Runarorn

Document: Runarorn Powder for concentrate for solution for infusion ENG SmPC change

1. NAME OF THE MEDICINAL PRODUCT

Runarorn 100 mgpowderforconcentrateforsolutionfor infusion

Runarorn 500 mg powder forconcentrateforsolutionfor infusion

Runarorn 1000 mg powder forconcentrateforsolutionfor infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 100 mg of pemetrexed (as pemetrexed disodium hemipentahydrate).

Each vial contains 500 mg of pemetrexed (as pemetrexed disodium hemipentahydrate).

Each vial contains 1000 mg of pemetrexed (as pemetrexed disodium hemipentahydrate).

After reconstitution (see section 6.6), each vial contains 25 mg/ml of pemetrexed.

Excipientwith known effect:

Each 100 mg vial contains approximately 11.29 mg sodium.

Each 500 mg vial contains approximately 53.77 mg sodium.

Each 1000 mg vial contains approximately 107.54 mg sodium.

For thefulllistof excipientssee section 6.1.

3. PHARMACEUTICAL form

Powderforconcentrateforsolution forinfusion.

White to yellow or greenish-yellow lyophilisate powder

4. Clinical particulars

4.1 Therapeutic indications

Malignantpleuralmesothelioma

Pemetrexed incombination withcisplatin isindicated forthetreatmentofchemotherapynaïvepatients with unresectablemalignantpleuralmesothelioma.

Non-smallcelllungcancer

Pemetrexed incombination withcisplatin isindicated forthefirstlinetreatmentofpatientswith locally advanced ormetastaticnon-smallcelllungcancerotherthan predominantlysquamouscellhistology (see section 5.1).

Pemetrexed isindicated as monotherapyforthemaintenancetreatmentoflocallyadvanced ormetastatic non-smallcelllungcancerotherthan predominantlysquamouscellhistologyin patientswhosedisease has notprogressed immediatelyfollowingplatinum-based chemotherapy(seesection 5.1).

Pemetrexed isindicated as monotherapyforthesecondlinetreatmentofpatientswith locallyadvanced ormetastaticnon-smallcelllungcancerotherthan predominantlysquamouscellhistology(seesection 5.1).

4.2 Posology and method of administration

Pemetrexed mustonlybe administered underthesupervision of aphysician qualified intheuseof anti-cancerchemotherapy.

Posology

_Pemetrexed _i_n_co_m_b_i_na_t_i_on _w_it_h_c_i_s_p_l_a_t_i_n

Therecommended dose ofpemetrexed is500 mg/m²of bodysurfacearea(BSA)administered asan intravenousinfusion over10 minuteson thefirstday ofeach 21-daycycle. Therecommended dose of cisplatinis75 mg/m²BSAinfused overtwo hoursapproximately30 minutesaftercompletion of the pemetrexedinfusion on thefirstday ofeach 21-daycycle. Patients mustreceive adequate anti-emetic treatmentand appropriate hydrationpriortoand/orafterreceivingcisplatin(seealso cisplatin _Su_m_m_a_r_y_of_P_r_oduct_C_h_a_r_a_c_t_e_ri_s_t_i_cs_f_or_sp_e_c_i_fi_c_do_s_i_n_g_ad_v_i_ce₎_.

Pemetrexed assingleagent

In patientstreatedfornon-smallcelllungcancerafterpriorchemotherapy, therecommended dose of pemetrexed is500 mg/m²BSAadministeredas an intravenousinfusion over10 minuteson thefirstday ofeach 21-daycycle.

Premedication regimen

Toreducetheincidenceand severityof skinreactions,a corticosteroidshould begiven theday prior to, ontheday of, and thedayafterpemetrexed administration.Thecorticosteroidshould beequivalent to 4 mgof dexamethasoneadministered orallytwicea day(seesection 4.4).

Toreducetoxicity, patientstreated with pemetrexed mustalsoreceivevitamin supplementation(see section4.4). Patientsmusttakeoralfolicacid ora multivitamin containingfolicacid (350 to 1000 micrograms)on a dailybasis. Atleastfivedoses offolicacid mustbe takenduringtheseven daysprecedingthefirstdoseof pemetrexed, and dosing mustcontinueduringthefullcourseof therapyand for21 daysafterthelastdoseof pemetrexed. Patientsmustalso receivean intramuscular injection ofvitamin B₁₂(1000 micrograms)in theweekprecedingthefirstdose ofpemetrexed and onceeverythreecyclesthereafter.SubsequentvitaminB₁₂injectionsmaybe givenon thesameday as pemetrexed.

