GEMCITABINE EBEWE

Main information

  • Trade name:
  • GEMCITABINE EBEWE
  • Dosage:
  • 40 Mg/Ml
  • Pharmaceutical form:
  • Concentrate for Soln for Inf
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0789/022/001
  • Authorization date:
  • 21-01-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

GemcitabineEbewe40mg/mlconcentrateforsolutionforinfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

1mlcontains45.6mggemcitabinehydrochloridewhichcorrespondsto40mgoftheactiveingredientgemcitabine.

Each5mlvialcontains200mggemcitabine(ashydrochloride).

Each25mlvialcontains1000mggemcitabine(ashydrochloride).

Each50mlvialcontains2000mggemcitabine(ashydrochloride).

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Concentrateforsolutionforinfusion

Clear,colourlessoralmostcolourlesssolution.

pH:2.0–2.8

Osmolarity:270–280mOsmol/kg

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/m²,givenby30-minuteinfusion.Thedoseshouldbegivenon

days1,8and15ofeach28-daycycleincombinationwithcisplatin.Cisplatinisgivenatarecommendeddoseof

70mg/m²onday1followinggemcitabineorday2ofeach28-daycycle.This4-weekcycleisthenrepeated.Dosage

reductionwitheachcycleorwithinacyclemaybeappliedbaseduponthegradeoftoxicityexperiencedbythepatient.

Pancreaticcancer

Monotherapy

Therecommendeddoseofgemcitabineis1000mg/m²,givenby30-minuteintravenousinfusion.Thisshouldbe

repeatedonceweeklyforupto7weeksfollowedbyaweekofrest.Subsequentcyclesshouldconsistofinjectionsonce

weeklyfor3consecutiveweeksoutofevery4weeks.Dosagereductionwitheachcycleorwithinacyclemaybe

appliedbaseduponthegradeoftoxicityexperiencedbythepatient.

NonsmallCelllungcancer

Monotherapy

Therecommendeddoseofgemcitabineis1000mg/m²,givenby30-minuteintravenousinfusion.Thisshouldbe

repeatedonceweeklyfor3weeks,followedbya1-weekrestperiod.This4-weekcycleisthenrepeated.Dosage

reductionwitheachcycleorwithinacyclemaybeappliedbaseduponthegradeoftoxicityexperiencedbythepatient.

Combinationuse

Therecommendeddoseforgemcitabineis1250mg/m²bodysurfaceareagivenasa30-minuteintravenousinfusionon

day1and8ofthetreatmentcycle(21days)incombinationwithcisplatin.Cisplatinhasbeenusedatdosesbetween75

-100mg/m²onday1followinggemcitabineorday2onceevery3weeks.Dosagereductionwitheachcycleorwithin

acyclemaybeappliedbaseduponthegradeoftoxicityexperiencedbythepatient.

Breastcancer

Combinationuse

Gemcitabineincombinationwithpaclitaxelisrecommendedusingpaclitaxel(175mg/m²)administeredonday1over

approximately3-hoursasanintravenousinfusion,followedbygemcitabine(1250mg/m²)asa30-minuteintravenous

infusionondays1and8ofeach21-daycycle.Dosereductionwitheachcycleorwithinacyclemaybeappliedbased

uponthegradeoftoxicityexperiencedbythepatient.Patientsshouldhaveanabsolutegranulocytecountofatleast

1,500(x10 6

/l)priortoinitiationofgemcitabine+paclitaxelcombination.

Ovariancancer

Combinationuse

Gemcitabineincombinationwithcarboplatinisrecommendedusinggemcitabine1000mg/m²administeredondays1

and8ofeach21-daycycleasa30-minuteintravenousinfusion.Aftergemcitabine,carboplatinwillbegivenonday1

consistentwithatargetAreaundercurve(AUC)of4.0mg/ml·min.Dosagereductionwitheachcycleorwithinacycle

maybeappliedbaseduponthegradeoftoxicityexperiencedbythepatient.

Monitoringfortoxicityanddosemodificationduetotoxicity

Dosemodificationduetononhaematologicaltoxicity

Periodicphysicalexaminationandchecksofrenalandhepaticfunctionshouldbemadetodetectnon-haematological

toxicity.Dosagereductionwitheachcycleorwithinacyclemaybeappliedbaseduponthegradeoftoxicity

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

therapywithgemcitabineshouldbewithheldordecreaseddependingonthejudgementofthetreatingphysician.Doses

shouldbewithhelduntiltoxicityhasresolvedintheopinionofthephysician.

