GEMCITABINE

Main information

  • Trade name:
  • GEMCITABINE Pdr for Soln for Infusion 1 Grams
  • Dosage:
  • 1 Grams
  • Pharmaceutical form:
  • Pdr for Soln for Infusion
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • GEMCITABINE Pdr for Soln for Infusion 1 Grams
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0437/058/002
  • Authorization date:
  • 09-11-2007
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Gemcitabine1gPowderforSolutionforInfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Onevialcontainsgemcitabinehydrochloride,equivalentto1ggemcitabine.

Afterreconstitution,thesolutioncontains38mg/mlgemcitabine(ashydrochloride).

Excipients

Each1gvialcontainsapproximately17.5mg(0.75mmol)sodium.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Powderforsolutionforinfusion(powderforinfusion)

Whitetooff-white plugorpowder.

4CLINICALPARTICULARS

4.1TherapeuticIndications

BladderCancer:

Locallyadvancedormetastaticbladdercancer,incombinationwithcisplatin.

PancreaticCancer:

Locallyadvancedormetastaticadenocarcinomaofthepancreas.

Non-SmallCellLungCancer:

First-linetreatmentofpatientswithlocallyadvancedormetastaticnon-smallcelllungcancer,incombinationwith

cisplatin.Gemcitabinemonotherapycanbeconsideredinelderlypatientsorthosewithperformancestatus2.

OvarianCancer:

Locallyadvancedormetastaticepithelialovariancarcinoma,incombinationwithcarboplatin,inpatientswithrelapsed

diseasefollowingarecurrence-freeintervalofatleast6monthsafterplatinum-based,firstlinetherapy.

BreastCancer:

Unresectable,locallyrecurrentormetastaticbreastcancer,incombinationwithpaclitaxel,inpatientsexperiencinga

relapseafteradjuvant/neoadjuvantchemotherapy.Theprecedingchemotherapyshouldhaveincludedananthracycline,

unlessclinicallycontraindicated.

4.2Posologyandmethodofadministration

Forintravenousinfusion,followingreconstitution.Uponreconstitutionacolourlessorslightlyyellowsolutionis

produced.

Gemcitabineshouldonlybeprescribedbyaphysicianqualifiedintheuseofanti-cancerchemotherapy.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/02/2012 CRN 2102301 page number: 1

Adults:Therecommendeddoseforgemcitabineis1000mg/m 2

,givenasa30minuteinfusion.Thedoseshouldbe

givenondays1,8,and15ofeach28daycycleincombinationwithcisplatin.Cisplatinisgivenatarecommended

doseof70mg/m 2

onday1followinggemcitabine,orday2ofeach28daycycle.Thisfourweekcycleisthen

repeated.Dosagereductionwitheachcycleorwithinacyclemaybeapplied,basedupontheamountoftoxicity

experiencedbythepatient.

PancreaticCancer:

Adults:Therecommendeddoseofgemcitabineis1000mg/m 2

,givenby30minuteintravenousinfusion.Thisshould

berepeatedonceweeklyforupto7weeks,followedbyaoneweekrestperiod.Subsequentcyclesshouldconsistof

gemcitabineinfusionsonceweeklyfor3consecutiveweeksoutofeveryfourweeks.Dosagereductionwitheachcycle

orwithinacyclemaybeapplied,basedupontheamountoftoxicityexperiencedbythepatient.

Non-smallcelllungcancer(monotherapy):

Adults:Therecommendeddoseofgemcitabineis1000mg/m 2

,givenby30minuteintravenousinfusion.Thisshould

berepeatedonceweeklyforthreeweeks,followedbyaoneweekrestperiod.Thisfour-weekcycleisthenrepeated.

Dosagereductionwitheachcycleorwithinacyclemaybeapplied,basedupontheamountoftoxicityexperiencedby

thepatient.

Non-smallcelllungcancer(combinationtherapy):

Adults:Therecommendeddoseofgemcitabineis1250mg/m 2

,givenby30minuteintravenousinfusion,ondays1

and8ofeach21daycycle.Dosagereductionwitheachcycleorwithinacyclemaybeapplied,basedupontheamount

oftoxicityexperiencedbythepatient.

Cisplatinhasbeenusedatdosesbetween75-100mg/m 2

onceevery3weeks.

Ovariancancer(combinationtherapy):

Therecommendeddoseofgemcitabine,whenusedincombinationwithcarboplatin,is1000mg/m 2

,givenby30

minuteintravenousinfusionondays1and8ofeach21daycycle.Aftergemcitabine,carboplatinwillbegivenonday

1,consistentwithatargetAreaUnderCurve(AUC)of4.0mg/ml/min.Dosagereductionwitheachcycleorwithina

cyclemaybeapplied,basedupontheamountoftoxicityexperiencedbythepatient.

