabinedoseshouldbereducedto75%oftheoriginalcycleinitiationdose,inthecaseofthefollowing

haematologicaltoxicities:

Absolutegranulocytecount<500x10 6

/lformorethan5days

Absolutegranulocytecount<100x10 6

/lformorethan3days

Febrileneutropaenia

Platelets<25,000x10 6

Cycledelayofmorethan1weekduetotoxicity

Methodofadministration

Gemcitabineistoleratedwellduringinfusionandmaybeadministeredambulant.Ifextravasationoccurs,generallythe

infusionmustbestoppedimmediatelyandstartedagaininanotherbloodvessel.Thepatientshouldbemonitored

carefullyaftertheadministration.

Forinstructionsonreconstitution,seesection6.6.

Specialpopulations

Patientswithrenalorhepaticimpairment

Gemcitabineshouldbeusedwithcautioninpatientswithhepaticorrenalinsufficiencyasthereisinsufficient

informationfromclinicalstudiestoallowforcleardoserecommendationsforthesepatientpopulations(seesections

4.4and5.2).

Elderlypopulation(>65years)

Gemcitabinehasbeenwelltoleratedinpatientsovertheageof65.Thereisnoevidencetosuggestthatdose

adjustments,otherthanthosealreadyrecommendedforallpatients,arenecessaryintheelderly(seesection5.2).

Paediatricpopulation(<18years)

Gemcitabineisnotrecommendedforuseinchildrenunder18yearsofageduetoinsufficientdataonsafetyand

efficacy.

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients.

Breast-feeding(seesection4.6).

4.4Specialwarningsandprecautionsforuse

Prolongationoftheinfusiontimeandincreaseddosingfrequencyhavebeenshowntoincreasetoxicity.

Haematologicaltoxicity

Gemcitabinecansuppressbonemarrowfunctionasmanifestedbyleucopaenia,thrombocytopaeniaandanaemia.

Patientsreceivinggemcitabineshouldbemonitoredpriortoeachdoseforplatelet,leucocyteandgranulocytecounts.

Suspensionormodificationoftherapyshouldbeconsideredwhendrug-inducedbonemarrowdepressionisdetected

(seesection4.2).However,myelosuppressionisshortlivedandusuallydoesnotresultindosereductionandrarelyin

discontinuation.Peripheralbloodcountsmaycontinuetodeteriorateaftergemcitabineadministrationhasbeenstopped.

Inpatientswithimpairedbonemarrowfunction,thetreatmentshouldbestartedwithcaution.Aswithothercytotoxic

treatments,theriskofcumulativebone-marrowsuppressionmustbeconsideredwhengemcitabinetreatmentisgiven

togetherwithotherchemotherapy.

Hepaticinsufficiency

Administrationofgemcitabineinpatientswithconcurrentlivermetastasesorapre-existingmedicalhistoryof

hepatitis,alcoholismorlivercirrhosismayleadtoexacerbationoftheunderlyinghepaticinsufficiency.

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Gemcitabineshouldbeusedwithcautioninpatientswithhepaticinsufficiencyorwithimpairedrenalfunctionasthere

isinsufficientinformationfromclinicalstudiestoallowcleardoserecommendationforthispatientpopulation(see

section4.2).

Concomitantradiotherapy

Concomitantradiotherapy(giventogetheror ≤7daysapart):Toxicityhasbeenreported(seesection4.5fordetailsand

recommendationsforuse).

Livevaccinations

Yellowfevervaccineandotherliveattenuatedvaccinesarenotrecommendedinpatientstreatedwithgemcitabine(see

section4.5).

Cardiovascular

Duetotheriskofcardiacand/orvasculardisorderswithgemcitabine,particularcautionmustbeexercisedwithpatients

presentingahistoryofcardiovascularevents.

Pulmonary

Pulmonaryeffects,sometimessevere(suchaspulmonaryoedema,interstitialpneumonitisoradultrespiratorydistress

syndrome(ARDS))havebeenreportedinassociationwithgemcitabinetherapy.Theaetiologyoftheseeffectsis

unknown.Ifsucheffectsdevelop,considerationshouldbemadetodiscontinuinggemcitabinetherapy.Earlyuseof

supportivecaremeasuremayhelpamelioratethecondition.

