GEMCITABINE TEVA

Main information

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

Documents

Localization

  • Available in:
  • GEMCITABINE TEVA
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0749/097/003
  • Authorization date:
  • 09-04-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

GemcitabineTeva2gPowderforSolutionforInfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Onevialcontainsgemcitabinehydrochlorideequivalentto2000mggemcitabine.

Afterreconstitution,thesolutioncontains38mg/mlofgemcitabine.

Excipients

Each2000mgvialcontains35mg(1.5mmol)sodium.

Forafulllistofexcipientsseesection6.1.

3PHARMACEUTICALFORM

Powderforsolutionforinfusion.

Whitetooff-white,plugorpowder.

pHafterreconstitutionin0.9%sodiumchloride:2.7–3.3

Osmolarityafterreconstitutionin0.9%sodiumchlorideapproximately:0.79Osm/l.

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.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.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/ml·min.Dosagereductionwitheachcycleorwithinacycle

maybeappliedbaseduponthegradeoftoxicityexperiencedbythepatient.

Monitoringfortoxicityanddosemodificationduetotoxicity

Dosemodificationduetonon-haematologicaltoxicity

Periodicphysicalexaminationandchecksofrenalandhepaticfunctionshouldbemadetodetectnon-haematological

toxicity.Dosagereductionwitheachcycleorwithinacyclemaybeappliedbaseduponthegradeoftoxicity

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

therapywithgemcitabineshouldbewithheldordecreaseddependingonthejudgmentofthetreatingphysician.Doses

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Forcisplatin,carboplatin,andpaclitaxeldosageadjustmentincombinationtherapy,pleaserefertothecorresponding

SummaryofProductCharacteristics.

Dosemodificationduetohaematologicaltoxicity

Initiationofacycle

Forallindications,thepatientmustbemonitoredbeforeeachdoseforplateletandgranulocytecounts.Patientsshould

haveanabsolutegranulocytecountofatleast1,500(x10 6

/l)andplateletcountof100,000(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

/l).

Dosemodificationsduetohaematologicaltoxicityinsubsequentcycles,forallindications

Thegemcitabinedoseshouldbereducedto75%oftheoriginalcycleinitiationdose,inthecaseofthefollowing

haematologicaltoxicities:

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,givenincombination

withpaclitaxel

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,givenincombination

withcarboplatin

Absolutegranulocytecount

(x10 6

/l) Plateletcount

(x10 6

/l) Percentageofstandarddose

ofgemcitabine(%)

>1,500 and ≥100,000 100

1000–1,500 or 75,000–100,000 50

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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.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(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

Gemcitabine2gcontains35mg(<1.5mmol)sodiumpervial.Thisshouldbetakenintoconsiderationbypatientsona

controlledsodiumdiet.

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

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Non-concurrent(given>7daysapart)-Analysisofthedatadoesnotindicateanyenhancedtoxicitywhengemcitabine

isadministeredmorethan7daysbeforeorafterradiation,otherthanradiationrecall.Datasuggestthatgemcitabinecan

bestartedaftertheacuteeffectsofradiationhaveresolvedoratleastoneweekafterradiation.

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

bothconcurrentandnon-concurrentuseofgemcitabine.

Others

Yellowfeverandotherliveattenuatedvaccinesarenotrecommendedduetotheriskofsystemic,possiblyfatal,

disease,particularlyinimmunosuppressedpatients.

4.6Fertility,pregnancyandlactation

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%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

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

Constipation

Hepatobiliarydisorders VeryCommon

Elevationoflivertransaminases(AST

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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

nature.

Injury,poisoning,andprocedural

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Post-marketingexperience(spontaneousreports)frequencynotknown(can’tbeestimatedfromtheavailabledata)

Nervoussystemdisorders

Cerebrovascularaccident

Cardiacdisorders

Arrhythmias,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,increaseswhengemcitabineis

usedincombinationwithpaclitaxel.However,theincreaseintheseadversereactionsisnotassociatedwithan

increasedincidenceofinfectionsorhaemorrhagicevents.Fatigueandfebrileneutropaeniaoccurmorefrequentlywhen

gemcitabineisusedincombinationwithpaclitaxel.Fatigue,whichisnotassociatedwithanaemia,usuallyresolves

afterthefirstcycle.

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)

Thrombocytopenia 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

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Grade4neutropaenialastingformorethan7daysoccurredin12.6%ofpatientsinthecombinationarmand5.0%

ofpatientsinthepaclitaxelarm.

Combinationuseinbladdercancer

Combinationuseinovariancancer

Sensoryneuropathywasalsomorefrequentinthecombinationarmthanwithsingleagentcarboplatin.

4.9Overdose

Thereisnoknownantidoteforoverdoseofgemcitabine.Dosesashighas5700mg/m 2

havebeenadministeredby

intravenousinfusionover30-minutesevery2weekswithclinicallyacceptabletoxicity.Intheeventofsuspected

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

Grade3and4AdverseEvents

MVACversusgemcitabinepluscisplatin

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)

Thrombocytopenia 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) 1(0)

Grade3and4AdverseEvents

MVACversusgemcitabinepluscarboplatin

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)

Thrombocytopenia 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)

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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,itcanbeadministeredinnon-lethaldoseswithsubstantialantitumoural

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

ArandomisedphaseIIIstudyof405patientswithadvancedormetastaticurothelialtransitionalcellcarcinomashowed

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

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Astatisticallysignificantprolongationofthetimetoprogression,from3.7to5.6months(log-rankp<0.0012)anda

statisticallysignificantprolongationofmediansurvivalfrom7.6monthsto9.1months(log-rankp<0.004)was

observedinpatientstreatedwithgemcitabine/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.Differencesin

responserateof47.2%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)were3.2to45.5µg/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.Gemcitabinedoes

notaccumulatewhenadministeredonceweekly.