Breastcancer(combinationtherapy):

Adults:Itisrecommendedthatgemcitabineisusedtogetherwithpaclitaxelaccordingtothefollowingprocedure:

Paclitaxel(175mg/m 2

)isintravenouslyinfusedover3hoursonday1,followedbygemcitabine(1250mg/m 2

intravenouslyinfusedfor30minutesondays1and8ofeach21daytreatmentcycle.Dosagereductionwitheachcycle

orwithinacyclemaybeappliedbasedupontheamountoftoxicityexperiencedbythepatient.Theabsolute

granulocytecountshouldbeatleast1.5x10 9

/lbeforetreatmentwiththegemcitabine+paclitaxelcombination.

Monitoringfortoxicityanddosemodificationduetotoxicity

Dosageadjustmentduetononhaematologicaltoxicity:

Periodicphysicalexaminationandchecksofrenalandhepaticfunctionshouldbemadetodetectnon-haematological

toxicity.Dosagereductionwitheachcycleorwithinacyclemaybeapplied,basedupontheamountoftoxicity

experiencedbythepatient.Ingeneral,forsevere(Grade3or4)non-haematologicaltoxicity,exceptnausea/vomiting,

therapywithgemcitabineshouldbewithheldordecreaseddependingonthejudgementofthetreatingphysician.

Dosesshouldbewithhelduntiltoxicityhasbeenresolved.

Forcisplatin,carboplatin,andpaclitaxeldosageadjustmentincombinationtherapy,pleaserefertothecorresponding

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/02/2012 CRN 2102301 page number: 2

Dosageadjustmentinthepresenceofhaematologicaltoxicity:

Initiationofacycle

Forallindications,patientsmustbemonitoredbeforeeachdoseforplateletandgranulocytecounts.Patientsshould

haveanabsolutegranulocytecountofatleast1,500(x10 6

/l)andaplateletcountof100,000(x10 6

/l)priortothe

administrationofacycle.

Withinacycle

Dosemodificationsofgemcitabinewithinacycleshouldbeperformedaccordingtothefollowingtables:

*Withheldtreatmentwillnotbereinstatedwithinacyclebeforetheabsolutegranulocytecountreachesatleast0.5(x

/l)andtheplateletcountreaches50(x10 9

/l).

*Withheldtreatmentwillnotbereinstatedwithinacycle.Treatmentwillstartonday1ofthenextcycleoncethe

absolutegranulocytecountreachesatleast1.5(x10 9

/l)andtheplateletcountreaches100(x10 9

*Withheldtreatmentwillnotbereinstatedwithinacycle.Treatmentwillstartonday1ofthenextcycleoncethe

absolutegranulocytecountreachesatleast1.5(x10 9

/l)andtheplateletcountreaches100(x10 9

/l).

Doseadjustmentduetohaematologicaltoxicityinsubsequentcycles,forallindications

Thegemcitabinedoseshouldbereducedto75%oftheoriginalcycleinitiationdose,inthecaseofthefollowing

haematologicaltoxicities:

Absolutegranulocytecount<0.5x10 9

/lformorethan5days

Absolutegranulocytecount<0.1x10 9

/lformorethan3days

Febrileneutropaenia

Platelets<25x10 9

Dosemodificationofgemcitabinewithinacycleforbladdercancer,pancreatic

cancer,andNSCLC,giveninmonotherapyorincombinationwithcisplatin

AbsoluteGranulocyteCount

(x10 9

/l) PlateletCount

(x10 9

/l) %of

TotalDose

>1 and >100 100

0.5-1 or 50-100 75

<0.5 or <50 Withhold*

Dosemodificationofgemcitabinewithinacycleforovariancancer,givenin

combinationwithcarboplatin

AbsoluteGranulocyteCount

(x10 9

/l) PlateletCount

(x10 9

/l) %of

TotalDose

>1.5 and >100 100

1-1.5 or 75-100 50

<1 or <75 Withhold*

Dosemodificationofgemcitabinewithinacycleforbreastcancer,givenin

combinationwithpaclitaxel

AbsoluteGranulocyteCount

(x10 9

/l) PlateletCount

(x10 9

/l) %of

TotalDose

>75 100

1-<1.2 or 50-75 75

0.7-<1 and 50 50

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/02/2012 CRN 2102301 page number: 3

Methodofadministration

Gemcitabineistoleratedwellduringinfusionandmaybeadministeredambulant.Ifextravasationoccurs,generallythe

infusionmustbestoppedimmediatelyandstartedagaininanotherbloodvessel.Thepatientshouldbemonitored

carefullyaftertheadministration.

Forinstructionsonreconstitution,seesection6.6

SpecialPopulations

Patientswithhepaticorrenalimpairment:

Gemcitabineshouldbeusedwithcautioninpatientswithhepaticorrenalinsufficiencyasthereisinsufficient

informationfromclinicalstudiestoallowforcleardoserecommendationsforthesepatientpopulations(seesections

4.4and5.2).

Elderlypopulation(>65years):

Gemcitabinehasbeenwelltoleratedinpatientsovertheageof65.Thereisnoevidencetosuggestthatdose

adjustments,otherthanthosealreadyrecommendedforallpatients,arenecessaryintheelderly(seesection5.2).

