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Pemetrexed Reig Jofre

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Document: Pemetrexed Reig Jofre 500 mg powder for concentrate for solution for infusion ENG SmPC change

NAME OF THE MEDICINAL PRODUCT


Pemetrexed Reig Jofre 500mgpowderforconcentrateforsolutionforinfusion


QUALITATIVE AND QUANTITATIVE COMPOSITION


Eachvialcontains500mgofpemetrexed(aspemetrexeddisodium 2.5 H2O).

Afterreconstitution(seesection6.6),eachvialcontains25mg/mlofpemetrexed.Excipientswithknowneffect:

Eachvialcontainsapproximately54mgsodium.


Forthefulllistofexcipients,seesection6.1.


PHARMACEUTICAL FORM


Powderforconcentrateforsolutionforinfusion.


Whitetoeitherlightyelloworgreen-yellowlyophilisedpowder.


CLINICAL PARTICULARS


Therapeutic indications


Malignantpleuralmesothelioma

Pemetrexed Reig Jofre incombinationwithcisplatinisindicatedforthetreatmentofchemotherapynaïvepatientswithunresectablemalignantpleuralmesothelioma.


Non-smallcelllungcancer

Pemetrexed Reig Jofre incombinationwithcisplatinisindicatedforthefirstlinetreatmentofpatientswithlocallyadvancedormetastaticnon-smallcelllungcancerotherthanpredominantlysquamouscellhistology(seesection5.1).


Pemetrexed Reig Jofre isindicatedasmonotherapyforthemaintenancetreatmentoflocallyadvancedormetastaticnon-smallcelllungcancerotherthanpredominantlysquamouscellhistologyinpatientswhosediseasehasnotprogressedimmediatelyfollowingplatinum-basedchemotherapy(seesection5.1).


Pemetrexed Reig Jofre isindicatedasmonotherapyforthesecondlinetreatmentofpatientswithlocallyadvancedormetastaticnon-smallcelllungcancerotherthanpredominantlysquamouscellhistology(seesection5.1).


Posology and method of administration


Posology:


Pemetrexed Reig Jofre mustonlybeadministeredunderthesupervisionofaphysicianqualifiedintheuseofanti-cancer chemotherapy.


Pemetrexed Reig Jofre incombinationwithcisplatin

TherecommendeddoseofPemetrexed Reig Jofreis500mg/m2ofbodysurfacearea(BSA)administeredasanintravenousinfusionover10minutesonthefirstdayofeach21-daycycle.Therecommendeddoseofcisplatinis75mg/m2BSAinfusedovertwohoursapproximately30minutesaftercompletionofthepemetrexedinfusiononthefirstdayofeach21-daycycle.Patientsmustreceiveadequateanti-emetic treatmentandappropriatehydrationpriortoand/orafterreceivingcisplatin(seealsocisplatinSummaryofProductCharacteristicsforspecificdosingadvice).


Pemetrexed Reig Jofre as single agent

Inpatientstreatedfornon-smallcelllungcancerafterpriorchemotherapy,therecommendeddoseofPemetrexed Reig Jofre is 500 mg/m2BSA administered as an intravenous infusion over 10 minutes on the first day of each21-daycycle.


Premedication regimen

Toreducetheincidenceandseverityofskinreactions,acorticosteroidshouldbegiventhedaypriorto,onthedayof,andthedayafterpemetrexedadministration.Thecorticosteroidshouldbeequivalentto4mgofdexamethasoneadministeredorallytwiceaday(seesection4.4).


Toreducetoxicity,patientstreatedwithpemetrexedmustalsoreceivevitaminsupplementation(seesection4.4).Patientsmusttakeoralfolicacidoramultivitamincontainingfolicacid(350to 1000micrograms)onadailybasis.Atleastfivedosesoffolicacidmustbetakenduringthesevendaysprecedingthefirstdoseofpemetrexed,anddosingmustcontinueduringthefullcourseof therapyandfor21daysafterthelastdoseofpemetrexed.PatientsmustalsoreceiveanintramuscularinjectionofvitaminB12(1000micrograms)intheweekprecedingthefirstdoseofpemetrexedandonceeverythreecyclesthereafter.SubsequentvitaminB12injectionsmaybegivenonthesamedayaspemetrexed.


Monitoring

Patientsreceivingpemetrexedshouldbemonitoredbeforeeachdosewithacompletebloodcount,includingadifferentialwhitecellcount(WCC)andplateletcount.Priortoeachchemotherapyadministrationbloodchemistrytestsshouldbecollectedtoevaluaterenalandhepaticfunction.Beforethestartofanycycleofchemotherapy,patientsarerequiredtohavethefollowing:absoluteneutrophilcount(ANC)shouldbe≥1500cells/mm3andplateletsshouldbe≥100,000cells/mm3.

Creatinineclearanceshouldbe≥45ml/min.

Thetotalbilirubinshouldbe≤1.5timesupperlimitofnormal.Alkalinephosphatase(AP),aspartateaminotransferase(ASTorSGOT)andalanineaminotransferase(ALTorSGPT)shouldbe≤3times upperlimitofnormal.Alkalinephosphatase,ASTandALT≤5timesupperlimitofnormalisacceptableifliverhastumourinvolvement.


Doseadjustments

Doseadjustmentsatthestartofasubsequentcycleshouldbebasedonnadirhaematologiccountsormaximumnon-haematologictoxicityfromtheprecedingcycleoftherapy.Treatmentmaybedelayedtoallowsufficienttimeforrecovery.UponrecoverypatientsshouldberetreatedusingtheguidelinesinTables1,2and3,whichareapplicableforPemetrexed Reig Jofre usedasasingleagentorincombinationwithcisplatin.


Table 1 - Dose modification table for Pemetrexed (as single agent or in combination) and cisplatin-Haematologic toxicities

cisplatin –Haematologic toxicities

Nadir ANC < 500 /mm3 and nadir platelets

≥50,000 /mm3

75 % of previous dose (both Pemetrexed and cisplatin)

Nadir platelets < 50,000 /mm3 regardless of nadir ANC

75 % of previous dose (both Pemetrexed and cisplatin )

Nadir platelets < 50,000 /mm3 with bleedinga, regardless of nadir ANC

50 % of previous dose (both Pemetrexed and cisplatin)

a ThesecriteriameettheNationalCancerInstituteCommonToxicityCriteria(CTCv2.0;NCI1998)definitionof≥CTCGrade2bleeding


Ifpatientsdevelopnon-haematologictoxicities≥Grade3(excludingneurotoxicity),Pemetrexed Reig Jofreshouldbewithhelduntilresolutiontolessthanorequaltothepatient’spre-therapyvalue.TreatmentshouldberesumedaccordingtotheguidelinesinTable2.


Table 2 - Dose modification table for Pemetrexed (as single agent or in combination) and cisplatin– Non-haematologic toxicities a, b

Dose of pemetrexed (mg/m2)

Dose for cisplatin (mg/m2)

Any Grade 3 or 4 toxicities except mucositis

75 % of previous dose

75 % of previous dose

Any diarrhoea requiring hospitalisation (irrespective of grade) or grade 3 or 4 diarrhoea.

75 % of previous dose

75 % of previous dose

Grade 3 or 4 mucositis

50 % of previous dose

100 % of previous dose

aNationalCancerInstituteCommonToxicityCriteria(CTCv2.0;NCI1998)

bExcludingneurotoxicity


Intheeventofneurotoxicity,therecommendeddoseadjustmentforPemetrexed Reig JofreandcisplatinisdocumentedinTable3.PatientsshoulddiscontinuetherapyifGrade3or4neurotoxicityisobserved.


Table 3 - Dose modification table for Pemetrexed (as single agent or in combination) and cisplatin – Neurotoxicity

CTCa Grade

Dose of pemetrexed (mg/m2)

Dose for cisplatin (mg/m2)

0 – 1

100 % of previous dose

100 % of previous dose

2

100 % of previous dose

50 % of previous dose

aNationalCancerInstituteCommonToxicityCriteria(CTCv2.0;NCI1998)


TreatmentwithPemetrexed Reig Jofre shouldbediscontinuedifapatientexperiencesanyhaematologicornon-haematologicGrade3or4toxicityafter2dosereductionsorimmediatelyifGrade3or4neurotoxicityisobserved.