Metabolism

Gemcitabineisrapidlymetabolisedbycytidinedeaminaseintheliver,kidney,bloodandothertissues.Intracellular

metabolismofgemcitabineproducesthegemcitabinemono,diandtriphosphates(dFdCMP,dFdCDPanddFdCTP)of

whichdFdCDPanddFdCTPareconsideredactive.Theseintracellularmetaboliteshavenotbeendetectedinplasmaor

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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.

Troughconcentrationfollowingonceweeklydosing:0.07-1.12µg/ml,withnoapparentaccumulation.Triphasic

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

FormationofdFdUfromparentcompound:91%-98%.

Meanvolumeofdistributionofcentralcompartment:18l/m 2

(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-

dependenthaematopoieticsuppressionwhichwasreversible.

Gemcitabineismutagenicinaninvitromutationtestandaninvivobonemarrowmicronucleustest.Longtermanimal

studiesevaluatingthecarcinogenicpotentialhavenotbeenperformed.

Infertilitystudies,gemcitabinecausedreversiblehypospermatogenesisinmalemice.Noeffectonthefertilityof

femaleshasbeendetected.

Evaluationofexperimentalanimalstudieshasshownreproductivetoxicitye.g.birthdefectsandothereffectsonthe

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Mannitol(E421)

Sodiumacetate(E262)

Hydrochloricacid(forpHadjustment)

Sodiumhydroxide(forpHadjustment)

6.2Incompatibilities

Thismedicinalproductmustnotbemixedwithothermedicinalproductsexceptthosementionedinsection6.6.

6.3ShelfLife

Unopenedvials:2years.

Reconstitutedsolution:

Chemicalandphysicalin-usestabilityhasbeendemonstratedfor24hoursat25°Cforthereconstitutedproductwitha

concentrationof38mg/ml.Solutionsofreconstitutedgemcitabineshouldnotberefrigerated,ascrystallisationmay

occur.

Chemicalandphysicalin-usestabilityhasbeendemonstratedforambientconditions(15-25°C,ambientlight)orina

refrigerator(2-8°C)foratmost72hours(3days)forthedilutedsolutionatconcentrationsbetween0.1mg/mLand30

mg/mLin0.9%sodiumchlorideforinjection.

Fromamicrobiologicalpointofview,thereconstitutedanddilutedproductshouldbeusedimmediately.Ifnotused

immediately,in-usestoragetimesandconditionspriortousearetheresponsibilityoftheuserandwouldnormallynot

belongerthan24hoursatroomtemperature,unlessreconstitution(andfurtherdilution,ifapplicable)hastakenplace

incontrolledandvalidatedasepticconditions.

6.4Specialprecautionsforstorage

Unopenedvial:

Nospecialstorageconditionsarerequired.

Afteropening:

Forstorageconditionsofthereconstitutedmedicinalproductseesection6.3.

6.5Natureandcontentsofcontainer

ColourlessTypeIglassvial,stopperedwithagreybromobutylrubberstopperandsealedwithanaluminiumsealwith

acolouredpolypropylenecap.Vialsmaybesheathedinprotectivesleeves.

Packsizes:1,5or10vials.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Handling

Thenormalsafetyprecautionsforcytostaticagentsmustbeobservedwhenpreparinganddisposingoftheinfusion

solution.Handlingofthesolutionforinfusionshouldbedoneinasafetyboxandprotectivecoatsandglovesshouldbe

used.Ifnosafetyboxisavailable,theequipmentshouldbesupplementedwithamaskandprotectiveglasses.Ifthe

preparationcomesintocontactwiththeeyes,thismaycauseseriousirritation.Theeyesshouldberinsedimmediately

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Ifthereislastingirritation,adoctorshouldbeconsulted.Ifthesolutionisspilledontheskin,rinsethoroughlywith

water.

Instructionsforreconstitution(andfurtherdilution,ifperformed)

Theonlyapproveddiluentforreconstitutionofgemcitabinesterilepowderissodiumchloride9mg/ml(0.9%)solution

forinjection(withoutpreservative).Duetosolubilityconsiderations,themaximumconcentrationforgemcitabineupon

reconstitutionis40mg/ml.Reconstitutionatconcentrationsgreaterthan40mg/mlmayresultinincompletedissolution

andshouldbeavoided.

Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

TevaPharmaB.V.

Computerweg10

3542DRUtrecht

TheNetherlands

8MARKETINGAUTHORISATIONNUMBER

PA749/97/3

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:9thApril2010

Useaseptictechniqueduringthereconstitutionandanyfurtherdilutionofgemcitabinefor

intravenousinfusionadministration.

Toreconstitute,add50mlofsterilesodiumchloride9mg/ml(0.9%)solutionfor

injection,withoutpreservative,tothe2gvial.Thetotalvolumeafterreconstitutionis52.6

ml(2gvial).Thisyieldsagemcitabineconcentrationof38mg/ml,whichincludes

accountingforthedisplacementvolumeofthelyophilisedpowder.Shaketodissolve.

Furtherdilutionwithsterilesodiumchloride9mg/ml(0.9%)solutionforinjection,

withoutpreservativecanbedone.Reconstitutedsolutionisaclearcolourlesstolight

straw-colouredsolution.

Parenteralmedicinalproductsshouldbeinspectedvisuallyforparticulatematterand

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