Forcisplatin,carboplatin,andpaclitaxeldosageadjustmentincombinationtherapy,pleaserefertothecorresponding

SummaryofProductCharacteristics.

Dosemodificationduetohaematologicaltoxicity

Initiationofacycle

Forallindications,thepatientmustbemonitoredbeforeeachdoseforplateletandgranulocytecounts.Patientsshould

haveanabsolutegranulocytecountofatleast1,500(x10 6

/l)andplateletaccountof100,000(x10 6

/l)priortothe

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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

Cycledelayofmorethan1weekduetotoxicity

Methodofadministration

Gemcitabineistoleratedwellduringinfusionandmaybeadministeredambulant.Ifextravasationoccurs,generallythe

infusionmustbestoppedimmediatelyandstartedagaininanotherbloodvessel.Thepatientshouldbemonitored

Dosemodificationofgemcitabinewithinacycleforbladdercancer,NSCLCand

pancreaticcancer,giveninmonotherapyorincombinationwithcisplatin

Absolutegranulocytecount

(x10 6

Plateletcount

(x10 6

Percentageofstandard

doseof

Gemcitabine(%)

>1,000 and >100,000 100

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

<500 or <50,000 Omitdose*

Dosemodificationofgemcitabinewithinacycleforbreastcancer,givenincombination

withpaclitaxel

Absolutegranulocytecount

(x10 6

Plateletcount

(x10 6

Percentageofstandarddose

ofGemcitabine(%)

≥1,200

>75,000 100

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

700-<1,000 and ≥50,000 50

<700 or <50,000 Omitdose*

Dosemodificationofgemcitabinewithinacycleforovariancancer,givenincombination

withcarboplatin

Absolutegranulocytecount

(x10 6

Plateletcount

(x10 6

Percentageofstandard

doseofGemcitabine(%)

>1,500 and ≥100,000 100

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

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Nationalapprovedname40mg/mlconcentrateforsolutionforinfusionmustbedilutedbeforeuse(seesection4.4and

6.6).Itisrecommendedtouselargeveinsforinfusiontopreventdamagetothevesselandextravasation.

Forfurtherinstructionsonreconstitution,seesection6.6

Specialpopulations

Patientswithrenalorhepaticimpairment

Gemcitabineshouldbeusedwithcautioninpatientswithhepaticorrenalinsufficiencyasthereisinsufficient

informationfromclinicalstudiestoallowforcleardoserecommendationsforthesepatientpopulations(seesections

4.4,4.8and5.2).

Elderlypopulation(>65years)

Gemcitabinehasbeenwelltoleratedinpatientsovertheageof65.Thereisnoevidencetosuggestthatdose

adjustments,otherthanthosealreadyrecommendedforallpatients,arenecessaryintheelderly(seesection5.2).

Paediatricpopulation(<18years)

Gemcitabineisnotrecommendedforuseinchildrenunder18yearsofageduetoinsufficientdataonsafetyand

efficacy.

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients.

Breast-feeding(seesection4.6).

4.4Specialwarningsandprecautionsforuse

Prolongationoftheinfusiontimeandincreaseddosingfrequencyhavebeenshowntoincreasetoxicity.

Nationalapprovedname40mg/mlconcentrateforsolutionforinfusionmustbedilutedbeforeuse(seesection4.2and

6.6).Itisrecommendedtouselargeveinsforinfusiontopreventdamagetothevesselandextravasation.

Haematologicaltoxicity

Gemcitabinecansuppressbonemarrowfunctionasmanifestedbyleucopaenia,thrombocytopaeniaandanaemia.

Patientsreceivinggemcitabineshouldbemonitoredpriortoeachdoseforplatelet,leucocyteandgranulocytecounts.

Suspensionormodificationoftherapyshouldbeconsideredwhendrug-inducedbonemarrowdepressionisdetected

(seesection4.2).However,myelosuppressionisshortlivedandusuallydoesnotresultindosereductionandrarelyin

discontinuation.

