BLEOMYCIN PFI

Bleomycin

– Summary of Product Characteristics

Warning:

ItisrecommendedthatBleomycinbeadministeredunderthesupervisionofa

qualifiedphysicianexperiencedintheuseofcancerchemotherapeuticagents.

Appropriatemanagementoftherapyandcomplicationsispossibleonlywhen

adequatediagnosticandtreatmentfacilitiesarereadilyavailable.Pulmonary

fibrosisisthemostseveretoxicityassociatedwithBleomycin.Themost

frequentpresentationispneumonitisoccasionallyprogressingtopulmonary

fibrosis.Itsoccurrenceishigherinelderlypatientsandthosereceivinggreater

than400unitstotaldose,butpulmonarytoxicityhasbeenobservedinyoung

patients and those treated with low doses.

Asevereidiosyncraticreactionconsistingofhypotension,mentalconfusion,

fever,chillsandwheezinghasbeenreportedinapproximately1%oflymphoma

patients treated withBleomycin.

1. NAME OF THE MEDICINALPRODUCT

BleomycinPFI

2. QUALITATIVEAND QUANTITATIVE COMPOSITION

OnevialcontainsBleomycinsulphateequivalentto15units(USP)or15000

InternationalUnits(I.U)Bleomycin.1unit(USP)(correspondingto1000I.U.)

correspondsto1mgpotency.Note1mgpotencyisdefinedbybioassayand,

therefore,isnotidenticalto1mgdryweight(1mgdryweightaccordingUSP

corresponds to 1.5 to 2.0 mg potency).

3. PHARMACEUTICALFORM

Powder for solution for infusion, injection or instillation.

4. CLINICALPARTICULARS

4.1 Therapeutic indications

Bleomycinis useful in the management of the following neoplasms:

1)Squamouscellcarcinomaaffectingthemouth,nasopharynxandparanasal

sinuses,larynx,esophagus,cervix,vagina,penisandskin.Well-differentiated

tumors usually respond better than anaplastic ones.

2)Hodgkin’sdiseaseandothermalignantlymphomas,includingmycosis

fungoides.

3)Testicular carcinoma (seminoma and non-seminomas).

4)Malignant effusions of serouscavities (pleura and peritoneum).

5)AdditionalindicationsinwhichBleomycinhasbeenshowntobeofsome

valueincludemetastaticmalignantmelanoma,carcinomaofthethyroid,lung

and bladder.

Local treatment of refractory warts.

Bleomycincanbeusedasasingleagent,butisgenerallyusedincombination

with other cytotoxics and/or with radiation therapy.

4.2 Posology and method of administration

Bleomycinisadministeredparenterallyasintramuscularinjection,intravenous

injection/infusion,intraarterialinjection/infusion,subcutaneousinjection,

intratumoral injection or intracavitary instillation.

Posology

Adults

1.)Squamouscellcarcinoma

Intramuscularorintravenousinjectionof10-15units(USP)/m².Intravenous

infusionfor6-24hoursof10-15units(USP)/m²/dayin4to7consecutivedays

every3-4weeks.

2.)Hodgkin’slymphomaandnon-Hodgkin’slymphoma

Intramuscularorintravenousinjectionof5-10units(USP)/m²onceortwice

aweek.Becauseofthepossibilityofananaphylactoidreaction,lymphoma

patientsshouldbetreatedwith1-2units(USP)/doseforthefirsttwodoses.Ifno

acutereactionsoccur,theregulardosageregimencanbeadministered.

3.)Testicularcarcinoma

Intramuscularorintravenousinjectionof10-15units(USP)/m²onceortwicea

week.Intravenousinfusionfor6-24hoursof15-20units(USP)/m²/dayfor5-6

4.)Malignanteffusions

60units(USP)in100mlphysiologicalsalineintrapleurallyorintraperitoneally

asasingledoseandrepeated,ifnecessary.

5.)Refractorywarts

IntralesionallyinjectionofBleomycinhasbeengivenasa0.1%solution,

usuallyasa0.1mlinjection.

ImprovementofHodgkin’sdiseaseandtesticulartumorsispromptandnoted

withintwoweeks.Ifnoimprovementisseenbythistime,improvementis

unlikely.Squamouscellcancersrespondmoreslowly,sometimesrequiringas

long as 3 weeks before any improvement is noted.

Age in years Total dose Dose per week

80 and over 100 units (USP) 15 units (USP)

70-79 150-200 units (USP) 30 units (USP)

60-69 200-300 units (USP) 30-60 units (USP)

Under 60 400 units (USP) 30-60 units (USP)

TotaldosesofBleomycininpatientsnotolderthan60yearsshouldnot

exceed400units(USP)(approximately225units/m²bodysurface),unlessan

examinationofthelungfunctionhasensuredcontinuedadministration.Doses

mayneedtobeadjustedwhengivenincombinationwithotherantineoplastic

agents or with radiotherapy, and in patients older than 60 years (see below).

