GEMCITABINE MEDAC

Main information

  • Trade name:
  • GEMCITABINE MEDAC
  • Dosage:
  • 200 Milligram
  • Pharmaceutical form:
  • Pdr for Soln for Infusion
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0623/012/001
  • Authorization date:
  • 31-07-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Gemcitabinemedac200mgpowderforsolutionforinfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Onevialcontainsgemcitabinehydrochlorideequivalentto200mggemcitabine.

Afterreconstitution,thesolutioncontains38mg/mlofgemcitabine.

Excipients

Each200mgvialcontains3.5mgsodium(<1mmol)sodium.

Forafulllistofexcipientsseesection6.1.

3PHARMACEUTICALFORM

Powderforsolutionforinfusion

Whitetooff-whitepowder.

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 -minuteintravenousinfusion.Thedoseshouldbe

givenonDays1,8and15ofeach28 -daycycleincombinationwithcisplatin.

Cisplatinisgivenatarecommendeddoseof70mg/m 2

onDay1followinggemcitabineorday2ofeach28 -daycycle.

This4 -weekcycleisthenrepeated.Dosagereductionwitheachcycleorwithinacyclemaybeappliedbaseduponthe

gradeoftoxicityexperiencedbythepatient.

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 -minuteintravenousinfusion

onDay1and8ofthetreatmentcycle(21days).Dosagereductionwitheachcycleorwithinacyclemaybeapplied

baseduponthegradeoftoxicityexperiencedbythepatient.

Cisplatinhasbeenusedatdosesbetween75-100mg/m 2

onceevery3weeks.

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

Dosemodificationduetononhaematologicaltoxicity

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toxicity.Dosagereductionwitheachcycleorwithinacyclemaybeappliedbaseduponthegradeoftoxicity

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

therapywithgemcitabineshouldbewithheldordecreaseddependingonthejudgementofthetreatingphysician.Doses

shouldbewithhelduntiltoxicityhasresolvedintheopinionofthephysician.

Forcisplatin,carboplatin,andpaclitaxeldosageadjustmentincombinationtherapy,pleaserefertothecorresponding

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Dosemodificationduetohaematologicaltoxicity

Initiationofacycle

Forallindications,thepatientmustbemonitoredbeforeeachdoseforplateletandgranulocytecounts.Patientsshould

haveanabsolutegranulocytecountofatleast1,500(x10 6

/l)andplateletaccountof100,000(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) Percentageofstandard

doseofgemcitabine(%)

>1,000

>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) Percentageofstandard

doseofgemcitabine(%)

1,200

>75,000 100

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

700-<1,000 and 50,000 50

<700 or <50,000 Omitdose*

Dosemodificationofgemcitabinewithinacycleforovariancancer,givenin

combinationwithcarboplatin

Absolutegranulocytecount

(x10 6

/l) Plateletcount

(x10 6

/l) Percentageofstandard

doseofgemcitabine(%)

>1,500

100,000 100

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

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Methodofadministration

Gemcitabineistoleratedwellduringinfusionandmaybeadministeredambulant.Ifextravasationoccurs,generallythe

infusionmustbestoppedimmediatelyandstartedagaininanotherbloodvessel.

Thepatientshouldbemonitoredcarefullyaftertheadministration.

Forinstructionsonreconstitution,seesection6.6

Specialpopulations

Patientswithrenalorhepaticimpairment

Gemcitabineshouldbeusedwithcautioninpatientswithhepaticorrenalinsufficiencyasthereisinsufficient

informationfromclinicalstudiestoallowforcleardoserecommendationsforthesepatientpopulations(seesections

4.4and5.2).

Elderlypopulation(>65years)

Gemcitabinehasbeenwelltoleratedinpatientsovertheageof65.Thereisnoevidencetosuggestthatdose

adjustments,otherthanthosealreadyrecommendedforallpatients,arenecessaryintheelderly(seesection5.2).

Children

GemcitabinehasbeenstudiedinlimitedPhaseIandIItrialsinchildreninavarietyoftumourtypes.Thesestudiesdid

notprovidesufficientdatatoestablishtheefficacyandsafetyofgemcitabineinchildren.

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(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

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

The200mgvialofGemcitabinemedaccontains3.5mg(<1mmol)sodiumpervial.

Thisshouldbetakenintoconsiderationbypatientsonacontrolledsodiumdiet.

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

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Theoptimumregimenforsafeadministrationofgemcitabinewiththerapeuticdosesofradiationhasnotyetbeen

determinedinalltumourtypes.

