BICNU 100 MG POWDER AND SOLVENT FOR SOLUTION FOR I

Main information

  • Trade name:
  • BICNU 100 MG POWDER AND SOLVENT FOR SOLUTION FOR I
  • Dosage:
  • 100 Milligram
  • Pharmaceutical form:
  • Pdr+Solv for Soln for Inj
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • BICNU 100 MG POWDER AND SOLVENT FOR SOLUTION FOR I
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0048/016/001
  • Authorization date:
  • 06-02-1979
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACT1995

MEDICINALPRODUCTS(LICENSINGANDSALE)REGULATIONS,1998

(S.I.No.142of1998)

PA0048/016/001

CaseNo:2030569

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

Bristol-MyersSquibb(Holdings)

Swords,Co.Dublin,Ireland

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

BiCNU100mgPowderandSolventforSolutionforInfusion

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom18/05/2007until05/02/2009.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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Date Printed 12/06/2007 CRN 2030569 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

BiCNU100mgPowderandSolventforSolutionforInfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachvialofpowdercontains100mgcarmustine.

Reconstitutedsolutionmustbefurtherdilutedasrecommended(seeSection6.6InstructionsforUse/Handling).

Forexcipients,seesection6.1.

3PHARMACEUTICALFORM

Powderandsolventforsolutionforinfusion

Powder:Whitelyophilisedpowder.

Solvent:Contains3mlofethanol.

4CLINICALPARTICULARS

4.1TherapeuticIndications

BiCNUisindicatedaspalliativetherapyasasingleagentorinestablishedcombinationtherapywithotherapproved

chemotherapeuticagentsinthefollowing:

4.2Posologyandmethodofadministration

Adults:

Intravenousadministration:

SingleAgentTherapy:TheusualdoseofBiCNUis200mg/m²everysixweeks,givenasasingledoseorindivided

dailydosessuchas100mg/m²ontwosuccessivedays.

Dosageshouldbeadjustedasappropriateifcombinedwithothermarrowdepressantdrugsorusedinpatientswith

compromisedmarrowfunction.

Repeatdosageshouldbewithhelduntiladequaterecoveryhasoccurredofcirculatingbloodcells,andshouldbe

adjustedtotakeaccountofthepreviousresponse.Recoveryinwhitecellsandplateletsusuallytakes6weeks.Blood

countsshouldbemonitoredregularlyandrepeatcoursesshouldnotbegivenmorefrequentlythanevery6weeks.

Braintumours-Glioblastoma,brainstemglioma,medulloblastoma,astrocytoma,

ependymoma,andmetastaticbraintumours.

Multiplemyeloma-Incombinationwithprednisone.

Hodgkin'sDisease-Assecondarytherapyincombinationwithotherapproveddrugsin

patientswhorelapsewhilebeingtreatedwithprimarytherapy,orwhofailtorespondto

primarytherapy.

Non-Hodgkin'slymphomas-Assecondarytherapyincombinationwithotherapproved

drugsinpatientswhorelapsewhilebeingtreatedwithprimarytherapy,orwhofailto

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precedingdose.Thefollowingscheduleissuggestedasaguidetodosageadjustment.

Children:BiCNUshouldbeusedwithextremecautioninchildrenduetothehighriskofpulmonarytoxicity(see4.4

SpecialWarningsandSpecialPrecautionsforUse).

Elderly:Nodosageadjustmentisrequiredonthegroundsofage.

4.3Contraindications

BiCNUshouldnotbeusedinpregnancyorinwomenwhoarebreastfeeding.

BiCNUshouldnotbegiventoindividualswhohavedemonstratedaprevioushypersensitivitytoit.

BiCNUshouldnotbeusedinpatientswithseverebonemarrowdepression.

BiCNUshouldnotbegiventoindividualswithdecreasedcirculatingplatelets,leucocytes,orerythrocyteseitherfrom

previouschemotherapyorothercauses.

4.4Specialwarningsandprecautionsforuse

Pulmonarytoxicitycharacterisedbypulmonaryinfiltratesand/orfibrosishasbeenreportedtooccurwithafrequency

rangingupto30%.Thismayoccurwithin3yearsoftherapyandappearstobedoserelatedwithtotalcumulativedoses

of1200-1500mg/m²beingassociatedwithincreasedlikelihoodoflungfibrosis.Riskfactorsincludesmoking,the

presenceofarespiratorycondition,pre-existingradiographicabnormalities,sequentialorconcomitantthoracic

irradiationandassociationwithotheragentsthatcauselungdamage.