Peripheralbloodcountsmaycontinuetodeteriorateaftergemcitabineadministrationhasbeenstopped.Inpatientswith

impairedbonemarrowfunction,thetreatmentshouldbestartedwithcaution.Aswithothercytotoxictreatments,the

riskofcumulativebone-marrowsuppressionmustbeconsideredwhengemcitabinetreatmentisgiventogetherwith

otherchemotherapy.

Hepaticand/orrenalinsufficiency

Administrationofgemcitabineinpatientswithconcurrentlivermetastasesorapre-existingmedicalhistoryof

hepatitis,alcoholismorlivercirrhosismayleadtoexacerbationoftheunderlyinghepaticinsufficiency.

PatientswithASTelevationstoleratedgemcitabinewithoutincreasedtoxicity,butpatientswithelevatedbilirubin

levels(>1.6mg/dl)hadasignificantlyincreasedriskofhepatotoxicityaftergemcitabinetherapy.Arecommendation

fordosereductioninthesettingofliverdysfunctionispromoted.

Patientswithrenaldysfunctionpresentedwithunusualsideeffectsinresponsetogemcitabine,especiallyskintoxicity

intheformofdiffuseerythemaanddesquamation(seesection4.8).

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Gemcitabineshouldbeusedwithcautioninpatientswithhepaticinsufficiencyorwithimpairedrenalfunctionasthere

isinsufficientinformationfromclinicalstudiestoallowcleardoserecommendationforthispatientpopulation(see

section4.2).

Concomitantradiotherapy

Concomitantradiotherapy(giventogetheror7daysapart):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).

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Nospecificinteractionstudieshavebeenperformed(seesection5.2)

Radiotherapy

Concurrent(giventogetheror 7daysapart)-Toxicityassociatedwiththismultimodalitytherapyisdependenton

manydifferentfactors,includingdoseofgemcitabine,frequencyofgemcitabineadministration,doseofradiation,

radiotherapyplanningtechnique,thetargettissue,andtargetvolume.Pre-clinicalandclinicalstudieshaveshownthat

gemcitabinehasradiosensitisingactivity.

Inasingletrial,wheregemcitabineatadoseof1,000mg/m²wasadministeredconcurrentlyforupto6consecutive

weekswiththerapeuticthoracicradiationtopatientswithnon-smallcelllungcancer,significanttoxicityintheformof

severe,andpotentiallylifethreateningmucositis,especiallyoesophagitis,andpneumonitiswasobserved,particularly

inpatientsreceivinglargevolumesofradiotherapy[mediantreatmentvolumes4,795cm³].Studiesdonesubsequently

havesuggestedthatitisfeasibletoadministergemcitabineatlowerdoseswithconcurrentradiotherapywith

predictabletoxicity,suchasaphaseIIstudyinnon-smallcelllungcancer,wherethoracicradiationdosesof66Gy

wereappliedconcomitantlywithanadministrationwithgemcitabine(600mg/m²,fourtimes)andcisplatin(80mg/m²

twice)during6weeks.Theoptimumregimenforsafeadministrationofgemcitabinewiththerapeuticdosesofradiation

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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(seesection4.2).

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

Heartfailure

Arrhythmia(mainlysupraventricular)

Vasculardisorders Rare

Hypotension

Veryrare

Clinicalsignsofperipheralvasculitis

Respiratory,thoracicandmediastinal

disorders Verycommon

Dyspnoea–usuallymildandpasses

rapidlywithouttreatment

Bronchospasm–usuallymildand

transientbutmayrequireparenteral

treatment

Common

Cough

Rhinitis

Uncommon

Interstitialpneumonitis(seesection

4.4)

Lungedema

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ARDS(seesection4.4)

Gastrointestinaldisorders Verycommon

Vomiting

Nausea

Common

Diarrhoea

Stomatitisandulcerationofthe

mouth

Constipation

Hepatobiliarydisorders Verycommon

Elevationoflivertransaminases

(ASTandALT)andalkaline

phosphatase

Common

Increasedbilirubin

Rare

Increasedgamma-glutamyl

transferase(GGT)