Elderly:Inclinicalstudies,therehasbeennoindicationthatpatients65yearsofageorolderareatincreasedriskofadverseeventscomparedtopatientsyoungerthan65yearsold.Nodosereductionsotherthanthoserecommendedforallpatientsarenecessary.


Paediatricpopulation

ThereisnorelevantuseofPemetrexed Reig Jofre inthepaediatricpopulationinmalignantpleuralmesotheliomaandnon-smallcelllungcancer.


Patientswithrenalimpairment(StandardCockcroftandGaultformulaorGlomerularFiltrationRatemeasuredTc99m-DPTAserumclearancemethod):Pemetrexedisprimarilyeliminatedunchangedbyrenalexcretion.Inclinicalstudies,patientswithcreatinineclearanceof≥45ml/minrequirednodoseadjustmentsotherthanthoserecommendedforallpatients.Thereareinsufficientdataontheuseofpemetrexedinpatientswithcreatinineclearancebelow45ml/min;thereforetheuseofpemetrexedisnotrecommended(seesection4.4).


Patientswithhepaticimpairment:NorelationshipsbetweenAST(SGOT),ALT(SGPT),ortotalbilirubinandpemetrexedpharmacokineticswereidentified.Howeverpatientswithhepaticimpairmentsuchasbilirubin>1.5timestheupperlimitofnormaland/oraminotransferase >3.0timestheupperlimitofnormal(hepaticmetastasesabsent)or>5.0timestheupperlimitofnormal(hepatic metastasespresent)havenotbeenspecificallystudied.

Methodofadministration:


ForPrecautionstobetakenbeforehandlingoradministeringPemetrexed Reig Jofre,seesection6.6.

Pemetrexed Reig Jofre shouldbeadministeredasanintravenousinfusionover10minutesonthefirstdayofeach21-daycycle.ForinstructionsonreconstitutionanddilutionofPemetrexed Reig Jofrebeforeadministration,seesection6.6.


Contraindications


Hypersensitivitytotheactivesubstanceortoanyoftheexcipientslistedinsection6.1.


Breast-feeding(seesection4.6).


Concomitantyellowfevervaccine(seesection4.5).


Special warnings and precautions for use


Pemetrexedcansuppressbonemarrowfunctionasmanifestedbyneutropenia,thrombocytopeniaandanaemia(orpancytopenia)(seesection4.8).Myelosuppressionisusuallythedose-limitingtoxicity.Patientsshouldbemonitoredformyelosuppressionduringtherapyandpemetrexedshouldnotbe giventopatientsuntilabsoluteneutrophilcount(ANC)returnsto≥1500cells/mm3andplateletcountreturnsto≥100,000cells/mm3.DosereductionsforsubsequentcyclesarebasedonnadirANC,plateletcountandmaximumnon-haematologictoxicityseenfromthepreviouscycle(seesection4.2).


LesstoxicityandreductioninGrade3/4haematologicandnon-haematologictoxicitiessuchasneutropenia,febrileneutropeniaandinfectionwithGrade3/4neutropeniawerereportedwhen pre-treatmentwithfolicacidandvitaminB12wasadministered.Therefore,allpatientstreatedwithpemetrexedmustbeinstructedtotakefolicacidandvitaminB12asaprophylacticmeasuretoreducetreatment-relatedtoxicity(seesection4.2).


Skinreactionshavebeenreportedinpatientsnotpre-treatedwithacorticosteroid.Pre-treatmentwithdexamethasone(orequivalent)canreducetheincidenceandseverityofskinreactions(see section4.2).


Aninsufficientnumberofpatientshasbeenstudiedwithcreatinineclearanceofbelow45ml/min.Therefore,theuseofpemetrexedinpatientswithcreatinineclearanceof<45ml/minisnotrecommended(seesection4.2).


Patientswithmildtomoderaterenalinsufficiency(creatinineclearancefrom45to79ml/min)shouldavoidtakingnon-steroidalanti-inflammatorydrugs(NSAIDs)suchasibuprofen,andaspirin(>1.3gdaily)for2daysbefore,onthedayof,and2daysfollowingpemetrexedadministration(seesection4.5).

InpatientswithmildtomoderaterenalinsufficiencyeligibleforpemetrexedtherapyNSAIDswithlongeliminationhalf-livesshouldbeinterruptedforatleast5dayspriorto,onthedayof,andatleast2daysfollowingpemetrexedadministration(seesection4.5).


Seriousrenalevents,includingacuterenalfailure,havebeenreportedwithpemetrexedaloneorinassociationwithotherchemotherapeuticagents.Manyofthepatientsinwhomtheseoccurredhadunderlyingriskfactorsforthedevelopmentofrenaleventsincludingdehydrationorpre-existinghypertensionordiabetes.


Theeffectofthirdspacefluid,suchaspleuraleffusionorascites,onpemetrexedisnotfullydefined. Aphase2studyofpemetrexedin31solidtumourpatientswithstablethirdspacefluiddemonstratednodifferenceinpemetrexeddosenormalizedplasmaconcentrationsorclearancecomparedtopatientswithoutthirdspacefluidcollections.Thus,drainageofthirdspacefluidcollectionpriortopemetrexedtreatmentshouldbeconsidered,butmaynotbenecessary.


Duetothegastrointestinaltoxicityofpemetrexedgivenincombinationwithcisplatin,severedehydrationhasbeenobserved.Therefore,patientsshouldreceiveadequateantiemetictreatmentandappropriatehydrationpriortoand/orafterreceivingtreatment.


Seriouscardiovascularevents,includingmyocardialinfarctionandcerebrovasculareventshavebeenuncommonlyreportedduringclinicalstudieswithpemetrexed,usuallywhengivenincombinationwithanothercytotoxicagent.Mostofthepatientsinwhomtheseeventshavebeenobservedhadpre-existingcardiovascularriskfactors(seesection4.8).


Immunodepressedstatusiscommonincancerpatients.Asaresult,concomitantuseofliveattenuatedvaccinesisnotrecommended(seesection4.3and4.5).


Pemetrexedcanhavegeneticallydamagingeffects.Sexuallymaturemalesareadvisednottofatherachildduringthetreatmentandupto6monthsthereafter.Contraceptivemeasuresorabstinencearerecommended.Owingtothepossibilityofpemetrexedtreatmentcausingirreversibleinfertility,menareadvisedtoseekcounsellingonspermstoragebeforestartingtreatment.


Womenofchildbearingpotentialmustuseeffectivecontraceptionduringtreatmentwithpemetrexed(seesection4.6).


Casesofradiationpneumonitishavebeenreportedinpatientstreatedwithradiationeitherprior,duringorsubsequenttotheirpemetrexedtherapy.Particularattentionshouldbepaidtothesepatientsandcautionexercisedwithuseofotherradiosensitisingagents.


Casesofradiationrecallhavebeenreportedinpatientswhoreceivedradiotherapyweeksoryearspreviously.


Thismedicinalproductcontainsapproximately54mgofsodiumpervial.Tobetakenintoconsiderationbypatientsonacontrolledsodiumdiet.


Interaction with other medicinal products and other forms of interaction


Pemetrexedismainlyeliminatedunchangedrenallybytubularsecretionandtoalesserextentbyglomerularfiltration.Concomitantadministrationofnephrotoxicdrugs(e.g.aminoglycoside,loopdiuretics,platinumcompounds,cyclosporin)couldpotentiallyresultindelayedclearanceofpemetrexed.Thiscombinationshouldbeusedwithcaution.Ifnecessary,creatinineclearanceshouldbecloselymonitored.