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

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Thefollowingtableofundesirableeffectsandfrequenciesisbasedondatafromclinicaltrials.Withineachfrequency

grouping,undesirableeffectsarepresentedinorderofdecreasingseriousness.

SystemOrganClass Frequencygrouping

Bloodandlymphaticsystemdisorders Verycommon

Leucopaenia(Neutropaenia

Grade3=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

Uncommon

Cerebrovascularaccident

Cardiacdisorders Uncommon

Arrhythmias,predominantly

supraventricularinnature

Heartfailure

Rare

Myocardialinfarct

Vasculardisorders Rare

Clinicalsignsofperipheral

vasculitisandgangrene

Hypotension

Respiratory,thoracicandmediastinal

disorders Verycommon

Dyspnoea–usuallymildand

passesrapidlywithouttreatment

Common

Cough

Rhinitis

Uncommon

Interstitialpneumonitis(see

section4.4)

Bronchospasm–usuallymild

andtransientbutmayrequire

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Rare

Pulmonaryoedema

Adultrespiratorydistress

syndrome(seesection4.4)

Gastrointestinaldisorders Verycommon

Vomiting

Nausea

Common

Diarrhoea

Stomatitisandulcerationof

themouth

Constipation

VeryRare

Ischaemiccolitis

Hepatobiliarydisorders Verycommon

Elevationoflivertransaminases

(ASTandALT)andalkaline

phosphatase

Common

Increasedbilirubin

Uncommon

Serioushepatotoxicity,

includingliverfailureanddeath

Rare

Increasedgamma-glutamyl

transferase(GGT)

Skinandsubcutaneoustissuedisorders Verycommon

Allergicskinrashfrequently

associatedwithpruritus

Alopecia

Common

Itching

Sweating

Rare

Severeskinreactions,including

desquamationandbullousskin

eruptions

Ulceration

Vesicleandsoreformation

Scaling

Veryrare

Toxicepidermalnecroylsis

Stevens-JohnsonSyndrome

Musculoskeletalandconnectivetissue

disorders Common

Backpain

Myalgia

Renalandurinarydisorders VeryCommon

Haematuria

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Combinationuseinbreastcancer

Thefrequencyofgrade3and4haematologicaltoxicities,particularlyneutropaenia,increaseswhengemcitabineis

usedincombinationwithpaclitaxel.However,theincreaseintheseadversereactionsisnotassociatedwithan

increasedincidenceofinfectionsorhaemorrhagicevents.Fatigueandfebrileneutropaeniaoccurmorefrequentlywhen

gemcitabineisusedincombinationwithpaclitaxel.Fatigue,whichisnotassociatedwithanaemia,usuallyresolves

Uncommon

Renalfailure(seesection4.4)

Haemolyticuraemicsyndrome

(seesection4.4)

Generaldisordersandadministrationsite

conditions Verycommon

Influenza-likesymptoms-the

mostcommonsymptomsare

fever,headache,chills,myalgia,

astheniaandanorexia.Cough,

rhinitis,malaise,perspiration

andsleepingdifficultieshave

alsobeenreported.

Oedema/peripheraloedema-

includingfacialoedema.

Oedemaisusuallyreversible

afterstoppingtreatment

Common

Fever

Asthenia

Chills

Rare

Injectionsitereactions-mainly

mildinnature

Injury,poisoning,andprocedural

complications Rare

Radiationtoxicity(seesection

4.5).

Radiationrecall

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)

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*Grade4neutropaenialastingformorethan7daysoccurredin12.6%ofpatientsinthecombinationarmand5.0%of

patientsinthepaclitaxelarm.

Combinationuseinbladdercancer

Combinationuseinovariancancer

Sensoryneuropathywasalsomorefrequentinthecombinationarmthanwithsingleagentcarboplatin

4.9Overdose

Thereisnoknownantidoteforoverdoseofgemcitabine.Dosesashighas5700mg/m 2

havebeenadministeredby

intravenousinfusionover30 -minutesevery2weekswithclinicallyacceptabletoxicity.Intheeventofsuspected

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

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: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

ArandomisedphaseIIIstudyof405patientswithadvancedormetastaticurothelialtransitionalcellcarcinomashowedno

differencebetweenthetwotreatmentarms,gemcitabine/cisplatinversusmethotrexate/vinblastine/adriamycin/cisplatin

(MVAC),intermsofmediansurvival(12.8and14.8monthsrespectively,p=0.547),timetodiseaseprogression(7.4and

7.6monthsrespectively,p=0.842)andresponserate(49.4%and45.7%respectively,p=0.512).However,thecombination

ofgemcitabineandcisplatinhadabettertoxicityprofilethanMVAC.

