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Document: Pemetrexed Reig Jofre 100 mg powder for concentrate for solution for infusion ENG SmPC change

• Pemetrexed Reig Jofre 100 mg powder for concentrate for solution for infusion SmPC
• Pemetrexed Reig Jofre 100 mg powder for concentrate for solution for infusion ENG SmPC

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Pemetrexed Reig Jofre 100mgpowderforconcentrateforsolutionforinfusion

Eachvialcontains100mgofpemetrexed(aspemetrexeddisodium 2.5 H₂O).

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

Eachvialcontainsapproximately11mgsodium.

Forthefulllistofexcipients,seesection6.1.

Powderforconcentrateforsolutionforinfusion.

Whitetoeitherlightyelloworgreen-yellowlyophilisedpowder.

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:

Pemetrexed Reig Jofre mustonlybeadministeredunderthesupervisionofaphysicianqualifiedintheuseofanti-cancerchemotherapy.

Pemetrexed Reig Jofre incombinationwithcisplatin

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

Pemetrexed Reig Jofre assingleagent

Inpatientstreatedfornon-smallcelllungcancerafterpriorchemotherapy,therecommendeddoseofPemetrexed Reig Jofreis500mg/m²BSAadministeredasanintravenousinfusionover10minutesonthefirstdayofeach21-daycycle.

Premedicationregimen

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

Toreducetoxicity,patientstreatedwithpemetrexedmustalsoreceivevitaminsupplementation(seesection4.4).Patientsmusttakeoralfolicacidoramultivitamincontainingfolicacid(350to 1000micrograms)onadailybasis.Atleastfivedosesoffolicacidmustbetakenduringthesevendaysprecedingthefirstdoseofpemetrexed,anddosingmustcontinueduringthefullcourseoftherapyandfor21daysafterthelastdoseofpemetrexed.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 Jofreusedasasingleagentorincombinationwithcisplatin.

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)

^aThesecriteriameettheNationalCancerInstituteCommonToxicityCriteria(CTCv2.0;NCI1998)definitionof≥CTCGrade2bleeding

Ifpatientsdevelopnon-haematologictoxicities≥Grade3(excludingneurotoxicity),Pemetrexed Reig Jofre shouldbewithhelduntilresolutiontolessthanorequaltothepatient’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 Jofre andcisplatinisdocumentedinTable3.PatientsshoulddiscontinuetherapyifGrade3or4neurotoxicityisobserved.

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

Treatmentwith Pemetrexed Reig Jofreshouldbediscontinuedifapatientexperiencesanyhaematologicornon-haematologicGrade3or4toxicityafter2dosereductionsorimmediatelyifGrade3or4neurotoxicityisobserved.

Elderly:Inclinicalstudies,therehasbeennoindicationthatpatients65yearsofageorolderareatincreasedriskofadverseeventscomparedtopatientsyoungerthan65yearsold.Nodosereductionsotherthanthoserecommendedforallpatientsarenecessary.

Paediatricpopulation

Thereisnorelevantuseof Pemetrexed 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.

Hypersensitivitytotheactivesubstanceortoanyoftheexcipientslistedinsection6.1.Breast-feeding(seesection4.6).

Concomitantyellowfevervaccine(seesection4.5).

Pemetrexedcansuppressbonemarrowfunctionasmanifestedbyneutropenia,thrombocytopeniaandanaemia(orpancytopenia)(seesection4.8).Myelosuppressionisusuallythedose-limitingtoxicity.Patientsshouldbemonitoredformyelosuppressionduringtherapyandpemetrexedshouldnotbegiventopatientsuntilabsoluteneutrophilcount(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).

InpatientswithmildtomoderaterenalinsufficiencyeligibleforpemetrexedtherapyNSAIDswith longeliminationhalf-livesshouldbeinterrupted foratleast5dayspriorto,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.

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).IfconcomitantadministrationofNSAIDsisnecessary,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).

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,menareadvisedtoseekcounsellingonspermstoragebefore startingtreatment.

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.However,ithasbeenreportedthatpemetrexedmaycausefatigue.Thereforepatientsshouldbecautionedagainstdrivingoroperatingmachinesifthiseventoccurs.

