BLEOMYCIN SULPHATE

Main information

  • Trade name:
  • BLEOMYCIN SULPHATE
  • Dosage:
  • 15000IU/ vi %v/ v
  • Pharmaceutical form:
  • Unknown
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • BLEOMYCIN SULPHATE
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0437/038/001
  • Authorization date:
  • 18-09-1998
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0437/038/001

CaseNo:2045348

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

HOSPIRAUKLtd

Queensway,RoyalLeamingtonSpa,WarwickshireCV313RW,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

BLEOMYCIN15,000IUPowderforInjection

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom20/02/2008until17/09/2008.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Bleomycin15,000IUPowderforInjection

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachvialcontainsbleomycin15,000IU(asbleomycinsulphate).

Forexcipients,see6.1.

3PHARMACEUTICALFORM

Powderforsolutionforinjection

Vialscontainingawhitetocreamcolouredpowder.

4CLINICALPARTICULARS

4.1TherapeuticIndications

4.2Posologyandmethodofadministration

Adults

Bleomycinisusuallyadministeredintramuscularlybutmaybegivenintravenously(bolusordrip),intra-arterially,

intrapleurallyorintraperitoneallyasasolutioninphysiologicalsaline.Localinjectiondirectlyintothetumourmay

occasionallybeindicated.

1.Squamouscellcarcinomaandtesticularteratoma:

Usedalonethenormaldosageis15x10 3

I.U.threetimesaweekor30x10 3

I.U.twiceaweek,eitherintramuscularly

orintravenously.

Treatmentmaycontinueonconsecutiveweeks,ormoreusuallyatintervalsof3-4weeks,uptoatotalcumulativedose

of500x10 3

I.U.althoughyoungmenwithtesticulartumourshavefrequentlytoleratedtwicethisamount.Continuous

intravenousinfusionatarateof15x10 3

I.U.per24hoursforupto10days,or30x10 3

I.U.per24hoursforupto5

daysmayproduceatherapeuticeffectmorerapidly.Thedevelopmentofstomatitisisthemostusefulguidetothe

1.Squamouscellcarcinomaaffectingthemouthnasopharynxandparanasalsinuses,larynx,oesophagus,external

genitalia,cervixorskin.Well-differentiatedtumoursusuallyrespondbetterthananaplasticones.

2.Hodgkin'sdiseaseandothermalignantlymphomasincludingmycosisfungoides.

3.Testicularteratoma.

4.Malignanteffusionsofserouscavities.

5.Secondaryindicationsinwhichbleomycinhasbeenshowntobeofsomevalue(aloneorincombinationwith

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bleomycinisusedincombinationchemotherapy.Useinelderlyorchildren-seebelow.

2.Malignantlymphomas:

Usedalonetherecommendeddosageregimenis15x10 3

I.U.onceortwiceaweek,intramuscularly,toatotaldoseof

225x10 3

I.U.dosageshouldbereducedintheelderly.Thedosemayneedtobeadjustedwhenbleomycinisusedin

combinationchemotherapy.Useinchildren-seebelow.

3.Malignanteffusions:

Afterdrainageoftheaffectedserouscavity,60x10 3

I.U.bleomycindissolvedin100mlphysiologicalsalineis

introducedviathedrainageneedleorcannula.Afterinstillation,thedrainageneedleorcannulamaybewithdrawn.

Administrationmayberepeatedifnecessarysubjecttoatotalcumulativedoseof500x10 3

I.U.Useinelderlyor

children-seebelow.

Combinationtherapy:

Bleomyciniscommonlyusedinconjunctionwithradiotherapy,particularlyinthetreatmentofcanceroftheheadand

neckregion.Suchacombinationmayenhancemucosalreactionsiffulldosesofbothformsoftreatmentareusedand

bleomycindosagemayrequirereduction,e.g.to5x10 3

I.U.atthetimeofeachradiotherapyfractionfivedaysaweek.

