DACARBAZINE MEDAC

Main information

  • Trade name:
  • DACARBAZINE MEDAC
  • Dosage:
  • 100 Milligram
  • Pharmaceutical form:
  • Pdr for Soln Inj/Inf
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0623/003/001
  • Authorization date:
  • 14-11-1997
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Dacarbazinemedac100mg,Powderforsolutionforinjectionorinfusion.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachsingle-dosevialofDacarbazinemedac100mgcontains100mgdacarbazine(asdacarbazinecitrate,formedin

situ).

AfterreconstitutionDacarbazinemedac100mgcontains10mg/mldacarbazine(seesection6.6).

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Dacarbazinemedac100mg:Powderforsolutionforinjectionorinfusion.

Dacarbazinemedacisawhiteorpaleyellowpowder.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Dacarbazineisindicatedforthetreatmentofpatientswithmetastasizedmalignantmelanoma.

Furtherindicationsfordacarbazineaspartofacombinationchemotherapyare:

AdvancedHodgkin’sdisease.

Advancedadultsofttissuesarcomas(exceptmesothelioma,Kaposisarcoma).

4.2Posologyandmethodofadministration

Theuseofdacarbazineshouldbeconfinedtophysiciansexperiencedinoncologyorhaematologyrespectively.

Dacarbazineissensitivetolightexposure.Allreconstitutedsolutionsshouldbesuitablyprotectedfromlightalso

duringadministration(light-resistantinfusionset).

Careshouldbetakenofadministrationoftheinjectiontoavoidextravasationintotissuessincethiswillcauselocal

painandtissuedamage.Ifextravasationoccurs,theinjectionshouldbediscontinuedimmediatelyandanyremaining

portionofthedoseshouldbeintroducedintoanothervein.

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MalignantMelanoma

Dacarbazinecanbeadministeredassingleagentindosesof200to250mg/m²bodysurfacearea/dayasanIVinjection

for5daysevery3weeks.

Asanalternativetoanintravenousbolusinjectiondacarbazinecanbeadministeredasashort-terminfusion(over15-

30minutes).

Itisalsopossibletogive850mg/m²bodysurfaceareaonday1andthenonceevery3weeksasintravenousinfusion.

Hodgkin'sDisease

Dacarbazineisadministeredinadailydoseof375mg/m²bodysurfaceareaIVevery15daysincombinationwith

doxorubicin,bleomycinandvinblastine(ABVDregimen).

Adultsofttissuesarcoma

Foradultsofttissuesarcomasdacarbazineisgivenindailydosesof250mg/m²bodysurfaceareaIV(days1-5)in

combinationwithdoxorubicinevery3weeks(ADICregimen).

Duringdacarbazinetreatmentfrequentmonitoringofbloodcountsshouldbeconductedaswellasmonitoringof

hepaticandrenalfunction.Sinceseveregastrointestinalreactionsfrequentlyoccur,anti-emeticandsupportive

measuresareadvisable.

Becauseseveregastrointestinalandhaematologicaldisturbancescanoccuranextremelycarefulbenefit-riskanalysis

hastobemadebeforeeverycourseoftherapywithdacarbazine.

Durationoftherapy

Thetreatingphysicianshouldindividuallydecideaboutthedurationoftherapytakingintoaccountthetypeandstage

oftheunderlyingdisease,thecombinationtherapyadministeredandtheresponsetoandadverseeffectsofdacarbazine.

InadvancedHodgkin'sdisease,ausualrecommendationistoadminister6cyclesofABVDcombinationtherapy.In

metastasizedmalignantmelanomaandinadvancedtissuesarcoma,thedurationoftreatmentdependsontheefficacy

andtolerabilityintheindividualpatient.

Rateofadministration

Dosesupto200mg/m²maybegivenasaslowintravenousinjection.Largerdoses(rangingfrom200to850mg/m²)

shouldbeadministeredasanIVinfusionover15-30minutes.

Itisrecommendedtotestthepatencyoftheveinfirstwitha5-to10-mlflushofsodiumchlorideinfusionsolutionor

glucose5%.Thesamesolutionsshouldbeusedafterinfusiontoflushanyremainingdrugfromthetubing.

