DACARBAZINE FOR INJECTION BP

Main information

  • Trade name:
  • DACARBAZINE FOR INJECTION BP
  • Dosage:
  • 200 Milligram
  • Pharmaceutical form:
  • Pdr for Soln for Injection
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • DACARBAZINE FOR INJECTION BP
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0437/040/002
  • Authorization date:
  • 15-05-1998
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0437/040/002

CaseNo:2072705

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

HOSPIRAUKLtd

Queensway,RoyalLeamingtonSpa,WarwickshireCV313RW,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Dacarbazine200mgPowderforSolutionforInjection

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom15/01/2010.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Dacarbazine200mgPowderforSolutionforInjection.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachvialcontains200mgofdacarbazine.

Whenreconstitutedasdirectedinsections4.2and6.6,eachmlofmedicinalsolutioncontains10mgof

dacarbazine.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Powderforsolutionforinjection.

Whiteorverypaleyellowpowderorplug.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Metastaticmalignantmelanoma

Solidtumours

Hodgkin'sdisease

Inaddition,dacarbazinehasbeenshown,whenusedincombinationwithotheragents,tobeofuseinthetreatmentof

othermalignantdiseases.

4.2Posologyandmethodofadministration

DosageandAdministration

Dosage:

Standarddose:Thefollowingdosageschedulesarerecommended:

2.0-4.5mg/kg/dayfor10days,whichmayberepeatedat4weekintervals.

250mg/m 2

/dayfor5dayswhichmayberepeatedatthreeweekintervals.

Afurtheralternativeistoadministerthetotalscheduledoseonthefirstday.

Otherschedulesmaybeusedatthediscretionoftheprescribingphysician.

Children:

Thedosageforchildreniscalculatedonthemg/kgormg/m 2

basisasperthestandarddosage.Thereisno

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Geriatric:

Asforpaediatricuse.

WithImpairedHepaticFunction

Asthedrugpartlyundergoesmetabolismintheliver,impairmentofliverfunctionislikelytonecessitatea

variationindosage.

WithImpairedRenalFunction

Asthedrugisexcreted50%unchangedintheurinebytubularsecretion,impairmentofrenalfunctionislikelyto

necessitateachangeindosage.

Administration

AdministrationisbytheIVrouteonly.

Dacarbazine100mgand200mgvialsshouldbereconstitutedwith9.9mland19.7mlrespectively,withWaterfor

InjectionsBP.Theresultingsolutionscontaintheequivalentof10mg/mlofdacarbazineandhaveapHof3to4.

Theresultantsolutionshouldbeinjectedintravenouslyoveronetotwominutes.

Ifdesiredthereconstitutedsolutioncanbefurtherdilutedwith125-250mlofDextroseInjectionBP5%orSodium

ChlorideInjectionBP0.9%andadministeredbyintravenousinfusionover15-30minutes.

4.3Contraindications

DacarbazineiscontraindicatedinpatientswhohavedemonstratedahypersensitivitytoDacarbazineinthepast.

Dacarbazineshouldnotbeadministeredtopatientswhoarepregnantormaybecomepregnantorbreastfeeding

mothers.

Patientswhohavepreviouslyhadseveremyelosuppression.

4.4Specialwarningsandprecautionsforuse

Warnings

Haemopoieticdepressionisthemostcommontoxicside-effectofdacarbazineandinvolvesprimarilytheleucocytes

andplatelets,althoughmildanaemiamaysometimesoccur.Leucopeniaandthrombocytopeniamaybesevereenough

tocausedeath.Possiblebonemarrowdepressionrequirescarefulmonitoringofwhitebloodcells,redbloodcellsand

plateletlevels.Suchtoxicitymaynecessitatetemporarysuspensionorcessationoftherapy.

Hepatictoxicity,accompaniedbyhepaticveinthrombosisandhepatocellularnecrosisresultingindeath,havebeen

reported.Theincidenceofsuchreactionshasbeenlow.Thistoxicityhasbeenobservedmostlywhendacarbazinehas

beenadministeredconcomitantlywithotheranti-neoplasticdrugs;however,ithasalsobeenreportedinsomepatients

treatedwithdacarbazinealone.

