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:
  • PA0711/178/002
  • Authorization date:
  • 12-12-2008
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0711/178/002

CaseNo:2062433

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

RowexLtd

Bantry,Co.Cork,Ireland

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Gemcitabine1gpowderforsolutionforinfusion

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom17/11/2009until21/08/2013.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 08/12/2009 CRN 2062433 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Gemcitabine1gpowderforsolutionforinfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Onevialcontainsgemcitabinehydrochlorideequivalentto1000mggemcitabine.

Afterreconstitution,thesolutioncontains38mg/mlofgemcitabine.

Excipients

Each1000mgvialcontains17.5mg(<1mmol)sodium.

Forafulllistofexcipientsseesection6.1.

3PHARMACEUTICALFORM

Powderforsolutionforinfusion.

Whitetooff-whitelyophilizedcake.

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

chemotherapyshouldhaveincludedananthracyclineunlessclinicallycontraindicated.

4.2Posologyandmethodofadministration

Gemcitabineshouldonlybeprescribedbyaphysicianqualifiedintheuseofanti-cancerchemotherapy.

Recommendedposology

Bladdercancer

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Therecommendeddoseforgemcitabineis1000mg/m 2

,givenby30-minuteinfusion.Thedoseshouldbegivenon

Days1,8and15ofeach28-daycycleincombinationwithcisplatin.Cisplatinisgivenatarecommendeddoseof70

mg/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/m 2

once

every3weeks.

Breastcancer

Combinationuse

Gemcitabineincombinationwithpaclitaxelisrecommendedusingpaclitaxel(175mg/m 2

)administeredonDay1over

approximately3-hoursasanintravenousinfusion,followedbygemcitabine(1250mg/m 2

)asa30-minuteintravenous

infusiononDays1and8ofeach21-daycycle.

Dosereductionwitheachcycleorwithinacyclemaybeappliedbaseduponthegradeoftoxicity

experiencedbythepatient.Patientsshouldhaveanabsolutegranulocytecountofatleast1,500(x

/l)priortoinitiationofgemcitabine+paclitaxelcombination.

Ovariancancer

Combinationuse

Gemcitabineincombinationwithcarboplatinisrecommendedusinggemcitabine1000mg/m 2

administeredonDays1and8ofeach21-daycycleasa30-minuteintravenousinfusion.After

gemcitabine,carboplatinwillbegivenonDay1consistentwithatargetAreaundercurve(AUC)of

4.0mg/ml·min.Dosagereductionwitheachcycleorwithinacyclemaybeappliedbaseduponthe

gradeoftoxicityexperiencedbythepatient.

Monitoringfortoxicityanddosemodificationduetotoxicity

Dosemodificationduetononhaematologicaltoxicity

Periodicphysicalexaminationandchecksofrenalandhepaticfunctionshouldbemadetodetectnonhaematological

toxicity.Dosagereductionwitheachcycleorwithinacyclemaybeappliedbaseduponthegradeoftoxicity

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

therapywithgemcitabineshouldbewithheldordecreaseddependingonthejudgementofthetreatingphysician.Doses

shouldbewithhelduntiltoxicityhasresolvedintheopinionofthephysician.

Forcisplatin,carboplatin,andpaclitaxeldosageadjustmentincombinationtherapy,pleaserefertothe

correspondingSummaryofProductCharacteristics.

Dosemodificationduetohaematologicaltoxicity

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Forallindications,thepatientmustbemonitoredbeforeeachdoseforplateletandgranulocytecounts.

Patientsshouldhaveanabsolutegranulocytecountofatleast1,500(x10 6

/l)andplateletaccountof

100,000(x10 6

/l)priortotheinitiationofacycle.

Withinacycle

Dosemodificationsofgemcitabinewithinacycleshouldbeperformedaccordingtothefollowing

tables:

*Treatmentomittedwillnotbere-instatedwithinacyclebeforetheabsolutegranulocytecountreachesatleast500

(x10 6

/l)andtheplateletcountreaches50,000(x10 6

/l).

