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:
  • PA1226/008/002
  • Authorization date:
  • 09-10-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA1226/008/002

CaseNo:2071993

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

FlynnPharmaLtd

AltonHouse,4HerbertStreet,Dublin2,Ireland

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Gemcitabine1gpowderforsolutionforinfusion

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom17/11/2009until08/10/2014.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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Date Printed 17/11/2009 CRN 2071993 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Gemcitabine1gpowderforsolutionforinfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Onevialcontainsgemcitabinehydrochlorideequivalentto1,000mggemcitabine.

Afterreconstitution,thesolutioncontains38mg/mlofgemcitabine.

Excipients

Each1,000mgvialcontains17.5mg(<1mmol)sodium.

Forafulllistofexcipientsseesection6.1.

3PHARMACEUTICALFORM

Powderforsolutionforinfusion.

Whitetooff-whiteplugorpowder.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Gemcitabineisindicatedforthetreatmentoflocallyadvancedormetastaticbladdercancerincombinationwith

cisplatin.

Gemcitabineisindicatedfortreatmentofpatientswithlocallyadvancedormetastaticadenocarcinomaofthepancreas.

Gemcitabine,incombinationwithcisplatinisindicatedasfirstlinetreatmentofpatientswithlocallyadvancedor

metastaticnon-smallcelllungcancer(NSCLC).Gemcitabinemonotherapycanbeconsideredinelderlypatientsor

thosewithperformancestatus2.

Gemcitabineisindicatedforthetreatmentofpatientswithlocallyadvancedormetastaticepithelialovariancarcinoma,

incombinationwithcarboplatin,inpatientswithrelapseddiseasefollowingarecurrence-freeintervalofatleast

6monthsafterplatinum-based,first-linetherapy.

Gemcitabine,incombinationwithpaclitaxel,isindicatedforthetreatmentofpatientswithunresectable,locally

recurrentormetastaticbreastcancerwhohaverelapsedfollowingadjuvant/neoadjuvantchemotherapy.Prior

chemotherapyshouldhaveincludedananthracyclineunlessclinicallycontraindicated.

4.2Posologyandmethodofadministration

Gemcitabineshouldonlybeprescribedbyaphysicianqualifiedintheuseofanti-cancerchemotherapy.

Recommendedposology

BladderCancer

Combinationuse

Therecommendeddoseforgemcitabineis1,000mg/m 2

,givenby30-minuteinfusion.Thedoseshouldbegivenon

Days1,8,and15ofeach28-daycycleincombinationwithcisplatin.Cisplatinisgivenatarecommendeddoseof

70mg/m 2

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Dosagereductionwitheachcycleorwithinacyclemaybeappliedbaseduponthegradeoftoxicityexperiencedbythe

patient.

Pancreaticcancer

Therecommendeddoseofgemcitabineis1,000mg/m 2

,givenby30-minuteintravenousinfusion.Thisshouldbe

repeatedonceweeklyforupto7weeksfollowedbyaweekofrest.Subsequentcyclesshouldconsistofinjectionsonce

weeklyfor3consecutiveweeksoutofevery4weeks.Dosagereductionwitheachcycleorwithinacyclemaybe

appliedbaseduponthegradeoftoxicityexperiencedbythepatient.

Non-smallcelllungcancer

Monotherapy

Therecommendeddoseofgemcitabineis1,000mg/m 2

,givenby30-minuteintravenousinfusion.Thisshouldbe

repeatedonceweeklyfor3weeks,followedbya1-weekrestperiod.This4-weekcycleisthenrepeated.Dosage

reductionwitheachcycleorwithinacyclemaybeappliedbaseduponthegradeoftoxicityexperiencedbythepatient.

Combinationuse

Therecommendeddoseforgemcitabineis1,250mg/m 2

bodysurfaceareagivenasa30-minuteintravenousinfusion

onDay1and8ofthetreatmentcycle(21days).Dosagereductionwitheachcycleorwithinacyclemaybeapplied

baseduponthegradeoftoxicityexperiencedbythepatient.Cisplatinhasbeenusedatdosesbetween75-100mg/m 2

onceevery3weeks.