Pancreaticcancer

InarandomisedphaseIIIstudyof126patientswithadvancedormetastaticpancreaticcancer,gemcitabineshoweda

statisticallysignificanthigherclinicalbenefitresponseratethan5-fluorouracil(23.8%and4.8%respectively,p=0.0022).

Also,astatisticallysignificantprolongationofthetimetoprogressionfrom0.9to2.3months(log-rankp<0.0002)anda

statisticallysignificantprolongationofmediansurvivalfrom4.4to5.7months(log-rankp<0.0024)wasobservedin

patientstreatedwithgemcitabinecomparedtopatientstreatedwith5-fluorouracil.

Nonsmallcelllungcancer

InarandomisedphaseIIIstudyof522patientswithinoperable,locallyadvancedormetastaticNSCLC,gemcitabinein

combinationwithcisplatinshowedastatisticallysignificanthigherresponseratethancisplatinalone(31.0%and12.0%,

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

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

patientstreatedwithgemcitabine/cisplatincomparedtopatientstreatedwithcisplatin.

InanotherrandomisedphaseIIIstudyof135patientswithstageIIIBorIVNSCLC,acombinationofgemcitabineand

cisplatinshowedastatisticallysignificanthigherresponseratethanacombinationofcisplatinandetoposide(40.6%and

21.2%,respectively,p=0.025).Astatisticallysignificantprolongationofthetimetoprogression,from4.3to6.9months

(p=0.014)wasobservedinpatientstreatedwithgemcitabine/cisplatincomparedtopatientstreatedwithetoposide/cisplatin.

Inbothstudiesitwasfoundthattolerabilitywassimilarinthetwotreatmentarms.

Ovariancarcinoma

InarandomisedphaseIIIstudy,356patientswithadvancedepithelialovariancarcinomawhohadrelapsedatleast6

monthsaftercompletingplatinumbasedtherapywererandomisedtotherapywithgemcitabineandcarboplatin(GCb),or

carboplatin(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,locallyrecurrentormetastaticbreastcancerwithrelapse

afteradjuvant/neoadjuvantchemotherapy,gemcitabineincombinationwithpaclitaxelshowedastatisticallysignificant

prolongationoftimetodocumenteddiseaseprogressionfrom3.98to6.14months(log-rankp=0.0002)inpatientstreated

withgemcitabine/paclitaxelcomparedtopatientstreatedwithpaclitaxel.After377deaths,theoverallsurvivalwas18.6

monthsversus15.8months(logrankp=0.0489,HR0.82)inpatientstreatedwithgemcitabine/paclitaxelcomparedto

patientstreatedwithpaclitaxelandtheoverallresponseratewas41.4%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

-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

to92.2/hr/m 2

dependingongenderandage(inter -individualvariability

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

bothmenandwomenappearstodecreasewithage.Fortherecommendedgemcitabinedoseof1000mg/m 2

givenasa

-minuteinfusion,lowerclearancevaluesforwomenandmenshouldnotnecessitateadecreaseinthegemcitabine

dose.

Urinaryexcretion:Lessthan10%isexcretedasunchangeddrug.

Renalclearancewas2to7l/hr/m 2

Duringtheweekfollowingadministration,92to98%ofthedoseofgemcitabineadministeredisrecovered,99%inthe

urine,mainlyintheformofdFdUand1%ofthedoseisexcretedinfaeces.

dFdCTPkinetics

Thismetabolitecanbefoundinperipheralbloodmononuclearcellsandtheinformationbelowreferstothesecells.

Intracellularconcentrationsincreaseinproportiontogemcitabinedosesof35 -350mg/m 2

-minutes,whichgive

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

notincrease,suggestingthattheformationissaturableinthesecells.

Half -lifeofterminalelimination:0.7-12hours.

dFdUkinetics

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

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

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Evaluationofexperimentalanimalstudieshasshownreproductivetoxicitye.g.birthdefectsandothereffectsonthe

developmentoftheembryoorfoetus,thecourseofgestationorperi-andpostnataldevelopment.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Mannitol(E421)

Sodiumacetatetrihydrate(E262)

Hydrochloricacid(E507)(forpH-adjustment)

Sodiumhydroxide(E524)(forpH-adjustment)

6.2Incompatibilities

Thismedicinalproductmustnotbemixedwithothermedicinalproductexceptthosementionedinsection6.6.

