Pemetrexed Reig Jofre
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.
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Table 1 - Dose modification table for Pemetrexed (as single agent or in combination) and cisplatin-Haematologic toxicities cisplatin –Haematologic toxicities |
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Nadir ANC < 500 /mm3 and nadir platelets ≥50,000 /mm3 |
75 % of previous dose (both Pemetrexed and cisplatin) |
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Nadir platelets < 50,000 /mm3 regardless of nadir ANC |
75 % of previous dose (both Pemetrexed and cisplatin ) |
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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.
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Table 2 - Dose modification table for Pemetrexed (as single agent or in combination) and cisplatin– Non-haematologic toxicities a, b |
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Dose of pemetrexed (mg/m2) |
Dose for cisplatin (mg/m2) |
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Any Grade 3 or 4 toxicities except mucositis |
75 % of previous dose |
75 % of previous dose |
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Any diarrhoea requiring hospitalisation (irrespective of grade) or grade 3 or 4 diarrhoea. |
75 % of previous dose |
75 % of previous dose |
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Grade 3 or 4 mucositis |
50 % of previous dose |
100 % of previous dose |
aNationalCancerInstituteCommonToxicityCriteria(CTCv2.0;NCI1998)
bExcludingneurotoxicity
Intheeventofneurotoxicity,therecommendeddoseadjustmentforPemetrexed Reig JofreandcisplatinisdocumentedinTable3.PatientsshoulddiscontinuetherapyifGrade3or4neurotoxicityisobserved.
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Table 3 - Dose modification table for Pemetrexed (as single agent or in combination) and cisplatin – Neurotoxicity |
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CTCa Grade |
Dose of pemetrexed (mg/m2) |
Dose for cisplatin (mg/m2) |
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0 – 1 |
100 % of previous dose |
100 % of previous dose |
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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,and2daysfol