Afterreconstitutionwithwaterforinjectionwithoutfurtherdilutionwithsodiumchlorideinfusionsolutionorglucose

5%,dacarbazine100mgand200mgpreparationsarehypo-osmolar(ca.100mOsmol/kg)andshouldthereforebe

givenbyslowintravenousinjectione.g.over1minuteratherthanrapidintravenousbolusoverafewseconds.

Specialpopulations

Patientswithkidney/liverinsufficiency

Ifthereismildtomoderaterenalorhepaticinsufficiencyalone,adosereductionisnotusuallyrequired.Inpatients

withcombinedrenalandhepaticimpairmenteliminationofdacarbazineisprolonged.However,novalidated

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Elderlypatients

Aslimitedexperienceinelderlypatientsisavailablenospecialinstructionsfortheuseinelderlypatientscanbegiven.

Children

Nospecialrecommendationsfortheuseofdacarbazineinthepaediatricagegroupcanbegivenuntilfurtherdata

becomeavailable.

4.3Contraindications

Dacarbazineiscontraindicatedinpatients:

Whohaveahistoryofhypersensitivityreactionstodacarbazineortoanyoftheexcipients.

Inpregnantorbreastfeedingwomen.

Inpatientswithleucopeniaand/orthrombocytopenia.

Inpatientswithsevereliverorkidneydiseases.

4.4Specialwarningsandprecautionsforuse

Itisrecommendedthatdacarbazineshouldonlybeadministeredunderthesupervisionofaphysicianspecialisedin

oncology,havingthefacilitiesforregularmonitoringofclinical,biochemicalandhaematologicaleffects,duringand

aftertherapy.

Ifsymptomsofaliverorkidneyfunctionaldisorderorsymptomsofahypersensitivityreactionareobservedimmediate

cessationoftherapyisrequired.Ifveno-occlusivediseaseoftheliveroccurs,furthertherapywithdacarbazineis

contra-indicated.

Note:Theresponsiblephysicianshouldbeawareofararelyobservedseverecomplicationduringtherapyresulting

fromlivernecrosisduetoocclusionofintrahepaticveins.Thereforefrequentmonitoringofliversize,functionand

bloodcounts(especiallyeosinophils)isrequired.Insinglecasesofsuspectedveno-occlusivediseaseearlytherapywith

high-dosecorticosteroids(forexamplehydrocortisone300mg/day)withorwithoutfibrinolyticagentslikeheparinor

tissueplasminogenactivatorwassuccessful(seesection4.8).

Long-termtherapycancausecumulativebonemarrowtoxicity.Thepossiblebonemarrowdepressionrequirescareful

monitoringofwhitebloodcells,redbloodcellsandplateletlevels.Haemopoetictoxicitymaywarranttemporary

suspensionorcessationoftherapy.

ExtravasationofthedrugduringIVadministrationmayresultintissuedamageandseverepain.

Furthermoredacarbazineisamoderateimmunosuppressiveagent.

Hepatotoxicdrugsandalcoholshouldbeavoidedduringchemotherapy.

Contraceptivemeasures

Menareadvisedtotakecontraceptivemeasuresduringandfor6monthsaftercessationoftherapy.

Administrationofdacarbazineinthepaediatricagegroup

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Handlingofdacarbazine

Dacarbazineshouldbehandledaccordingtostandardproceduresforcytostaticsthathavemutagenic,carcinogenicand

teratogeniceffects.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Incaseofpreviousorconcomitanttreatmenthavingadverseeffectsonthebonemarrow(particularlycytostaticagents,

irradiation)myelotoxicinteractionsarepossible.

Studiestoinvestigatethepresenceofphenotypicmetabolismhavenotbeenundertakenbuthydroxylationoftheparent

compoundtometaboliteswithanti-tumouractivityhasbeenidentified.

DacarbazineismetabolisedbycytochromeP450(CYP1A1,CYP1A2,andCYP2E1).Thishastobetakenintoaccount

ifotherdrugsareco-administeredwhicharemetabolisedbythesamehepaticenzymes.