Concomitantadministrationofsubstancesthatarealsotubularlysecreted(e.g.probenecid,penicillin)couldpotentiallyresultindelayedclearanceofpemetrexed.Cautionshouldbemadewhenthesedrugsarecombinedwithpemetrexed.Ifnecessary,creatinineclearanceshouldbecloselymonitored.


Inpatientswithnormalrenalfunction(creatinineclearance≥ 80ml/min),highdosesofnon-steroidalanti-inflammatorydrugs(NSAIDs,suchasibuprofen>1600mg/day)andaspirinathigherdose

(≥ 1.3gdaily)maydecreasepemetrexedeliminationand,consequently,increasetheoccurrenceofpemetrexedadverseevents.Therefore,cautionshouldbemadewhenadministeringhigherdosesofNSAIDsoraspirin,concurrentlywithpemetrexedtopatientswithnormalfunction(creatinineclearance≥ 80ml/min).


Inpatientswithmildtomoderaterenalinsufficiency(creatinineclearancefrom45to79ml/min),theconcomitantadministrationofpemetrexedwithNSAIDs(e.g.ibuprofen)oraspirinathigherdoseshouldbeavoidedfor2daysbefore,onthedayof,and2daysfollowingpemetrexedadministration(seesection4.4).


IntheabsenceofdataregardingpotentialinteractionwithNSAIDshavinglongerhalf-livessuchaspiroxicamorrofecoxib,theconcomitantadministrationwithpemetrexedinpatientswithmildtomoderaterenalinsufficiencyshouldbeinterruptedforatleast5dayspriorto,onthedayof,andatleast2daysfollowingpemetrexedadministration(seesection4.4).Ifconcomitantadministrationof NSAIDsisnecessary,patientsshouldbemonitoredcloselyfortoxicity,especiallymyelosuppressionandgastrointestinaltoxicity.


Pemetrexedundergoeslimitedhepaticmetabolism.ResultsfrominvitrostudieswithhumanlivermicrosomesindicatedthatpemetrexedwouldnotbepredictedtocauseclinicallysignificantinhibitionofthemetabolicclearanceofdrugsmetabolisedbyCYP3A,CYP2D6,CYP2C9,andCYP1A2.


Interactionscommontoallcytotoxics:

Duetotheincreasedthromboticriskinpatientswithcancer,theuseofanticoagulationtreatmentisfrequent.Thehighintra-individualvariabilityofthecoagulationstatusduringdiseasesandthepossibilityofinteractionbetweenoralanticoagulantsandanticancerchemotherapyrequireincreasedfrequencyofINR(InternationalNormalisedRatio)monitoring,ifitisdecidedtotreatthepatientwithoralanticoagulants.

Concomitantusecontraindicated:Yellowfevervaccine:riskoffatalgeneralisedvaccinaledisease(seesection4.3).

Concomitantusenotrecommended:Liveattenuatedvaccines(exceptyellowfever,forwhichconcomitantuseiscontraindicated):riskofsystemic,possiblyfatal,disease.Theriskisincreasedinsubjectswhoarealreadyimmunosuppressedbytheirunderlyingdisease.Useaninactivatedvaccinewhereitexists(poliomyelitis)(seesection4.4).


Fertility, pregnancy and lactation


Contraceptioninmalesandfemales

Womenofchildbearingpotentialmustuseeffectivecontraceptionduringtreatmentwithpemetrexed.Pemetrexedcanhavegeneticallydamagingeffects.Sexuallymaturemalesareadvisednottofatherachildduringthetreatmentandupto6monthsthereafter.Contraceptivemeasuresorabstinencearerecommended.


Pregnancy

Therearenodatafromtheuseofpemetrexedinpregnantwomenbutpemetrexed,likeother anti-metabolites,issuspectedtocauseseriousbirthdefectswhenadministeredduringpregnancy.Animalstudieshaveshownreproductivetoxicity(seesection5.3).Pemetrexedshouldnotbeusedduringpregnancyunlessclearlynecessary,afteracarefulconsiderationoftheneedsofthemotherandtheriskforthefoetus(seesection4.4).


Breastfeeding

Itisnotknownwhetherpemetrexedisexcretedinhumanmilkandadversereactionsonthesucklingchildcannotbeexcluded.Breast-feedingmustbediscontinuedduringpemetrexedtherapy(seesection4.3).


Fertility

Owingtothepossibilityofpemetrexedtreatmentcausingirreversibleinfertility,menareadvisedtoseekcounsellingonspermstoragebeforestartingtreatment.


Effects on ability to drive and use machines


Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.However,ithasbeenreportedthatpemetrexedmaycausefatigue.Thereforepatientsshouldbecautionedagainstdrivingoroperatingmachinesifthiseventoccurs.


Undesirable effects

Summaryofthesafetyprofile

Themostcommonlyreportedundesirableeffectsrelatedtopemetrexed,whetherusedasmonotherapyorincombination,arebonemarrowsuppressionmanifestedasanaemia,neutropenia,leukopenia,thrombocytopenia;andgastrointestinaltoxicities,manifestedasanorexia,nausea,vomiting,diarrhoea, constipation,pharyngitis,mucositis,andstomatitis.Otherundesirableeffectsincluderenaltoxicities,increasedaminotransferases,alopecia,fatigue,dehydration,rash,infection/sepsisandneuropathy.RarelyseeneventsincludeStevens-JohnsonsyndromeandToxicepidermalnecrolysis.


Tabulatedlistofadversereactions


Thetablebelowprovidesthefrequencyandseverityofundesirableeffectsthathavebeenreportedin >5%of168patientswithmesotheliomawhowererandomisedtoreceivecisplatinandpemetrexedand163patientswithmesotheliomarandomisedtoreceivesingleagentcisplatin.Inbothtreatmentarms,thesechemonaivepatientswerefullysupplementedwithfolicacidandvitaminB12.


Adversereactions

Frequencyestimate:Verycommon(≥1/10),Common(1/100and<1/10),Uncommon(≥1/1000and <1/100),Rare(≥1/10,000and<1/1000),Veryrare(<1/10,000)andnotknown(cannotbeestimatedfromavailabledata-spontaneousreports).


Withineachfrequencygrouping,undesirableeffectsarepresentedinorderofdecreasingseriousness.


System organ class

Frequency

Event*

Pemetrexed/cisplatin

Cisplatin

(N = 168)

(N = 163)

All grades toxicity

(%)

Grade 3 - 4

toxicity (%)

All grades toxicity

(%)

Grade 3 - 4

toxicity (%)

Blood and

lymphatic system disorders

Very

common

Neutrophils/

Granulocytes decreased

56.0

23.2

13.5

3.1

Leukocytes

decreased

53.0

14.9

16.6

0.6

Haemoglobin decreased

26.2

4.2

10.4

0.0

Platelets

decreased

23.2

5.4

8.6

0.0

Metabolism

and nutrition disorders

Common

Dehydration

6.5

4.2

0.6

0.6

Nervous system

disorders

Very common

Neuropathy- Sensory

10.1

0.0

9.8

0.6

Common

Taste disturbance

7.7

0.0***

6.1

0.0***

Eye disorders

Common

Conjunctivitis

5.4

0.0

0.6

0.0

Gastrointestinal

disorders

Very

common

Diarrhoea

16.7

3.6

8.0

0.0

Vomiting

56.5

10.7

49.7

4.3

Stomatitis/ Pharyngitis

23.2

3.0

6.1

0.0

Nausea

82.1

11.9

76.7

5.5

Anorexia

20.2

1.2

14.1

0.6

Constipation

11.9

0.6

7.4

0.6

Common

Dyspepsia

5.4

0.6

0.6

0.0

Skin and

subcutaneous tissue disorders

Very

common

Rash

16.1

0.6

4.9

0.0

Alopecia

11.3

0.0***

5.5

0.0***

Renal and

urinary disorders

Very

common

Creatinine

elevation

10.7

0.6

9.8

1.2

Creatinine clearance decreased**

16.1

0.6

17.8

1.8

General Disorders and

administration site conditions

Very common

Fatigue

47.6

10.1

42.3

9.2

*RefertoNationalCancerInstituteCTCversion2foreachgradeoftoxicityexcepttheterm“creatinineclearancedecreased”

**whichisderivedfromtheterm“renal/genitourinaryother”.

***AccordingtoNationalCancerInstituteCTC(v2.0;NCI1998),tastedisturbanceandalopeciashouldonlybereportedasGrade1or2.

Forthepurposeofthistableacutoffof5%wasusedforinclusionofalleventswherethereporterconsideredapossiblerelationshiptopemetrexedandcisplatin.