Renal

Clinicalfindingsconsistentwiththehaemolyticuraemicsyndrome(HUS)wererarelyreportedinpatientsreceiving

gemcitabine(seesection4.8).Gemcitabineshouldbediscontinuedatthefirstsignsofanyevidenceof

microangiopathichaemolyticanaemia,suchasrapidlyfallinghaemoglobinwithconcomitantthrombocytopaenia,

elevationofserumbilirubin,serumcreatinine,bloodureanitrogen,orLDH.Renalfailuremaynotbereversiblewith

discontinuationoftherapyanddialysismayberequired.

Fertility

Infertilitystudiesgemcitabinecausedhypospermatogenesisinmalemice(seesection5.3).Therefore,menbeing

treatedwithgemcitabineareadvisednottofatherachildduringandupto6monthsaftertreatmentandtoseekfurther

adviceregardingcryoconservationofspermpriortotreatmentbecauseofthepossibilityofinfertilityduetotherapy

withgemcitabine(seesection4.6).

Sodium

Gemabin,powderforsolutionforinfusion1000mgcontains17.5mg(<1mmol)sodiumpervial.Thisshouldbetaken

intoconsiderationbypatientsonacontrolledsodiumdiet.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Nospecificinteractionstudieshavebeenperformed(seesection5.2).

Radiotherapy

Concurrent(giventogetheror ≤7daysapart)-Toxicityassociatedwiththismultimodalitytherapyisdependenton

manydifferentfactors,includingdoseofgemcitabine,frequencyofgemcitabineadministration,doseofradiation,

radiotherapyplanningtechnique,thetargettissue,andtargetvolume.Pre-clinicalandclinicalstudieshaveshownthat

gemcitabinehasradiosensitisingactivity.Inasingletrial,wheregemcitabineatadoseof1,000mg/m 2

administeredconcurrentlyforupto6consecutiveweekswiththerapeuticthoracicradiationtopatientswithnon-small

celllungcancer,significanttoxicityintheformofsevere,andpotentiallylifethreateningmucositis,especially

oesophagitis,andpneumonitiswasobserved,particularlyinpatientsreceivinglargevolumesofradiotherapy[median

treatmentvolumes4,795cm 3

].Studiesdonesubsequentlyhavesuggestedthatitisfeasibletoadministergemcitabine

atlowerdoseswithconcurrentradiotherapywithpredictabletoxicity,suchasaphaseIIstudyinnon-smallcelllung

cancer,wherethoracicradiationdosesof66Gywereappliedconcomitantlywithanadministrationwithgemcitabine

(600mg/m 2

,fourtimes)andcisplatin(80mg/m 2

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ofgemcitabinewiththerapeuticdosesofradiationhasnotyetbeendeterminedinalltumourtypes.

Non-concurrent(given>7daysapart)-Analysisofthedatadoesnotindicateanyenhancedtoxicitywhengemcitabine

isadministeredmorethan7daysbeforeorafterradiation,otherthanradiationrecall.Datasuggestthatgemcitabinecan

bestartedaftertheacuteeffectsofradiationhaveresolvedoratleastoneweekafterradiation.

Radiationinjuryhasbeenreportedontargetedtissues(e.g.oesophagitis,colitis,andpneumonitis)inassociationwith

bothconcurrentandnon-concurrentuseofgemcitabine.

Others

Yellowfeverandotherliveattenuatedvaccinesarenotrecommendedduetotheriskofsystemic,possiblyfatal,

disease,particularlyinimmunosuppressedpatients.

4.6Pregnancyandlactation

Pregnancy

Therearenoadequatedatafromtheuseofgemcitabineinpregnantwomen.Studiesinanimalshaveshown

reproductivetoxicity(seesection5.3).Basedonresultsfromanimalstudiesandthemechanismofactionof

gemcitabine,thissubstanceshouldnotbeusedduringpregnancyunlessclearlynecessary.Womenshouldbeadvised

nottobecomepregnantduringtreatmentwithgemcitabineandtowarntheirattendingphysicianimmediately,should

thisoccurafterall.