Elderly patients

The total dose should be reduced as indicated below

Children

IfadministrationofBleomycintochildrenisindicated,thedosageshouldbe

based on that recommended for adults and adjusted to body surface area.

Reduced renal function

Inpatientswithreducedkidneyfunction,dosesshouldbereduced.Ifcreatinine

clearance decreases to 20 ml/min, 50% ofBleomycindose should be given.

Combination therapy

InconjunctionwithradiotherapytheBleomycindosageshouldbereduced.The

dosemayneedtobeadjustedwhenBleomycinisusedincombinationwith

other cytotoxic drugs.

Methodofadministration/preparationofsolutions

Note:Forpreparationofthesolutiondissolvethewholecontentofavial(15

units)intheappropriateamountofsolvent.Fromthissolutionuseanaliquot

accordingtotheunitsneededfortreatment.Example:requireddosage8.5units

(5units/m 2

x1.7m 2

);dissolvethecontentofavial(15units)in5mlsolvent;

take out 2.83 ml (8.5 units) for application.

Intramuscular injection

Dissolvethecontentsofavialin1-5mlphysiologicalsalinesolvent.Since

repeatedi.m.injectionsatthesamesitemaycauselocaldiscomfort,itis

advisabletochangetheinjectionsite.Incaseofunduelocaldiscomfort,alocal

anaestheticsuchas1½-2ml1%lidocainehydrochloridecanbeaddedtothe

injection solution.

Intravenous injection

Dissolvethecontentsofavialin5-10mlofphysiologicalsalinesolventand

administeroveraperiodof5-10minutes.Avoidafastbolusinjection,whichwill

giveahighbloodconcentrationpassingthroughthelungs,increasingtherisk

of damage to the lungs.

Intravenous infusion

DissolveBleomycinin 200-1000 ml of physiological saline.

Intra-arterial injection

DissolvethecontentsofavialofBleomycinin5mlormoreofphysiological

saline and administer over a period of 5-10 minutes.

Intra-arterial infusion

DissolveBleomycinin200-1000mlofphysiologicalsaline.Theinfusionmay

begivenoverafewhourstoseveraldays.Topreventthrombosisattheinjection

siteheparincanbeadministered,especiallyifaninfusionisgivenoveralong

period of time.

Injection/infusionintothearterysupplyingthetumorshowsatendencyfor

higherefficacythanotherroutesofsystemicadministration.Thetoxiceffects

are as with i.v. injection/infusion.

Subcutaneous injection

Absorptionaftersubcutaneousinjectionisdelayedandmayimitateslowi.v.

infusion;thisformofadministrationisnotusedsooften.Caremustbetakento

Intratumoral injection

Bleomycinisdissolvedinphysiologicalsalinetomakea1-3units(USP)/ml

solutionwhichisinjectedintothetumoranditssurroundingtissues.Thisform

of application is rarely used.

Intracavitary instillation

Followingaspirationofthepleuralorperitonealcavity,Bleomycindissolvedin

physiologicalsalineisinstilledviatheneedleorcatheterusedforaspiration.The

needleorcatheteristhenremoved.Inordertoensuretheuniformdispersion

ofBleomycinwithintheserouscavitythepatient’spostureshouldbechanged

every 5 minutes, for 20 minutes.

ExtravasaladministrationofBleomycindoesnotusuallydemandextraordinary

precautions.Incaseofdoubt(concentratedsolution,sclerotictissue,etc.)

perfusion with physiological saline may be performed.

4.3 Contra-indications

Bleomyciniscontra-indicatedinpatientswithacutepulmonaryinfection,

severelyimpairedlungfunctionorcirculatorydisturbancesinthelungsandin

patientswhohavedemonstratedahypersensitiveoranidiosyncraticreactionto

the drug(Pregnancy and lactation: see item 4.6).

4.4 Special warnings and special precautions for use

PatientsreceivingBleomycinchemotherapyshouldbecarefullymonitoredby

experienced oncologists.

BecauseofthepossibleteratogeniceffectofBleomycinonmaleandfemale

germcellsadequateconceptioncontrolshouldbeestablishedduring,andfora

period of 6 months after treatment.

PulmonaryReactions

PatientsundergoingtreatmentwithBleomycinshouldbecarefullymonitored

foranysignoflungdysfunction.Pulmonaryreactionsarethemostseriousside

effects,occurringinapproximately10%oftreatedpatientsduring,oroccasionally

afteracourseoftreatment.Themostfrequentformisinterstitialpneumonitis.