Precautions

Thedrugcanproducesevereandpossiblyfatal,haematologicorhepatictoxicityandsevereGIreactionsandshouldbe

administeredtopatientspreferablywithinthehospitalsetting,wheretheycanbeobservedfrequentlyduringandafter

therapy,particularlywithregardstothehaemopoietictoxicity.

Itisrecommendedthatdacarbazinebeadministeredunderthesupervisionofaspecialistoncologyservicehaving

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Restrictionoffoodintakefor4-6hourspriortotreatmentmayreducetheseverityofthenauseaandvomitingwhich

occursinmostpatientsparticularlyduringthefirsttwodaysoftreatment.Administrationofananti-emeticmayalso

reducetheseverityoftheseeffects.

Impairmentofrenalandliverfunction:Seedosageinimpairedrenalandliverfunction.

Caremustbetakentoavoidextravasationduringintravenousadministrationasthismaycausetissuedamageand

severepain.

Careshouldbetakentoavoidcontactwiththeskinandeyeswhenreconstitutingoradministeringdacarbazine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Microsomalliverenzymeinducereg.barbiturates,rifampicin,phenytoinmaytheoreticallyhastentheactivationof

dacarbazinetoaminoimidazole-carboxamide.

Mercaptopurine,azathioprine,allopurinol:dacarbazineinhibitsxanthineoxidaseandmaytheoreticallypotentiatethe

activityofthesedrugs.

PatientsreceivingDacarbazineshouldnotreceiveimmunisationwithlivevaccines.Dacarbazinemayimpairthe

immunologicalresponsetothevaccinewiththedevelopmentofageneralisedvaccinia.

4.6Pregnancyandlactation

Studieshavedemonstratedthatthisagentiscarcinogenicandteratogenicwhenadministeredtoanimals.Dacarbazine

thereforeshouldnotbeadministeredtopregnantorlactatingwomenunlessthebenefitclearlyjustifiesthepotential

risktothefoetus.

4.7Effectsonabilitytodriveandusemachines

Dacarbazineinappropriatedosesshouldnotimpairtheabilitytodrive.However,rareadversereactionsaffectingthe

nervoussystemmaycauseblurredvision,seizures,headache,confusion,malaiseandlethargy.Patientsaffectedby

theseadverseeffectsshouldnotdriveoroperatemachinery.

4.8Undesirableeffects

AdverseEffects

CommonReactions

Symptomsofanorexia,nausea,andvomitingarethemostfrequentside-effects.Vomitingmaylastfor1-12hoursand

isincompletelyandunpredictablypalliatedwithprochlorperazine.Diarrhoeaisararerside-effectofDacarbazine

therapy.Rarelyhaveintractablenauseaandvomitinghavenecessitateddiscontinuationoftherapy.

Itissuggestedthatrestrictionofthepatientsoralfluidintakeandfood4-6hourspriortotreatmentmaybehelpful.The

rapidtolerationofthesesymptomssuggestsacentralnervoussystemmechanism,andusuallythesesymptomssubside

afterthefirst1-2days.

Haematological:Bonemarrowdepression,leucocytopenia,thrombocytopenia.

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LessCommonReactions

Cardiovascular:Facialflushing.

Dermatological:Transientrash,alopecia

General:Infrequentlysomepatientshaveexperiencedaninfluenzatypesyndromeoffever,myalgiasandmalaise.This

syndromeusuallyoccursafterlargesingledosesandapproximatelysevendaysaftertreatmentwithdacarbazineand

lasts7-21days,andmayreoccurwithsuccessivetreatments.

Hepatic:Increasesintransamineases(AST,ALT)alkalinephosphatase,LDH.Levelsusuallyreturntonormalwithin

twoweeks;hepatictoxicityaccompaniedbyhepaticveinthrombosisandhepatocellularnecrosis,(Budd-Chiari

Syndrome)resultingindeath.

NervousSystem:Blurredvision,seizures,headache,facialparaesthesia,confusion,malaise,lethargy.

AnaphylaxiscanoccurveryrarelyfollowingadministrationofDacarbazine.

Photosensitivityreactionsmayoccurrarely.

4.9Overdose

SignsandSymptoms:

Severebonemarrowdepressionandgastrointestinaleffectssuchasnausea,vomitinganddiarrhoeamaybeexpected.