ClinicallyrelevantCTCtoxicitiesthatwerereportedin≥1%and≤ 5%ofthepatientsthatwererandomlyassignedtoreceivecisplatinandpemetrexedinclude:renalfailure,infection,pyrexia,febrileneutropenia,increasedAST,ALT,andGGT,urticariaandchestpain.

ClinicallyrelevantCTCtoxicitiesthatwerereportedin<1%ofthepatientsthatwererandomlyassignedtoreceivecisplatinandpemetrexedincludearrhythmiaandmotorneuropathy.


Thetablebelowprovidesthefrequencyandseverityofundesirableeffectsthathavebeenreportedin >5%of265patientsrandomlyassignedtoreceivesingleagentpemetrexedwithfolicacidandvitaminB12supplementationand276patientsrandomlyassignedtoreceivesingleagentdocetaxel.Allpatientswerediagnosedwithlocallyadvancedormetastaticnon-smallcelllungcancerandreceivedpriorchemotherapy.


System

organ

class

Frequency

Event*

Pemetrexed

N = 265

Docetaxel

N = 276

All grades toxicity (%)

Grade

3 –4 toxicity (%)

All grades toxicity (%)

Grade

3 –4 toxicity (%)

Blood and

lymphatic system disorders

Very

common

Neutrophils/

Granulocytes decreased

10.9

5.3

45.3

40.2

Leukocytes

decreased

12.1

4.2

34.1

27.2

Haemoglobin

decreased

19.2

4.2

22.1

4.3

Common

Platelets decreased

8.3

1.9

1.1

0.4

Gastrointestinal

disorders

Very

common

Diarrhoea

12.8

0.4

24.3

2.5

Vomiting

16.2

1.5

12.0

1.1

Stomatitis/

Pharyngitis

14.7

1.1

17.4

1.1

Nausea

30.9

2.6

16.7

1.8

Anorexia

21.9

1.9

23.9

2.5

Common

Constipation

5.7

0.0

4.0

0.0

Hepatobiliary

disorders

Common

SGPT (ALT)

elevation

7.9

1.9

1.4

0.0

SGOT (AST)

elevation

6.8

1.1

0.7

0.0

Skin and sub-

cutaneous tissue disorders

Very

common

Rash/

desquamation

14.0

0.0

6.2

0.0

Common

Pruritus

6.8

0.4

1.8

0.0

Alopecia

6.4

0.4**

37.7

2.2**

General

disorders and administration site conditions

Very

Common

Fatigue

34.0

5.3

35.9

5.4

Common

Fever

8.3

0.0

7.6

0.0

*RefertoNationalCancerInstituteCTCversion2foreachgradeoftoxicity.

**AccordingtoNationalCancerInstituteCTC(v2.0;NCI1998),alopeciashouldonlybereportedasGrade1or2.


Forthepurposeofthistableacutoffof5%wasusedforinclusionofalleventswherethereporterconsideredapossiblerelationshiptopemetrexed.

ClinicallyrelevantCTCtoxicitiesthatwerereportedin≥1%and≤ 5%ofthepatientsthatwererandomlyassignedtopemetrexedinclude:infectionwithoutneutropenia,febrileneutropenia,allergicreaction/hypersensitivity,increasedcreatinine,motorneuropathy,sensoryneuropathy,erythemamultiforme,andabdominalpain.


ClinicallyrelevantCTCtoxicitiesthatwerereportedin<1%ofthepatientsthatwererandomlyassignedtopemetrexedincludesupraventriculararrhythmias.


ClinicallyrelevantGrade3andGrade4laboratorytoxicitiesweresimilarbetweenintegratedPhase2resultsfromthreesingleagentpemetrexedstudies(n=164)andthePhase3singleagentpemetrexedstudydescribedabove,withtheexceptionofneutropenia(12.8%versus5.3%,respectively)andalanineaminotransferaseelevation(15.2%versus1.9%,respectively).Thesedifferenceswerelikelyduetodifferencesinthepatientpopulation,sincethePhase2studiesincludedbothchemonaiveandheavilypre-treatedbreastcancerpatientswithpre-existinglivermetastasesand/orabnormalbaselineliverfunctiontests.


Thetablebelowprovidesthefrequencyandseverityofundesirableeffectsconsideredpossiblyrelatedtostudydrugthathavebeenreportedin>5%of839patientswithNSCLCwhowererandomizedtoreceivecisplatinandpemetrexedand830patientswithNSCLCwhowererandomizedtoreceivecisplatinandgemcitabine.AllpatientsreceivedstudytherapyasinitialtreatmentforlocallyadvancedormetastaticNSCLCandpatientsinbothtreatmentgroupswerefullysupplementedwithfolicacidandvitaminB12.


System

organ

class

Frequency

Event**

Pemetrexed/ cisplatin

(N = 839)

Gemcitabine/ cisplatin

(N = 830)

All grades toxicity (%)

Grade 3 - 4

toxicity

(%)

All grades toxicity (%)

Grade

3 - 4

toxicity

(%)

Blood and lymphatic system disorders

Very common

Hemoglobin decreased

33.0*

5.6*

45.7*

9.9*

Neutrophils/ Granulocytes decreased

29.0*

15.1*

38.4*

26.7*

Leukocytes decreased

17.8

4.8*

20.6

7.6*

Platelets decreased

10.1*

4.1*

26.6*

12.7*

Nervous system disorders

Common

Neuropathy- sensory

8.5*

0.0*

12.4*

0.6*

Taste disturbance

8.1

0.0***

8.9

0.0***

Gastrointestinal disorders

Very common

Nausea

56.1

7.2*

53.4

3.9*

Vomiting

39.7

6.1

35.5

6.1

Anorexia

26.6

2.4*

24.2

0.7*

Constipation

21.0

0.8

19.5

0.4

Stomatitis/ Pharyngitis

13.5

0.8

12.4

0.1

Diarrhoea without colostomy

12.4

1.3

12.8

1.6

Common

Dyspepsia/ Heartburn

5.2

0.1

5.9

0.0

Skin and subcutaneous tissue disorders

Very common

Alopecia

11.9*

0***

21.4*

0.5***

Common

Rash/desquamation

6.6

0.1

8.0

0.5

Renal and urinary disorders

Very common

Creatinine elevation

10.1*

0.8

6.9*

0.5

General disorders and administration site conditions

Very common

Fatigue

42.7

6.7

44.9

4.9

*P-values<0.05comparingpemetrexed/cisplatintogemcitabine/cisplatin,usingFisherExacttest.

**RefertoNationalCancerInstituteCTC(v2.0;NCI1998)foreachGradeofToxicity.

***AccordingtoNationalCancerInstituteCTC(v2.0;NCI1998),tastedisturbanceandalopeciashouldonlybereportedasGrade1or2.


Forthepurposeofthistable,acut-offof5%wasusedforinclusionofalleventswherethereporterconsideredapossiblerelationshiptopemetrexedandcisplatin.


Clinicallyrelevanttoxicitythatwasreportedin≥1%and≤5%ofthepatientsthatwererandomlyassignedtoreceivecisplatinandpemetrexedinclude:ASTincrease,ALTincrease,infection,febrileneutropenia,renalfailure,pyrexia,dehydration,conjunctivitis,andcreatinineclearancedecrease.Clinicallyrelevanttoxicitythatwasreportedin<1%ofthepatientsthatwererandomlyassignedtoreceivecisplatinandpemetrexedinclude:GGTincrease,chestpain,arrhythmia,andmotorneuropathy.