BreastCancer

Combinationuse

Gemcitabineincombinationwithpaclitaxel,isrecommendedusingpaclitaxel(175mg/m 2

)administeredonDay1over

approximately3hoursasanintravenousinfusion,followedbygemcitabine(1,250mg/m 2

)asa30-minuteintravenous

infusiononDays1and8ofeach21-daycycle.Dosereductionwitheachcycleorwithinacyclemaybeappliedbased

uponthegradeoftoxicityexperiencedbythepatient.Patientsshouldhaveanabsolutegranulocytecountofatleast

1,500(x10 6

/l)priortoinitiationofgemcitabine+paclitaxelcombination.

Ovariancancer

Combinationuse

Gemcitabineincombinationwithcarboplatinisrecommendedusinggemcitabine1,000mg/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,

therapywithgemcitabineshouldbewithheldordecreaseddependingonthejudgementofthetreatingphysician.Doses

shouldbewithhelduntiltoxicityhasresolvedintheopinionofthephysician.

Forcisplatin,carboplatin,andpaclitaxeldosageadjustmentincombinationtherapy,pleaserefertothecorresponding

SummaryofProductCharacteristics.

Dosemodificationduetohaematologicaltoxicity

Initiationofacycle

Forallindications,thepatientmustbemonitoredbeforeeachdoseforplateletandgranulocytecounts.Patientsshould

haveanabsolutegranulocytecountofatleast1,500(x10 6

/l)andplateletcountof100,000(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

carefullyaftertheadministration.

Dosemodificationofgemcitabinewithinacycleforbladdercancer,NSCLC

andpancreaticcancer,giveninmonotherapyorincombinationwith

cisplatin

Absolutegranulocytecount

(x10 6

/l) Plateletcount

(x10 6

/l) Percentageofstandard

doseofgemcitabine(%)

>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) Percentageofstandard

doseofgemcitabine(%)

≥1,200 and >75,000 100

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

700-<1,000 and ≥50,000 50

<700 or <50,000 Omitdose*

Dosemodificationofgemcitabinewithinacycleforovariancancer,givenin

combinationwithcarboplatin

Absolutegranulocytecount

(x10 6

/l) Plateletcount

(x10 6

/l) Percentageofstandard

doseofgemcitabine(%)

>1,500 and ≥100,000 100

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

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Specialpopulations

Patientswithrenalorhepaticimpairment

Gemcitabineshouldbeusedwithcautioninpatientswithhepaticorrenalinsufficiencyasthereisinsufficient

informationfromclinicalstudiestoallowforcleardoserecommendationforthesepatientpopulations(seesections4.4

and5.2).

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

section4.2).

Concomitantradiotherapy

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

recommendationsforuse).

Livevaccinations

Yellowfevervaccineandotherliveattenuatedvaccinesarenotrecommendedinpatientstreatedwithgemcitabine(see

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Cardiovascular

Duetotheriskofcardiacand/orvasculardisorderswithgemcitabine,particularcautionmustbeexercisedwithpatients

presentingahistoryofcardiovascularevents.

Pulmonary

Pulmonaryeffects,sometimessevere(suchaspulmonaryoedema,interstitialpneumonitisoradultrespiratorydistress

syndrome(ARDS))havebeenreportedinassociationwithgemcitabinetherapy.Theaetiologyoftheseeffectsis

unknown.Ifsucheffectsdevelop,considerationshouldbemadetodiscontinuinggemcitabinetherapy.Earlyuseof

supportivecaremeasuresmayhelpamelioratethecondition.

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

Gemcitabine200mgcontains3.5mg(<1mmol)sodiumpervial.Thisshouldbetakenintoconsiderationbypatients

onacontrolledsodiumdiet.

Gemcitabine1,000mgcontains17.5mg(<1mmol)sodiumpervial.Thisshouldbetakenintoconsiderationby

patientsonacontrolledsodiumdiet.

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

isadministeredmorethan7daysbeforeorafterradiation,otherthanradiationrecall.Datasuggestthatgemcitabinecan

bestartedaftertheacuteeffectsofradiationhaveresolvedoratleastoneweekafterradiation.

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

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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%of

patients;proteinuriaandhaematuriareportedinapproximately50%patients;dyspnoeareportedin10-40%ofpatients

(highestincidenceinlungcancerpatients);allergicskinrashesoccurinapproximately25%ofpatientsandare

associatedwithitchingin10%ofpatients.

Thefrequencyandseverityoftheadversereactionsareaffectedbythedose,infusionrateandintervalsbetweendoses

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

section4.2).