Paediatricpopulation(<18years):

Gemcitabineisnotrecommendedforuseinchildrenunder18yearsofageduetoinsufficientdataonsafetyand

efficacy.

4.3Contraindications

Hypersensitivitytogemcitabineortoanyoftheexcipients

Breast-feeding(seesection4.6)

4.4Specialwarningsandprecautionsforuse

Prolongationoftheinfusiontimeandincreaseddosingfrequencyhavebeenshowntoincreasetoxicity.

Haematologicaltoxicity

Gemcitabinecansuppressbonemarrowfunctionasmanifestedbyleucopaenia,thrombocytopaenia,andanaemia.

Patientsreceivinggemcitabineshouldbemonitoredpriortoeachdoseforplatelet,leucocyteandgranulocytecounts.

Suspensionormodificationoftherapyshouldbeconsideredwhendrug-inducedbonemarrowdepressionisdetected

(seesection4.2).However,myelosuppressionisshortlivedandusuallydoesnotresultindosereductionandrarelyin

discontinuation.

Peripheralbloodcountsmaycontinuetodeteriorateaftergemcitabineadministrationhasbeen

stopped.Inpatientswithimpairedbonemarrowfunction,thetreatmentshouldbestartedwithcaution.Aswithother

cytotoxictreatments,theriskofcumulativebone-marrowsuppressionmustbeconsideredwhengemcitabinetreatment

isgiventogetherwithotherchemotherapy.

Hepaticinsufficiency

Administrationofgemcitabinetopatientswithconcurrentlivermetastasesorapre-existingmedicalhistoryof

hepatitis,alcoholismorcirrhosisofthelivermayresultinexacerbationoftheunderlyingliverinsufficiency.

Laboratoryevaluationofrenalandhepaticfunction(includingvirologicaltests)shouldbeperformedperiodically.

Gemcitabineshouldbeusedwithcautioninpatientswithhepaticinsufficiencyorwithimpairedrenalfunctionasthere

isinsufficientinformationfromclinicalstudiestoallowcleardoserecommendationforthispatientpopulation(see

section4.2).

Concomitantradiotherapy

Concomitantradiotherapy(giventogetheror7daysapart):Toxicityhasbeenreported(seesection4.5fordetailsand

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/02/2012 CRN 2102301 page number: 4

Livevaccinations

Yellowfevervaccineandotherliveattenuatedvaccinesarenotrecommendedinpatientstreatedwithgemcitabine(see

section4.5).

Cardiovascular

Duetotheriskofcardiacand/orvasculardisorderswithgemcitabine,particularcautionmustbeexercisedwithpatients

presentingahistoryofcardiovascularevents.

Pulmonary

Pulmonaryeffects,sometimessevere(suchaspulmonaryoedema,interstitialpneumonitis,oradultrespiratorydistress

syndrome(ARDS),havebeenreportedinassociationwithgemcitabinetherapy.Theaetiologyoftheseeffectsis

unknown.Ifsucheffectsdevelop,considerationshouldbegiventodiscontinuinggemcitabinetherapy.Earlyuseof

supportivecaremeasuresmayhelpamelioratethecondition.

Renal

Clinicalfindingsconsistentwiththehaemolyticuraemicsyndrome(HUS)wererarelyreportedinpatientsreceiving

gemcitabine(seesection4.8).Treatmentshouldbediscontinuedatthefirstsignsofanyevidenceofmicro-angiopathic

haemolyticanaemia,suchasrapidlyfallinghaemoglobinlevelswithconcurrentthrombocytopenia,elevationofserum

bilirubin,serumcreatinine,bloodureanitrogenorlactatedehydrogenase(LDH).Renalfailuremaynotbereversible

withdiscontinuationoftherapy,anddialysismayberequired.

Fertility

Infertilitystudies,gemcitabinecausedhypospermatogenesisinmalemice(seesection5.3).Therefore,menbeing

treatedwithgemcitabineareadvisednottofatherachildduringandupto6monthsaftertreatmentandtoseekfurther

adviceregardingcryoconservationofspermpriortotreatmentbecauseofthepossibilityofinfertilityduetotherapy

withgemcitabine(seesection4.6).

Sodium

Gemcitabine1gcontains17.5mg(0.75mmol)sodiumpervial.Thisshouldbetakenintoconsiderationbypatientson

asodium-controlleddiet.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Nospecificinteractionstudieshavebeenperformed(seesection5.2)

Radiotherapy

Concurrent(giventogetheror7daysapart)-Toxicityassociatedwiththismultimodalitytherapyisdependenton

manydifferentfactors,includingdoseofgemcitabine,frequencyofgemcitabineadministration,doseofradiation,

radiotherapyplanningtechnique,thetargettissue,andtargetvolume.