Bleomycinisfrequentlyusedasoneofthedrugsinmultiplechemotherapyregimens(e.g.insquamouscellcarcinoma,

testicularteratoma,andlymphoma).

Themucosaltoxicityofbleomycinshouldbeborneinmindintheselectionanddosageofdrugswithsimilartoxic

potentialusedinsuchcombinations.

Elderlypatients:

Thetotaldoseofbleomycinusedinthetreatmentofsquamouscellcarcinoma,testicularteratomaormalignant

effusionsshouldbereducedasindicatedbelow.

Children:

Untilfurtherdataareavailable,administrationofbleomycintochildrenshouldtakeplaceonlyunderexceptional

circumstancesandinspecialcentres.Thedosageshouldbebasedonthatrecommendedforadultsandadjustedtobody

surfaceareaorbodyweight.

Reducedkidneyfunction:

Withserumcreatininevaluesof177-354micromol/l(2-4mg%),halftheaboveindividualdosageisrecommended.

Withserumcreatinineabove354micromol/l(4mg%),afurtherreductionindoseisindicated.

Preparationofsolutions:

Forintramuscularinjectionstherequireddoseisdissolvedinupto5mlofasuitablesolventsuchasphysiological

Ageinyears Totaldose(IU) Doseperweek(IU)

80andover

100x10 3

15x10 3

70–79

150-200x10 3

30x10 3

60–69

200-300x10 3

30-60x10 3

Under60

500x10 3

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Forintravenousinjectionsthedoserequiredisdissolvedin5-200mlofphysiologicalsalineandinjectedslowlyor

addedtothereservoirofarunningintravenousinfusion.Forintra-arterialadministrationaslowinfusionin

physiologicalsalineisused.Forintra-cavitaryinjection60x10 3

I.U.isdissolvedin100mlnormalsaline.

Forlocalinjectionsbleomycinisdissolvedinphysiologicalsalinetomakea1-3x10 3

I.U./mlsolution.

4.3Contraindications

Bleomcyciniscontraindicatedinpatientswithacutepulmonaryinfectionorgreatlyreducinglungfunction.

Lungfunctiontestswhichuse100%oxygenshouldnotbeusedinpatientswhohavebeentreatedwithbleomycin.

Lungfunctiontestsusinglessthan21%oxygenarerecommendedasanalternative.

4.4Specialwarningsandprecautionsforuse

ItisrecommendedthatBleomycinbeadministeredunderthesupervisionofaqualifiedphysicianexperiencedinthe

useofcancerchemotherapeuticagents.Appropriatemanagementoftherapyandcomplicationsispossibleonlywhen

adequatediagnosticandtreatmentfacilitiesareavailable.Patientsreceivingbleomycinmustbeobservedcarefullyand

frequentlyduringandaftertherapy.

Afterinjection,bleomycinisreadilyabsorbedanddistributedinthebody,particularlyintheskin,lungsandany

susceptibletumourtissue,leadingtopossibleskinandpulmonarytoxicity,aswellasantitumouractivity.

PatientsundergoingtreatmentwithbleomycinshouldhavechestX-raysweekly.Theseshouldcontinuetobetakenfor

uptofourweeksaftercompletionofthecourse.Ifbreathlessnessorinfiltrates,notobviouslyattributabletotumouror

toco-existentlungdisease,appear,administrationofthedrugmustbestoppedimmediatelyandpatientsshouldbe

treatedwithacorticosteroid(e.g.hydrocortisone100mgi.m.asthesodiumsuccinatedailyforfivedays,followedby

oralprednisolone10mgtwicedaily)andabroad-spectrumantibiotic.

Ithasbeensuggestedthatsequentialmeasurementofpulmonarydiffusioncapacityforcarbonmonoxide(DLco)during

bleomycintherapymaybeofvalueinpredictingpulmonarytoxicity.Whenusedtodetectpulmonarytoxicity,DLco

determinationsshouldbeperformedmonthlyandthedrugshouldbediscontinuedwhentheDLcoislessthan30-35%

ofthepre-treatmentvalue.