Skinandsubcutaneoustissuedisorders Verycommon

Allergicskinrashfrequently

associatedwithpruritus

Alopecia

Common

Itching

Sweating

Rare

Ulceration

Vesicleandsoreformation

Scaling

Veryrare

Severeskinreactions,including

desquamationandbullousskin

eruptions

Musculoskeletalandconnectivetissue

disorders Common

Backpain

Myalgia

Renalandurinarydisorders VeryCommon

Haematuria

Mildproteinuria

Increasedcreatinine

Rare

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Postmarketingexperience(spontaneousreports)frequencynotknown(can’tbeestimatedfromtheavailabledata)

Nervoussystemdisorders

Cerebrovascularaccident

Vasculardisorders

Clinicalsignsofgangrene

Gastrointestinaldisorders

Ischaemiccolitis

Hepatobiliarydisorders

Serioushepatotoxicity,includingliverfailureanddeath

Skinandsubcutaneoustissuedisorders

Lyell’sSyndrome,Steven-JohnsonSyndrome

Diffuseerythemaanddesquamationobservedinpatientswithrenaldysfunction(seesection4.4)

Injury,poisoningandproceduralcomplications

Radiationrecall

Combinationuseinbreastcancer

Thefrequencyofgrade3and4haematologicaltoxicities,particularlyneutropaenia,increaseswhengemcitabineis

usedincombinationwithpaclitaxel.However,theincreaseintheseadversereactionsisnotassociatedwithan

increasedincidenceofinfectionsorhaemorrhagicevents.Fatigueandfebrileneutropaeniaoccurmorefrequentlywhen

gemcitabineisusedincombinationwithpaclitaxel.Fatigue,whichisnotassociatedwithanaemia,usuallyresolves

Hemolyticuremicsyndrome(see

section4.4)

Generaldisordersandadministrationsite

conditions Verycommon

Influenza-likesymptoms-themost

commonsymptomsarefever,

headache,chills,myalgia,asthenia

andanorexia.Cough,rhinitis,

malaise,perspirationandsleeping

difficultieshavealsobeenreported.

Oedema/peripheraloedema-including

facialoedema.Oedemaisusually

reversibleafterstoppingtreatment

Common

Fever

Asthenia

Chills

Rare

Injectionsitereactions-mainlymild

innature

Injury,poisoning,andprocedural

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*Grade4neutropaenialastingformorethan7daysoccurredin12.6%ofpatientsinthecombinationarmand5.0%

ofpatientsinthepaclitaxelarm.

Combinationuseinbladdercancer

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,

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)

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

Grade3and4AdverseEvents

GemcitabineplusCisplatinvsPaclitaxelplusCisplatin

%ofPatients

Gemcitabineplus

Cisplatinarm

(N=293) PaclitaxelplusCisplatin

(N=300)

Grade3 Grade4 Grade3 Grade4

HematologicToxicity

Neutrophilcount 24 39 18 57

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Combinationuseinovariancancer

Sensoryneuropathywasalsomorefrequentinthecombinationarmthanwithsingleagentcarboplatin

4.9Overdose

Thereisnoknownantidoteforoverdoseofgemcitabine.Dosesashighas5700mg/m²havebeenadministeredby

intravenousinfusionover30minutesevery2weekswithclinicallyacceptabletoxicity.Intheeventofsuspected

Anaemia 27 1 12 1

Infection 2 1 4 2

Febrileneutropaenia 1 3 2 14

Non-hematologicToxicity

Cardiactoxicity 3 1 0 1

Renaltoxicity 2 1 0 0

Nausea 37 0 25 0

Vomiting 7 28 3 21

Diarrhea 2 1 1 6

Hypersensitivity 0 0 2 1

Weakness 17 0 13 1

Neuropathy 9 0 5 0

Alltoxiceffects,highestGrade 21 68

4Grade5 19 68

5Grade5

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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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:pyrimidineanalogues

ATCcode:L01BC05

Cytotoxicactivityincellcultures

Gemcitabineshowssignificantcytotoxiceffectsagainstavarietyofculturedmurineandhumantumourcells.Itsaction

isphase-specificsuchthatgemcitabineprimarilykillscellsthatareundergoingDNAsynthesis(Sphase)and,under

certaincircumstances,blockstheprogressionofcellsatthejunctionoftheG1/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.Differences

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

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

Breastcancer

InarandomisedphaseIIIstudyof529patientswithinoperable,locallyrecurrentormetastaticbreastcancerwith

relapseafteradjuvant/neoadjuvantchemotherapy,gemcitabineincombinationwithpaclitaxelshowedastatistically

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

patientstreatedwithgemcitabine/paclitaxelcomparedtopatientstreatedwithpaclitaxel.After377deaths,theoverall

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

gemcitabine/paclitaxelcomparedtopatientstreatedwithpaclitaxelandtheoverallresponseratewas41.4%and26.2%

respectively(p=0.0002).