Pre-clinicalandclinicalstudieshaveshownthatgemcitabinehasradiosensitisingactivity.Inasingletrial,where

gemcitabineatadoseof1,000mg/m 2

wasadministeredconcurrentlyforupto6consecutiveweekswiththerapeutic

thoracicradiationtopatientswithnon-smallcelllungcancer,significanttoxicityintheformofsevere,andpotentially

lifethreateningmucositis,especiallyoesophagitis,andpneumonitiswasobserved,particularlyinpatientsreceiving

largevolumesofradiotherapy[mediantreatmentvolumes4,795cm 3

].Studiesdonesubsequentlyhavesuggestedthatit

isfeasibletoadministergemcitabineatlowerdoseswithconcurrentradiotherapywithpredictabletoxicity,suchasa

phaseIIstudyinnon-smallcelllungcancer,wherethoracicradiationdosesof66Gywereappliedconcomitantlywith

anadministrationwithgemcitabine(600mg/m 2

,fourtimes)andcisplatin(80mg/m 2

twice)during6weeks.The

optimumregimenforsafeadministrationofgemcitabinewiththerapeuticdosesofradiationhasnotyetbeen

determinedinalltumourtypes.

Non-concurrent(given>7daysapart)-Availableinformationdoesnotindicateanyenhancedtoxicitywhen

gemcitabineisadministeredmorethan7daysbeforeorafterradiation,otherthanradiationrecall.Datasuggestthat

gemcitabinecanbestartedaftertheacuteeffectsofradiationhaveresolvedoratleastoneweekafterradiation.

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

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/02/2012 CRN 2102301 page number: 5

Others

Yellowfeverandotherliveattenuatedvaccinesarenotrecommendedduetotheriskofsystemic,possiblyfatal,

disease,particularlyinimmunosuppressedpatients.

4.6Fertility,pregnancyandlactation

Pregnancy:

Therearenoadequatedatafromtheuseofgemcitabineinpregnantpatients.Studiesinanimalshaveshown

reproductivetoxicity(seesection5.3).Basedonresultsfromanimalstudiesandthemechanismofactionof

gemcitabine,thissubstanceshouldnotbeusedduringpregnancy,unlessclearlynecessary.Womenshouldbeadvised

nottobecomepregnantduringtreatmentwithgemcitabineandtowarntheirattendingphysicianimmediately,should

thisoccur.

Lactation:

Itisnotknownwhethergemcitabineisexcretedinhumanmilkandadverseeventsonthesucklingchildcannotbe

excluded.Breast-feedingmustbediscontinuedduringgemcitabinetherapy.

Fertility:

Infertilitystudies,gemcitabinecausedhypospermatogenesisinmalemice(seesection5.3).Therefore,menbeing

treatedwithgemcitabineareadvisednottofatherachildduringandupto6monthsaftertreatmentandtoseekfurther

adviceregardingcryoconservationofspermpriortotreatmentbecauseofthepossibilityofinfertilityduetotherapy

withgemcitabine.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.However,gemcitabinehas

beenreportedtocausemildtomoderatesomnolence,especiallyincombinationwithalcoholconsumption.Patients

shouldbecautionedagainstdrivingoroperatingmachineryuntilitisestablishedthattheydonotbecomesomnolent.

4.8Undesirableeffects

Themostcommonlyreportedadversereactionsassociatedwithgemcitabinetreatmentinclude:nausea,withorwithout

vomiting,andraisedlivertransaminases(aspartateaminotransferase(AST)/alanineaminotransferase(ALT))and

alkalinephosphatase,reportedinapproximately60%ofpatients;proteinuriaandhaematuriareportedinapproximately

50%ofpatients;dyspnoeareportedin10-40%ofpatients(highestincidenceinlungcancerpatients);allergicskin

rashesoccurringinapproximately25%ofpatients,andassociatedwithitchingin10%ofpatients.

Thefrequencyandseverityoftheadversereactionsareaffectedbythedose,infusionrate,andintervalsbetweendoses

(seesection4.4).Dose-limitingadversereactionsarereductionsinthrombocyte,leucocyte,andgranulocytecounts

(seesection4.2).

Thefollowingtableofundesirableeffectsandfrequenciesisbasedonclinicaltrials.Withineachfrequencygrouping,

undesirableeffectsarepresentedinorderofdecreasingseriousness.