Casesoflatepulmonaryfibrosis,occurringupto17yearsaftertreatment,havealsobeenreported.Inalong-term

follow-upof17patientswhosurvivedchildhoodbraintumourseight(47%)diedoflungfibrosis.Oftheseeightdeaths,

twooccurredwithin3yearsoftreatmentand6occurred8-13yearsaftertreatment.Ofthepatientswhodied,the

medianageattreatmentwas2.5years(range1-12);themedianageofthelong-termsurvivorswas10years(5-16years

attreatment).Allfivepatientstreatedundertheageof5yearshavediedofpulmonaryfibrosis.Inthisstudy,thedose

ofBiCNUdidnotinfluencefataloutcomenordidco-administrationofvincristineorspinalirradiation.Ofthe

remainingsurvivorsavailableforfollow-up,evidenceoflungfibrosiswasdetectedinallpatients.Therisksand

benefitsofBiCNUtherapymustbecarefullyconsideredespeciallyinyoungpatients,duetoextremelyhighriskof

pulmonarytoxicity.

BiCNUshouldbeadministeredbyindividualsexperiencedinantineoplastictherapy.Bonemarrowtoxicityisa

commonandseveretoxiceffectofBiCNU.Completebloodcountsshouldbemonitoredfrequentlyforatleastsix

weeksafteradose.RepeatdosesofBiCNUshouldnotbegivenmorefrequentlythaneverysixweeks.

ThebonemarrowtoxicityofBiCNUiscumulativeandthereforedosageadjustmentmustbeconsideredonthebasisof

nadirbloodcountsfrompriordose(seeDosageAdjustmentTableunder4.2PosologyandMethodofAdministration).

Carmustineshouldonlybeusedunderthedirectandfrequentsurveillanceofspecialistoncologistswithfacilities

NadirafterPriorDose Percentageofpriordosetobegiven

Leucocytes(mm³) Platelets(mm³)

>4000 >100,000 100

3000-3999 75,000-99,999 100

2000-2999 25,000-74,999 70

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Noneknown.

4.6Pregnancyandlactation

BiCNUshouldnotnormallybeadministeredtopatientswhoarepregnantormotherswhoarebreast-feeding.Male

patientsshouldbeadvisedtouseadequatecontraceptivemeasures.

Safeuseinpregnancyhasnotbeenestablishedandthereforethebenefittoriskoftoxicitymustbecarefullyweighed.

BiCNUisembryotoxicandteratogenicinratsandembryotoxicinrabbitsatdoselevelsequivalenttothehumandose.

BiCNUalsoaffectsfertilityinmaleratsatdosessomewhathigherthanthehumandose.

BiCNUiscarcinogenicinratsandmice,producingamarkedincreaseintumourincidenceindosesapproximating

thoseemployedclinically.

4.7Effectsonabilitytodriveandusemachines

Noneknown.

4.8Undesirableeffects

Haematological:DelayedmyelosuppressionisafrequentandseriousadverseeventassociatedwithBiCNU

administration.Itusuallyoccursfourtosixweeksafterdrugadministrationandisdose-related.Plateletnadirsoccurat

fourtofiveweeks;leucocytenadirsoccuratfivetosixweeksposttherapy.Thrombocytopeniaisgenerallymore

severethanleucopenia.Howeverbothmaybedoselimitingtoxicities.Anaemiaalsooccurs,butisgenerallyless

severe.Theoccurrenceofacuteleukemiaandbonemarrowdysplasiashavebeenreportedinpatientsfollowinglong

termnitrosoureatherapy.

Gastro-intestinal:Nauseaandvomitingafteri.v.administrationofBiCNUarenotedfrequently.Thisreactionappears

withintwohoursofdosing,usuallylastingfourtosixhoursandisdose-related.Prioradministrationofanti-emeticsis

effectiveindiminishingandsometimespreventingthisside-effect.

Hepatic:WhenhighdosesofBiCNUhavebeenemployed,areversibletypeofhepatictoxicity,manifestedby

increasedtransaminase,alkalinephosphataseandbilirubinlevels,hasbeenreportedinasmallpercentageofpatients.

Pulmonary:SeeSpecialWarningsandPrecautionsforUse(4.4)(asperSPCSection4.4title)

Renal:Renalabnormalitiesconsistingofdecreaseinkidneysize,progressiveazotaemiaandrenalfailurehavebeen

reportedinpatientswhoreceivelargecumulativedosesafterprolongedtherapywithBiCNUandrelatednitrosoureas:

Kidneydamagehasalsobeenreportedinpatientsreceivinglowertotaldoses.

Cardiovascular:Hypotension,tachycardiahavebeenreported.

Local:Burningatthesiteofinjectioniscommonbuttruethrombosisisrare.

Other:Rapidi.v.infusionofBiCNUmayproduceintenseflushingoftheskinandsuffusionoftheconjunctivawithin

twohours,lastingaboutfourhours.

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4.9Overdose

Noneknown.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

BiCNUalkylatesDNAandRNAhasalsobeenshowntoinhibitseveralenzymesbycarbamoylationofaminoacidsin

proteins.ItisthoughtthattheantineoplasticandtoxicactivitiesofBiCNUmaybeduetometabolites.