5.2Pharmacokineticproperties

Thepharmacokineticsofgemcitabinehavebeenexaminedin353patientsinsevenstudies.The121womenand232

menrangedinagefrom29to79years.Ofthesepatients,approximately45%hadnonsmallcelllungcancerand35%

werediagnosedwithpancreaticcancer.Thefollowingpharmacokineticparameterswereobtainedfordosesranging

from500to2,592mg/m²thatwereinfusedfrom0.4to1.2hours.

Peakplasmaconcentrations(obtainedwithin5minutesoftheendoftheinfusion)were3.2to45.5µg/ml.Plasma

concentrationsoftheparentcompoundfollowingadoseof1,000mg/m²/30minutesaregreaterthan5µg/mlfor

approximately30minutesaftertheendoftheinfusion,andgreaterthan0.4µg/mlforanadditionalhour.

Distribution

Thevolumeofdistributionofthecentralcompartmentwas12.4l/m²forwomenand17.5l/m²formen(interindividual

variabilitywas91.9%).Thevolumeofdistributionoftheperipheralcompartmentwas47.4l/m².Thevolumeofthe

peripheralcompartmentwasnotsensitivetogender.

Theplasmaproteinbindingwasconsideredtobenegligible.

Halflife:Thisrangedfrom42to94minutesdependingonageandgender.Fortherecommendeddosingschedule,

gemcitabineeliminationshouldbevirtuallycompletewithin5to11hoursofthestartoftheinfusion.Gemcitabinedoes

notaccumulatewhenadministeredonceweekly.

Metabolism

Gemcitabineisrapidlymetabolisedbycytidinedeaminaseintheliver,kidney,bloodandothertissues.Intracellular

metabolismofgemcitabineproducesthegemcitabinemono,diandtriphosphates(dFdCMP,dFdCDPanddFdCTP)of

whichdFdCDPanddFdCTPareconsideredactive.Theseintracellularmetaboliteshavenotbeendetectedinplasmaor

urine.Theprimarymetabolite,2'deoxy2',2'difluorouridine(dFdU),isnotactiveandisfoundinplasmaandurine.

Excretion

Systemicclearancerangedfrom29.2l/hr/m²to92.2/hr/m²dependingongenderandage(interindividualvariability

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Althoughrapid,clearanceforbothmenandwomenappearstodecreasewithage.Fortherecommendedgemcitabine

doseof1000mg/m²givenasa30minuteinfusion,lowerclearancevaluesforwomenandmenshouldnotnecessitatea

decreaseinthegemcitabinedose.

Urinaryexcretion:Lessthan10%isexcretedasunchangeddrug.

Renalclearancewas2to7l/hr/m².

Duringtheweekfollowingadministration,92to98%ofthedoseofgemcitabineadministeredisrecovered,99%inthe

urine,mainlyintheformofdFdUand1%ofthedoseisexcretedinfaeces.

dFdCTPkinetics

Thismetabolitecanbefoundinperipheralbloodmononuclearcellsandtheinformationbelowreferstothesecells.

Intracellularconcentrationsincreaseinproportiontogemcitabinedosesof35-350mg/m²/30minutes,whichgive

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

notincrease,suggestingthattheformationissaturableinthesecells.

Halflifeofterminalelimination:0.7-12hours.

dFdUkinetics

Peakplasmaconcentrations(3-15minutesafterendof30minuteinfusion,1000mg/m²):28-52µg/ml.Trough

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

concentrationversustimecurve,meanhalflifeofterminalphase65hours(range33-84hr).

FormationofdFdUfromparentcompound:91%-98%.

Meanvolumeofdistributionofcentralcompartment:18l/m²(range11-22l/m²).

Meansteadystatevolumeofdistribution(Vss):150l/m²(range96-228l/m²).

Tissuedistribution:Extensive.