Clinicallyrelevanttoxicitieswithrespecttogenderweresimilartotheoverallpopulationinpatientsreceivingpemetrexedpluscisplatin.


Thetablebelowprovidesthefrequencyandseverityofundesirableeffectsconsideredpossiblyrelatedtostudydrugthathavebeenreportedin>5%of800patientsrandomlyassignedtoreceivesingleagentpemetrexedand402patientsrandomlyassignedtoreceiveplacebointhesingle-agentpemetrexedmaintenance(JMEN:N=663)andcontinuationpemetrexedmaintenance(PARAMOUNT:N=539)studies.AllpatientswerediagnosedwithStageIIIBorIVNSCLCandhadreceivedpriorplatinum-basedchemotherapy.PatientsinbothstudyarmswerefullysupplementedwithfolicacidandvitaminB12.



System organ class

Frequency*

Event**

Pemetrexed*** (N =800)

Placebo***

(N =402)

All grades toxicity (%)

Grade 3/4 toxicity (%)

All grades toxicity (%)

Grade 3/4 toxicity (%)

Blood and Lymphatic system disorders

Very common

Hemoglobin decreased

18.0

4.5

5.2

0.5

Common

Leukocytes decreased

5.8

1.9

0.7

0.2

Neutrophils decreased

8.4

4.4

0.2

0.0

Nervous system disorders

Common

Neuropathy- sensory

7.4

0.6

5.0

0.2

Gastrointestinal disorders

Very common

Nausea

17.3

0.8

4.0

0.2

Anorexia

12.8

1.1

3.2

0.0

Common

Vomiting

8.4

0.3

1.5

0.0

Mucositis/ stomatitis

6.8

0.8

1.7

0.0

Hepatobiliary disorders

Common

ALT (SGPT)

elevation

6.5

0.1

2.2

0.0

AST (SGOT)

elevation

5.9

0.0

1.7

0.0

Skin and Subcutaneous tissue disorders

Common

Rash/ desquamation

8.1

0.1

3.7

0.0

General disorders and administration site conditions

Very common

Fatigue

24.1

5.3

10.9

0.7

Common

Pain

7.6

0.9

4.5

0.0

Edema

5.6

0.0

1.5

0.0

Renal Disorders

Common

Renal disorders****

7.6

0.9

1.7

0.0

Abbreviations:ALT = alanine aminotransferase; AST =aspartate aminotransferase; CTCAE = Common Terminology Criteria forAdverse Event; NCI =NationalCancer Institute; SGOT =serumglutamic oxaloacectic aminotransferase;SGPT = serumglutamic pyruvic aminotransferase.

* Definitionoffrequencyterms: Verycommon- ≥10%;Common - >5%and<10%.Forthepurposeofthis table, a cutoffof5%wasusedfor inclusionofallevents wherethereporter consideredapossiblerelationship topemetrexed.

**Refer to NCI CTCAE Criteria (Version 3.0; NCI2003)for each gradeof toxicity.Thereportingratesshown are accordingtoCTCAEversion3.0.

***Integratedadversereactions table combines the resultsofthe JMENpemetrexedmaintenance(N=663) and PARAMOUNT continuationpemetrexedmaintenance (N=539)studies

**** Combined termincludes increased serum/blood creatinine,decreasedglomerularfiltration rate, renal failure andrenal/genitourinary- other.


ClinicallyrelevantCTCtoxicityofanygradethatwasreportedin≥1%and≤5%ofthepatientsthatwererandomlyassignedtopemetrexedinclude:febrileneutropenia,infection,decreasedplatelets, diarrhoea,constipation,alopecia,pruritis/itching,fever(intheabsenceofneutropenia),ocularsurfacedisease(includingconjunctivitis),increasedlacrimation,dizzinessandmotorneuropathy.


ClinicallyrelevantCTCtoxicitythatwasreportedin<1%ofthepatientsthatwererandomlyassignedtopemetrexedinclude:allergicreaction/hypersensitivity,erythemamultiforme,supraventriculararrhythmiaandpulmonaryembolism.


Safetywasassessedforpatientswhowererandomisedtoreceivepemetrexed(N=800).Theincidenceofadversereactionswasevaluatedforpatientswhoreceived≤6cyclesofpemetrexedmaintenance(N=519),andcomparedtopatientswhoreceived>6cyclesofpemetrexed(N=281).Increasesinadversereactions(allgrades)wereobservedwithlongerexposure.Asignificantincreaseintheincidenceofpossiblystudy-drug-relatedGrade3/4neutropeniawasobservedwithlongerexposuretopemetrexed(≤6cycles:3.3%,>6cycles:6.4%;p=0.046).NostatisticallysignificantdifferencesinanyotherindividualGrade3/4/5adversereactionswereseenwithlongerexposure.


Seriouscardiovascularandcerebrovascularevents,includingmyocardialinfarction,anginapectoris,cerebrovascularaccidentandtransientischaemicattackhavebeenuncommonlyreportedduringclinicalstudieswithpemetrexed,usuallywhengivenincombinationwithanothercytotoxicagent.Mostofthepatientsinwhomtheseeventshavebeenobservedhadpre-existingcardiovascularriskfactors.


Rarecasesofhepatitis,potentiallyserious,havebeenreportedduringclinicalstudieswithpemetrexed.


Pancytopeniahasbeenuncommonlyreportedduringclinicaltrialswithpemetrexed.


Inclinicaltrials,casesofcolitis(includingintestinalandrectalbleeding,sometimesfatal,intestinalperforation,intestinalnecrosisandtyphlitis)havebeenreporteduncommonlyinpatientstreatedwithpemetrexed.


Inclinicaltrials,casesofinterstitialpneumonitiswithrespiratoryinsufficiency,sometimesfatal,havebeenreporteduncommonlyinpatientstreatedwithpemetrexed.


Uncommoncasesofoedemahavebeenreportedinpatientstreatedwithpemetrexed.


Oesophagitis/radiationoesophagitishasbeenuncommonlyreportedduringclinicaltrialswith

pemetrexed.


Sepsis,sometimesfatal,hasbeencommonlyreportedduringclinicaltrialswithpemetrexed.


Duringpostmarketingsurveillance,thefollowingadversereactionshavebeenreportedinpatients treatedwithpemetrexed:


Uncommoncasesofacuterenalfailurehavebeenreportedwithpemetrexedaloneorinassociationwithotherchemotherapeuticagents(seesection4.4).


Uncommoncasesofradiationpneumonitishavebeenreportedinpatientstreatedwithradiationeitherprior,duringorsubsequenttotheirpemetrexedtherapy(seesection4.4).


Rarecasesofradiationrecallhavebeenreportedinpatientswhohavereceivedradiotherapypreviously(seesection4.4).


Uncommoncasesofperipheralischaemialeadingsometimestoextremitynecrosishavebeenreported.


RarecasesofbullousconditionshavebeenreportedincludingStevens-JohnsonsyndromeandToxic epidermalnecrolysiswhichinsomecaseswerefatal.


Rarely,haemolyticanaemiahasbeenreportedinpatientstreatedwithpemetrexed.

Rarecasesofanaphylacticshockhavebeenreported.


Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system (see details below) [to be completed nationally]:


Overdose


Reportedsymptomsofoverdoseincludeneutropenia,anaemia,thrombocytopenia,mucositis,sensorypolyneuropathyandrash.Anticipatedcomplicationsofoverdoseincludebonemarrowsuppressionasmanifestedbyneutropenia,thrombocytopeniaandanaemia.Inaddition,infectionwithorwithoutfever,diarrhoea,and/ormucositismaybeseen.Intheeventofsuspectedoverdose,patientsshouldbemonitoredwithbloodcountsandshouldreceivesupportivetherapyasnecessary.Theuseofcalciumfolinate/folinicacidinthemanagementofpemetrexedoverdoseshouldbeconsidered.



PHARMACOLOGICAL PROPERTIES


Pharmacodynamic properties


Pharmacotherapeuticgroup:Folicacidanalogues,ATCcode:L01BA04


Pemetrexed Reig Jofre(pemetrexed)isamulti-targetedanti-cancerantifolateagentthatexertsitsactionbydisruptingcrucialfolate-dependentmetabolicprocessesessentialforcellreplication.