Breast-feeding

Itisnotknownwhethergemcitabineisexcretedinhumanmilkandadverseeffectsonthesucklingchildcannotbe

excluded.Breast-feedingmustbediscontinuedduringgemcitabinetherapy.

Fertility

Infertilitystudiesgemcitabinecausedhypospermatogenesisinmalemice(seesection5.3).Therefore,menbeing

treatedwithgemcitabineareadvisednottofatherachildduringandupto6monthsaftertreatmentandtoseekfurther

adviceregardingcryoconservationofspermpriortotreatmentbecauseofthepossibilityofinfertilityduetotherapy

withgemcitabine.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.However,gemcitabinehas

beenreportedtocausemildtomoderatesomnolence,especiallyincombinationwithalcoholconsumption.Patients

shouldbecautionedagainstdrivingoroperatingmachineryuntilitisestablishedthattheydonotbecomesomnolent.

4.8Undesirableeffects

Themostcommonlyreportedadversedrugreactionsassociatedwithmencitabinetreatmentinclude:nauseawithor

withoutvomiting,raisedlivertransaminases(AST/ALT)andalkalinephosphatase,reportedinapproximately60%of

patients;proteinuriaandhaematuriareportedinapproximately50%patients;dyspnoeareportedin10-40%ofpatients

(highestincidenceinlungcancerpatients);allergicskinrashesoccurinapproximately25%ofpatientsandare

associatedwithitchingin10%ofpatients.

Thefrequencyandseverityoftheadversereactionsareaffectedbythedose,infusionrateandintervalsbetweendoses

(seesection4.4).Dose-limitingadversereactionsarereductionsinthrombocyte,leucocyteandgranulocytecounts(see

section4.2).

Clinicaltrialdata

Frequenciesaredefinedas:Verycommon( ≥1/10),Common(≥1/100to<1/10),Uncommon(≥1/1000to<1/100),Rare

≥1/10,000to<1/1000),VeryRare(<1/10,000).

Thefollowingtableofundesirableeffectsandfrequenciesisbasedondatafromclinicaltrials.Withineachfrequency

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SystemOrganClass Frequencygrouping

Bloodandlymphaticsystem

disorders Verycommon

Leucopaenia(NeutropaeniaGrade3=19.3%;Grade4=6%).Bone-marrow

suppressionisusuallymildtomoderateandmostlyaffectsthegranulocytecount

(seesection4.2)

Thrombocytopaenia

Anaemia

Common

Febrileneutropaenia

Veryrare

Thrombocytosis

Immunesystemdisorders VeryRare

Anaphylactoidreaction

Metabolismandnutrition

disorders Common

Anorexia

Nervoussystemdisorders Common

Headache

Insomnia

Somnolence

Cardiacdisorders Rare

Myocardialinfarct

Vasculardisorders Rare

Hypotension

Respiratory,thoracicand

mediastinaldisorders Verycommon

Dyspnoea–usuallymildandpassesrapidlywithouttreatment

Common

Cough

Rhinitis

Uncommon

Interstitialpneumonitis(seesection4.4)

Bronchospasm–usuallymildandtransientbutmayrequireparenteraltreatment

Gastrointestinaldisorders Verycommon

Vomiting

Nausea

Common

Diarrhoea

Stomatitisandulcerationofthemouth

Constipation

Hepatobiliarydisorders Verycommon

Elevationoflivertransaminases(ASTandALT)andalkalinephosphatase

Common

Increasedbilirubin

Rare

Increasedgamma-glutamyltransferase(GGT)

Skinandsubcutaneoustissue

disorders Verycommon

Allergicskinrashfrequentlyassociatedwithpruritus

Alopecia

Common

Itching

Sweating

Rare

Ulceration

Vesicleandsoreformation

Scaling

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Postmarketingexperience(spontaneousreports)frequencynotknown(can’tbeestimatedfromtheavailable

data)

Nervoussystemdisorders

Cerebrovascularaccident

Cardiacdisorders

Arrythmias,predominantlysupraventricularinnatureHeartfailure

Vasculardisorders

Clinicalsignsofperipheralvasculitisandgangrene

Respiratory,thoracicandmediastinaldisorders

Pulmonaryoedema

Adultrespiratorydistresssyndrome(seesection4.4)