Dacarbazinecanenhancetheeffectsofmethoxypsoralenbecauseofphotosensitization.

4.6Fertility,pregnancyandlactation

Pregnancy/Lactation

Dacarbazinehasbeenshowntobemutagenic,teratogenicandcarcinogenicinanimals.Itmustbeassumedthatan

increasedriskforteratogeniceffectsexistsinhumans.Thereforedacarbazinemustnotbeusedduringpregnancyand

duringbreastfeeding(seesections4.3and4.4).

Womenofchildbearingpotential

Womenofchildbearingagemustavoidpregnancyduringdacarbazinetreatment.

4.7Effectsonabilitytodriveandusemachines

Dacarbazinemayinfluencetheabilitytodriveoroperatemachinesbecauseofitscentralnervoussideeffectsor

becauseofnauseaandvomiting.

4.8Undesirableeffects

Frequencies:

Verycommon(>1/10)

Common(>1/100,<1/10)

Uncommon(>1/1,000,<1/100)

Rare(>1/10,000,<1/1,000)

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ThemostcommonlyreportedADRsaregastrointestinaldisorders(anorexia,nauseaandvomiting)andbloodand

lymphaticsystemdisorderssuchasanaemia,leukopeniaandthrombocytopenia.Thelatteraredose-dependantand

delayed,withthenadirsoftenonlyoccurringafter3to4weeks.

Disturbancesofthedigestivetractsuchasanorexia,nauseaandvomitingarecommonandsevere.Inrarecases

diarrhoeahasbeenobserved.

Changesinbloodcountsoftenobserved(anaemia,leukopenia,thrombocytopenia)aredose-dependentanddelayed,

withthenadirsoftenonlyoccurringafter3to4weeks.Inrarecasespancytopeniaandagranulocytosishavebeen

described.

Flu-likesymptomswithexhaustion,chills,feverandmuscularpainareoccasionallyobservedduringoroftenonlydays

afterdacarbazineadministration.Thesedisturbancesmayrecurwiththenextinfusion.

Bloodandlymphaticsystemdisorders Common(>1/100,<1/10)

Anaemia,leukopenia,thrombocytopenia

Rare(>1/10,000,<1/1,000)

Pancytopenia,agranulocytosis

Immunesystemdisorders Rare(>1/10,000,<1/1,000)

Anaphylacticreactions

Nervoussystemdisorders Rare(>1/10,000,<1/1,000)

Headaches,impairedvision,confusion,lethargy,

convulsions,facialparaesthesia

Vasculardisorders Rare(>1/10,000,<1/1,000)

Facialflushing

Gastrointestinaldisorders Common(>1/100,<1/10)

Anorexia,nausea,vomiting

Rare(>1/10,000,<1/1,000)

Diarrhoea

Hepatobiliarydisorders Rare(>1/10,000,<1/1,000),

Hepaticnecrosisduetoveno-occlusivedisease

(VOD)oftheliver

Renalandurinarydisorders Rare(>1/10,000,<1/1,000)

Impairedrenalfunction

Skinandsubcutaneoustissuedisorders Uncommon(>1/1,000,<1/100)

Alopecia,hyperpigmentation,photosensitivity

Rare(>1/10,000,<1/1,000)

Erythema,maculopapularexanthema,urticaria

Generaldisordersandadministration

siteconditions Uncommon(>1/1,000,<1/100)

Flu-likesymptoms

Rare(>1/10,000,<1/1,000)

Applicationsiteirritation

Investigations Rare(>1/10,000,<1/1,000)

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Rarelylivernecrosisduetoocclusionofintrahepaticveins(veno-occlusivediseaseoftheliver)hasbeenobservedafter

administrationofdacarbazineinmonotherapyorincombinedtreatmentmodalities.Ingeneralthesyndromeoccurred

duringthesecondcycleoftherapy.Symptomsincludedfever,eosinophilia,abdominalpain,enlargedliver,jaundice

andshockwhichworsenedrapidlyoverafewhoursordays.Asfataloutcomehasbeendescribedspecialcarehastobe

takenoffrequentlymonitoringofliversize,functionandbloodcounts(especiallyeosinophils).Insinglecasesof

suspectedveno-occlusivediseaseearlytherapywithhigh-dosecorticosteroids(forexamplehydrocortisone300

mg/day)withorwithoutfibrinolyticagentslikeheparinortissueplasminogenactivatorwassuccessful(seesections

4.2and4.4).