Invitrostudieshaveshownthatpemetrexedbehavesasamultitargetedantifolatebyinhibitingthymidylatesynthase(TS),dihydrofolatereductase(DHFR),andglycinamideribonucleotideformyltransferase(GARFT),whicharekeyfolate-dependentenzymesforthedenovobiosynthesisofthymidineandpurinenucleotides.Pemetrexedistransportedintocellsbyboththereducedfolatecarrierandmembranefolatebindingproteintransportsystems.Onceinthecell,pemetrexedisrapidlyandefficientlyconvertedtopolyglutamateformsbytheenzymefolylpolyglutamatesynthetase.ThepolyglutamateformsareretainedincellsandareevenmorepotentinhibitorsofTSandGARFT.Polyglutamationisatime-andconcentration-dependentprocessthatoccursintumourcellsand,toalesserextent,innormaltissues.Polyglutamatedmetaboliteshaveanincreasedintracellularhalf-liferesultinginprolongeddrugactioninmalignantcells.


TheEuropeanMedicinesAgencyhaswaivedtheobligationtosubmittheresultsofstudieswithPemetrexed inallsubsetsofthepaediatricpopulationinthegrantedindications(seeSection4.2).


Clinicalefficacy:


Mesothelioma:


EMPHACIS,amulticentre,randomised,single-blindphase3studyofPemetrexed pluscisplatinversuscisplatininchemonaivepatientswithmalignantpleuralmesothelioma,hasshownthatpatientstreatedwithPemetrexedandcisplatinhadaclinicallymeaningful2.8-monthmediansurvivaladvantageoverpatientsreceivingcisplatinalone.


Duringthestudy,low-dosefolicacidandvitaminB12supplementationwasintroducedtopatients’therapytoreducetoxicity.Theprimaryanalysisofthisstudywasperformedonthepopulationofallpatientsrandomlyassignedtoatreatmentarmwhoreceivedstudydrug(randomisedandtreated).AsubgroupanalysiswasperformedonpatientswhoreceivedfolicacidandvitaminB12supplementationduringtheentirecourseofstudytherapy(fullysupplemented).Theresultsoftheseanalysesofefficacyaresummarisedinthetablebelow:

EfficacyofPemetrexed pluscisplatinvs.cisplatin

inmalignantpleuralmesothelioma

Randomized and treated

patients

Fully supplemented

Patients

Efficacy parameter

Pemetrexed /

cisplatin

(N = 226)

Cisplatin


(N = 222)

Pemetrexed/

cisplatin

(N = 168)

Cisplatin


(N = 163)

Median overall survival (months)

12.1

9.3

13.3

10.0

(95 % CI)

(10.0 - 14.4)

(7.8 - 10.7)

(11.4 - 14.9)

(8.4 - 11.9)

Log Rank p-value*

0.020

0.051

Median time to tumour progression

5.7

3.9

6.1

3.9

(months)



(95 % CI)

(4.9 – 6.5)

(2.8 - 4.4)

(5.3 - 7.0)

(2.8 - 4.5)

Log Rank p-value*

0.001

0.008

Time to treatment failure (months)

4.5

2.7

4.7

2.7

(95 % CI)

(3.9 – 4.9)

(2.1 - 2.9)

(4.3 - 5.6)

(2.2 - 3.1)

Log Rank p-value*

0.001

0.001

Overall response rate**

41.3 %

16.7 %

45.5 %

19.6 %

(95 % CI)

(34.8 - 48.1)

(12.0 – 22.2)

(37.8 - 53.4)

(13.8 - 26.6)

Fisher’s exact p-value*

< 0.001

< 0.001

Abbreviation:CI=confidenceinterval

*p-valuereferstocomparisonbetweenarms.

**InthePemetrexed /cisplatinarm,randomizedandtreated(N=225)andfullysupplemented(N=167)


Astatisticallysignificantimprovementoftheclinicallyrelevantsymptoms(painanddyspnoea)associatedwithmalignantpleuralmesotheliomainthePemetrexed /cisplatinarm(212patients)versusthecisplatinarmalone(218patients)wasdemonstratedusingtheLungCancerSymptomScale.Statisticallysignificantdifferencesinpulmonaryfunctiontestswerealsoobserved.TheseparationbetweenthetreatmentarmswasachievedbyimprovementinlungfunctioninthePemetrexed /cisplatinarmanddeteriorationoflungfunctionovertimeinthecontrolarm.


TherearelimiteddatainpatientswithmalignantpleuralmesotheliomatreatedwithPemetrexed alone.Pemetrexed atadoseof500mg/m2wasstudiedasasingle-agentin64chemonaivepatientswithmalignantpleuralmesothelioma.Theoverallresponseratewas14.1%.


NSCLC,second-linetreatment:


Amulticentre,randomised,openlabelphase3studyofPemetrexedversusdocetaxelinpatientswithlocallyadvancedormetastaticNSCLCafterpriorchemotherapyhasshownmediansurvivaltimesof 8.3monthsforpatientstreatedwithPemetrexed (IntentToTreatpopulationn=283)and7.9monthsforpatientstreatedwithdocetaxel(ITTn=288).PriorchemotherapydidnotincludePemetrexed.AnanalysisoftheimpactofNSCLChistologyonthetreatmenteffectonoverallsurvivalwasinfavourofPemetrexedversusdocetaxelforotherthanpredominantlysquamoushistologies(n=399,9.3versus 8.0months,adjustedHR=0.78;95%CI=0.61-1.00,p=0.047)andwasinfavourofdocetaxelforsquamouscellcarcinomahistology(n=172,6.2versus7.4months,adjustedHR=1.56; 95%CI=1.08-2.26,p=0.018).TherewerenoclinicallyrelevantdifferencesobservedforthesafetyprofileofPemetrexed withinthehistologysubgroups.


Limitedclinicaldatafromaseparaterandomized,Phase3,controlledtrial,suggestthatefficacydata(overallsurvival,progressionfreesurvival)forpemetrexedaresimilarbetweenpatientspreviouslypretreatedwithdocetaxel(n=41)andpatientswhodidnotreceivepreviousdocetaxeltreatment (n=540).

Efficacy of PemetrexedvsdocetaxelinNSCLC-ITTpopulation

Pemetrexed

Docetaxel

Survival Time (months)

(n = 283) (n = 288)

Median (m)

8.3 7.9

95 % CI for median

(7.0 - 9.4) (6.3 - 9.2)

HR

0.99

95 % CI for HR

(.82 - 1.20)

Non-inferiority p-value (HR)

.226

Progression free survival (months)

(n = 283) (n = 288)

Median

2.9 2.9

HR (95 % CI)

0.97 (.82 – 1.16)

Time to treatment failure (TTTF – months)

(n = 283) (n = 288)

Median

2.3 2.1

HR (95 % CI)

0.84 (.71 - .997)

Response (n: qualified for response)

(n = 264)

(n = 274)

Response rate (%) (95 % CI)

9.1 (5.9 - 13.2)

8.8 (5.7 - 12.8)

Stable disease (%)

45.8

46.4

Abbreviations: CI=confidenceinterval;HR=hazardratio;ITT=intenttotreat;n=total populationsize.



NSCLC,first-linetreatment:


Amulticentre,randomised,open-label,Phase3studyofPemetrexed pluscisplatinversusgemcitabinepluscisplatininchemonaivepatientswithlocallyadvancedormetastatic(StageIIIborIV)non-smallcelllungcancer(NSCLC)showedthatPemetrexed pluscisplatin(Intent-To-Treat[ITT]population n=862)metitsprimaryendpointandshowedsimilarclinicalefficacyasgemcitabinepluscisplatin(ITTn=863)inoverallsurvival(adjustedhazardratio0.94;95%CI=0.84-1.05).AllpatientsincludedinthisstudyhadanECOGperformancestatus0or1.

