AMSIDINE

Main information

  • Trade name:
  • AMSIDINE Concentrate and solvent for solution for infusion 50 Mg/Ml
  • Dosage:
  • 50 Mg/Ml
  • Pharmaceutical form:
  • Concentrate and solvent for solution for infusion
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • AMSIDINE Concentrate and solvent for solution for infusion 50 Mg/Ml
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0899/002/001
  • Authorization date:
  • 05-03-1994
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Amsidine50mg/mlConcentrateandSolventforSolutionforInfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachampoulecontains75mgamsacrinein1.5ml(50mgperml).

Eachsolventvialcontains13.5mlofLacticAcidandwaterforinjectiontogiveaconcentrationof0.0353ML-Lactic

acid.

Eachmlofthecombinedsolutionoftheconcentratewhendilutedwiththesolventcontains5mgamsacrineperml

Forafulllistofexipients,seesection6.1.

3PHARMACEUTICALFORM

ConcentrateandsolventforsolutionforInfusion.

Concentrateisaclear,brightorange/redcolouredsolutionandsolventforinfusionisclearcolourlesssolution.

ThepHofthecombinedsolutionis3.5-4.5.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Amsidineisindicatedfortheinductionandmaintenanceofremissioninacuteleukaemiaofadults.Itiseffectivein

patientsrefractorytotheanthracyclineantibioticsusedsinglyorincombinationwithotherchemotherapeuticagents,

andinpatientswhowereformerlytreatedwithmaximumcumulativedosesoftheseantibiotics.

4.2Posologyandmethodofadministration

Intravenousinfusion

Amsidinemustbedilutedin500ml5%DextroseInjectionBPandinfusedover60to90minutes.Phlebitisorpainat

theinjectionsitemayoccuratdosesgreaterthan70mg/m 2

.(NOTE:DONOTUSEOTHERDILUENTS.

AMSIDINEISINCOMPATIBLEWITHSALINE).Caremustbetakenthatnoextravasationoccurswhichmight

producesevereirritationornecrosis.Cautioninthehandlingandpreparationofthesolutionshouldbeexercised,and

theuseofpolyethyleneglovesisrecommended.IfthesolutionofAmsidinecontactstheskinormucosae,immediately

washthoroughlywithsoapandwater.

Adults

Inductionofremissionphase

TheusualdosageofAmsidineintheinductionphaseis90mg/m 2

everydayforfiveconsecutivedays(totaldose450

mg/m 2

percourseoftreatment).Ifbonemarrowbiopsyperformedondaysixdisplaysover50%cellularityandthe

blastscountisover30%,thetreatmentmaybeextendedforanadditionalthreedays,bringingthetotaldosepercourse

oftreatmentto720mg/m 2

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Morethanonecourseoftreatmentmayberequiredtoachieveinduction.Dependingontheeffectivenessofthefirst

courseinproducingmyelosuppression,thesubsequentcoursesaregivenattwo-week(ifnoteffective)tofour-week(if

effective)intervals.Incaseswhereahypocellularmarrowhasnotbeenachievedafterthefirstcourseoftreatment,the

dailydoseofAmsidinemaybeescalatedto120mg/m 2

perdayforthesubsequentcourses,providedthatthisisnot

contra-indicatedforreasonsofnon-myelosuppressivetoxicity.

Forpatientswithimpairedliverfunctionorimpairedrenalfunction,thedoseofAmsidineshouldbedecreasedby20-

30%(to60-75mg/m 2

perday).

Maintenancephase

Themaintenancedoseisaboutonethirdtheinductiondose,giveneitherasasingleIVinfusionordividedinthree

dailydosese.g.150mg/m 2

givenonceevery3-4weeksor50mg/m 2

perdayforthreeconsecutivedays,repeatedevery

3-4weeks.

Eachmaintenancecourseshouldbringdownthegranulocytecountto1,000-1,500/µlandPlateletcountto50,000-

100,000/µl.Thegranulocyteandplateletcountsshouldbeallowedtorecoverbetweenthecoursestoover1,500/µlabd

100,000/µlrespectively;otherwisethesubsequentcourseshouldbedelayed.

Elderly

Eliminationmaybeslowerinthisgroup.Thisshouldbeconsideredwhendesigningdoseschedulesfortheelderly.

Childrenunder12Years

Notrecommended.

4.3Contraindications

Amsidinetreatmentshouldnotbestartedinpatientswhohavepre-existingmarkedbonemarrowsuppressioninduced

byotherchemotherapeuticagentsorradiotherapy.

4.4Specialwarningsandprecautionsforuse

Patientsshouldbehospitalisedduringtheinductionphaseoftreatmentforcloseobservationandextensivelaboratory

monitoring.Amsidineshouldbeusedonlybyphysiciansexperiencedincancerchemotherapy.