*Treatmentomittedwillnotbere-instatedwithinacycle.Treatmentwillstartonday1ofthenext

cycleoncetheabsolutegranulocytecountreachesatleast1,500(x10 6

/l)andtheplateletcountreaches

100,000(x10 6

/l).

*Treatmentomittedwillnotbere-instatedwithinacycle.Treatmentwillstartonday1ofthenext

cycleoncetheabsolutegranulocytecountreachesatleast1,500(x10 6

/l)andtheplateletcountreaches

100,000(x10 6

/l).

Dosemodificationsduetohaematologicaltoxicityinsubsequentcycles,forallindications

Thegemcitabinedoseshouldbereducedto75%oftheoriginalcycleinitiationdose,inthecaseofthe

followinghaematologicaltoxicities:

Absolutegranulocytecount<500x10 6

/lformorethan5days

Absolutegranulocytecount<100x10 6

/lformorethan3days

Febrileneutropaenia

Platelets<25,000x10 6

Dosemodificationofgemcitabinewithinacycleforbladdercancer,NSCLCand

pancreaticcancer,giveninmonotherapyorincombinationwithcisplatin

Absolutegranulocytecount

(x10 6

/l) Plateletcount

(x10 6

/l) Percentageofstandarddose

ofGemcitabine(%)

>1,000 and >100,000 100

500-1,000 or 50,000–100,000 75

<500 or <50,000 Omitdose*

Dosemodificationofgemcitabinewithinacycleforbreastcancer,givenin

combinationwithpaclitaxel

Absolutegranulocytecount

(x10 6

/l) Plateletcount

(x10 6

/l) Percentageofstandarddose

ofGemcitabine(%)

≥1,200

>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,givenin

combination

withcarboplatin

Absolutegranulocytecount

(x10 6

/l) Plateletcount

(x10 6

/l) Percentageofstandarddose

ofGemcitabine(%)

>1,500 and ≥100,000 100

1,000–1,500 or 75,000–100,000 50

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Methodofadministration

Gemcitabineistoleratedwellduringinfusionandmaybeadministeredambulant.Ifextravasationoccurs,generallythe

infusionmustbestoppedimmediatelyandstartedagaininanotherbloodvessel.Thepatientshouldbemonitored

carefullyaftertheadministration.

Forinstructionsonreconstitution,seesection6.6

Specialpopulations

Patientswithrenalorhepaticimpairment

Gemcitabineshouldbeusedwithcautioninpatientswithhepaticorrenalinsufficiencyasthereis

insufficientinformationfromclinicalstudiestoallowforcleardoserecommendationsforthesepatient

populations(seesections4.4and5.2).

Elderlypopulation(>65years)

Gemcitabinehasbeenwelltoleratedinpatientsovertheageof65.Thereisnoevidencetosuggest

thatdoseadjustments,otherthanthosealreadyrecommendedforallpatients,arenecessaryinthe

elderly(seesection5.2).

Paediatricpopulation(<18years)

Gemcitabineisnotrecommendedforuseinchildrenunder18yearsofageduetoinsufficientdataon

safetyandefficacy.

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients.

Breast-feeding(seesection4.6).

4.4Specialwarningsandprecautionsforuse

Prolongationoftheinfusiontimeandincreaseddosingfrequencyhavebeenshowntoincrease

toxicity.

Haematologicaltoxicity

Gemcitabinecansuppressbonemarrowfunctionasmanifestedbyleucopaenia,thrombocytopaeniaandanaemia.

Patientsreceivinggemcitabineshouldbemonitoredpriortoeachdoseforplatelet,leucocyteandgranulocytecounts.

Suspensionormodificationoftherapyshouldbeconsideredwhendrug-inducedbonemarrowdepressionisdetected

(seesection4.2).However,myelosuppressionisshortlivedandusuallydoesnotresultindosereductionandrarelyin

discontinuation.

Peripheralbloodcountsmaycontinuetodeteriorateaftergemcitabineadministrationhasbeenstopped.Inpatientswith

impairedbonemarrowfunction,thetreatmentshouldbestartedwithcaution.Aswithothercytotoxictreatments,the

riskofcumulativebone-marrowsuppressionmustbeconsideredwhengemcitabinetreatmentisgiventogetherwith

otherchemotherapy.