Monitoring

Patientsreceivingpemetrexed should bemonitored beforeeach dosewitha completebloodcount, includinga differentialwhitecellcount(WCC)and plateletcount. Priorto each chemotherapy administrationblood chemistrytestsshould becollected to evaluaterenaland hepaticfunction. Before thestartofanycycleof chemotherapy, patientsarerequired tohavethefollowing:absolute neutrophil count (ANC)shouldbe ≥ 1500 cells/mm³and plateletsshould be≥ 100,000 cells/mm³.

Creatinineclearanceshouldbe ≥ 45 ml/min.

Thetotalbilirubin should be≤ 1.5 timesupper limitof normal. Alkalinephosphatase(AP), aspartate aminotransferase(ASTorSGOT)and alanineaminotransferase(ALT or SGPT)should be≤ 3 times upper limitofnormal. Alkalinephosphatase, ASTand ALT≤ 5 timesupperlimitof normalis acceptableifliverhas tumourinvolvement.

Dose adjustments

Doseadjustmentsatthestartofa subsequentcycleshould be based on nadirhaematologiccountsor maximumnon-haematologictoxicityfromtheprecedingcycleof therapy. Treatmentmaybe delayed to allowsufficienttimefor recovery. Upon recoverypatientsshould beretreated usingtheguidelines inTables1, 2 and 3, whichareapplicableforpemetrexed used asa singleagentorin combination with cisplatin.

Table 1 - Dose modification table for pemetrexed (as single agent or in combination) and cisplatin – Haematologic toxicities
Nadir ANC < 500 /mm³ and nadir platelets _≥ _50,₀₀₀ _/_m_m³	75 % of previous dose (both pemetrexed and cisplatin)
Nadir platelets < 50,000 /mm ³ regardless of nadir ANC	75 % of previous dose (both pemetrexed and cisplatin)
Nadir platelets < 50,000/mm ³ with bleeding^a, regardless of nadir ANC	50 % of previous dose (both pemetrexed and cisplatin)

^aThesecriteriameettheNationalCancerInstituteCommon ToxicityCriteria(CTCv2.0;NCI 1998)definition of≥CTCGrade2bleeding.

Ifpatientsdevelop non-haematologictoxicities≥ Grade3 (excludingneurotoxicity), pemetrexed should be withheld untilresolutionto lessthan or equalto thepatient’spre-therapyvalue.Treatmentshould be resumed accordingtotheguidelinesin Table2.

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

^aNationalCancerInstituteCommon ToxicityCriteria(CTCv2.0;NCI1998)

^bExcluding neurotoxicity

In theeventof neurotoxicity, therecommended dose adjustmentforpemetrexed and cisplatin is documentedinTable3. PatientsshoulddiscontinuetherapyifGrade3 or 4 neurotoxicityisobserved.

Table 3 - Dose modification table for pemetrexed (as single agent or in combination) and cisplatin – Neurotoxicity
_CT_C^a _G_rade	_D_ose _o_f _pemetrexed ₍_m_g_/_m²₎	_D_ose _f_o_r _c_i_sp_l_a_t_i_n ₍_m_g_/_m²₎
0 – 1	100 % of previous dose	100 % of previous dose
2	100 % of previous dose	50 % of previous dose

^aNationalCancerInstituteCommon ToxicityCriteria(CTCv2.0;NCI1998)

Treatmentwithpemetrexed should bediscontinuedifa patientexperiencesany haematologicor non-haematologicGrade3 or4 toxicityafter2 dosereductionsor immediatelyifGrade3 or4 neurotoxicityisobserved.

Elderly:In clinicalstudies,therehasbeen noindication thatpatients65 yearsofageor olderareat increased riskof adverseeventscomparedto patientsyoungerthan 65 yearsold. No dosereductions otherthan thoserecommended forallpatientsarenecessary.

Paediatricpopulation

Thereisno relevantuse ofpemetrexed inthepaediatricpopulation in malignantpleuralmesothelioma and non-smallcelllungcancer.

Renalimpairment:(Standard Cockcroftand GaultformulaorGlomerularFiltration Rate measuredTc99m-DPTAserumclearancemethod):Pemetrexedisprimarilyeliminatedunchanged by renalexcretion. In clinicalstudies, patientswithcreatinineclearanceof≥ 45 ml/min required no dose adjustmentsotherthanthoserecommended forallpatients.Thereareinsufficientdataon theuseof pemetrexedin patientswithcreatinineclearancebelow45 ml/min;thereforetheuseof pemetrexed is notrecommended (seesection 4.4).