Gastrointestinaldisorders

Ischaemiccolitis

Hepatobiliarydisorders

Serioushepatotoxicity,includingliverfailureanddeath

Skinandsubcutaneoustissuedisorders

Severeskinreactions,includingdesquamationandbullousskineruptions,Lyell’sSyndrome,Steven-Johnson

Syndrome

Renalandurinarydisorders

Renalfailure(seesection4.4)

Haemolyticuraemicsyndrome(seesection4.4)

Injury,poisoningandproceduralcomplications

Radiationrecall

Severeskinreactions,includingdesquamationandbullousskineruptions

Musculoskeletaland

connectivetissuedisorders Common

Backpain

Myalgia

Renalandurinarydisorders VeryCommon

Haematuria

Mildproteinuria

Generaldisordersand

administrationsiteconditions Verycommon

Influenza-likesymptoms-themostcommonsymptomsarefever,headache,

chills,myalgia,astheniaandanorexia.Cough,rhinitis,malaise,perspirationand

sleepingdifficultieshavealsobeenreported.

Oedema/peripheraloedema-includingfacialoedema.Oedemaisusually

reversibleafterstoppingtreatment

Common

Fever

Asthenia

Chills

Rare

Injectionsitereactions-mainlymildinnature

Injury,poisoning,and

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Thefrequencyofgrade3and4haematologicaltoxicities,particularlyneutropaenia,increaseswhengemcitabineis

usedincombinationwithpaclitaxel.However,theincreaseintheseadversereactionsisnotassociatedwithan

increasedincidenceofinfectionsorhaemorrhagicevents.Fatigueandfebrileneutropaeniaoccurmorefrequentlywhen

gemcitabineisusedincombinationwithpaclitaxel.Fatigue,whichisnotassociatedwithanaemia,usuallyresolves

afterthefirstcycle.

*Grade4neutropaenialastingformorethan7daysoccurredin12.6%ofpatientsinthecombinationarmand5.0%of

patientsinthepaclitaxelarm.

Combinationuseinbladdercancer

Grade3and4AdverseEvents

Paclitaxelversusgemcitabinepluspaclitaxel

Number(%)ofPatients

Paclitaxelarm

(N=259) GemcitabineplusPaclitaxelarm

(N=262)

Grade3 Grade4 Grade3 Grade4

Laboratory

Anaemia 5(1.9) 1(0.4) 15(5.7) 3(1.1)

Thrombocytopaenia 0 0 14(5.3) 1(0.4)

Neutropaenia 11(4.2) 17(6.6)* 82(31.3) 45(17.2)*

Non-laboratory

Febrileneutropaenia 3(1.2) 0 12(4.6) 1(0.4)

Fatigue 3(1.2) 1(0.4) 15(5.7) 2(0.8)

Diarrhoea 5(1.9) 0 8(3.1) 0

Motorneuropathy 2(0.8) 0 6(2.3) 1(0.4)

Sensoryneuropathy 9(3.5) 0 14(5.3) 1(0.4)

Grade3and4AdverseEvents

MVACversusGemcitabinepluscisplatin

Number(%)ofPatients

MVAC(methotrexate,vinblastine,

doxorubicinandcisplatin)arm

(N=196) Gemcitabinepluscisplatinarm

(N=200)

Grade3 Grade4 Grade3 Grade4

Laboratory

Anaemia 30(16) 4(2) 47(24) 7(4)

Thrombocytopaenia 15(8) 25(13) 57(29) 57(29)

Non-laboratory

Nauseaandvomiting 37(19) 3(2) 44(22) 0(0)

Diarrhoea 15(8) 1(1) 6(3) 0(0)

Infection 19(10) 10(5) 4(2) 1(1)

Stomatitis 34(18) 8(4) 2(1) 0(0)

Grade3and4AdverseEvents

CarboplatinversusGemcitabinepluscarboplatin

Number(%)ofPatients

Carboplatinarm

(N=174) Gemcitabinepluscarboplatinarm

(N=175)

Grade3 Grade4 Grade3 Grade4

Laboratory

Anaemia 10(5.7) 4(2.3) 39(22.3) 9(5.1)

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Sensoryneuropathywasalsomorefrequentinthecombinationarmthanwithsingleagent