Hepaticinsufficiency

Administrationofgemcitabineinpatientswithconcurrentlivermetastasesorapre-existingmedicalhistoryof

hepatitis,alcoholismorlivercirrhosismayleadtoexacerbationoftheunderlyinghepaticinsufficiency.

Laboratoryevaluationofrenalandhepaticfunction(includingvirologicaltests)shouldbeperformedperiodically.

Gemcitabineshouldbeusedwithcautioninpatientswithhepaticinsufficiencyorwithimpairedrenalfunctionasthere

isinsufficientinformationfromclinicalstudiestoallowcleardoserecommendationforthispatientpopulation(see

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Concomitantradiotherapy

Concomitantradiotherapy(giventogetheror ≤7daysapart):Toxicityhasbeenreported(seesection

4.5fordetailsandrecommendationsforuse).

Livevaccinations

Yellowfevervaccineandotherliveattenuatedvaccinesarenotrecommendedinpatientstreatedwith

gemcitabine(seesection4.5).

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,

menbeingtreatedwithgemcitabineareadvisednottofatherachildduringandupto6monthsafter

treatmentandtoseekfurtheradviceregardingcryoconservationofspermpriortotreatmentbecauseof

thepossibilityofinfertilityduetotherapywithgemcitabine(seesection4.6).

Sodium

Gemcitabine1000mgcontains17.5mg(<1mmol)sodiumpervial.Thisshouldbetakeninto

considerationbypatientsonacontrolledsodiumdiet.

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

twice)during6weeks.Theoptimumregimenforsafeadministration

ofgemcitabinewiththerapeuticdosesofradiationhasnotyetbeendeterminedinalltumourtypes.

Non-concurrent(given>7daysapart)-Analysisofthedatadoesnotindicateanyenhancedtoxicitywhengemcitabine

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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

ThemostcommonlyreportedadversedrugreactionsassociatedwithGemcitabinetreatmentinclude:nauseawithor

withoutvomiting,raisedlivertransaminases(AST/ALT)andalkalinephosphatase,

reportedinapproximately60%ofpatients;proteinuriaandhaematuriareportedinapproximately50%patients;

dyspnoeareportedin10-40%ofpatients(highestincidenceinlungcancerpatients);allergicskinrashesoccurin

approximately25%ofpatientsandareassociatedwithitchingin10%ofpatients.

Thefrequencyandseverityoftheadversereactionsareaffectedbythedose,infusionrateandintervalsbetweendoses

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

section4.2).

Clinicaltrialdata

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

to<1/100),Rare( ≥1/10,000to<1/1000),VeryRare(<1/10,000).

Thefollowingtableofundesirableeffectsandfrequenciesisbasedondatafromclinicaltrials.Within

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SystemOrganClass Frequencygrouping

Bloodandlymphaticsystemdisorders Verycommon

Leucopaenia(NeutropaeniaGrade3=

19.3%;Grade4=6%).

Bone-marrowsuppressionisusuallymildto

moderateandmostlyaffectsthegranulocyte

count(seesection4.2)

Thrombocytopaenia

Anaemia

Common

Febrileneutropaenia

Veryrare

Thrombocytosis

Immunesystemdisorders Veryrare

Anaphylactoidreaction

Metabolismandnutritiondisorders Common

Anorexia

Nervoussystemdisorders Common

Headache

Insomnia

Somnolence

Cardiacdisorders Rare

Myocardialinfarct

Vasculardisorders Rare

Hypotension

Respiratory,thoracicandmediastinal

disorders Verycommon

Dyspnoea–usuallymildandpasses

rapidlywithouttreatment

Common

Cough

Rhinitis

Uncommon

Interstitialpneumonitis(seesection4.4)

Bronchospasm–usuallymildand

transientbutmayrequireparenteral

treatment

Gastrointestinaldisorders Verycommon

Vomiting

Nausea

Common

Diarrhoea

Stomatitisandulcerationofthemouth

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SystemOrganClass Frequencygrouping