Treatment

Ceasedacarbazineadministrationandinstitutesupportivemeasures,eg.appropriatetransfusionforbonemarrow

suppression.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Dacarbazineisanimidazoledimethyltriazenewithreproducibleactivityinpatientswithmetastaticmelanoma.The

structureofDacarbazinebearsastrikingresemblancetothemetabolite5-aminoimidazole-4-carboxamide(AIC)which

isconvertedtoinosinicacidbyenzymesinvolvedinpurinesynthesis.

Itwasthereforeinitiallythoughttoactasanantimetabolite,byinhibitingpurinemetabolismandnucleicacidsynthesis.

HoweverthesimilarityofstructureisoflittlerelevancesinceDacarbazineisextensivelymetabolisedbythe

cytochromeP450systemintheliverbyN-demethylationreaction.

ThemonoemthylderivativethenspontaneouslycleavestoyieldAICandanintermediatecompound,probably

diazomethane,whichdecomposestoproducethemethylcarboniumion.Thisionattachedtonucleophilicgroupson

nucleicacidsandothermacromolecules,thusactingasanalkylatingagent.The7-positionofguanineonDNAis

especiallysusceptibletoalkylation.

Dacarbazineisthoughttoactasanalkylatingagentinman.ItinterfereswiththesynthesisofDNA,RNAandproteins

butitscytotoxicityisnotspecificforanyphaseofthecellcycle.Ingeneral,itismosteffectiveininhibitingsynthesis

ofRNA.Dacarbazinekillscellsslowlyandnoimmunosuppressiveactionhasbeenshowninman.Thereareno

systemicstudiesofdose-responseeffectsbutoneanecdotalreporthassuggestedthattheremaybeanincreasedchance

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Dacarbazineundergoesspontaneousphotodegradationinlight,decomposinginto5-diazoimidazole-4-carboxamideand

dimethylamine.5-Diazoimidazole-4-carboxamidecanattacknucleophilicgroupsofDNAandalsoundergoes

structuralrearrangementtoform2-azahypoxanthine.However,theproductsofphotodegradationofdacarbazine

probablydonotcontributegreatlytoitscytotoxicity,althoughtheymaybeimplicatedinthelocalburningpainon

intravenousinjectionandsystemicproblemsassociatedwiththedrug.

5.2Pharmacokineticproperties

Thevolumeofdistributionofdacarbazineexceedsbodywatercontent,suggestinglocalisationinsomebodytissues,

probablytheliver.Dacarbazineisonlyslightly(approximately5%)boundtoplasmaproteins.Itsplasmahalf-life

afterintravenousadministrationisapproximately35minutes.Inanimalstudies,approximately46%ofradio-labelled

dosewasrecoveredfromtheurineafter6hours.Ofthis46%,almosthalf,wasunchangeddacarbazineandasimilar

quantitywasamino-imidazolecarboxamide,ametabolite.Dacarbazineissubjecttorenaltubularsecretionratherthan

glomerularfiltration.

Dacarbazinecrossestheblood-brainbarriertoalimitedextent;CSFconcentrationsarereportedtobeabout14%of

plasmaconcentrations.Itisnotknownifdacarbazinecrossestheplacentaordistributesintomilk.

5.3Preclinicalsafetydata

NotApplicable.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

CitricAcidMonohydrate

Mannitol

SodiumHydroxide1.0N(forpHadjustmentonly)

6.2Incompatibilities

Thismedicinalproductshouldnotbemixedwithothermedicinalproductsexceptforthosementionedinsection6.6.

Dacarbazineisincompatiblewithhydrocortisonesodiumsuccinateinsolution,forminganimmediateprecipitate.

Ithasbeenreportedtobeincompatiblewithheparin,althoughonlywithconcentratedsolutions(25mg/ml).

6.3ShelfLife

Priortouse:

3years

In-use:

Forsingleuseonly.

Discardanyunusedcontents.

Containsnoantimicrobialpreservative.

Ifasepticpreparationcannotbeensured,theinjection/infusionshouldbepreparedimmediatelybeforeuse.

Ifthereconstituted/dilutedsolution,asdirectedinsection6.6.,hasbeenasepticallypreparedandisnotused

immediately,in-usestoragetimesandconditionspriortousearetheresponsibilityoftheuserandwouldnormallynot

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6.4Specialprecautionsforstorage

Priortouse:

Storeinarefrigerator(2°C–8°C).