Hepaticimpairment:No relationshipsbetween AST (SGOT), ALT (SGPT),or total bilirubinand pemetrexedpharmacokineticswereidentified. Howeverpatientswith hepaticimpairment such asbilirubin > 1.5 timesthe upperlimitof normaland/oraminotransferase> 3.0 timesthe upper limitofnormal(hepaticmetastasesabsent)or > 5.0 timesthe upperlimitof normal(hepatic metastasespresent)havenotbeen specificallystudied.

Method ofadministration:

For precautionsto betakenbeforehandlingor administeringpemetrexed, seesection 6.6.

Runarorn should beadministeredas anintravenousinfusionover10 minuteson thefirstday ofeach 21-daycycle. For instructionson reconstitution and dilution of Runarorn beforeadministration,see section6.6.

4.3 Contraindications

Hypersensitivityto theactivesubstanceorto anyof theexcipientslistedin section 6.1.

Breast-feeding(seesection4.6).

Concomitantyellowfevervaccine(seesection 4.5).

4.4 Special warnings and precautions for use

Pemetrexedcan suppressbone marrowfunctionas manifested by neutropenia, thrombocytopeniaand anaemia(orpancytopenia)(seesection4.8). Myelosuppressionisusuallythedose-limitingtoxicity. Patientsshouldbe monitored formyelosuppressionduringtherapyand pemetrexedshould notbe given to patientsuntilabsoluteneutrophilcount(ANC)returnsto ≥ 1500 cells/mm³and plateletcount returnsto≥ 100,000 cells/mm³.Dose reductionsforsubsequentcyclesarebasedon nadirANC, plateletcountand maximumnon-haematologictoxicityseen fromthepreviouscycle(seesection 4.2).

Less toxicityand reductionin Grade3/4 haematologicand non-haematologictoxicitiessuch as neutropenia,febrileneutropeniaand infection with Grade3/4neutropeniawerereported when pre-treatmentwithfolicacid and vitamin B₁₂wasadministered.Therefore, allpatientstreated with pemetrexedmustbe instructedto takefolicacid and vitamin B₁₂as aprophylacticmeasureto reduce treatment-relatedtoxicity(seesection 4.2).

Skin reactionshavebeen reported in patientsnot pre-treated with a corticosteroid.Pre-treatmentwith dexamethasone(orequivalent)can reducetheincidenceand severityof skinreactions(see section4.2).

An insufficientnumberof patientshasbeen studied with creatinineclearanceofbelow45 ml/min. Therefore, theuseof pemetrexedin patientswithcreatinineclearanceof <45 ml/min isnot recommended (seesection4.2).

Patientswithmildtomoderaterenalimpairment (creatinineclearancefrom45 to79 ml/min)should avoidtakingnon-steroidalanti-inflammatorydrugs(NSAIDs)such asibuprofen,and aspirin(> 1.3 g daily)for2 daysbefore,ontheday of,and 2 daysfollowingpemetrexedadministration(seesection 4.5).

In patientswith mild tomoderaterenalimpairment eligibleforpemetrexedtherapyNSAIDswith longelimination half-livesshould beinterruptedforatleast5 dayspriorto, ontheday of, and atleast 2 daysfollowingpemetrexed administration (seesection 4.5).

Seriousrenalevents, includingacuterenalfailure,havebeen reported with pemetrexed aloneor in association with otherchemotherapeuticagents. Manyof thepatientsin whomtheseoccurred had underlyingriskfactorsforthe developmentofrenaleventsincludingdehydrationor pre-existing hypertensionor diabetes.

Theeffectofthird spacefluid, such aspleuraleffusionor ascites,on pemetrexedisnot fullydefined. A phase2 studyof pemetrexed in31 solid tumourpatients withstablethird spacefluid demonstrated no differencein pemetrexed dose normalized plasmaconcentrationsorclearancecompared topatients withoutthird spacefluidcollections.Thus,drainageofthird spacefluidcollectionpriorto pemetrexed treatmentshouldbe considered,but maynot benecessary.

Dueto thegastrointestinaltoxicityof pemetrexed given in combination with cisplatin, severe dehydration hasbeen observed. Therefore, patientsshould receiveadequateantiemetictreatmentand appropriatehydrationpriorto and/orafterreceivingtreatment.

Seriouscardiovascularevents,includingmyocardialinfarctionand cerebrovasculareventshavebeen uncommonlyreported duringclinicalstudieswith pemetrexed, usuallywhen given incombination with anothercytotoxicagent. Mostofthepatientsin whomtheseeventshavebeenobserved had pre- existingcardiovascularriskfactors(seesection 4.8).

Immunodepressed statusiscommon in cancerpatients.Asa result, concomitantuseof liveattenuated vaccinesisnot recommended (seesection4.3 and 4.5).