Frequenciesaredefinedas:Verycommon(1/10);common(1/100to<1/10);uncommon(1/1,000to<1/100);rare

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/02/2012 CRN 2102301 page number: 6

SystemOrganClass FrequencyGrouping

Bloodandlymphaticsystemdisorders Verycommon:

Leucopenia(frequencyofneutropaeniagrade3is

19.3%andofgrade4is6%)

Thrombocytopaenia

Anaemia

Bonemarrowsuppressionisusuallymildtomoderateand

mostlyaffectsthegranulocytecount(seesection4.2)

Common:

Febrileneutropenia

Veryrare:

Thrombocytosis

Immunesystemdisorders VeryRare:

Anaphylactoidreaction

Metabolismandnutritiondisorders Common:

Anorexia

Nervoussystemdisorders Common:

Headache

Insomnia

Somnolence

Cardiacdisorders Rare:

Myocardialinfarct

Vasculardisorders Rare:

Hypotension

Respiratory,thoracicandmediastinal

disorders Verycommon:

Dyspnoea(usuallymildandpassesrapidlywithout

treatment)

Common:

Cough

Rhinitis

Uncommon:

Interstitialpneumonitis(seesection4.4)

Bronchospasm–usuallymildandtransientbutmay

requireparenteraltreatment

Gastrointestinaldisorders Verycommon:

Vomiting

Nausea

Common:

Diarrhoea

Stomatitis&ulcerationofthemouth

Constipation

Hepatobiliarydisorders Verycommon:

Elevationoflivertransaminases(aspartate

aminotransferase(AST)andalanineaminotransferase

(ALT))andalkalinephosphatase

Common:

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/02/2012 CRN 2102301 page number: 7

Post-marketingexperience(spontaneousreports)frequencynotknown(cannotbeestimatedfromtheavailable

data)

Nervoussystemdisorders

Cerebrovascularaccident

Cardiacdisorders

Arrythmias,predominantlysupraventricularinnature

Heartfailure

Vasculardisorders

Rare:

Increasedgammaglutamyltransferase(GGT)

Skinandsubcutaneoustissuedisorders Verycommon:

Allergicskinrashfrequentlyassociatedwithpruritus

Alopecia

Common:

Itching

Sweating

Rare:

Ulceration

Vesicleandsoreformation

Scaling

Veryrare:

Severeskinreactions,includingdesquamationand

bullousskineruptions

Musculoskeletalandconnectivetissue

disorders Common:

Backpain

Myalgia

Renalandurinarydisorders Verycommon:

Haematuria

Mildproteinurea

Generaldisordersandadministration

siteconditions Verycommon:

Influenza-likesymptoms(themostcommonsymptoms

arefever,headache,chills,myalgia,asthenia,and

anorexia.Cough,rhinitis,malaise,perspirationand

sleepingdifficultieshavealsobeenreported)

Oedema/peripheraloedema–includingfacialoedema.

Oedemaisusuallyreversibleafterstoppingtreatment

Common:

Fever

Asthenia

Chills

Rare:

Injectionsitereactions(mainlymildinnature)

Injury,poisoning,andprocedural

complications Verycommon:

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/02/2012 CRN 2102301 page number: 8

Respiratory,thoracicandmediastinaldisorders

Pulmonaryoedema

Adultrespiratorydistresssyndrome(seesection4.4)

Gastrointestinaldisorders

Ischaemiccolitis

Hepatobiliarydisorders

Serioushepatotoxicity,includingliverfailureanddeath

Skinandsubcutaneoustissuedisorders

Severeskinreactions,includingdesquamationandbullousskineruptions,Lyell’sSyndrome,Stevens-Johnson

Syndrome

Renalandurinarydisorders

Renalfailure(seesection4.4)

Haemolyticuraemicsyndrome(seesection4.4)

Injury,poisoningandproceduralcomplications

Radiationrecall

Combinationuseinbreastcancer

Thefrequencyofgrade3and4haematologicaltoxicities,particularlyneutropaenia,increaseswhengemcitabineis

usedincombinationwithpaclitaxel.However,theincreaseintheseadversereactionsisnotassociatedwithan

increasedincidenceofinfectionsorhaemorrhagicevents.Fatigueandfebrileneutropaeniaoccurmorefrequentlywhen

gemcitabineisusedincombinationwithpaclitaxel.Fatigue,whichisnotassociatedwithanaemia,usuallyresolves

afterthefirstcycle.

Grade3and4AdverseEvents.Paclitaxelversusgemcitabinepluspaclitaxel:

*Grade4neutropenialastingformorethan7daysoccurredin12.6%ofpatientsinthecombinationarmand5.0%of

Number(%)ofPatients

PaclitaxelArm

(n=259) Gemcitabineplus

PaclitaxelArm(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

Febrileneutropenia 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)

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/02/2012 CRN 2102301 page number: 9

Combinationuseinbladdercancer

Grade3and4AdverseEvents.MVACversusgemcitabinepluscisplatin:

Combinationuseinovariancancer

Grade3and4AdverseEvents.Carboplatinversusgemcitabinepluscarboplatin:

Sensoryneuropathywasalsomorefrequentinthecombinationarmthanwithsingleagent

carboplatin.