Keepthevialintheoutercartoninordertoprotectfromlight

In-use:

Pleaserefertosections6.3and6.6forin-usestorageprecautions.

6.5Natureandcontentsofcontainer

20mlamberTypeIglassvial,20mmWestType1816rubberclosure,aluminumcapwithplastic‘flip-off’top(withor

withoutOnco-Tainshinkwrapping).

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Handlingprecautions

Dacarbazineiscytotoxicandaswithotherpotentiallytoxiccompounds,cautionshouldbeexercisedwhenhandling

andpreparingdacarbazinepreparations.

Refertolocalcytotoxichandlingguidelinesbeforepreparinginjectionsorinfusions.

Pregnantpersonnelshouldnothandlecytotoxics.

Thehandlingofthiscytotoxicagentbyhealthcarepersonnelrequireseveryprecautiontoguaranteetheprotectionof

thehandlerandhissurroundings.

Thepreparationofinjectablesolutionsofcytotoxicagentsmustbecarriedoutbytrainedspecialistpersonnelwith

knowledgeofthemedicinesused,inconditionsthatguaranteetheintegrityofthemedicinalproduct,theprotectionof

theenvironmentandinparticulartheprotectionofthepersonnelhandlingthemedicines,inaccordancewiththe

hospitalpolicy.Itrequiresapreparationareareservedforthispurpose.Itisforbiddentosmoke,eatordrinkinthis

area.Operationssuchasreconstitutionofpowderandtransfertosyringes/infusionbagsshouldbecarriedoutonlyin

thedesignatedarea.

Thepersonnelcarryingouttheseproceduresmustbeprovidedwithappropriatehandlingmaterials,notablylong

sleevedgowns,protectionmasks,caps,protectivegoggles,sterilesingle-usegloves,protectivecoversforthework

area,containersandcollectionbagsforwaste.

Anybrokencontainermustbetreatedwiththesameprecautionsandconsideredascontaminatedwaste.Contaminated

wasteshouldbeincineratedinsuitablylabelledrigidcontainers.Seeparagraphbelowondisposal.

Ifsubstanceshouldcomeintocontactwithmucousmembranes,washimmediatelyandthoroughlywithwater.

Incaseofcontactofthedrugwiththeeye,washtheeyethoroughlywithwater.Ifthesubstanceissplashed

accidentallyontotheskin,washtheskinwithlargeamountsofwaterandthenwithasoftsoap.Rinsethoroughly.

Excretaandvomitmustbehandledwithcare.

Preparationinstructions

Dacarbazine100mgand200mgvialsshouldbereconstitutedwith9.9ml

and19.7mlrespectively,withWaterforInjectionsBP.AsepticallytransfertherequiredamountofWaterforInjections

intothevialandshakeuntilasolutionisobtained.Theresultingsolutionscontaintheequivalentof10mg/mlof

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Ifdesiredthereconstitutedsolutioncanbefurtherdilutedwith125-250mlofDextroseInjectionBP5%orSodium

ChlorideInjectionBP0.9%andadministeredbyintravenousinfusionover15-30minutes.

Priortoadministrationthesolutionshouldbeclear,colourlesstopaleyellowandfreefromvisibleparticles.

Dacarbazineisphotosensitive;exposuretolightcausingacolourchangefrompaleyellowtopink.Theproductshould

notbeusedifitappearspinkincolour.

Duringadministrationofaninfusion,theinfusionsetshouldbeprotectedfromlight,e.g.byusinglight-resistantPVC

infusionsets.Ifnormalinfusionsetsareused,thentheseshouldbecoveredtoprotectfromlight.

Disposal

Remnantsofthemedicinalproductaswellasallmaterialsthathavebeenusedforreconstitution,dilutionand

administrationmustbedestroyedaccordingtohospitalstandardproceduresapplicabletocytotoxicagentsin

accordancewithlocalrequirementsrelatedtothedisposalofhazardouswaste.

7MARKETINGAUTHORISATIONHOLDER

HospiraUKLimited

Queensway

RoyalLeamingtonSpa

Warwickshire

CV313RW

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA0437/040/002

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation: 15May1998

Dateoflastrenewal: 15May2008

10DATEOFREVISIONOFTHETEXT

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