Anaesthesia

Becauseofbleomycin’seffectsonlungtissue,patientswhohavereceivedthedrugareatincreasedriskofdeveloping

pulmonarytoxicitywhenoxygenisadministeredduringsurgery.Longexposuretoveryhighconcentrationsofoxygen

isaknowncauseoflungdamage,butafteradministrationofbleomycin,lungdamagecanoccuratoxygen

concentrationslowerthanthoseusuallyconsideredsafe.Optimalintraoperativemanagementthusrequiresthe

administrationofthelowestinspiredOxygenfraction(FIO

)compatiblewithadequateoxygenation.

Pneumonitis

Pneumonitisduetobleomycinhasbeentreatedwithcorticosteroidsinanefforttopreventprogressiontopulmonary

fibrosis.Infectiouspneumonitisshouldreceiveappropriateantibiotictherapy.

Lungcancer

Bleomycinshouldbeusedwithextremecautioninpatientswithlungcancerasthesepatientsshowanincreased

incidenceofpulmonarytoxicity.

AgeRelated

Patientsover70yearsofageshouldbecloselyobservedforsignsofpulmonarytoxicityduetobleomycintherapy(See

adverseReactions).

Cumulativedose

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Renalorhepatictoxicity

Renalorhepatictoxicity,beginningasdeteriorationinrenalorliverfunctiontests,havebeenreportedinfrequently.

Thesetoxicitiesmayoccur,however,atanytimeafterinitiationoftherapy.

IdiosyncraticReactions

Idiosyncraticreactionssimilartoanaphylaxishavebeenreportedin1%oflymphomapatientstreatedwithbleomycin.

Sincetheseusuallyoccurafterthefirstorseconddose,carefulmonitoringisessentialafterthesedoses.

Lymphomapatients

Alllymphomapatientsshouldreceivetestdosesofbleomycinbeforeinitiatingfull-dosetherapy.

Thisproductshouldnotnormallybeadministeredtopatientswhoarepregnantormotherswhoarebreast-feeding.

Animalexperienceshaverevealedthatbleomycin,likemostcytotoxics,mayhaveteratogenicandcarcinogenic

potential.

Becauseofpossibleskinchanges,directcontactofbleomycinwiththeskinshouldbeavoided.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Digoxin-serumlevelsofDigoxinmaybereducedanditsactionsmaybedecreased.Itisthoughtthatdrug-induced

alterationsoftheintestinalmucosamaybeinvolvedinthereducedG.I.absorption.

Phenytoin-serumconcentrationsofphenytoinmaybedecreasedduetodecreasedabsorptionorincreasedmetabolism

ofphenytoin.

NephrotoxicAgents,e.g.Cisplatin-enhancedpulmonarytoxicity,insomecasesfatal,hasbeenreportedinpatients

givenbleomycinandcisplatin.Concurrentuseofrenallytoxicdrugsshouldthereforebeundertakenwithcaution.

Oxygensupportduringgeneralanaesthesiamayresultinpulmonaryfibrosis.Concurrentradiotherapymayincreasethe

incidenceofpulmonaryanddermatologicaltoxicities.

4.6Pregnancyandlactation

Bleomycinhascaused,issuspectedtohavecausedormaybeexpectedtocause,anincreaseincidenceofhumanfoetal

malformationsorirreversibledamage.Itmayalsohaveadversepharmacologicaleffects.

Itisnotknownwhetherbleomycinisexcretedinbreastmilkorwhetherithasaharmfuleffectonthenewborn.

Thereforeitisnotrecommendedfornursingmothersunlesstheexpectedbenefitsoutweighanypotentialriskstothe

newborn.

4.7Effectsonabilitytodriveandusemachines

None.