Withrecommendeddoseschedules,leucopeniaisusuallytransient,reachingitsnadirat10-13daysaftertreatment,

withrecoveryusuallyfollowingbythe17thto25thday.Whitebloodcellcountsof1000/µlorloweraretobeexpected

duringtreatmentwithappropriatedosesofAmsidine.Doseshigherthanrecommendedmayproducemoresevereor

prolongedmarrowsuppression.

Periodicmonitoringofbonemarrow,cardiac,liver,kidneyandCNSfunctionsshouldbecarriedoutinpatients

receivingAmsidineandparticularlyinthosewithpre-existingdisordersofthesesymptoms.Inthecaseofan

exceedinglylargefallinwhitecellcountandexcessivedepressionofbonemarrow,suspensionoftreatmentor

reductionofdosagemaybenecessary.

Pharmaceuticalprecautions:Cautioninhandlingandpreparationofthesolutionshouldbeexercised,andtheuseof

polyethyleneglovesisrecommended(seeenclosureleaflet).IfthesolutionofAmsidinecontactstheskinormucosae,

immediatelywashthoroughlywithsoapandwater.Amsidinemustbedilutedin500ml5%DextroseInjectionBPand

infusedover60to90minutes(Note:donotuseotherdiluents,Amsidineisincompatiblewithsaline).Thesolution

whendilutedforinfusionisstableforeighthoursatroomtemperature.Itshouldbeprotectedfromexposureto

sunlight,andanyunusedsolutionshouldbediscarded.(seeenclosureleaflet).GlasssyringesmustbeusedasAmsidine

insolutionreactswithplasticsyringes.

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Noneknown.

4.6Fertility,pregnancyandlactation

AnimalstudieshaveindicatedthatAmsacrinehasfoetotoxicandteratogenicproperties.Inadditiontheremaybean

effectonfertility.Thereisnoinformationonuseinhumanpregnancy;thereforethebenefit/riskconsiderationshould

becarefullyweighedwhenadministeringAmsidine.

4.7Effectsonabilitytodriveandusemachines

Noneknown.

4.8Undesirableeffects

Studieshavedemonstratedamutagenicpotential.Nocarcinogenicstudieshavebeencarriedout.Aswithother

antineoplasticagentsthereisapossibilitythatprolongedusemayleadtoacarcinogeniceffect.Thisshouldbebornein

mindwhenundertakinglong-termtreatment.

AdverseEvents

HaematopoieticSystem: ThedoselimitingtoxicityassociatedwithAmsidineismyelosuppressionand

panocytopenia,requiringsupportivetreatmentwithwhiteandredbloodcellsandplatelets.Majorcomplicationsduring

therapywereinfectionsandhaemorrhagestreated,respectively,withantibioticsandplatelettransfusions.

Gastro-intestinal:Nausea,withorwithoutvomitingoccurredfrequently,butthesesymptomswereusuallymildto

moderate.Mucositis(stomatitisandoesophagitis)wasalmostasfrequentandrangedinseverityfrommildtolife

threatening;itsfrequencyandseveritywerenotstrictlydose-related.

CentralNervousSystem:Afewcasesofgrandmalseizuresinacuteleukaemiapatientshaveoccurredduring

treatmentwithAmsidine.Thesepatientsweresuffering,however,fromanumberofconditionsrelatedtofar-advanced

diseaseandwereheavilypre-treated;anditisunclearwhethertheseizureswereattributabletoAmsidine.Theseizures

generallywereresponsivetostandardtreatment,suchasPhenytoin.

Renal:Occasionaloccurrenceofhaematuria,anuriaandrarelyacuterenalfailurehavebeenreported.

Hepatic:Liverfunctiontestshaveshowedoccasionaltransientelevationsofserumbilirubinandalkalinephosphatase,

sometimesaccompaniedbyjaundice,whichrequiredloweringthedoseofAmsidine.

Cardiac:Cardiotoxicityoccurredinseveralpatients.Itrangedfromgrandmalseizuresfollowedbyventricular

tachycardiatocongestiveheartfailureorcardiacarrest.

Cutaneous:Localtissueirritation,necrosisandphlebitishavebeenreported.Theproblemisrelatedtothe

concentrationofthedruginfusedperunittime;itisamelioratedbydilutingthedruginalargevolumeof5%Dextrose

InjectionBPandinfusingoveralongerperiodoftime(1to2hours).Alopeciaoccurredinabout1in7patients,

sometimesprecipitously.Sincemostpatientswerepreviouslytreatedwithotherchemotherapeuticagents/orradiation,

itisnotclearwhetherthiswasacumulativeeffectofalltreatment.