Carboplatin

4.9Overdose

Thereisnoknownantidoteforoverdoseofgemcitabine.Dosesashighas5700mg/m 2

havebeenadministeredby

intravenousinfusionover30-minutesevery2weekswithclinicallyacceptabletoxicity.Intheeventofsuspected

overdose,thepatientshouldbemonitoredwithappropriatebloodcountsandreceivesupportivetherapy,asnecessary.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:pyrimidineanalogue

ATCcode:L01BC05

Cytotoxicactivityincellcultures

Gemcitabineshowssignificantcytotoxiceffectsagainstavarietyofculturedmurineandhumantumourcells.Itsaction

isphase-specificsuchthatgemcitabineprimarilykillscellsthatareundergoingDNAsynthesis(S-phase)and,under

certaincircumstances,blockstheprogressionofcellsatthejunctionoftheG

/Sphaseboundary.Invitro,thecytotoxic

effectofgemcitabineisdependentonbothconcentrationandtime.

Antitumoralactivityinpreclinicalmodels

Inanimaltumourmodels,antitumouralactivityofgemcitabineisschedule-dependent.Whengemcitabineis

administereddaily,highmortalityamongtheanimalsbutminimalantitumouralactivityisobserved.If,however,

gemcitabineisgiveneverythirdorfourthday,itcanbeadministeredinnonlethaldoseswithsubstantialantitumoural

activityagainstabroadspectrumofmousetumours.

Mechanismofaction

Cellularmetabolismandmechanismofaction:Gemcitabine(dFdC),whichisapyrimidineantimetabolite,is

metabolisedintracellularlybynucleosidekinasetotheactivediphosphate(dFdCDP)andtriphosphate(dFdCTP)

nucleosides.ThecytotoxiceffectofgemcitabineisduetoinhibitionofDNAsynthesisbytwomechanismsofactionby

dFdCDPanddFdCTP.First,dFdCDPinhibitsribonucleotidereductase,whichisuniquelyresponsibleforcatalysing

thereactionsthatproducedeoxynucleosidetriphosphates(dCTP)forDNAsynthesis.Inhibitionofthisenzymeby

dFdCDPreducestheconcentrationofdeoxynucleosidesingeneraland,inparticular,dCTP.Second,dFdCTPcompetes

withdCTPforincorporationintoDNA(self-potentiation).

Likewise,asmallamountofgemcitabinemayalsobeincorporatedintoRNA.Thus,thereducedintracellular

concentrationofdCTPpotentiatestheincorporationofdFdCTPintoDNA.DNApolymeraseepsilonlackstheability

toeliminategemcitabineandtorepairthegrowingDNAstrands.AftergemcitabineisincorporatedintoDNA,one

additionalnucleotideisaddedtothegrowingDNAstrands.Afterthisadditionthereisessentiallyacompleteinhibition

infurtherDNAsynthesis(maskedchaintermination).AfterincorporationintoDNA,gemcitabineappearstoinducethe

programmedcelldeathprocessknownasapoptosis.

Clinicaldata

Bladdercancer

Thrombocytopaenia 18(10.3) 2(1.1) 53(30.3) 8(4.6)

Leucopaenia 11(6.3) 1(0.6) 84(48.0) 9(5.1)

Non-laboratory

Haemorrhage 0(0.0) 0(0.0) 3(1.8) (0.0)

Febrileneutropaenia 0(0.0) 0(0.0) 2(1.1) (0.0)

Infectionwithout

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nodifferencebetweenthetwotreatmentarms,gemcitabine/cisplatinversus

methotrexate/vinblastine/adriamycin/cisplatin(MVAC),intermsofmediansurvival(12.8and14.8months

respectively,p=0.547),timetodiseaseprogression(7.4and7.6monthsrespectively,p=0.842)andresponserate

(49.4%and45.7%respectively,p=0.512).However,thecombinationofgemcitabineandcisplatinhadabettertoxicity

profilethanMVAC.