Applicationsiteirritationsandsomeofthesystemicadversereactionsarethoughttoresultfromformationof

photodegradationproducts.

Impairedrenalfunctionwithincreasedbloodlevelsofsubstancesobligatoryexcretedbyurineisrare.

Centralnervoussideeffectssuchasheadaches,impairedvision,confusion,lethargyandconvulsionsrarelymayoccur.

Facialparaesthesiaandflushingmayoccurshortlyafterinjection.

Allergicreactionsoftheskinintheformoferythema,maculopapularexanthemaorurticariaareobservedrarely.

Infrequentlyalopecia,hyperpigmentationandphotosensitivityoftheskinmayoccur.Inrarecasesanaphylactic

reactionshavebeendescribed.

Inadvertentparavenousinjectionisexpectedtocauselocalpainandnecrosis.

4.9Overdose

Theprimaryanticipatedcomplicationsofoverdoseareseverebonemarrowsuppression,eventuallybonemarrow

aplasiawhichmaybedelayedbyuptotwoweeks.

Timetooccurrenceofnadirsofleucocytesandthrombocytescanbe4weeks.Evenifoverdosageisonlysuspected,

long-termcarefulhaematologicmonitoringisessential.Thereisnoknownantidotefordacarbazineoverdose.

Therefore,specialcarehastobetakentoavoidoverdoseofthisdrug.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Alkylatingagents;ATCcode:L01AX04.

Dacarbazineisacytostaticagent.Theanti-neoplasticeffectisduetoaninhibitionofcellgrowthwhichisindependent

ofthecellcycleandduetoaninhibitionofDNAsynthesis.Analkylatingeffecthasalsobeenshownandother

cytostaticmechanismsmayalsobeinfluencedbydacarbazine.

Dacarbazineisconsiderednottoshowananti-neoplasticeffectbyitself.HoweverbymicrosomalN-demethylationitis

quicklyconvertedto5-amino-imidazole-4-carboxamideandamethylcation,whichisresponsibleforthealkylating

effectofthedrug.

5.2Pharmacokineticproperties

Afterintravenousadministrationdacarbazineisquicklydistributedintotissue.Plasmaproteinbindingis5%.Kinetics

inplasmaisbiphasic;theinitial(distribution)halflifeisonly20minutes,terminalhalflifeis0.5-3.5hours.

DacarbazineisinactiveuntilmetabolisedintheliverbycytochromesP450toformthereactiveN-demethylatedspecies

HMMTICandMTIC.ThisiscatalysedbyCYP1A1,CYP1A2,andCYP2E1.MTICisfurthermetabolisedto5-

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Dacarbazineismetabolisedmainlyintheliverbybothhydroxylationanddemethylation,approx.20-50%ofthedrugis

excretedunmodifiedbythekidneyviarenaltubularsecretion.

5.3Preclinicalsafetydata

Becauseofitspharmacodynamicpropertiesdacarbazineshowsmutagenic,carcinogenicandteratogeniceffectswhich

aredetectableinexperimentaltestsystems.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Citricacid,anhydrous

Mannitol

6.2Incompatibilities

Dacarbazine-solutionischemicallyincompatiblewithheparin,hydrocortisone,L-cysteineandsodiumhydrogen

carbonate.

6.3Shelflife

Theshelflifeis3years.

ShelflifeofthereconstitutedsolutionofDacarbazinemedac100mg

Achemicalandphysicalin-usestabilityhasbeendemonstratedfor24hoursat20°Cprotectedfromlight.

Fromamicrobiologicalpointofview,theproductshouldbeusedimmediately.Ifnotusedimmediately,in-usestorage

timesandconditionspriortousearetheresponsibilityoftheuserandwouldnormallybenolongerthan24hoursat2

to8°C,unlessreconstitutionhastakenplaceincontrolledandvalidatedasepticconditions.