4.9Overdose

Thetreatmentofoverdosageshouldbesupportiveandthebloodpictureshouldbecloselymonitoredwithappropriate

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Amsidineisasterileantitumourchemotherapeuticagentforintravenousinfusion.Althoughnotcompletelyclarified,

themodeofactionofamsacrineisrelatedtoitspropertyofbindingtheDNAthroughintercalationandexternal

(electrostatic)forces.AmsacrineinhibitsthesynthesisofDNAwhiletheRNAmaynotbedirectlyaffected.An

additionalmodeofaction,involvingmodificationofcellmembranefunction,hasbeensuggested.

5.2Pharmacokineticproperties

Amsidineisadministeredbyintravenousinfusion.Amsidinehasalowlipidsolubility,andarelativelyhighmolecular

weight,sothatitisunlikelythatitwouldcrosstheblood-brainbarrier.Amsidinedistributeswellinthebody,exceptto

thebrainandCSF,andisthereforeinactiveagainstcerebraltumours.

StudieshaveshownthattheplasmaconcentrationtimeprofilesofAmsidineinmanarebestdescribedusingathree

compartmentopenmodel.Theterminalhalf-lifewasfoundtobeprolongedinpatientswithseverehepatic

dysfunction.Workinanimalshasshownthatafterbiotransformationintheliver,themetabolitesofAmsidineare

finallyexcretedinthebilebyanactivetransportmechanism.ThemajorityofAmsidineisexcretedinitsmetabolised

form.Studiesinmanhaveshownthat20%oftheadministereddrug(freeandmetabolised)waseliminatedintheurine

withinthefirst8hours,andatotalofabout42%within72hoursinonepatientwithnormalrenalfunction.

5.3Preclinicalsafetydata

Noadditionaldataofrelevance.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Concentrate

N,NDimethylacetamide

Solvent

L-lacticAcid

WaterforInjection

6.2Incompatibilities

Amsidineisincompatiblewithsaline.Amsidineinsolutionreactswithplasticsyringes.

Thismedicinalproductmustnotbemixedwithothermedicinalproductsexceptthosementionedinsection6.6.

6.3Shelflife

Unopened:Amsacrineconcentrateampoule:-3years

Unopened:Solventvial:-3years

OnceopenedanddilutedwithAmsidinesolvent:Chemicalandphysicalin-usestabilityofthereconstitutedanddiluted

drughasbeendemonstratedfor8hourswhenstoredbelow25 o

Candprotectedfromsunlight.Unusedsolutionshould

bediscarded.

Fromamicrobiologicalpointofview,unlessthemethodofdilutionprecludestheriskofmicrobialcontamination,the

productshouldbeusedimmediatelyafterfirstopeningorfollowingreconstitution.Ifnotusedimmediately,in-use

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6.4Specialprecautionsforstorage

Donotstoreabove25 o

Storeintheoriginalpackinordertoprotectfromlightandmoisture.

6.5Natureandcontentsofcontainer

Concentrateampoule-2mlclearTypeI,Ph.Eur.neutralglassampoulecontaining1.5mlamsacrinesolution.

Solventvial-20mlamber,TypeI,Ph.Eur.glassvialcontains13.5mlof0.0353ML-lacticacid.

Eachcartoncontains6ampoulesofconcentrateand6vialsofsolvent.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Amsidineshouldbehandledinaccordancewithlocalhospitalguidelinesforhandlingcytotoxicdrugs.Anyunused

productorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

Preparationofthemedicinalproduct:1.5mlofthedrugsolutioniswithdrawnfromtheconcentrateampouleandadded

tothesolventvial.Thedilutedconcentrateisfurtherdilutedwith500mlof5%DextroseInjectionBPsolution.The

concentrationwhendilutedwith500mlof5%Dextrosesolutionis0.146mgAmsacrineperml.

Useimmediatelyoncedilutedfurtherwith500mlof5%DextroseInjectionBP.

Appearanceofthedilutedsolution:Thedilutedsolutioniscleardeeporangeredsolution.

Dextrose5%InjectionBPmustbeusedfordilutionofAmsidine.Otherdiluentsshouldnotbeused.

Cautioninhandlingandpreparationofthesolutionshouldbeexcercised,andtheuseofpolyethyleneglovesis

recommended(seepatientinformationleaflet).IfthesolutionofAmsidinecontactstheskinormucosae,immediately

washthoroughlywithsoapandwater.

GlasssyringesmustbeusedasAmsidineinsolutionreactswithplasticsyringes.

Donotusethesolutionifthecontentsarediscolouredinanywayorcontainsparticlesinit.

7MARKETINGAUTHORISATIONHOLDER

GoldshieldPharmaceuticalsLtd.

NLATower

12-16AddiscombeRoad

Croydon

Surrey

CR00XT

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

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9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorization:05Marchl984

Dateoflastrenewal:05March2009

10DATEOFREVISIONOFTHETEXT

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