Pancreaticcancer

InarandomisedphaseIIIstudyof126patientswithadvancedormetastaticpancreaticcancer,gemcitabineshoweda

statisticallysignificanthigherclinicalbenefitresponseratethan5-fluorouracil(23.8%and4.8%respectively,

p=0.0022).Also,astatisticallysignificantprolongationofthetimetoprogressionfrom0.9to2.3months(log-rank

p<0.0002)andastatisticallysignificantprolongationofmediansurvivalfrom4.4to5.7months(log-rankp<0.0024)

wasobservedinpatientstreatedwithgemcitabinecomparedtopatientstreatedwith5-fluorouracil.

Nonsmallcelllungcancer

InarandomisedphaseIIIstudyof522patientswithinoperable,locallyadvancedormetastaticNSCLC,gemcitabinein

combinationwithcisplatinshowedastatisticallysignificanthigherresponseratethancisplatinalone(31.0%and

12.0%,respectively,p<0.0001).Astatisticallysignificantprolongationofthetimetoprogression,from3.7to5.6

months(log-rankp<0.0012)andastatisticallysignificantprolongationofmediansurvivalfrom7.6monthsto9.1

months(log-rankp<0.004)wasobservedinpatientstreatedwithgemcitabine/cisplatincomparedtopatientstreated

withcisplatin.InanotherrandomisedphaseIIIstudyof135patientswithstageIIIBorIVNSCLC,acombinationof

gemcitabineandcisplatinshowedastatisticallysignificanthigherresponseratethanacombinationofcisplatinand

etoposide(40.6%and21.2%,respectively,p=0.025).Astatisticallysignificantprolongationofthetimetoprogression,

from4.3to6.9months(p=0.014)wasobservedinpatientstreatedwithgemcitabine/cisplatincomparedtopatients

treatedwithetoposide/cisplatin.Inbothstudiesitwasfoundthattolerabilitywassimilarinthetwotreatmentarms.

Ovariancarcinoma

InarandomisedphaseIIIstudy,356patientswithadvancedepithelialovariancarcinomawhohadrelapsedatleast6

monthsaftercompletingplatinumbasedtherapywererandomisedtotherapywithgemcitabineandcarboplatin(GCb),

orcarboplatin(Cb).Astatisticallysignificantprolongationofthetimetoprogressionofdisease,from5.8to8.6months

(log-rankp=0.0038)wasobservedinthepatientstreatedwithGCbcomparedtopatientstreatedwithCb.Differences

inresponserateof47.2%intheGCbarmversus30.9%intheCbarm(p=0.0016)andmediansurvival18months

(GCb)versus17.3(Cb)(p=0.73)favouredtheGCbarm.

Breastcancer

InarandomisedphaseIIIstudyof529patientswithinoperable,locallyrecurrentormetastaticbreastcancerwith

relapseafteradjuvant/neoadjuvantchemotherapy,gemcitabineincombinationwithpaclitaxelshowedastatistically

significantprolongationoftimetodocumenteddiseaseprogressionfrom3.98to6.14months(log-rankp=0.0002)in

patientstreatedwithgemcitabine/paclitaxelcomparedtopatientstreatedwithpaclitaxel.After377deaths,theoverall

survivalwas18.6monthsversus15.8months(logrankp=0.0489,HR0.82)inpatientstreatedwith

gemcitabine/paclitaxelcomparedtopatientstreatedwithpaclitaxelandtheoverallresponseratewas41.4%and26.2%

respectively(p=0.0002).

5.2Pharmacokineticproperties

Thepharmacokineticsofgemcitabinehavebeenexaminedin353patientsinsevenstudies.The121womenand232

menrangedinagefrom29to79years.Ofthesepatients,approximately45%hadnon-smallcelllungcancerand35%

werediagnosedwithpancreaticcancer.Thefollowingpharmacokineticparameterswereobtainedfordosesranging

from500to2,592mg/m 2

thatwereinfusedfrom0.4to1.2hours.

Peakplasmaconcentrations(obtainedwithin5minutesoftheendoftheinfusion)were3.2to

45.5µg/ml.Plasmaconcentrationsoftheparentcompoundfollowingadoseof1,000mg/m 2

/30-minutesaregreater

than5µg/mlforapproximately30-minutesaftertheendoftheinfusion,andgreaterthan0.4µg/mlforanadditional

hour.