Hepatobiliarydisorders Verycommon

Elevationoflivertransaminases(AST

andALT)andalkalinephosphatase

Common

Increasedbilirubin

Rare

Increasedgamma-glutamyltransferase

(GGT)

Skinandsubcutaneoustissuedisorders Verycommon

Allergicskinrashfrequentlyassociated

withpruritus

Alopecia

Common

Itching

Sweating

Rare

Ulceration

Vesicleandsoreformation

Scaling

Veryrare

Severeskinreactions,including

desquamationandbullousskineruptions

Musculoskeletalandconnectivetissue

disorders Common

Backpain

Myalgia

Renalandurinarydisorders VeryCommon

Haematuria

Mildproteinuria

Generaldisordersandadministrationsite

conditions Verycommon

Influenza-likesymptoms-themost

commonsymptomsarefever,headache,

chills,myalgia,astheniaandanorexia.

Cough,rhinitis,malaise,perspirationand

sleepingdifficultieshavealsobeen

reported.

Oedema/peripheraloedemaincluding

facialoedema.Oedemaisusually

reversibleafterstoppingtreatment

Common

Fever

Asthenia

Chills

Rare

Injectionsitereactions-mainlymildin

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Postmarketingexperience(spontaneousreports)frequencynotknown(can’tbeestimatedfromthe

availabledata)

Nervoussystemdisorders

Cerebrovascularaccident

Cardiacdisorders

Arrythmias,predominantlysupraventricularinnature

Heartfailure

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

Combinationuseinbreastcancer

Thefrequencyofgrade3and4haematologicaltoxicities,particularlyneutropaenia,increaseswhen

gemcitabineisusedincombinationwithpaclitaxel.However,theincreaseintheseadversereactionsis

notassociatedwithanincreasedincidenceofinfectionsorhaemorrhagicevents.Fatigueandfebrile

neutropaeniaoccurmorefrequentlywhengemcitabineisusedincombinationwithpaclitaxel.Fatigue,

SystemOrganClass Frequencygrouping

Injury,poisoning,andprocedural

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*Grade4neutropaenialastingformorethan7daysoccurredin12.6%ofpatientsinthecombination

armand5.0%ofpatientsinthepaclitaxelarm.

Grade3and4AdverseEvents

Paclitaxelversusgemcitabinepluspaclitaxel

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

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,vin-

blastine,doxorubicinand

cisplatin)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)

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Combinationuseinovariancancer

Sensoryneuropathywasalsomorefrequentinthecombinationarmthanwithsingleagentcarboplatin.

4.9Overdose

Thereisnoknownantidoteforoverdoseofgemcitabine.Dosesashighas5700mg/m 2

havebeen

administeredbyintravenousinfusionover30-minutesevery2weekswithclinicallyacceptable

toxicity.Intheeventofsuspectedoverdose,thepatientshouldbemonitoredwithappropriateblood

countsandreceivesupportivetherapy,asnecessary.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:pyrimidineanaloguesATCcode: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

Grade3and4AdverseEvents

CarboplatinversusGemcitabinepluscarboplatin

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)

Infectionwithout

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Likewise,asmallamountofgemcitabinemayalsobeincorporatedintoRNA.Thus,thereduced

intracellularconcentrationofdCTPpotentiatestheincorporationofdFdCTPintoDNA.DNA

polymeraseepsilonlackstheabilitytoeliminategemcitabineandtorepairthegrowingDNAstrands.

AftergemcitabineisincorporatedintoDNA,oneadditionalnucleotideisaddedtothegrowingDNA

strands.AfterthisadditionthereisessentiallyacompleteinhibitioninfurtherDNAsynthesis(masked

chaintermination).AfterincorporationintoDNA,gemcitabineappearstoinducetheprogrammedcell

deathprocessknownasapoptosis.

Clinicaldata

Bladdercancer

ArandomisedphaseIIIstudyof405patientswithadvancedormetastaticurothelialtransitionalcell

carcinomashowednodifferencebetweenthetwotreatmentarms,gemcitabine/cisplatinversus

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

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

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

hadabettertoxicityprofilethanMVAC.