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.

Clinicallyrelevanttoxicitieswithrespecttogenderweresimilartotheoverallpopulationinpatientsreceiving pemetrexedpluscisplatin.

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 disorders	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, sometimes fatal, has been commonly reported during clinical trials with pemetrexed.

During post marketing surveillance, the following adverse reactions have been reported in patients treated with pemetrexed:

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]:

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

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.

TheEuropeanMedicinesAgencyhaswaivedtheobligationtosubmittheresultsofstudieswithPemetrexedinallsubsetsofthepaediatricpopulationinthegrantedindications(seeSection4.2).

Clinicalefficacy:

Mesothelioma:

EMPHACIS,amulticentre,randomised,single-blindphase3studyofPemetrexed pluscisplatinversuscisplatininchemonaivepatientswithmalignantpleuralmesothelioma,hasshownthatpatientstreatedwithPemetrexed andcisplatinhadaclinicallymeaningful2.8-monthmediansurvivaladvantageoverpatientsreceivingcisplatinalone.

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

EfficacyofPemetrexed pluscisplatinvs.cisplatininmalignantpleuralmesothelioma

	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.

** In the Pemetrexed /cisplatin arm, randomized and treated (N=225) and fully supplemented(N=167)

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

TherearelimiteddatainpatientswithmalignantpleuralmesotheliomatreatedwithPemetrexed alone.Pemetrexedatadoseof500mg/m²wasstudiedasasingle-agentin64chemonaivepatientswithmalignantpleuralmesothelioma.Theoverallresponseratewas14.1%.

NSCLC,second-line treatment:

Amulticentre,randomised,openlabelphase3studyofPemetrexed versusdocetaxelinpatientswithlocallyadvancedormetastaticNSCLCafterpriorchemotherapyhasshownmediansurvivaltimesof 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,Phase 3,controlledtrial,suggestthatefficacydata(overallsurvival,progressionfreesurvival)forpemetrexedaresimilarbetweenpatientspreviouslypretreatedwithdocetaxel(n=41)andpatientswhodidnotreceivepreviousdocetaxeltreatment (n=540).

Efficacyof Pemetrexed vsdocetaxelin NSCLC- 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=totalpopulationsize.

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.TheefficacyanalysesusingPQpopulationareconsistentwiththeanalysesfortheITTpopulationandsupportthenon-inferiorityofACversusGC.

Progressionfreesurvival(PFS)andoverallresponserateweresimilarbetweentreatmentarms:medianPFSwas4.8monthsforPemetrexed pluscisplatinversus5.1monthsforgemcitabineplus cisplatin(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.

Efficacyof pemetrexed +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	a 0.94 (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

NSCLC,maintenancetreatment:

JMEN

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

ThestudymetitsprimaryendpointandshowedastatisticallysignificantimprovementinPFSinthePemetrexedarmovertheplaceboarm(n=581,independentlyreviewedpopulation;medianof 4.0monthsand2.0months,respectively)(hazardratio=0.60,95%CI=0.49-0.73,p<0.00001).TheindependentreviewofpatientscansconfirmedthefindingsoftheinvestigatorassessmentofPFS.ThemedianOSfortheoverallpopulation(n=663)was13.4monthsforthePemetrexed armand10.6monthsfortheplaceboarm,hazardratio=0.79(95%CI=0.65-0.95,p=0.01192).

ConsistentwithotherPemetrexed studies,adifferenceinefficacyaccordingtoNSCLChistologywasobservedinJMEN.ForpatientswithNSCLCotherthanpredominantlysquamouscellhistology (n=430,independentlyreviewedpopulation)medianPFSwas4.4monthsforthePemetrexed armand 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:

Progression-FreeSurvival OverallSurvival

PARAMOUNT

Amulticentre,randomised,double-blind,placebo-controlledPhase3study(PARAMOUNT),comparedtheefficacyandsafetyofcontinuationmaintenancetreatmentwithPemetrexedplusBSC(n=359)withthatofplaceboplusBSC(n=180)inpatientswithlocallyadvanced(StageIIIB)or metastatic(StageIV)NSCLCotherthanpredominantlysquamouscellhistologywhodidnotprogressafter4cyclesoffirstlinedoublettherapyofPemetrexedincombinationwithcisplatin.Ofthe939 patientstreatedwithPemetrexedpluscisplatininduction,539patientswererandomisedtomaintenance treatmentwithpemetrexedorplacebo.Oftherandomisedpatients,44.9%hadacomplete/partialresponseand51.9%hadaresponseofstablediseasetoPemetrexedpluscisplatininduction.PatientsrandomisedtomaintenancetreatmentwererequiredtohaveanECOGperformancestatus0or1.ThemediantimefromthestartofPemetrexed pluscisplatininductiontherapytothestartofmaintenancetreatmentwas2.96monthsonboththepemetrexedarmandtheplaceboarm.Randomisedpatientsreceivedmaintenancetreatmentuntildiseaseprogression.Efficacyandsafetyweremeasuredfromthetimeofrandomisationaftercompletionoffirstline(induction)therapy.Patientsreceivedamedianof 4cyclesofmaintenancetreatmentwithPemetrexedand4cyclesofplacebo.Atotalof169patients(47.1%)completed≥6cyclesmaintenancetreatmentwithPemetrexed,representingatleast10totalcyclesofPemetrexed.

ThestudymetitsprimaryendpointandshowedastatisticallysignificantimprovementinPFSinthePemetrexed armovertheplaceboarm(n=472,independentlyreviewedpopulation;medianof 3.9monthsand2.6months,respectively)(hazardratio=0.64,95%CI=0.51-0.81,p=0.0002).TheindependentreviewofpatientscansconfirmedthefindingsoftheinvestigatorassessmentofPFS.Forrandomisedpatients,asmeasuredfromthestartof Pemetrexed pluscisplatinfirstlineinductiontreatment,themedianinvestigator-assessedPFSwas6.9monthsforthePemetrexed armand5.6monthsfortheplaceboarm(hazardratio=0.5995%CI=0.47-0.74).

FollowingPemetrexedpluscisplatininduction(4cycles),treatmentwithPemetrexed wasstatisticallysuperiortoplaceboforOS(median13.9monthsversus11.0months,hazardratio=0.78,95% CI=0.64-0.96,p=0.0195).Atthetimeofthisfinalsurvivalanalysis,28.7%ofpatientswerealiveorlosttofollowuponthePemetrexed armversus21.7%ontheplaceboarm.TherelativetreatmenteffectofPemetrexed wasinternallyconsistentacrosssubgroups(includingdiseasestage,inductionresponse,ECOGPS,smokingstatus,gender,histologyandage)andsimilartothatobservedintheunadjustedOSandPFSanalyses.The1yearand2yearsurvivalratesforpatientsonPemetrexed were58%and32%respectively,comparedto45%and21%forpatientsonplacebo.FromthestartofPemetrexedpluscisplatinfirstlineinductiontreatment,themedianOSofpatientswas16.9monthsforthePemetrexed armand 14.0monthsfor the placeboarm (hazardratio = 0.78,95%CI = 0.64-0.96).The percentageofpatientsthatreceivedpoststudytreatmentwas64.3%forPemetrexed and71.7%forplacebo.

PARAMOUNT: KaplanMeierplotofprogression-freesurvival(PFS)andOverallSurvival(OS)forcontinuationPemetrexed maintenanceversusplaceboinpatientswithNSCLCotherthanpredominantlysquamouscellhistology(measuredfromrandomisation)

Progression-FreeSurvival OverallSurvival

The Pemetrexed maintenancesafetyprofilesfromthetwostudiesJMENandPARAMOUNTweresimilar.

Thepharmacokineticpropertiesofpemetrexedfollowingsingle-agentadministrationhavebeenevaluatedin426cancerpatientswithavarietyofsolidtumoursatdosesrangingfrom0.2to 838mg/m²infusedovera10-minuteperiod.Pemetrexedhasasteady-statevolumeofdistributionof9l/m².Invitrostudiesindicatethatpemetrexedisapproximately81%boundtoplasmaproteins.