ShelflifeofthereconstitutedandfurtherdilutedsolutionofDacarbazinemedac100mg

Thereconstitutedandfurtherdilutedsolutionmustbeusedimmediately.

6.4Specialprecautionsforstorage

Donotstoreabove25°C,keepthevialinoutercartoninordertoprotectfromlight.

Reconstitutedsolutionsshouldalsobeprotectedfromlight.

Forstorageofthereconstitutedproduct,seesection6.3.

6.5Natureandcontentsofcontainer

Dacarbazinemedac100mgissuppliedasasterilepowderforsolutionforinjectionorinfusioninsingle-dosevials

madeofamberglass(TypeI,Ph.Eur.)andclosedwithbutylrubberstoppers.EachcartonofDacarbazinemedac100

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6.6Specialprecautionsfordisposalandotherhandling

Recommendationsforthesafehandling

Dacarbazineisananti-neoplasticagent.Beforecommencing,localcytotoxicguidelinesshouldbereferredto.

Dacarbazineshouldonlybeopenedbytrainedstaffandaswithallcytotoxicagents,precautionsshouldbetakento

avoidexposingstaff.Handlingofcytotoxicdrugsshouldbegenerallyavoidedduringpregnancy.Preparationof

solutionforadministrationshouldbecarriedoutinadesignatedhandlingareaandworkingoverawashabletrayor

disposableplastic-backedabsorbentpaper.

Suitableeyeprotection,disposablegloves,facemaskanddisposableapronshouldbeworn.Syringesandinfusionsets

shouldbeassembledcarefullytoavoidleakage(useofLuerlockfittingsisrecommended).

Oncompletion,anyexposedsurfaceshouldbethoroughlycleanedandhandsandfacewashed.

Intheeventofspillage,operatorsshouldputongloves,facemasks,eye-protectionanddisposableapronandmopup

thespilledmaterialwithanabsorbentmaterialtappedintheareaforthatpurpose.Theareashouldthenbecleanedand

allcontaminatedmaterialtransferredtoacytotoxicspillagebagorbinorsealedforincineration.

Preparationfortheintravenousadministration

Dacarbazine-solutionsarepreparedimmediatelybeforeuse.

Dacarbazineissensitivetolightexposure.Duringadministration,theinfusioncontainerandadministrationsetshould

beprotectedfromexposuretodaylight,e.g.byusinglight-resistantPVC-infusionsets.Normalinfusionsetsshouldbe

wrappedupine.g.UV-resistantfoils.

a)PreparationofDacarbazinemedac100mg

Asepticallytransfertherequiredamountofwaterforinjection(Dacarbazinemedac100mg:10ml)intothevialand

shakeuntilasolutionisobtained.Thisfreshlypreparedsolution(Dacarbazine:10mg/ml*)isadministeredasaslow

injection.

ForpreparationofDacarbazinemedac100mgforIVinfusionthefreshlypreparedsolutionisfurtherdilutedwith200-

300mlsodiumchlorideinfusionsolutionorglucose5%.Thissolutionisgivenasashortterminfusionoveraperiod

between15-30minutes.

Dacarbazinemedac100mgisforsingleuseonly.

Thedilutedsolutionforinfusionshouldbevisuallyinspectedandonlyclearsolutionspracticallyfreefromparticles

shouldbeused.Donotusethesolutionifparticlesarepresent.

Anyportionofthecontentsremainingafteruseshouldbediscarded,aswellassolutionswherethevisualappearance

oftheproducthaschanged.

Disposal:Allmaterialsthathavebeenutilizedfordilutionandadministrationshouldbedisposedofaccordingto

standardprocedures(incineration).

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7MARKETINGAUTHORISATIONHOLDER

medac

GesellschaftfürklinischeSpezialpräparatembH

Fehlandtstrasse3

D-20354Hamburg

Germany

8MARKETINGAUTHORISATIONNUMBER

PA0623/003/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:14 th

November1997

Dateoflastrenewal:24 th

April2010

10DATEOFREVISIONOFTHETEXT

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