TheprimaryefficacyanalysiswasbasedontheITTpopulation.SensitivityanalysesofmainefficacyendpointswerealsoassessedontheProtocolQualified(PQ)population.Theefficacyanalysesusing PQpopulation areconsistentwiththeanalysesfortheITTpopulationandsupportthenon-inferiority ofACversusGC.

Progressionfreesurvival(PFS)andoverallresponserateweresimilarbetweentreatmentarms:medianPFSwas4.8monthsforPemetrexed pluscisplatinversus5.1monthsforgemcitabinepluscisplatin(adjustedhazardratio1.04;95%CI=0.94-1.15),andoverallresponseratewas30.6% (95%CI=27.3-33.9)forPemetrexed pluscisplatinversus28.2%(95%CI=25.0-31.4)forgemcitabinepluscisplatin.PFSdatawerepartiallyconfirmedbyanindependentreview(400/1725patientswererandomlyselectedforreview).

TheanalysisoftheimpactofNSCLChistologyonoverallsurvivaldemonstratedclinicallyrelevantdifferencesinsurvivalaccordingtohistology,seetablebelow.

EfficacyofPemetrexed+cisplatinvs.gemcitabine+cisplatininfirst linenon-smallcelllungcancer–ITTpopulationandhistologysubgroups.



ITT population and histology subgroups

Median overall survival in months (95% CI)

Adjusted hazard ratio (HR) (95% CI)

Superiority p-value

Pemetrexed + cisplatin

Gemcitabine + cisplatin

ITT population (N = 1725)

10.3

(9.8– 11.2)

N=862

10.3

(9.6 – 10.9)

N=863

0.94 a

(0.84 -1.05)

0.259

Adenocarcinoma (N=847)

12.6

(10.7– 13.6)

N=436

10.9

(10.2 – 11.9)

N=411

0.84

(0.71–0.99)

0.033

Large cell (N=153)

10.4

(8.6– 14.1)

N=76

6.7

(5.5 – 9.0)

N=77

0.67

(0.48–0.96)

0.027

Other (N=252)

8.6

(6.8– 10.2)

N=106

9.2

(8.1 – 10.6)

N=146

1.08

(0.81–1.45)

0.586

Squamous cell (N=473)

9.4

(8.4– 10.2)

N=244

10.8

(9.5 – 12.1)

N=229

1.23

(1.00–1.51)

0.050

Abbreviations:CI=confidenceinterval;ITT=intent-to-treat;N=totalpopulationsize.

aStatisticallysignificantfornoninferiority,withtheentireconfidenceintervalforHRwellbelowthe1.17645noninferioritymargin(p<0.001).



Kaplan Meier plots of overall survival by histology



1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Adenocarcinoma


AC GC


1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Large Cell Carcinoma


AC GC

0 6 12 18 24 30

Survival Time (months)

0 6 12 18 24 30

Survival Time (months)




There were no clinically relevant differences observed for the safety profile of Pemetrexed plus cisplatin within the histology subgroups.

Patients treated with Pemetrexed and cisplatin required fewer transfusions (16.4% versus 28.9%, p<0.001), red blood cell transfusions (16.1% versus 27.3%, p<0.001) and platelet transfusions (1.8% versus 4.5%, p=0.002). Patients also required lower administration of erythropoietin/darbopoietin (10.4% versus 18.1%, p<0.001), G-CSF/GM-CSF (3.1% versus 6.1%, p=0.004), and iron preparations (4.3% versus 7.0%, p=0.021).

NSCLC,maintenancetreatment:


JMEN

Amulticentre,randomised,double-blind,placebo-controlledPhase3study(JMEN),comparedtheefficacyandsafetyofmaintenancetreatmentwithPemetrexedplusbestsupportivecare(BSC)(n=441)withthatofplaceboplusBSC(n=222)inpatientswithlocallyadvanced(StageIIIB)ormetastatic(StageIV)NonSmallCellLungCancer(NSCLC)whodidnotprogressafter4cyclesoffirstlinedoublettherapycontainingCisplatinorCarboplatinincombinationwithGemcitabine,Paclitaxel,orDocetaxel.FirstlinedoublettherapycontainingPemetrexedwasnotincluded.AllpatientsincludedinthisstudyhadanECOGperformancestatus0or1.Patientsreceivedmaintenancetreatmentuntildiseaseprogression.Efficacyandsafetyweremeasuredfromthetimeofrandomisationaftercompletionoffirstline(induction)therapy.Patientsreceivedamedianof5cyclesofmaintenancetreatmentwithPemetrexed and3.5cyclesofplacebo.Atotalof213patients(48.3%)completed ≥6cyclesandatotalof103patients(23.4%)completed≥10cyclesoftreatmentwithPemetrexed.


ThestudymetitsprimaryendpointandshowedastatisticallysignificantimprovementinPFSinthePemetrexed armovertheplaceboarm(n=581,independentlyreviewedpopulation;medianof 4.0monthsand2.0months,respectively)(hazardratio=0.60,95%CI=0.49-0.73,p<0.00001).TheindependentreviewofpatientscansconfirmedthefindingsoftheinvestigatorassessmentofPFS.ThemedianOSfortheoverallpopulation(n=663)was13.4monthsforthePemetrexedarmand10.6monthsfortheplaceboarm,hazardratio=0.79(95%CI=0.65-0.95,p=0.01192).


Consistentwithother Pemetrexedstudies,adifferenceinefficacyaccordingtoNSCLChistologywasobservedinJMEN.ForpatientswithNSCLCotherthanpredominantlysquamouscellhistology (n=430,independentlyreviewedpopulation)medianPFSwas4.4monthsforthePemetrexedarmand 1.8monthsfortheplaceboarm,hazardratio=0.47(95%CI=0.37-0.60,p=0.00001).ThemedianOSforpatientswithNSCLCotherthanpredominantlysquamouscellhistology(n=481)was 15.5monthsforthePemetrexed armand10.3monthsfortheplaceboarm,hazardratio=0.70(95%CI=0.56-0.88,p=0.002).IncludingtheinductionphasethemedianOSforpatientswith NSCLCotherthanpredominantlysquamouscellhistologywas18.6monthsforthePemetrexed armand 13.6monthsfortheplaceboarm,hazardratio=0.71(95%CI=0.56-0.88,p=0.002).


ThePFSandOSresultsinpatientswithsquamouscellhistologysuggestednoadvantageforPemetrexed overplacebo.


TherewerenoclinicallyrelevantdifferencesobservedforthesafetyprofileofPemetrexed withinthehistologysubgroups.


JMEN: Kaplan Meier plots of progression-free survival (PFS) and overall survival Pemetrexed versus placebo in patients with NSCLC other than predominantly squamous cell histology:




PARAMOUNT


A multicentre, randomised, double-blind, placebo-controlled Phase 3 study (PARAMOUNT), compared the efficacy and safety of continuation maintenance treatment with Pemetrexed plus BSC (n = 359) with that of placebo plus BSC (n = 180) in patients with locally advanced (Stage IIIB) or metastatic (Stage IV) NSCLC other than predominantly squamous cell histology who did not progress after 4 cycles of first line doublet therapy of Pemetrexed in combination with cisplatin. Of the 939 patients treated with Pemetrexed plus cisplatin induction, 539 patients were randomised to maintenance treatment with pemetrexed or placebo. Of the randomised patients, 44.9% had a complete/partial response and 51.9% had a response of stable disease to Pemetrexed plus cisplatin induction. Patients randomised to maintenance treatment were required to have an ECOG performance status 0 or 1. The median time from the start of Pemetrexed plus cisplatin induction therapy to the start of maintenance treatment was 2.96 months on both the pemetrexed arm and the placebo arm. Randomised patients received maintenance treatment until disease progression. Efficacy and safety were measured from the time of randomisation after completion of first line (induction) therapy. Patients received a median of 4 cycles of maintenance treatment with Pemetrexed and 4 cycles of placebo. A total of 169 patients (47.1%) completed ≥ 6 cycles maintenance treatment with Pemetrexed, representing at least 10 total cycles of Pemetrexed.