4.8Undesirableeffects

Likemostcytotoxicagentsbleomycincangiverisebothtoimmediateandtodelayedtoxiceffects.Themost

immediateeffectisfeveronthedayofinjection.Anorexia,tirednessornauseamayalsooccur.

Localpainmayoccurafterintravenousorintracavitaryinjectionandotherrareeffectsarehypotensionandlocal

thrombophlebitisafterintravenousadministration.

Themajorityofpatientswhoreceiveafullcourseofbleomycindeveloplesionsoftheskinororalmucosa.Flagellate

pigmentationisaformoflocalizedskinhyperpigmentationthatoccursin8%to38%ofpatientsreceivingbleomycin.

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hyperkeratosis,reddening,tenderness,andswellingofthetipsofthefingers,ridgingofthenails,bullaformationover

pressurepointssuchaselbows,lossofhairandstomatitisarerarelyseriousandusuallydisappearsoonafter

completionofthecourse.

Themostseriousdelayedeffectisinterstitialpneumonia,whichmaydevelopduring,oroccasionallyafter,acourseof

treatment.Thisconditionmaysometimesdevelopintofatalpulmonaryfibrosis,althoughsuchanoccurrenceisrareat

recommendeddoses.

Previousorconcurrentradiotherapytothechestisanimportantfactorinincreasingtheincidenceandseverityoflung

toxicity.Ithasbeensuggestedthatthosepatientswhohavereceivedbleomycinpreoperativelyareatgreaterariskof

developingpulmonarytoxicity,andareductionininspiredoxygenconcentrationduringtheoperationandpost-

operativelyisrecommended.

Acutefulminantreactionswithhyperpyrexiaandcardiorespiratorycollapsehavebeenreportedafterintravenous

injectionsofdoseshigherthanthoserecommended.Hypotension,hyperpyrexiaanddrugrelateddeathshavebeen

reportedrarelyfollowingintra-cavitaryinstillationofbleomycin.

Whenbleomycinisusedasoneofthedrugsinmultiplechemotherapyregimensthetoxicityofbleomycinshouldbe

borneinmindintheselectionanddosageofdrugswithsimilartoxicpotential.Theadditionofothercytotoxicdrugs

cannecessitatechangesanddosealterations.

Inpatientstreatedfortesticularcancerwithacombinationofbleomycinandvincaalkaloidsasyndromehasbeen

reportedcorrespondingtomorbusRaynaud,ischaemiawhichcanleadtonecrosisofperipheralpartsofthebody

(fingers,toes,nosetip).

4.9Overdose

Nospecificantidote.Theacutereactiontoanoverdosagewithbleomycinwouldprobablyincludehypotension,fever,

rapidpulseandgeneralsymptomsofshock.Treatmentispurelysymptomatic.Intheeventofrespiratory

complications,thepatientshouldbetreatedwithacorticosteroidandabroad-spectrumantibiotic.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Althoughtheprecisemechanismofactionofbleomycinisnotfullyknown,itisthoughtthattheprimaryactionisto

producesingleanddouble-strandedbreaksinDNA,leadingtoinhibitionofcelldivisionandgrowth,andinhibitionof

DNAsynthesisinthecells.

BleomycinisprobablymosteffectiveagainstcellsintheMandG2(premitotic)phaseofthecellcycle.Bleomycinhas

notbeenshowntohaveanimmunosuppressiveeffectinvitro,andshowsnosignificantinhibitionofimmuneresponse

inpatientstreatedwiththedrug.

Bleomycin-inactivatingenzymehasbeendetectedinbothnormalandmalignantcellsandisparticularlyprominentin

liver.Theenzymeisnotfoundinlungorskin,twonormaltissuessensitivetobleomycinaction.

5.2Pharmacokineticproperties

Bleomyciniswellabsorbedinanimalsuponintramuscularandsubcutaneousadministration.Intramuscularinjectionof

15unitsinmanresultedinamaximumserumconcentrationof1milliunit/ml30minutesafteradministration.