4.9Overdose

Thereisnoknownantidoteforoverdoseofgemcitabine.Singledosesofupto5.7g/m 2

havebeenadministeredas

intravenousinfusionsover30minuteseverytwoweeks,withclinicallyacceptabletoxicity.Intheeventofsuspected

overdose,thepatientshouldbemonitoredwithappropriatebloodcountsandshouldreceivesupportivetherapyas

necessary.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:pyrimidineanalogues

Number(%)ofPatients

MVAC(methotrexate,

vinblastine,doxorubicin

andcisplatin)Arm

(n=196) Gemcitabineplus

cisplatinArm(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)

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

Number(%)ofPatients

CarboplatinArm

(n=174) Gemcitabineplus

carboplatinArm(n=175)

Grade3 Grade4 Grade3 Grade4

Laboratory

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

Neutropaenia 19(10.9) 2(1.1) 73(41.7) 50(28.6)

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)

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/02/2012 CRN 2102301 page number: 10

CytotoxicActivityinCellCultureModels:

Gemcitabineexhibitssignificantcytotoxicityactivityagainstavarietyofculturedmurineandhumantumourcells.It

exhibitscellphasespecificity,primarilykillingcellsundergoingDNAsynthesis(S-phase)andundercertainconditions

blockingtheprogressionofcellsthroughtheG1/S-phaseboundary.Invitrothecytotoxicactionofgemcitabineisboth

concentrationandtimedependent.

AntitumourActivityinPreclinicalModels:

Inanimaltumourmodels,theantitumouractivityofgemcitabineisscheduledependent.Whengemcitabineis

administereddaily,highanimalmortalitybutminimalantitumouralactivityisseen.If,however,gemcitabineisgiven

everythirdorfourthday,itcanbeadministeredinnon-lethaldoseswithsubstantialantitumouralactivityagainsta

broadspectrumofmousetumours.

CellularMetabolismandMechanismsofAction:

Gemcitabine(dFdC),whichisapyrimidineantimetabolite,ismetabolisedintracellularlybynucleosidekinasetothe

activediphosphate(dFdCDP)andtriphosphate(dFdCTP)nucleosides.Thecytotoxicactionofgemcitabineisdueto

inhibitionofDNAsynthesisbytwoactionsofdFdCDPanddFdCTP.First,dFdCDPinhibitsribonucleotidereductase,

whichisuniquelyresponsibleforcatalysingthereactionsthatgeneratethedeoxynucleosidetriphosphates(dCTP)for

DNAsynthesis.InhibitionofthisenzymebydFdCDPcausesareductionintheconcentrationsofdeoxynucleosidesin

general,andespeciallyinthatofdCTP.Second,dFdCTPcompeteswithdCTPforincorporationintoDNA(self-

potentiation).

Likewise,asmallamountofgemcitabinemayalsobeincorporatedintoRNA.Thus,thereductionintheintracellular

concentrationofdCTPpotentiatestheincorporationofdFdCTPintoDNA.DNApolymeraseepsilonisessentially

unabletoremovegemcitabineandrepairthegrowingDNAstrands.AftergemcitabineisincorporatedintoDNA,one

additionalnucleotideisaddedtothegrowingDNAstrands.Afterthisadditionthereisessentiallyacomplete

inhibitioninfurtherDNAsynthesis(maskedchaintermination).AfterincorporationintoDNA,gemcitabinethen

appearstoinducetheprogrammedcellulardeathprocessknownasapoptosis.

Clinicaldata:

Bladdercancer:ArandomisedphaseIIIstudyof405patientswithadvancedormetastaticurothelialtransitionalcell

carcinomashowednodifferencebetweenthetwotreatmentarms,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,

gemcitabineshowedastatisticallysignificanthigherclinicalbenefitresponseratethan5-fluorouracil(23.8%and4.8%

respectively,p=0.0022).Also,astatisticallysignificantprolongationofthetimetoprogressionfrom0.9to2.3months

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

p<0.0024)wasobservedinpatientstreatedwithgemcitabinecomparedtopatientstreatedwith5-fluorouracil.

Nonsmallcelllungcancer:InarandomisedphaseIIIstudyof522patientswithinoperable,locallyadvancedor

metastaticNSCLC,gemcitabineincombinationwithcisplatinshowedastatisticallysignificanthigherresponserate

thancisplatinalone(31.0%and12.0%,respectively,p<0.0001).Astatisticallysignificantprolongationofthetimeto

progression,from3.7to5.6months(log-rankp<0.0012)andastatisticallysignificantprolongationofmediansurvival

from7.6monthsto9.1months(log-rankp<0.004)wasobservedinpatientstreatedwithgemcitabine/cisplatin

comparedtopatientstreatedwithcisplatin.

InanotherrandomisedphaseIIIstudyof135patientswithstageIIIBorIVNSCLC,acombinationofgemcitabineand

cisplatinshowedastatisticallysignificanthigherresponseratethanacombinationofcisplatinandetoposide(40.6%

and21.2%,respectively,p=0.025).Astatisticallysignificantprolongationofthetimetoprogression,from4.3to6.9

months(p=0.014)wasobservedinpatientstreatedwithgemcitabine/cisplatincomparedtopatientstreatedwith

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/02/2012 CRN 2102301 page number: 11

Inbothstudiesitwasfoundthattolerabilitywassimilarinthetwotreatmentarms.