6.3Shelflife

3years

Afterreconstitution:

Chemicalandphysicalin-usestabilityhasbeendemonstratedfor35daysat25°C.Fromamicrobiologicalpointof

view,theproductshouldbeusedimmediately.

Ifnotusedimmediately,in-usestoragetimesandconditionspriortousearetheresponsibilityoftheuserandwould

normallynotbelongerthan24hoursat25°C,unlessreconstitution/dilutionhastakenplaceincontrolledand

validatedasepticconditions.

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

Reconstitutedsolution:

Donotrefrigerate(crystallisationmayoccur).

Forstorageconditionofthereconstitutedmedicinalproduct,seesection6.3.

6.5Natureandcontentsofcontainer

TypeIclearglassvialsof10mlclosedwithchlorobutylrubberstoppers.

Packsizes:cartoncontainingasinglevialcontaining200mggemcitabine.

6.6Specialprecautionsfordisposalandotherhandling

Reconstitution:

Forsingleuseonly.

Thismedicinalproducthasonlybeenshowntobecompatiblewithsodiumchloride9mg/ml(0.9%)solutionfor

injection.Accordingly,onlythisdiluentshouldbeusedforreconstitution.Compatibilitywithotheractivesubstances

hasnotbeenstudied.Therefore,itisnotrecommendedtomixthismedicinalproductwithotheractivesubstanceswhen

reconstituted.

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

inthetablebelow)andshaketodissolve.

Theappropriateamountofmedicinalproductmaybefurtherdilutedwithsodiumchloride9mg/ml(0.9%)solutionfor

injection.

Parenteralmedicinalproductsshouldbeinspectedvisuallyforparticulatematteranddiscolouration,priorto

administration,wheneversolutionandcontainerpermit.

Anyunusedsolutionshouldbediscardedasdescribedbelow.

GuidelinesfortheSafeHandlingofCytotoxicMedicinalProducts:

Localguidelinesonsafepreparationandhandlingofcytotoxicmedicinalproductsmustbeadheredto.Cytotoxic

preparationsshouldnotbehandledbypregnantstaff.Thepreparationofinjectablesolutionsofcytotoxicagentsmust

becarriedoutbytrainedspecialistpersonnelwithknowledgeofthemedicinesused.Thisshouldbeperformedina

designatedarea.Theworksurfaceshouldbecoveredwithdisposableplastic-backedabsorbentpaper.

Suitableeyeprotection,disposablegloves,facemaskanddisposableapronshouldbeworn.Precautionsshouldbe

takentoavoidthemedicinalproductaccidentallycomingintocontactwiththeeyes.Ifaccidentalcontaminationoccurs,

theeyeshouldbewashedwithwaterthoroughlyandimmediately.

Syringesandinfusionsetsshouldbeassembledcarefullytoavoidleakage(useofLuerlockfittingsisrecommended).

Largeboreneedlesarerecommendedtominimisepressureandthepossibleformationofaerosols.Thelattermayalso

bereducedbytheuseofaventingneedle.

Actualspillageorleakageshouldbemoppedupwearingprotectivegloves.Excretaandvomitmustbehandledwith

care.

Disposal:

Adequatecareandprecautionshouldbetakeninthedisposalofitemsusedtoreconstitutethismedicinalproduct.Any

unuseddryproductorcontaminatedmaterialsshouldbeplacedinahigh-riskwastebag.Sharpobjects(needles,

syringes,vials,etc)shouldbeplacedinasuitablerigidcontainer.Personnelconcernedwiththecollectionanddisposal

ofthiswasteshouldbeawareofthehazardinvolved.Wastematerialshouldbedestroyedbyincineration.Anyunused

productorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

medac

Gesellschaftfürklinische

SpezialpräparatembH

Fehlandtstr.3

20354Hamburg

Germany

8MARKETINGAUTHORISATIONNUMBER

Presentation Presentationvolumeof

sodiumchloride9mg/ml

(0.9%)solutionfor

injectiontobeadded Reconstitutedvolume Finalconcentration

200mg 5ml 5.26ml 38mg/ml

1,000mg 25ml 26.3ml 38mg/ml

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9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:31stJuly2009

10DATEOFREVISIONOFTHETEXT

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