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Thevolumeofdistributionofthecentralcompartmentwas12.4l/m 2

forwomenand17.5l/m 2

formen(inter-

individualvariabilitywas91.9%).Thevolumeofdistributionoftheperipheralcompartmentwas47.4l/m 2

.The

volumeoftheperipheralcompartmentwasnotsensitivetogender.Theplasmaproteinbindingwasconsideredtobe

negligible.Half-life:Thisrangedfrom42to94minutesdependingonageandgender.Fortherecommendeddosing

schedule,gemcitabineeliminationshouldbevirtuallycompletewithin5to11hoursofthestartoftheinfusion.

Gemcitabinedoesnotaccumulatewhenadministeredonceweekly.

Metabolism

Gemcitabineisrapidlymetabolisedbycytidinedeaminaseintheliver,kidney,bloodandothertissues.Intracellular

metabolismofgemcitabineproducesthegemcitabinemono,diandtriphosphates(dFdCMP,dFdCDPanddFdCTP)of

whichdFdCDPanddFdCTPareconsideredactive.Theseintracellularmetaboliteshavenotbeendetectedinplasmaor

urine.Theprimarymetabolite,2'-deoxy-2',2'-difluorouridine(dFdU),isnotactiveandisfoundinplasmaandurine.

Excretion

Systemicclearancerangedfrom29.2l/hr/m 2

to92.2l/hr/m 2

dependingongenderandage(inter-individualvariability

was52.2%).Clearanceforwomenisapproximately25%lowerthanthevaluesformen.Althoughrapid,clearancefor

bothmenandwomenappearstodecreasewithage.Fortherecommendedgemcitabinedoseof1000mg/m 2

givenasa

30-minuteinfusion,lowerclearancevaluesforwomenandmenshouldnotnecessitateadecreaseinthegemcitabine

dose.Urinaryexcretion:Lessthan10%isexcretedasunchangeddrug.Renalclearancewas2to7l/hr/m 2

Duringtheweekfollowingadministration,92to98%ofthedoseofgemcitabineadministeredisrecovered,99%inthe

urine,mainlyintheformofdFdUand1%ofthedoseisexcretedinfaeces.

dFdCTPkinetics

Thismetabolitecanbefoundinperipheralbloodmononuclearcellsandtheinformationbelowreferstothesecells.

Intracellularconcentrationsincreaseinproportiontogemcitabinedosesof35-350mg/m 2

/30-minutes,whichgive

steadystateconcentrationsof0.4-5µg/ml.Atgemcitabineplasmaconcentrationsabove5µg/ml,dFdCTPlevelsdonot

increase,suggestingthattheformationissaturableinthesecells.

Half-lifeofterminalelimination:0.7-12hours.

dFdUkinetics

Peakplasmaconcentrations(3-15minutesafterendof30-minuteinfusion,1000mg/m 2

):28-52µg/ml.Trough

concentrationfollowingonceweeklydosing:0.07-1.12µg/ml,withnoapparentaccumulation.Triphasicplasma

concentrationversustimecurve,meanhalf-lifeofterminalphase–65hours(range33-84hr).

FormationofdFdUfromparentcompound:91%-98%.

Meanvolumeofdistributionofcentralcompartment:18l/m2(range11-22l/m 2

Meansteadystatevolumeofdistribution(Vss):150l/m 2

(range96-228l/m 2

Tissuedistribution:Extensive.

Meanapparentclearance:2.5l/hr/m 2

(range1-4l/hr/m 2

Urinaryexcretion:All.

Gemcitabineandpaclitaxelcombinationtherapy

Combinationtherapydidnotalterthepharmacokineticsofeithergemcitabineorpaclitaxel.

Gemcitabineandcarboplatincombinationtherapy

Whengivenincombinationwithcarboplatinthepharmacokineticsofgemcitabinewerenotaltered.

Renalimpairment

Mildtomoderaterenalinsufficiency(GFRfrom30ml/minto80ml/min)hasnoconsistent,significanteffecton

gemcitabinepharmacokinetics.

5.3Preclinicalsafetydata

Inrepeat-dosestudiesofupto6monthsindurationinmiceanddogs,theprincipalfindingwasscheduleanddose-

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Gemcitabineismutagenicinaninvitromutationtestandaninvivobonemarrowmicronucleustest.Longtermanimal

studiesevaluatingthecarcinogenicpotentialhavenotbeenperformed.