The study met its primary endpoint and showed a statistically significant improvement in PFS in the Pemetrexed arm over the placebo arm (n = 472, independently reviewed population; median of 3.9 months and 2.6 months, respectively) (hazard ratio = 0.64, 95% CI = 0.51-0.81, p = 0.0002). The independent review of patient scans confirmed the findings of the investigator assessment of PFS. For randomised patients, as measured from the start of Pemetrexed plus cisplatin first line induction treatment, the median investigator-assessed PFS was 6.9 months for the Pemetrexed arm and 5.6 months for the placebo arm (hazard ratio = 0.59 95% CI = 0.47-0.74).


Following Pemetrexed plus cisplatin induction (4 cycles), treatment with Pemetrexed was statistically superior to placebo for OS (median 13.9 months versus 11.0 months, hazard ratio = 0.78, 95%CI=0.64-0.96, p=0.0195). At the time of this final survival analysis, 28.7% of patients were alive or lost to follow up on the Pemetrexed arm versus 21.7% on the placebo arm. The relative treatment effect of Pemetrexed was internally consistent across subgroups (including disease stage, induction response, ECOG PS, smoking status, gender, histology and age) and similar to that observed in the unadjusted OS and PFS analyses. The 1 year and 2 year survival rates for patients on Pemetrexed were 58% and 32% respectively, compared to 45% and 21% for patients on placebo. From the start of Pemetrexed plus cisplatin first line induction treatment, the median OS of patients was 16.9 months for the Pemetrexed arm and 14.0 months for the placebo arm (hazard ratio= 0.78, 95% CI= 0.64-0.96). The percentage of patients that received post study treatment was 64.3% for Pemetrexed and 71.7% for placebo.



PARAMOUNT: Kaplan Meier plot of progression-free survival (PFS) and Overall Survival (OS) for continuation Pemetrexed maintenance versus placebo in patients with NSCLC other than predominantly squamous cell histology (measured from randomisation)



The Pemetrexed maintenance safety profiles from the two studies JMEN and PARAMOUNT were similar.


Pharmacokinetic properties


The pharmacokinetic properties of pemetrexed following single-agent administration have been evaluated in 426 cancer patients with a variety of solid tumours at doses ranging from 0.2 to 838 mg/m2 infused over a 10-minute period. Pemetrexed has a steady-state volume of distribution of 9 l/m2. In vitro studies indicate that pemetrexed is approximately 81 % bound to plasma proteins.

Binding was not notably affected by varying degrees of renal impairment. Pemetrexed undergoes limited hepatic metabolism. Pemetrexed is primarily eliminated in the urine, with 70 % to 90 % of the administered dose being recovered unchanged in urine within the first 24 hours following administration. In Vitro studies indicate that pemetrexed is actively secreted by OAT3 (organic anion transporter. Pemetrexed total systemic clearance is 91.8 ml/min and the elimination half-life from plasma is 3.5 hours in patients with normal renal function (creatinine clearance of 90 ml/min).

Between patient variability in clearance is moderate at 19.3 %. Pemetrexed total systemic exposure (AUC) and maximum plasma concentration increase proportionally with dose. The pharmacokinetics of pemetrexed are consistent over multiple treatment cycles.


The pharmacokinetic properties of pemetrexed are not influenced by concurrently administered cisplatin. Oral folic acid and intramuscular vitamin B12 supplementation do not affect the pharmacokinetics of pemetrexed.


Preclinical safety data


Administration of pemetrexed to pregnant mice resulted in decreased foetal viability, decreased foetal weight, incomplete ossification of some skeletal structures and cleft palate.


Administration of pemetrexed to male mice resulted in reproductive toxicity characterised by reduced fertility rates and testicular atrophy. In a study conducted in beagle dog by intravenous bolus injection for 9 months, testicular findings (degeneration/necrosis of the seminiferous epithelium) have been observed. This suggests that pemetrexed may impair male fertility. Female fertility was not investigated.


Pemetrexed was not mutagenic in either the in vitro chromosome aberration test in Chinese hamster ovary cells, or the Ames test. Pemetrexed has been shown to be clastogenic in the in vivo micronucleus test in the mouse.


Studies to assess the carcinogenic potential of pemetrexed have not been conducted.



PHARMACEUTICAL PARTICULARS


List of excipients


Mannitol

Hydrochloric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)


Incompatibilities


Pemetrexed is physically incompatible with diluents containing calcium, including lactated Ringer’s injection and Ringer’s injection. In the absence of other compatibility studies this medicinal product must not be mixed with other medicinal products.


Shelf life


Unopened vial 3 years.


Reconstituted and infusion solutions

When prepared as directed, reconstituted and infusion solutions of Pemetrexed Reig Jofre contain no antimicrobial preservatives. Chemical and physical in-use stability of reconstituted and infusion solutions of pemetrexed were demonstrated for 24 hours at refrigerated temperature or 25ºC. From a microbiological point of view, the product should be used immediately. If not used immediately, in- use storage times and conditions prior to use are the responsibility of the user and would not be longer than 24 hours at 2ºC to 8ºC.


Special precautions for storage


Unopened vial

This medicinal product does not require any special storage conditions.


For storage conditions after reconstitution of the medicinal product, see section 6.3.


Nature and contents of container


Type I glass vial with rubber stopper containing 500 mg of pemetrexed.

Pack of 1 vial.

Not all pack sizes may be marketed.


Special precautions for disposal and other handling


Use aseptic technique during the reconstitution and further dilution of pemetrexed for intravenous infusion administration.


Calculate the dose and the number of Pemetrexed Reig Jofre vials needed. Each vial contains an excess of pemetrexed to facilitate delivery of label amount.


Reconstitute 500 mg vials with 20 ml of sodium chloride 9 mg/ml (0.9 %) solution for injection, without preservative, resulting in a solution containing 25 mg/ml pemetrexed. Gently swirl each vial until the powder is completely dissolved. The resulting solution is clear and ranges in colour from colourless to yellow or green-yellow without adversely affecting product quality. The pH of the reconstituted solution is between 6.6 and 7.8. Further dilution is required.


The appropriate volume of reconstituted pemetrexed solution must be further diluted to 100 ml with sodium chloride 9 mg/ml (0.9 %) solution for injection, without preservative, and administered as an intravenous infusion over 10 minutes.


Pemetrexed infusion solutions prepared as directed above are compatible with polyvinyl chloride and polyolefin lined administration sets and infusion bags.


Parenteral medicinal products must be inspected visually for particulate matter and discolouration prior to administration. If particulate matter is observed, do not administer.


Pemetrexed solutions are for single use only. Any unused medicinal product or waste material must be disposed of in accordance with local requirements .


Preparation and administration precautions: As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of pemetrexed infusion solutions. The use of gloves is recommended. If a pemetrexed solution contacts the skin, wash the skin immediately and thoroughly with soap and water. If pemetrexed solutions contact the mucous membranes, flush thoroughly with water. Pemetrexed is not a vesicant. There is not a specific antidote for extravasation of pemetrexed. There have been few reported cases of pemetrexed extravasation, which were not assessed as serious by the investigator. Extravasation should be managed by local standard practice as with other non-vesicants.



MARKETING AUTHORISATION HOLDER


<MAH in DK, IS, NO, SE, UK:>


Laboratorio Reig Jofre S.A.

C/Gran Capitán, 10

08970 Sant Joan Despí (Barcelona)

Spain


<MAH in ES>


Laboratorio RAMÓN SALA, S.L.

C/Gran Capitán, 10

08970 Sant Joan Despí (Barcelona)

Spain



<Local representative in DK, NO, SE:>


Bioglan AB,

Box 50310,

SE-20213 Malmö

Sweden


MARKETING AUTHORISATION NUMBER


[To be completed nationally]



DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION


[To be completed nationally]



DATE OF REVISION OF THE TEXT


2016-11-04


Detailed information on this medicinal product is available on the website of (to be completed nationally)

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