Pemetrexedcan havegeneticallydamagingeffects. Sexuallymaturemalesareadvised not tofathera child duringthetreatmentand up to 6 monthsthereafter. Contraceptivemeasuresor abstinenceare recommended. Owingto thepossibilityof pemetrexedtreatmentcausingirreversibleinfertility, men areadvisedto seekcounsellingon spermstoragebeforestartingtreatment.

Women ofchildbearingpotentialmustuseeffectivecontraception duringtreatmentwith pemetrexed (seesection 4.6).

Casesofradiation pneumonitishavebeen reported inpatientstreated with radiation eitherprior, duringor subsequentto theirpemetrexed therapy. Particularattention should bepaidto thesepatients and caution exercised withuse ofotherradiosensitisingagents.

Casesofradiationrecallhavebeen reportedin patientswho received radiotherapyweeksor years previously.

One vial of 500 mg contains approximately 53.77 mg of sodium per vial. To be taken into consideration by patients on a controlled sodium diet.

One vial of 1000 mg contains approximately 107.54 mg of sodium per vial. To be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction

Pemetrexedismainlyeliminatedunchanged renallyby tubularsecretion and to a lesserextentby glomerularfiltration. Concomitantadministrationof nephrotoxicdrugs(e.g. aminoglycoside,loop diuretics,platinumcompounds, cyclosporin)could potentiallyresultin delayed clearanceof pemetrexed.Thiscombination shouldbe used withcaution.Ifnecessary, creatinineclearanceshould be closelymonitored.

Concomitantadministration of substancesthatarealso tubularlysecreted(e.g. probenecid, penicillin) couldpotentiallyresultin delayed clearanceofpemetrexed. Caution shouldbe madewhenthesedrugs arecombined with pemetrexed. Ifnecessary, creatinineclearanceshould beclosely monitored.

In patientswith normalrenalfunction(creatinineclearance> 80 ml/min), high dosesofnon-steroidal anti-inflammatorydrugs(NSAIDs, such as ibuprofen > 1600 mg/day)and aspirinat higherdose (> 1.3 gdaily)maydecreasepemetrexed eliminationand, consequently, increasetheoccurrenceof pemetrexedadverseevents.Therefore, caution shouldbe madewhen administeringhigherdoses of NSAIDsor aspirin, concurrentlywith pemetrexedto patientswithnormalfunction(creatinine clearance> 80 ml/min).

In patientswith mild tomoderaterenalimpairment (creatinineclearancefrom45 to 79 ml/min),the concomitantadministrationof pemetrexed with NSAIDs(e.g. ibuprofen)or aspirin at higherdose should be avoidedfor2 daysbefore,on theday of,and 2 daysfollowingpemetrexed administration (seesection 4.4).

In theabsenceof dataregardingpotentialinteractionwith NSAIDshavinglongerhalf-livessuch as piroxicamor rofecoxib,theconcomitantadministration withpemetrexed in patientswithmild to moderaterenalimpairment should be interruptedforat least5 dayspriorto, ontheday of, and at least2 daysfollowingpemetrexedadministration (seesection4.4). Ifconcomitantadministrationof NSAIDsis necessary, patientsshould be monitoredcloselyfortoxicity, especiallymyelosuppression and gastrointestinaltoxicity.

Pemetrexedundergoeslimited hepaticmetabolism. Resultsfromin vitrostudieswith human liver microsomesindicatedthatpemetrexedwouldnot bepredicted to causeclinicallysignificantinhibition of themetabolicclearanceof drugsmetabolised by CYP3A, CYP2D6, CYP2C9, and CYP1A2.

Interactionscommon to allcytotoxics:

Dueto theincreasedthromboticriskin patientswith cancer, theuseof anticoagulation treatmentis frequent.Thehigh intra-individualvariabilityof thecoagulation statusduringdiseasesand the possibilityof interaction between oralanticoagulantsand anticancerchemotherapyrequireincreased frequencyof INR(InternationalNormalised Ratio)monitoring, ifitisdecidedto treatthepatientwith oralanticoagulants.

Concomitantuse contraindicated:Yellowfevervaccine:riskof fatalgeneralised vaccinaledisease(see section 4.3).

Concomitantuse notrecommended:Liveattenuated vaccines(exceptyellowfever, forwhich concomitantuseiscontraindicated):riskof systemic, possiblyfatal, disease.Theriskisincreasedin subjectswho arealreadyimmunosuppressed by theirunderlyingdisease. Usean inactivated vaccine whereitexists(poliomyelitis)(seesection 4.4).

4.6 Fertility, pregnancy and lactation

Contracep