5.2Pharmacokineticproperties

IntravenouslyadministeredBiCNUisrapidlydegraded,withnointactdrugdetectableafter15minutes.However,in

studieswithC

labelleddrug,prolongedlevelsoftheisotopewereobservedintheplasmaandtissue,probably

representingradioactivefragmentsoftheparentcompound.

Approximately60to70%ofatotaldoseisexcretedintheurinein96hoursandabout10%asrespiratoryCO

.The

fateoftheremainderisundetermined.

BecauseofthehighlipidsolubilityandtherelativelackofionisationataphysiologicalpH,BiCNUcrossestheblood

brainbarrier.

LevelsofradioactivityintheCSFareatleast50%higherthanthosemeasuredconcurrentlyinplasma.

5.3Preclinicalsafetydata

Nofurtherrelevantdataavailable.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Powder:None

Solvent:Ethanol

6.2Incompatibilities

Compatibility/IncompatibilitywithContainers:Theintravenoussolutionissuitableforinfusioninpolytheneorglass

containers.StudieshaveshowncarmustinetobeincompatiblewithPVCcontainersasitisreadilyabsorbedonplastic.

6.3ShelfLife

Unopenedvialsofthedrypowder:36months.

Alcoholsolvent:42months.

NOTE:Theshelflifeofthesolventampouleisdifferenttothepowdervial.

Chemicalandphysicalin-usestabilityhasbeendemonstratedfor24hourswhenstoredat2-8°Candprotectedfrom

light.

Fromamicrobiologicalpointofview,theproductshouldbeusedimmediately.Ifnotusedimmediately,thein-use

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hourswhenstoredat2-8°C.

6.4Specialprecautionsforstorage

Storeinrefrigerator(2°C-8°C).

Oncereconstituted,resultingsolutions(dilutedorundiluted)maybestoreduptoatotalof24hourswhenstoredat2-8°

Candprotectedfromlight.

6.5Natureandcontentsofcontainer

Powder:TypeIamberglassvial(30ml)sealedwithagreybutyllyophilisingstopperandanaluminium

seal/polypropelenecap.

Solvent:TypeIglassampoule(5ml).

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Forsingleuseonly.Discardanyunusedcontainers.

IMPORTANTNOTE:Thelyophiliseddosageformulationcontainsnopreservativesandisnotintendedasmultiple

dosevial.Reconstitutionsandfurtherdilutionsshouldbecarriedoutunderasepticconditions.Theintravenoussolution

issuitableforinfusioninpolytheneorglasscontainersonly.

Preparationofintravenoussolution:DissolveBiCNUwith3mlofthesuppliedsterilediluent(absoluteethanol)and

thenasepticallyadd27mlofsterilewaterforinjectiontothealcoholsolution.Eachmloftheresultingsolutionwill

contain3.3mgofBiCNUin10%ethanolandhasapHof5.6to6.0.

Reconstitutionasrecommendedresultsinaclearcolourlesssolutionwhichmaybefurtherdilutedto500mlsodium

chlorideforinjection,or5%glucoseforinjection.Thereconstitutedsolutionmustbegivenintravenouslyandshould

beadministeredbyi.v.dripoveraone-totwo-hourperiod.Discardanyunsedcontents.InjectionofBiCNUover

shorterperiodsoftimemayproduceintensepainandburningatthesiteofinjection.

IMPORTANTNOTE:BiCNUhasalowmeltingpoint(approximately30.5-32.0°Cor86.9-89.6°F).Exposureofthe

drugtothistemperatureorabovewillcausethedrugtoliquefyandappearasanoilfilminthebottomofthevials.

Thisisasignofdecompositionandvialsshouldbediscarded.

Guidelinesforthesafehandlingofantineoplasticagents:

Trainedpersonnelshouldreconstitutethedrug.

Thisshouldbeperformedinadesignatedarea.

Adequateprotectiveglovesshouldbeworn.

Precautionsshouldbetakentoavoidthedrugaccidentallycomingintocontactwiththeeyes.Intheeventof

contactwiththeeyes,flushwithcopiousamountsofwaterand/orsaline.

Thecytotoxicpreparationshouldnotbehandledbypregnantstaff.

Adequatecareandprecautionshouldbetakeninthedisposalofitems(syringes,needlesetc)usedto

reconstitutecytotoxicdrugs.Excessmaterialandbodywastemaybedisposedofbyplacingindoublesealed

polythenebagsandincineratingatatemperatureof1,000°C.Liquidwastemaybeflushedwithcopious

amountsofwater.

Theworksurfaceshouldbecoveredwithdisposableplastic-backedabsorbentpaper.

UseLuer-Lockfittingsonallsyringesandsets.Largeboreneedlesarerecommendedtominimisepressureand

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7MARKETINGAUTHORISATIONHOLDER

Bristol-MyersSquibbHoldingsLimited

t/aBristol-MyersPharmaceuticals

Swords

CountyDublin

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA48/16/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:06February1979

Dateoflastrenewal:06February2004

10DATEOFREVISIONOFTHETEXT

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