Ovariancarcinoma:InarandomisedphaseIIIstudy,356patientswithadvancedepithelialovariancarcinomawhohad

relapsedatleast6monthsaftercompletingplatinumbasedtherapywererandomisedtotherapywithgemcitabineand

carboplatin(GCb),orcarboplatin(Cb).Astatisticallysignificantprolongationofthetimetoprogressionofdisease,

from5.8to8.6months(log-rankp=0.0038)wasobservedinthepatientstreatedwithGCbcomparedtopatientstreated

withCb.Differencesinresponserateof47.2%intheGCbarmversus30.9%intheCbarm(p=0.0016)andmedian

survival18months(GCb)versus17.3(Cb)(p=0.73)favouredtheGCbarm.

Breastcancer:InarandomisedphaseIIIstudyof529patientswithinoperable,locallyrecurrentormetastaticbreast

cancerwithrelapseafteradjuvant/neoadjuvantchemotherapy,gemcitabineincombinationwithpaclitaxelshoweda

statisticallysignificantprolongationoftimetodocumenteddiseaseprogressionfrom3.98to6.14months(log-rank

p=0.0002)inpatientstreatedwithgemcitabine/paclitaxelcomparedtopatientstreatedwithpaclitaxel.After377deaths,

theoverallsurvivalwas18.6monthsversus15.8months(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)were3.2to45.5µg/ml.Plasma

concentrationsoftheparentcompoundfollowingadoseof1,000mg/m 2

/30-minutesaregreaterthan5µg/mlfor

approximately30-minutesaftertheendoftheinfusion,andgreaterthan0.4µg/mlforanadditionalhour.

Distribution

Thevolumeofdistributionofthecentralcompartmentwas12.4l/m 2

forwomenand17.5l/m 2

formen(inter-

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

.The

volumeoftheperipheralcompartmentwasnotsensitivetogender.

Theplasmaproteinbindingwasconsideredtobenegligible.

Half-life:Thisrangedfrom42to94minutesdependingonageandgender.Fortherecommendeddosingschedule,

gemcitabineeliminationshouldbevirtuallycompletewithin5to11hoursofthestartoftheinfusion.Gemcitabine

doesnotaccumulatewhenadministeredonceweekly.

Metabolism:

Gemcitabineisrapidlymetabolisedbycytidinedeaminaseintheliver,kidney,blood,andothertissues.

Intracellularmetabolismofgemcitabineproducesthegemcitabinemono,di,andtriphosphates(dFdCMP,dFdCDP,

anddFdCTP),ofwhichdFdCDPanddFdCTPareconsideredactive.Theseintracellularmetaboliteshavenotbeen

detectedinplasmaorurine.

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.Fortherecommendedgemcitabinedoseof1,000mg/m 2

givenasa

30minuteinfusion,lowerclearancevaluesforwomenandmenshouldnotnecessitateadecreaseinthegemcitabine

dose.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/02/2012 CRN 2102301 page number: 12

Renalclearancewas2to7l/hr/m 2

Duringtheweekfollowingadministration,92to98%ofthedoseofgemcitabineadministeredisrecovered,99%inthe

urine,mainlyintheformofdFdUand1%ofthedoseisexcretedinfaeces.

dFdCTPKinetics:

Thismetabolitecanbefoundinperipheralbloodmononuclearcellsandtheinformationbelowreferstothesecells.

Intracellularconcentrationsincreaseinproportiontogemcitabinedosesof35-350mg/m 2

/30min,whichgivesteady-

stateconcentrationsof0.4-5µg/ml.Atgemcitabineplasmaconcentrationsabove5µg/ml,dFdCTPlevelsdonot

increase,suggestingthattheformationissaturableinthesecells.

Half-lifeofterminalelimination:0.7-12hours.

dFdUKinetics:

Peakplasmaconcentrations(3-15minutesafterendof30minuteinfusion,1,000mg/m 2

):

28-52µg/ml.

Troughconcentrationfollowingonceweeklydosing:

0.07-1.12µg/ml,withnoapparentaccumulation.

Triphasicplasmaconcentrationversustimecurve,meanhalf-lifeofterminalphase:

65hours(range33-84hours).

FormationofdFdUfromparentcompound:

91%-98%.

Meanvolumeofdistributionofcentralcompartment:

18l/m 2

(range11-22l/m 2

Meansteady-statevolumeofdistribution(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,

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/02/2012 CRN 2102301 page number: 13

5.3Preclinicalsafetydata

Inrepeateddosestudiesofupto6monthsdurationinmiceanddogs,theprincipalfindingwasscheduleanddose-

dependenthaematopoeticsuppression,whichwasreversible.Gemcitabineshowedmutagenicpotentialinanin-vitro

mutationtestandinanin-vivobonemarrowmicronucleustest.Long-termanimalstudieshavenotbeenconductedto

evaluatethecarcinogenicpotentialofgemcitabine.