Intravenousinjectionof15unitsinmanresultedinamaximumserumconcentrationof3.3milliunits/ml.

Theplasmahalf-liveshavevariedfrom15-60minutesinpatientswithnormalrenalfunctionfollowingI.V.

administration.Theserumhalf-lifeisprolongedinpatientswithrenaldysfunction.Inonepatientwithsevererenal

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thecreatinineclearancewas15.2ml/min.

Therewereundetectableserumlevelsofbleomycin72hoursaftertheI.V.dose.

AfterI.V.injectionanaverageof40%oftheadministereddoseisrecoveredunchangedintheurinewithin24hours.

AfterI.M.injection20%isrecoveredintheurineafter6hours.Bleomycinismetabolisedbyvarioustissuestosome

extentBleomycinwillcrosstheplacenta.Equilibriumdialysisandgelpermeationexperimentssuggeststhatlessthan

1.0%ofthedrugisprotein-boundafterincubationwithnormalhumanseruminvitro.

ThedrugconcentrationisverylowinthebrainandCSF.Inmicebleomycindiffusingfromthebloodproducehigh

concentrationsintheskin,lungs,kidneys,peritoneumlymphaticsystemandsusceptibletumourtissueifpresent.

5.3Preclinicalsafetydata

Thereisnopre-clinicaldataofrelevancetotheprescriberwhichareadditionaltothatalreadyincludedinother

sectionsoftheSPC.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

None.

6.2Incompatibilities

Bleomycinsolutionsshouldnotbemixedwithsolutionsofessentialaminoacids,riboflavin,ascorbicacid,

dexamethasone,aminophyllineorfrusemide,cephalotinsodium,benzylpenicillinsodium,methotrexate,mitomycin,

hydrocortisonesodiumsuccinate.

6.3ShelfLife

Aspackagedforsale:2years.

Inuse:Chemicalandphysicalin-usestabilityhasbeendemonstratedfor10daysat2-8°Cwhenprotectedfromlight.

Fromamicrobiologicalpointofview,theproductshouldbeusedimmediately.Ifnotusedimmediately,in-usestorage

timesandconditionspriortousearetheresponsibilityoftheuserandwouldnormallynotbelongerthan24hoursat2-

8°C,unlessreconstitutionhastakenplaceincontrolledandvalidatedasepticconditions.

6.4Specialprecautionsforstorage

Aspackagedforsale:Donotstoreabove25°C.Keepcontainerintheoutercarton.

Afterreconstitution/dilution:see6.3.

6.5Natureandcontentsofcontainer

10ml,clear20mmTypeIglassvial,20mmWestType1816rubberclosure,aluminiumwithplastic‘flip-off’topsin

singlesorpacksof10.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

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Preparationofsolutions:

Forintramuscularinjectionstherequireddoseisdissolvedinupto5mlofasuitablesolventsuchasphysiological

saline.Ifpainoccursatthesiteofinjectiona1%solutionoflignocainemaybeusedasasolvent.

Forintravenousinjectionsthedoserequiredisdissolvedin5-200mlofphysiologicalsalineandinjectedslowlyor

addedtothereservoirofarunningintravenousinfusion.Forintra-arterialadministrationaslowinfusionin

physiologicalsalineisused.Forintra-cavitaryinjection60x10 3

I.U.isdissolvedin100mlnormalsaline.

Forlocalinjectionsbleomycinisdissolvedinphysiologicalsalinetomakea1–3x10 3

I.U./mlsolution.

7MARKETINGAUTHORISATIONHOLDER

HospiraUKLimited

Queensway

RoyalLeamingtonSpa

WarwickshireCV313RW

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA437/38/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:18September1998

Dateoflastrenewal:18September2003

10DATEOFREVISIONOFTHETEXT

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