Infertilitystudies,gemcitabinecausedreversiblehypospermatogenesisinmalemice.Noeffectonthefertilityof

femaleshasbeendetected.

Evaluationofexperimentalanimalstudieshasshownreproductivetoxicitye.g.birthdefectsandothereffectsonthe

developmentoftheembryoorfoetus,thecourseofgestationorperi-andpostnataldevelopment.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Mannitol(E421)

Sodiumacetatetrihydrate

Sodiumhydroxide(forpHadjustment)

Hydrochloricacid(forpHadjustment)

6.2Incompatibilities

Thismedicinalproductmustnotbemixedwithothermedicinalproductsexceptthosementionedinsection6.6.

6.3ShelfLife

24months.

Reconstitutedsolution:

Chemicalandphysicalin-usestabilityhasbeendemonstratedfor24hoursat25°C.

Fromamicrobiologicalpointofview,theproductshouldbeusedimmediatelyunlessreconstitutionhastakenplacein

controlledandvalidatedasepticconditions.

Ifnotusedimmediately,in-usestoragetimesandconditionsaretheresponsibilityoftheuser.

6.4Specialprecautionsforstorage

Donotstoreabove30 °

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Reconstitutedsolution:

Donotstoreabove25 °

Donotrefrigerateorfreezeascrystallisationmayoccur.

Forstorageconditionsofthereconstitutedmedicinalproduct,seesection6.3.

6.5Natureandcontentsofcontainer

Gemabin1000mgPowderforSolutionforInfusion:50mlvialofcolourlesstypeIglasswithgreyrubber

lyophilisationstopperandblueflip-offaluminiumcap;

Packsizes:1,5and10vials.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Handling

Thenormalsafetyprecautionsforcytostaticagentsmustbeobservedwhenpreparinganddisposingoftheinfusion

solution.Handlingofthesolutionforinfusionshouldbedoneinasafetyboxandprotectivecoatsandglovesshouldbe

used.Ifnosafetyboxisavailable,theequipmentshouldbesupplementedwithamaskandprotectiveglasses.Ifthe

preparationcomesintocontactwiththeeyes,thismaycauseseriousirritation.Theeyesshouldberinsedimmediately

andthoroughlywithwater.Ifthereislastingirritation,adoctorshouldbeconsulted.Ifthesolutionisspilledonthe

skin,rinsethoroughlywithwater.

Instructionsforreconstitution(andfurtherdilution,ifperformed)

Theonlyapproveddiluentforreconstitutionofgemcitabinesterilepowderissodiumchloride9mg/ml(0.9%)solution

forinjection(withoutpreservative).Duetosolubilityconsiderations,themaximumconcentrationforgemcitabineupon

reconstitutionis40mg/ml.Reconstitutionatconcentrationsgreaterthan40mg/mlmayresultinincompletedissolution

andshouldbeavoided.

Useaseptictechniqueduringthereconstitutionandanyfurtherdilutionofgemcitabineforintravenousinfusion

administration.

Toreconstitute,add5mlofsterilesodiumchloride9mg/ml(0.9%)solutionforinjection,withoutpreservative,

tothe200mgvialor25mlsterilesodiumchloride9mg/ml(0.9%)solutionforinjection,withoutpreservative,

tothe1000mgvial.Thetotalvolumeafterreconstitutionis5.26ml(200mgvial)or26.3ml(1000mgvial)

respectively.Thisyieldsagemcitabineconcentrationof38mg/ml,whichincludesaccountingforthe

displacementvolumeofthelyophilisedpowder.Shaketodissolve.Furtherdilutionwithsterilesodiumchloride

9mg/ml(0.9%)solutionforinjection,withoutpreservativecanbedone.Reconstitutedsolutionisaclear

colourlesstolightstraw-colouredsolution.

Parenteralmedicinalproductsshouldbeinspectedvisuallyforparticulatematteranddiscolourationpriorto

administration.Ifparticulatematterisobserved,donotadminister.

Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

RowexLtd

Bantry

Co.Cork

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8MARKETINGAUTHORISATIONNUMBER

PA711/112/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Thedateoffirstauthorisation:26thOctober2007

10DATEOFREVISIONOFTHETEXT

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