Ifnotdiagnosedandtreatedimmediatelythisconditionmayprogressto

pulmonaryfibrosis.Approximately1%ofpatientstreateddiedbecauseof

pulmonaryfibrosis.FrequentchestX-rays(preferablyweekly)areadvisableand

shouldbecontinuedforupto4weeksaftercompletionofacourseoftreatment.

PulmonarytoxicityofBleomycinisbothdose-relatedandage-relatedwhen

thetotaldoseexceeds400units(USP)(approximately225units/m²body

surface)thismayalsooccurwhenlowerdosesareadministered,especiallyin

elderlypatients(over70yearsofage),patientswithreducedkidneyfunction,

pre-existinglungdisease,previousorconcurrentradiotherapytothechestand

inpatientswhoneedadministrationofoxygen.Itissignificantlyenhancedby

thoracicradiationandbyhyperoxiausedduringsurgicalanesthesia.Pulmonary

toxicityisunpredictableandhasbeenseenoccasionallyinyoungpatients

receivinglowdoses.Vascularchangesoccurinthelung,partlydestroying

theelasticityofthewallsofthevessel.Theearliestsymptomassociatedwith

pulmonarytoxicityofBleomycinisdyspnea.Fineralesaretheearliestsign.

Ifpulmonarychangesarenoted,treatmentshouldbediscontinueduntilitcan

bedeterminediftheyaredrugrelated.Patientsshouldbetreatedwithbroad

spectrum antibiotics and corticosteroids.

Bleomycinsensitivityincreasesinoldage.Ifbreathlessnessorlunginfiltrates

appear,notobviouslyattributabletotumorortoco-existentlungdisease,

administrationofthedrugmustbestoppedimmediatelyandpatientsshouldbe

treated with corticosteroid and broad-spectrum antibiotics.

Pyrexia

Likemost cytotoxic agentsBleomycincancauseimmediateanddelayedtoxic

effects.Themostimmediateeffectisfeveronthedayofinjection.Itsometimes

occurs2to6hoursafterthefirstinjectionofBleomycin.Incasesofpersistent

severepyrexiaitmaybenecessarytogiveantipyretics.Theincidenceofpyrexia

decreases with subsequent injections.

Skinandmucouschanges

IntheeventofcutaneoussideeffectsinpatientswithAIDS,Bleomycin

treatment should be stopped and should not be resumed.

Induration,edema,hyperkeratosis,nailchanges,bullaformationoverpressure

pointssuchaselbows,alopeciaandstomatitismayoccurduringtreatmentwith

Bleomycin.

Thesesideeffectsarerarelyseriousandusuallydisappearaftercompletion

oftreatment.MucosalulcerationseemstobeaggravatedwhenBleomycin

iscombinedwithirradiationorotherdrugstoxictomucousmembranes.Skin

toxicityisarelativelylatemanifestationcorrelatingwiththecumulativedoses,

usuallydevelopinginthe2ndand3rdweekoftreatmentafteradministrationof

150 to 200 units (USP) ofBleomycin.

Idiosyncraticreactions

Anidiosyncraticreaction,clinicallysimilartoanaphylaxis,hasbeenreported

inapproximately1%ofthelymphomapatientstreatedwithBleomycin.The

reactionmaybeimmediateordelayedforseveralhours,andusuallyoccurs

afterthefirstorseconddose.Itconsistsofhypotension,mentalconfusion,fever,

chills,andwheezing.Treatmentissymptomatic,includingvolumeexpansion,

pressor agents, antihistamines, and corticosteroids.

Hypersensitivity

Becauseofthepossibilityofananaphylactoidreaction(reportedin1%of

lymphomapatients)patientsshouldreceiveinitiallyatestdoseof1-2units

(USP)intotal.Ifnoacutereactionoccurstheregulardosageregimencanbe

administered.

Gastrointestinal

Gastrointestinalsideeffectssuchasnauseaandvomitingmayoccurbutare

moreoftenseeninhigh-doseschedules.Antiemeticdrugsmaybeofhelp.

Anorexiaandweightlossarecommonandmaypersistforalongtimeafter

termination of the treatment.

Others

Vascular toxicities have been reported rarely.The events are clinically

heterogeneous and may include myocardial infarction, cerebrovascular

accident, thrombotic microangiopathies like hemolytic-uremic-syndrome and

cerebral arteritis.

Likeothercytotoxicagents,Bleomycinmayinducetumorlysissyndrome

inpatientswithrapidlygrowingtumors.Adequatesupportingtreatmentand

pharmacological measures may prevent or relieve such complications.