Clinicaltrialdata

Frequenciesaredefinedas:Verycommon( ≥1/10),Common(≥1/100to<1/10),Uncommon(≥1/1,000to<1/100),

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

Thefollowingtableofundesirableeffectsandfrequenciesisbasedondatafromclinicaltrials.Withineachfrequency

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SystemOrganClass FrequencyGrouping

Bloodandlymphaticsystem

disorders Verycommon

Leucopaenia(Neutropaenia

Grade3=19.3%;Grade4=

6%).

Bone-marrowsuppressionisusually

mildtomoderateandmostlyaffects

thegranulocytecount(seesection

4.2).

Thrombocytopaenia

Anaemia

Common

Febrileneutropaenia

Veryrare

Thrombocytosis

Immunesystemdisorders Veryrare

Anaphylactoidreaction

Metabolismandnutritiondisorders Common

Anorexia

Nervoussystemdisorders Common

Headache

Insomnia

Somnolence

Cardiacdisorders Rare

Myocardialinfarct

Vasculardisorders Rare

Hypotension

Respiratory,thoracicand

mediastinaldisorders Verycommon

Dyspnoea-usuallymild

andpassesrapidlywithout

treatment

Common

Cough

Rhinitis

Uncommon

Interstitialpneumonitis(see

section4.4)

Bronchospasm-usually

mildandtransientbutmay

requireparenteraltreatment

Gastrointestinaldisorders Verycommon

Vomiting

Nausea

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Diarrhoea

Stomatitisandulcerationof

themouth

Constipation

Hepatobiliarydisorders Verycommon

Elevationofliver

transaminases(ASTand

ALT)andalkaline

phosphatase

Common

Increasedbilirubin

Rare

Increasedgamma-glutamyl

transferase(GGT)

Skinandsubcutaneoustissue

disorders Verycommon

Allergicskinrash

frequentlyassociatedwith

pruritus

Alopecia

Common

Itching

Sweating

Rare

Ulceration

Vesicleandsoreformation

Scaling

Veryrare

Severeskinreactions,

includingdesquamationand

bullousskineruptions

Musculoskeletalandconnective

tissuedisorders Common

Backpain

Myalgia

Renalandurinarydisorders Verycommon

Haematuria

Mildproteinuria

Generaldisordersand

administrationsiteconditions Verycommon

Influenza-likesymptoms-

themostcommonsymptoms

arefever,headache,chills,

myalgia,astheniaand

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Postmarketingexperience(spontaneousreports)frequencynotknown(can’tbeestimatedfromtheavailabledata)

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

Cough,rhinitis,malaise,

perspiration,andsleeping

difficultieshavealsobeen

reported.

Oedema/peripheraloedema

-includingfacialoedema.

Oedemaisusuallyreversible

afterstoppingtreatment.

Common

Fever

Asthenia

Chills

Rare

Injectionsitereactions-

mainlymildinnature

Injury,poisoningandprocedural

complications Radiationtoxicity(see

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CombinationUseinBreastCancer

ThefrequencyofGrade3and4haematologicaltoxicities,particularlyneutropaenia,increaseswhengemcitabineis

usedincombinationwithpaclitaxel.However,theincreaseintheseadversereactionsisnotassociatedwithan

increasedincidenceofinfectionsorhaemorrhagicevents.Fatigueandfebrileneutropaeniaoccurmorefrequentlywhen

gemcitabineisusedincombinationwithpaclitaxel.Fatigue,whichisnotassociatedwithanaemia,usuallyresolves

afterthefirstcycle.

*Grade4neutropaenialastingformorethan7daysoccurredin12.6%ofpatientsinthecombinationarmand5.0%of

patientsinthepaclitaxelarm.

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,

doxorubicinand

cisplatin)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)

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Combinationuseinovariancancer

Sensoryneuropathywasalsomorefrequentinthecombinationarmthanwithsingleagentcarboplatin.

4.9Overdose

Thereisnoknownantidoteforoverdoseofgemcitabine.Dosesashighas5,700mg/m 2

havebeenadministeredby

intravenousinfusionover30minutesevery2weekswithclinicallyacceptabletoxicity.Intheeventofsuspected

overdose,thepatientshouldbemonitoredwithappropriatebloodcountsandreceivesupportivetherapy,asnecessary.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:pyrimidineanaloguesATCcode:L01BC05

Cytotoxicactivityincellcultures

Gemcitabineshowssignificantcytotoxiceffectsagainstavarietyofculturedmurineandhumantumourcells.Itsaction

isphase-specificsuchthatgemcitabineprimarilykillscellsthatareundergoingDNAsynthesis(S-phase)and,under

certaincircumstances,blockstheprogressionofcellsatthejunctionoftheG

/S-phaseboundary.Invitro,thecytotoxic

effectofgemcitabineisdependentonbothconcentrationandtime.