Pancreaticcancer

InarandomisedphaseIIIstudyof126patientswithadvancedormetastaticpancreaticcancer,

gemcitabineshowedastatisticallysignificanthigherclinicalbenefitresponseratethan5-fluorouracil

(23.8%and4.8%respectively,p=0.0022).Also,astatisticallysignificantprolongationofthetimeto

progressionfrom0.9to2.3months(log-rankp<0.0002)andastatisticallysignificantprolongationof

mediansurvivalfrom4.4to5.7months(log-rankp<0.0024)wasobservedinpatientstreatedwith

gemcitabinecomparedtopatientstreatedwith5-fluorouracil.

Nonsmallcelllungcancer

InarandomisedphaseIIIstudyof522patientswithinoperable,locallyadvancedormetastaticNSCLC,gemcitabinein

combinationwithcisplatinshowedastatisticallysignificanthigherresponseratethancisplatinalone(31.0%and12.0

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

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

rankp<0.004)wasobservedinpatientstreatedwithgemcitabine/cisplatincomparedtopatientstreatedwithcisplatin.

InanotherrandomisedphaseIIIstudyof135patientswithstageIIIBorIVNSCLC,acombinationofgemcitabineand

cisplatinshowedastatisticallysignificanthigherresponseratethanacombinationofcisplatinandetoposide(40.6%

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

months(p=0.014)wasobservedinpatientstreatedwithgemcitabine/cisplatincomparedtopatientstreatedwith

etoposide/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(log-rankp=0.0489,HR0.82)inpatientstreatedwith

gemcitabine/paclitaxelcomparedtopatientstreatedwithpaclitaxelandtheoverallresponseratewas41.4%and26.2

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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%).Thevolumeofdistributionoftheperipheralcompartment

was47.4l/m 2

.Thevolumeoftheperipheralcompartmentwasnotsensitivetogender.

Theplasmaproteinbindingwasconsideredtobenegligible.

Half-life:Thisrangedfrom42to94minutesdependingonageandgender.Fortherecommendeddosingschedule,

gemcitabineeliminationshouldbevirtuallycompletewithin5to11hoursofthestartoftheinfusion.Gemcitabinedoes

notaccumulatewhenadministeredonceweekly.

Metabolism

Gemcitabineisrapidlymetabolisedbycytidinedeaminaseintheliver,kidney,bloodandothertissues.Intracellular

metabolismofgemcitabineproducesthegemcitabinemono,diandtriphosphates

(dFdCMP,dFdCDPanddFdCTP)ofwhichdFdCDPanddFdCTPareconsideredactive.These

intracellularmetaboliteshavenotbeendetectedinplasmaorurine.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%ofthedoseofgemcitabineadministeredis

recovered,99%intheurine,mainlyintheformofdFdUand1%ofthedoseisexcretedinfaeces.

dFdCTPkinetics

Thismetabolitecanbefoundinperipheralbloodmononuclearcellsandtheinformationbelowreferstothesecells.

Intracellularconcentrationsincreaseinproportiontogemcitabinedosesof35-350mg/

/30-minutes,whichgivesteadystateconcentrationsof0.4-5µg/ml.Atgemcitabineplasma

concentrationsabove5µg/ml,dFdCTPlevelsdonotincrease,suggestingthattheformationis

saturableinthesecells.

Half-lifeofterminalelimination:0.7-12hours.

dFdUkinetics

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

):28-52µg/ml.

Troughconcentrationfollowingonceweeklydosing:0.07-1.12µg/ml,withnoapparentaccumulation.

Triphasicplasmaconcentrationversustimecurve,meanhalf-lifeofterminalphase-65hours(range

33-84hr).

FormationofdFdUfromparentcompound:91%-98%.

Meanvolumeofdistributionofcentralcompartment:18l/m 2

(range11-22l/m 2

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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,

significanteffectongemcitabinepharmacokinetics.

5.3Preclinicalsafetydata

Inrepeat-dosestudiesofupto6monthsindurationinmiceanddogs,theprincipalfindingwasscheduleanddose-

dependenthaematopoieticsuppressionwhichwasreversible.