4.5Interactionswithothermedicinalproductsandotherformsof

interaction

WhenBleomycinisusedasoneofthedrugsinmultiplechemotherapy

regimensthetoxicityofBleomycinshouldbeborneinmindintheselection

and dosage of drugs with a similar toxic potential.

Anincreasedriskofpulmonarytoxicityhasbeendescribedwithconcomitant

useofBCNU,mitomycin-C,cyclophosphamide,methotrexateandgemcitabine.

Previousorconcurrentradiotherapytothechestisanimportantfactorin

increasing the incidence and severity of lung toxicity.

BecauseofthepotentialofBleomycintosensitizethelungtissue,therisk

ofdevelopingpulmonarytoxicityisincreasedinpatientswhohavereceived

Bleomycinwhenoxygenisbeingadministeredatsurgery.Areductionininspired

oxygen during operation and postoperatively is therefore recommended.

InpatientstreatedfortesticularcancerwithacombinationofBleomycin

andvincaalkaloidsasyndromehasbeenreportedcorrespondingtomorbus

Raynaud,ischemiawhichmayleadtonecrosisoftheperipheralpartsofthe

body (fingers, toes, nose tip).

Inpatientstreatedwithatriplecombinationregimenofcisplatin,vinblastine

andBleomycin,apositivecorrelationbetweenGFR(glomerularfiltrationrate)

andpulmonaryfunctionwasobserved.Therefore,Bleomycinshouldbeused

cautiouslyinpatientswithseverelyimpairedrenalfunction.Anotherstudy

showedthatanincreaseofthecisplatindosewasassociatedwithadecrease

of the creatinine clearance and theBleomycinelimination.

Theincreaseinneutrophilcountsandthestimulationoftheabilitytoproduce

superoxideradicalsaftertheuseofgranulocyte-colonystimulatingfactormay

potentiate lung injury.

Therateandextentofabsorptionoforalacetyldigoxinandofphenytoincould

be reduced byBleomycintreatments.

4.6 Use during pregnancy and lactation

AnimalexperimentshaverevealedthatBleomycinhasteratogenicand

carcinogenic potential.

TheuseofBleomycinshouldbeavoidedwheneverpossibleduringpregnancy

particularly during the first trimester.

Inavitalindicationduringthefirsttrimesterofpregnancyamedicalconsultation

regarding abortion is absolutely necessary.

Afterthefirsttrimesterofpregnancy,iftherapycannotbedelayedandthepatient

wishestocontinuewithherpregnancy,chemotherapymaybeundertakenafter

informing the patient of the minor but possible risk of teratogenic effects.

Bleomycinshould not be given to mothers who are breast feeding.

Contraceptive measures:

Bleomycincancausecongenitalanomalities.Conceptionduring

andsixmonthsaftertreatmentisnotadvisable.Womenshould

notbecomepregnantduringandsixmonthsaftertreatment.

4.7 Effects on ability to drive and use machines

PotentialsideeffectsofthechemotherapywithBleomycin,likenauseaand

4.8 Undesirable Effects

NEOPLASMS,BENIGNANDMALIGNANTANDUNSPECIFIED(INCLUDING

CYSTSAND POLYPS):Tumor pain,Tumor lysis syndrome

BLOODAND LYMPHATIC SYSTEM DISORDERS:

Febrileneutropenia,Neutropenia,Thrombocytopenia,Hemolyticuremic

syndrome,Thrombotic microangiopathy, Granulocytopenia, Leukopenia

METABOLISMAND NUTRITION DISORDERS:

Anorexia

PSYCHIATRIC DISORDERS:

Confusional state

NERVOUS SYSTEM DISORDERS:

Cerebral arteritis, Cerebrovascular accident

CARDIAC DISORDERS:

Myocardial infarction, Pericarditis

VASCULAR DISORDERS:

Hypotension,Phlebitis,Raynaud’sphenomenon,Thrombophlebitis,Arterial

thrombosis, deep vein thrombosis.

RESPIRATORY,THORACICAND MEDIASTINALDISORDERS:

Respiratoryfailure,pulmonaryembolism,Dyspnoea,Interstitiallungdisease,

Pulmonaryfibrosis,Pulmonarytoxicity,Rales,Wheezing,Acuterespiratory

distress syndrome.

GASTROINTESTINALDISORDERS:

Nausea, Stomatitis, Vomiting

SKINANDSUBCUTANEOUSTISSUEDISORDERS:Alopecia,Blister,

Erythema,Hyperkeratosis,Naildisorder,Pruritis,Rash,Rashvesicular,Skin

hyperpigmentation, Skin striae, Skin toxicity, Dermatitis, Drug eruption.