Antitumouralactivityinpreclinicalmodels

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

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,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.

Non-smallcelllungcancer

InarandomisedphaseIIIstudyof522patientswithinoperable,locallyadvancedormetastaticNSCLC,gemcitabinein

combinationwithcisplatinshowedastatisticallysignificanthigherresponseratethancisplatinalone(31.0%and

12.0%,respectively,p<0.0001).

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,from4.3to

6.9months(p=0.014)wasobservedinpatientstreatedwithgemcitabine/cisplatincomparedtopatientstreatedwith

etoposide/cisplatin.

Inbothstudiesitwasfoundthattolerabilitywassimilarinthetwotreatmentarms.

Ovariancarcinoma

InarandomisedphaseIIIstudy,356patientswithadvancedepithelialovariancarcinomawhohadrelapsedatleast

6monthsaftercompletingplatinumbasedtherapywererandomisedtotherapywithgemcitabineandcarboplatin

(GCb),orcarboplatin(Cb).Astatisticallysignificantprolongationofthetimetoprogressionofdisease,from5.8to

8.6months(log-rankp=0.0038)wasobservedinthepatientstreatedwithGCbcomparedtopatientstreatedwithCb.

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

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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

approximately30minutesaftertheendoftheinfusionandgreaterthan0.4µg/mlforanadditionalhour.

Distribution

Thevolumeofdistributionofthecentralcompartmentwas12.4l/m 2

forwomenand17.5l/m 2

formen(inter-

individualvariabilitywas91.9%).Thevolumeofdistributionoftheperipheralcompartment:47.4l/m 2

.Thevolumeof

theperipheralcompartmentwasnotsensitivetogender.

Theplasmaproteinbindingwasconsideredtobenegligible.

Half-life:thisrangedfrom42to94minutesdependingonageandgender.Fortherecommendeddosingschedule,

gemcitabineeliminationshouldbevirtuallycompletewithin5to11hoursofthestartoftheinfusion.Gemcitabinedoes

notaccumulatewhenadministeredonceweekly.

Metabolism

Gemcitabineisrapidlymetabolisedbycytidinedeaminaseintheliver,kidney,bloodandothertissues.

Intracellularmetabolismofgemcitabineproducesthegemcitabinemono,diandtriphosphates(dFdCMP,dFdCDPand

dFdCTP)ofwhichdFdCDPanddFdCTPareconsideredactive.Theseintracellularmetaboliteshavenotbeendetected

inplasmaorurine.Theprimarymetabolite,2'-deoxy-2',2'-difluorouridine(dFdU),isnotactiveandisfoundinplasma

andurine.

Excretion

Systemicclearancerangedfrom29.2l/hr/m 2

to92.2l/hr/m 2

dependingongenderandage(inter-individualvariability

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

bothmenandwomenappearstodecreasewithage.Fortherecommendedgemcitabinedoseof1,000mg/m 2

givenasa

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

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Half-lifeofterminalelimination:0.7-12hours.

dFdUkinetics

Peakplasmaconcentrations(3-15minutesafterendof30-minuteinfusion,1,000mg/m 2

):28-52µg/ml.Trough

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

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

FormationofdFdUfromparentcompound:91%-98%.

Meanvolumeofdistributionofcentralcompartment:18l/m 2

(range11-22l/m 2

Meansteady-statevolumeofdistribution(Vss):150l/m 2

(range96-228l/m 2

Tissuedistribution:extensive.

Meanapparentclearance:2.5l/hr/m 2

(range1-4l/hr/m 2

Urinaryexcretion:all.

Gemcitabineandpaclitaxelcombinationtherapy:

Combinationtherapydidnotalterthepharmacokineticsofeithergemcitabineorpaclitaxel.

Gemcitabineandcarboplatincombinationtherapy

Whengivenincombinationwithcarboplatinthepharmacokineticsofgemcitabinewerenotaltered.

Renalimpairment

Mildtomoderaterenalinsufficiency(GFRfrom30ml/minto80ml/min)hasnoconsistent,significanteffecton

gemcitabinepharmacokinetics.

5.3Preclinicalsafetydata

Inrepeat-dosestudiesofupto6monthsindurationinmiceanddogs,theprincipalfindingwasscheduleanddose-

dependenthaematopoieticsuppressionwhichwasreversible.