Gemcitabineismutagenicinaninvitromutationtestandaninvivobonemarrowmicronucleustest.

Longtermanimalstudiesevaluatingthecarcinogenicpotentialhavenotbeenperformed.

Infertilitystudies,gemcitabinecausedreversiblehypospermatogenesisinmalemice.Noeffectonthe

fertilityoffemaleshasbeendetected.

Evaluationofexperimentalanimalstudieshasshownreproductivetoxicitye.g.birthdefectsandother

effectsonthedevelopmentoftheembryoorfoetus,thecourseofgestationorperi-andpostnatal

development.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Mannitol(E421)

Sodiumacetatetrihydrate(E262)

Hydrochloricacid(E507)(forpH-adjustment)

Sodiumhydroxide(E524)(forpH-adjustment)

6.2Incompatibilities

Thismedicinalproductmustnotbemixedwithothermedicinalproductsexceptthosementionedinsection6.6.

6.3ShelfLife

Aspackagedforsale:

30months.

Afterreconstitution:

Chemicalandphysicalin-usestabilityhasbeendemonstratedfor24hoursat30 °

Fromamicrobiologicalpointofview,theproductshouldbeusedimmediately.Ifnotusedimmediately,in-usestorage

timesandconditionspriortousearetheresponsibilityoftheuserandwouldnormallynotbelongerthan24hoursat

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6.4Specialprecautionsforstorage

Unopenedvial:Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

Forstorageconditionsofthereconstitutedmedicinalproductseesection6.3

6.5Natureandcontentsofcontainer

Colourlesstype-Itubularglassvialwithbromobutylrubberstopperandwith20mmcrimp.

Eachpackcontains1vial.

6.6Specialprecautionsfordisposalandotherhandling

Handling

Thenormalsafetyprecautionsforcytostaticagentsmustbeobservedwhenpreparinganddisposingoftheinfusion

solution.Handlingofthesolutionforinfusionshouldbedoneinasafetyboxandprotectivecoatsandglovesshouldbe

used.Ifnosafetyboxisavailable,theequipmentshouldbesupplementedwithamaskandprotectiveglasses.

Cytotoxicpreparationsshouldnotbehandledbypregnantstaff.

Ifthepreparationcomesintocontactwiththeeyes,thismaycauseseriousirritation.Theeyesshouldberinsed

immediatelyandthoroughlywithwater.Ifthereislastingirritation,adoctorshouldbeconsulted.Ifthesolutionis

spilledontheskin,rinsethoroughlywithwater.

Instructionsforreconstitution(andfurtherdilution,ifperformed)

Theonlyapproveddiluentforreconstitutionofgemcitabinesterilepowderissodiumchloride9mg/ml(0.9%)solution

forinjection(withoutpreservative).Duetosolubilityconsiderations,themaximumconcentrationforgemcitabineupon

reconstitutionis38mg/ml.Reconstitutionatconcentrationsgreaterthan38mg/mlmayresultinincompletedissolution

andshouldbeavoided.

Useaseptictechniqueduringthereconstitutionandanyfurtherdilutionofgemcitabineforintravenousinfusion

administration.

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

tothe200mgvialor25mlsterilesodiumchloride9mg/ml(0.9%)solutionforinjection,withoutpreservative,to

the1000mgvial.Thetotalvolumeafterreconstitutionis5.26ml(200mgvial)or26.3ml(1000mgvial)

respectively.Thisyieldsagemcitabineconcentrationof38mg/ml,whichincludesaccountingforthedisplacement

volumeofthelyophilisedpowder.Shaketodissolve.Furtherdilutionwithsterilesodiumchloride9mg/ml(0.9%)

solutionforinjection,withoutpreservativecanbedone.Reconstitutedsolutionisclearandpracticallyparticle-free.

Parenteralmedicinalproductsshouldbeinspectedvisuallyforparticulatematteranddiscolourationpriorto

administration.Ifparticulatematterisobserved,donotadminister.

Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

RowexLtd

Bantry

Co.Cork

Ireland

8MARKETINGAUTHORISATIONNUMBER

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9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthoristation:22 nd

August2008

10DATEOFREVISIONOFTHETEXT

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