Meanapparentclearance:2.5l/hr/m²(range1-4l/hr/m²).

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

Waterforinjections

DilutedHydrochloricAcid(forpHadjustment)

6.2Incompatibilities

Thismedicinalproductmustnotbemixedwithothermedicinalproductsexceptthosementionedinsection6.6.

6.3ShelfLife

Aspackagedforsale:

18months

Stabilityafterfirstopening:

Chemicalandphysicalstabilityhasbeendemonstratedfor28daysat2°C–8°Candatroomtemperature(15°C–25°

Fromamicrobiologicalpointofview,theproductshouldbeusedimmediately.Ifnotusedimmediately,in-usestorage

timesandconditionspriortousearetheresponsibilityoftheuserandwouldnormallynotbelongerthan24hoursat2°

C–8°C,unlessdilutionhastakenplaceincontrolledandvalidatedasepticconditions.

Shelflifeafterdilution:

Chemicalandphysicalin-usestabilityhasbeendemonstratedfor28daysat2°C–8°Candatroomtemperaturein

glucose5%orsodiumchloride0.9%(1.0mg/ml,7.0mg/mland25mg/ml).

Fromamicrobiologicalpointofview,theproductshouldbeusedimmediately.Ifnotusedimmediately,in-usestorage

timesandconditionspriortousearetheresponsibilityoftheuserandwouldnormallynotbelongerthan24hoursat2°

C–8°C,unlessdilutionhastakenplaceincontrolledandvalidatedasepticconditions.

6.4Specialprecautionsforstorage

Aspackagedforsale:

Storeinarefrigerator(2°C–8°C).Donotfreeze.

Forstorageconditionofthedilutedmedicinalproduct,seesection6.3.

6.5Natureandcontentsofcontainer

Colourlessglass(typeI)vials,closedwithgreyrubberstoppersacc.toPh.Eur(typeI),withorwithoutaprotective

plasticoverwrap(Onco-Safe).“Onco-Safe”doesnotcomeintocontactwiththemedicinalproductandprovides

additionaltransportprotection,whichincreasesthesafetyforthemedicalandpharmaceuticalpersonnel.

Packsizes:

200mg/5ml:1vial,5vials,10vials

1000mg/25ml:1vial

2000mg/50ml:1vial

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Parenteraldrugsshouldbeinspectedvisuallyforparticulatematteranddiscolouration,priortoadministration,

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Ifthesolutionappearsdiscolouredorcontainsvisibleparticles,itshouldbediscarded.

GemcitabineEbewe40mg/mlconcentrateforsolutionforinfusionmustbedilutedbeforeuse(seesection4.2and4.4).

Itisrecommendedtouselargeveinsforinfusiontopreventdamagetothevesselandextravasation.

Transfertherequiredquantityofsolutionunderasepticconditionsintoasuitableinfusionbagorbottle.Thesolution

maybeadministeredaspreparedorfurtherdilutedwith0.9%sodiumchloridesolutionor5%glucosesolutionas

appropriate.Mixtheliquidsthoroughlybyrotatingbyhand.

Handling

Thenormalsafetyprecautionsforcytostaticagentsmustbeobservedwhenpreparinganddisposingoftheinfusion

solution.Handlingofthesolutionforinfusionshouldbedoneinanisolatororacytotoxicsafetycabinet.Protective

clothingshouldbeusedasrequired(protectivecoat,gloves,mask,protectivegoggles).

Ifthepreparationcomesintocontactwiththeeyes,thismaycauseseriousirritation.Theeyesshouldberinsed

immediatelyandthoroughlywithwater.Ifthereislastingirritation,adoctorshouldbeconsulted.Ifthesolutionis

spilledontheskin,rinsethoroughlywithwater.

Remnantsofthemedicinalproductaswellasallmaterialsthathavebeenusedforreconstitution,fordilutionand

administrationmustbedestroyedaccordingtohospitalstandardproceduresapplicabletocytotoxicagentsandin

accordancewithlocalrequirementsrelatedtothedisposalofhazardouswaste.

7MARKETINGAUTHORISATIONHOLDER

EbewePharmaGes.m.b.HNfg.KG

Mondseestrasse11

4866Unterach

Austria

8MARKETINGAUTHORISATIONNUMBER

PA789/22/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:21stJanuary2011

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