Gemcitabineismutagenicinaninvitromutationtestandaninvivobonemarrowmicronucleustest.Longtermanimal

studiesevaluatingthecarcinogenicpotentialhavenotbeenperformed.

Infertilitystudies,gemcitabinecausedreversiblehypospermatogenesisinmalemice.Noeffectonthefertilityof

femaleshasbeendetected.

Evaluationofexperimentalanimalstudieshasshownreproductivetoxicitye.g.birthdefectsandothereffectsonthe

developmentoftheembryoorfoetus,thecourseofgestationorperi-andpostnataldevelopment.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Gemcitabine1,000mgcontains:

Mannitol(E421)

Sodiumacetate(E262)

Hydrochloricacid(E507)(forpHadjustment)

Sodiumhydroxide(E524)(forpHadjustment)

6.2Incompatibilities

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6.3ShelfLife

Unopenedvials:2years.

Reconstitutedsolution:

Chemicalandphysicalin-usestabilityhasbeendemonstratedfor24hoursat20-25°C.Fromamicrobiologicalpointof

view,theproductshouldbeusedimmediately.Ifnotusedimmediately,in-usestoragetimesandconditionspriortouse

aretheresponsibilityoftheuserandwouldnormallynotbelongerthan24hoursatroomtemperature,unless

reconstitution(andfurtherdilution,ifapplicable)hastakenplaceincontrolledandvalidatedasepticconditions.

Solutionsofreconstitutedgemcitabineshouldnotberefrigerated,ascrystallisationmayoccur.

6.4Specialprecautionsforstorage

Unopenedvials:thismedicinalproductdoesnotrequireanyspecialstorageconditions.

Forstorageconditionsofthereconstitutedmedicinalproductseesection6.3.

6.5Natureandcontentsofcontainer

TypeIclearglassvials,stopperedwithagreybromobutylrubberstopperandsealedwithanaluminiumflip-offcap,

combinedwithapolypropylenedisk.

Eachpackcontains1vial.

6.6Specialprecautionsfordisposal

Handling

Thenormalsafetyprecautionsforcytostaticagentsmustbeobservedwhenpreparinganddisposingoftheinfusion

solution.Handlingofthesolutionforinfusionshouldbedoneinasafetyboxandprotectivecoatsandglovesshouldbe

used.Ifnosafetyboxisavailable,theequipmentshouldbesupplementedwithamaskandprotectiveglasses.

Ifthepreparationcomesintocontactwiththeeyes,thismaycauseseriousirritation.Theeyesshouldberinsed

immediatelyandthoroughlywithwater.Ifthereislastingirritation,adoctorshouldbeconsulted.Ifthesolutionis

spilledontheskin,rinsethoroughlywithwater.

Instructionsforreconstitution(andfurtherdilution,ifperformed)

Theonlyapproveddiluentforreconstitutionofgemcitabinesterilepowderissodiumchloride9mg/ml(0.9%)solution

forinjection(withoutpreservative).Duetosolubilityconsiderations,themaximumconcentrationforgemcitabineupon

reconstitutionis40mg/ml.Reconstitutionatconcentrationsgreaterthan40mg/mlmayresultinincompletedissolution

andshouldbeavoided.

Useaseptictechniqueduringthereconstitutionandanyfurtherdilutionofgemcitabineforintravenousinfusion

administration.

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

200mgvialor25mlofsterilesodiumchloride9mg/ml(0.9%)solutionforinjection,withoutpreservative,tothe

1,000mgvial.Thetotalvolumeafterreconstitutionis5.26ml(200mgvial)or26.3ml(1,000mgvial)respectively.

Thisyieldsagemcitabineconcentrationof38mg/ml,whichincludesaccountingforthedisplacementvolumeofthe

lyophilisedpowder.Shaketodissolve.Furtherdilutionwithsterilesodiumchloride9mg/ml(0.9%)solutionfor

injection,withoutpreservativecanbedone.Reconstitutedsolutionisaclearcolourlesstolightstraw-colouredsolution.

Parenteralmedicinaldrugsshouldbeinspectedvisuallyforparticulatematteranddiscolourationpriorto

administration.Ifparticulatematterisobserved,donotadminister.

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7MARKETINGAUTHORISATIONHOLDER

FlynnPharmaLtd

AltonHouse

4HerbertStreet

Dublin2

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA1226/8/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:9thOctober2009

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