Infertilitystudies,gemcitabinecausedreversiblehypospermatogenesisinmalemice.Noeffectonthefertilityof

femaleshasbeendetected.

Evaluationofexperimentalanimalstudieshasshownreproductivetoxicitye.g.birthdefectsandothereffectsonthe

developmentoftheembryoorfoetus,thecourseofgestationorperi-andpostnataldevelopment.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Mannitol,E421

Sodiumacetatetrihydrate

Hydrochloricacid(forpH-adjustment)

Sodiumhydroxide(forpH-adjustment)

6.2Incompatibilities

Thismedicinalproductmustnotbemixedwithothermedicinalproductexceptthosementionedinsection6.6.

6.3Shelflife

Aspackagedforsale:

2years

Afterreconstitution:

Chemicalandphysicalin-usestabilityhasbeendemonstratedfor35daysat25°C.

Fromamicrobiologicalpointofview,theproductshouldbeusedimmediately.

Solutionsshouldnotberefrigerated,ascrystallisationmayoccur.

6.4Specialprecautionsforstorage

Aspackagedforsale:

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

In-use:

Forstorageconditionofthereconstitutedmedicinalproduct,seesection6.3.

6.5Natureandcontentsofcontainer

1gvial:TypeIclearglassvialwithbromobutylstopper.VialsmaybesheathedinprotectiveONCO-TAINsleeves.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/02/2012 CRN 2102301 page number: 14

6.6Specialprecautionsfordisposalandotherhandling

Reconstitution:

Forsingleuseonly

Thismedicinalproducthasonlybeenshowntobecompatiblewithsodiumchloride9mg/ml(0.9%)solutionfor

injection.Accordingly,onlythisdiluentshouldbeusedforreconstitution.Compatibilitywithotheractivesubstances

hasnotbeenstudied.Therefore,itisnotrecommendedtomixthismedicinalproductwithotheractivesubstances

whenreconstituted.

Reconstitutionatconcentrationsgreaterthan38mg/mlmayresultinincompletedissolution,andshouldbeavoided.

Toreconstitute,slowlyaddtheappropriatevolumeofsodiumchloride9mg/ml(0.9%)solutionforinjection(asstated

inthetablebelow)andshaketodissolve.

Theappropriateamountofmedicinalproductmaybefurtherdilutedwithsodiumchloride9mg/ml(0.9%)solutionfor

injection.

Parenteralmedicinalproductsshouldbeinspectedvisuallyforparticulatematteranddiscolouration,priorto

administration,wheneversolutionandcontainerpermit.

Anyunusedsolutionshouldbediscardedasdescribedbelow.

GuidelinesfortheSafeHandlingofCytotoxicMedicinalProducts:

Localguidelinesonsafepreparationandhandlingofcytotoxicmedicinalproductsmustbeadheredto.Cytotoxic

preparationsshouldnotbehandledbypregnantstaff.Thepreparationofinjectablesolutionsofcytotoxicagentsmust

becarriedoutbytrainedspecialistpersonnelwithknowledgeofthemedicinesused.Thisshouldbeperformedina

designatedarea.Theworksurfaceshouldbecoveredwithdisposableplastic-backedabsorbentpaper.

Suitableeyeprotection,disposablegloves,facemaskanddisposableapronshouldbeworn.Precautionsshouldbe

takentoavoidthemedicinalproductaccidentallycomingintocontactwiththeeyes.Ifaccidentalcontamination

occurs,theeyeshouldbewashedwithwaterthoroughlyandimmediately.

Syringesandinfusionsetsshouldbeassembledcarefullytoavoidleakage(useofLuerlockfittingsisrecommended).

Largeboreneedlesarerecommendedtominimisepressureandthepossibleformationofaerosols.Thelattermayalso

bereducedbytheuseofaventingneedle.

Actualspillageorleakageshouldbemoppedupwearingprotectivegloves.Excretaandvomitmustbehandledwith

care.

Disposal:

Adequatecareandprecautionshouldbetakeninthedisposalofitemsusedtoreconstitutethismedicinalproduct.Any

unuseddryproductorcontaminatedmaterialsshouldbeplacedinahigh-riskwastebag.Sharpobjects(needles,

syringes,vials,etc)shouldbeplacedinasuitablerigidcontainer.Personnelconcernedwiththecollectionanddisposal

ofthiswasteshouldbeawareofthehazardinvolved.Wastematerialshouldbedestroyedbyincineration.Anyunused

Presentation Volumeofsodium

chloride9mg/ml

(0.9%)solutionfor

injectiontobeadded Displacementvolume Finalconcentration

200mg 5ml 0.26ml 38mg/ml

1g 25ml 1.3ml 38mg/ml

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/02/2012 CRN 2102301 page number: 15

7MARKETINGAUTHORISATIONHOLDER

HospiraUKLimited

Queensway

RoyalLeamingtonSpa

Warwickshire

CV313RW

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA437/58/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:9thNovember2007

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/02/2012 CRN 2102301 page number: 16