Bindingwasnotnotablyaffectedbyvaryingdegreesofrenalimpairment.Pemetrexedundergoes

limitedhepaticmetabolism.Pemetrexedisprimarilyeliminatedintheurine,with70%to90%oftheadministereddosebeingrecoveredunchangedinurinewithinthefirst24hoursfollowingadministration.InVitrostudiesindicatethatpemetrexedisactivelysecretedbyOAT3(organicaniontransporter.Pemetrexedtotalsystemicclearanceis91.8ml/minandtheeliminationhalf-lifefromplasmais3.5hoursinpatientswithnormalrenalfunction(creatinineclearanceof90ml/min).Betweenpatientvariabilityinclearanceismoderateat19.3%.Pemetrexedtotalsystemicexposure(AUC)andmaximumplasmaconcentrationincreaseproportionallywithdose.Thepharmacokineticsofpemetrexedareconsistentovermultipletreatmentcycles.

Thepharmacokineticpropertiesofpemetrexedarenotinfluencedbyconcurrentlyadministeredcisplatin.OralfolicacidandintramuscularvitaminB₁₂supplementationdonotaffectthepharmacokineticsofpemetrexed.

Administrationofpemetrexedtopregnantmiceresultedindecreasedfoetalviability,decreasedfoetalweight,incompleteossificationofsomeskeletalstructuresandcleftpalate.

Administrationofpemetrexedtomalemiceresultedinreproductivetoxicitycharacterisedbyreducedfertilityratesandtesticularatrophy.Inastudyconductedinbeagledogbyintravenousbolusinjectionfor9months,testicularfindings(degeneration/necrosisoftheseminiferousepithelium)havebeenobserved.Thissuggeststhatpemetrexedmayimpairmalefertility.Femalefertilitywasnotinvestigated.

PemetrexedwasnotmutagenicineithertheinvitrochromosomeaberrationtestinChinesehamsterovarycells,ortheAmestest.Pemetrexedhasbeenshowntobeclastogenicintheinvivomicronucleustestinthemouse.

Studiestoassessthecarcinogenicpotentialofpemetrexedhavenotbeenconducted.

Mannitol

Hydrochloric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)

Pemetrexedisphysicallyincompatiblewithdiluentscontainingcalcium,includinglactatedRinger’sinjectionandRinger’sinjection.Intheabsenceofothercompatibilitystudiesthismedicinalproductmustnotbemixedwithothermedicinalproducts.

Unopenedvial 3years

Reconstitutedandinfusionsolutions

Whenpreparedasdirected,reconstitutedandinfusionsolutionsofPemetrexed Reig Jofre containnoantimicrobialpreservatives.Chemicalandphysicalin-usestabilityofreconstitutedandinfusionsolutionsofpemetrexedweredemonstratedfor24hoursatrefrigeratedtemperatureor25ºC.Fromamicrobiologicalpointofview,theproductshouldbeusedimmediately.Ifnotusedimmediately,in-usestoragetimesandconditionspriortousearetheresponsibilityoftheuserandwouldnotbelongerthan24hoursat2ºCto8ºC.

Unopenedvial

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

Forstorageconditionsafterreconstitutionofthemedicinalproduct,seesection6.3.

TypeIglassvialwithrubberstoppercontaining100mgofpemetrexed.Packof1vial.

Notallpacksizesmaybemarketed.

Preparationandadministrationprecautions:Aswithotherpotentiallytoxicanticanceragents,careshouldbeexercisedinthehandlingandpreparationofpemetrexedinfusionsolutions.Theuseofglovesisrecommended.Ifapemetrexedsolutioncontactstheskin,washtheskinimmediatelyandthoroughlywithsoapandwater.Ifpemetrexedsolutionscontactthemucousmembranes,flushthoroughlywithwater.Pemetrexedisnotavesicant.Thereisnotaspecificantidoteforextravasationofpemetrexed.Therehavebeenfewreportedcasesofpemetrexedextravasation,whichwerenotassessedasseriousbytheinvestigator.Extravasationshouldbemanagedbylocalstandardpracticeaswithothernon-vesicants.

<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

[To be completed nationally]

[To be completed nationally]

2016-11-04

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