MUSCULOSKELETALAND CONNECTIVETISSUE DISORDERS:

Arthralgia, Myalgia, Scleroderma

GENERALDISORDERSANDADMINISTRATIVE SITE CONDITIONS:

Chestpain,Chills,Induration,Injectionsitepain,Localreaction,Mucosal

inflammation,Mucosalulceration,Oedema,Oedemaperipheral,Pyrexia,

Tenderness, Idiosyncratic drug reaction

4.9 Overdose

ObservationsindicatethatitisdifficulttoeliminateBleomycinfromthebody

bydialysis.TheacutereactionfollowinganoverdosageofBleomycinwould

probablyincludehypotension,fever,rapidpulseandgeneralsymptomsof

shock.Treatmentispurelysymptomatic.Intheeventofrespiratoryproblemsthe

patient should be treated with a corticosteroid and a broad-spectrum antibiotic.

5. PHARMACOLOGICALPROPERTIES

5.1 Pharmacodynamic properties

ATC-code: L01 DC 01

Bleomycinisamixtureofbasic,water-solubleglucopeptide-antibioticswith

cytotoxicactivity.Bleomycinactsbyintercalatingwithbothsingleanddouble-

strandedDNA(deoxyribonucleicacid)resultinginbothsingleanddouble-strand

scission,leadingtoinhibitionofcelldivision,ofgrowthandofDNAsynthesis;to

alesserdegreeBleomycinmayinfluenceRNA(ribonucleicacid)andprotein

synthesis.

ThemostimportantfactorinthetissueselectivityofBleomycinisthedifference

inintracellularinactivation.Squamouscells,withtheirlowcontentofBleomycin

hydrolase,haveahighsusceptibilityforBleomycin.Insensitivetissues,both

normalandneoplastic,chromosomeaberrationssuchasfragmentation,

chromatide breaks, and translocations appear to be regularly produced.

Bleomycinis pyrogenic.

Bleomycincauseslittleornobone-marrowtoxicityandnoimmunosuppression.

Bleomycincanbeusedalone,incombinationwithradiotherapyandtogether

with other cytotoxic drugs.

5.2 Pharmacokinetic properties

Absorption

Bleomycinisadministeredparenterally.Afterintravenousadministrationofa

bolusdoseof15units(USP)/m²bodysurfacepeakconcentrationsof1to10mU/

mlareachievedinplasma.Followingthei.m.injectionof15unitspeakplasma

concentrationsofabout1mU/mlareachievedafter30minutes.Continuous

infusionof30units(USP)ofBleomycindailyfor4to5daysresultedinan

Distribution

Bleomycinisrapidlydistributedtobodytissueswithhighestconcentrationsin

skin,lungs,peritoneumandlymphatictissue.Lowconcentrationsareseenin

the bone marrow.

Bleomycincouldnotbedetectedincerebrospinalfluidafterintravenous

injection.Bleomycinappearstocrosstheplacentalbarrier.Theapparent

volumeofdistribution(Vd)ßisabout0.27+0.09L/kg.Bleomycinisboundto

plasma proteins only to a slight extent.

Biotransformation

ThebiotransformationofBleomycinisnotfullymappedout.Inactivationtakes

placeduringenzymaticbreakdownbyBleomycinhydrolasewhichislocalized

primarilyinplasma,liver,spleen,intestineandbonemarrowandtoamuch

lesser extent in skin and lungs.

Elimination

Theeliminationhalf-life(T½ß)ofBleomycinisabout3hours.Aftercontinuous

i.v.infusiontheeliminationhalf-lifemaybeincreasedtoabout9hours.The

systemicplasmaclearance(Cls)isabout1.1ml/minxkg.Abouttwothirdsofthe

administereddrugisexcretedunchangedintheurine,probablybyglomerular

filtration.Approximately50%isrecoveredintheurinein24hoursafterani.v.

ori.m.injection.Therefore,therateofexcretionishighlyinfluencedbyrenal

function;concentrationsinplasmaaresignificantlyelevatedifusualdosesare

giventopatientswithrenalimpairmentwithonlyupto20%excretedin24

hours.ObservationsindicatethatitisdifficulttoeliminateBleomycinfromthe

body by dialysis.

5.3 Preclinical safety data

AnimalexperienceshaverevealedthatBleomycinhasteratogenicand

carcinogenic potential.

6. PHARMACEUTICALPARTICULARS

6.1 List of excipients

None.

6.2 Incompatibilities

Bleomycinsolutionshouldnotbemixedwithsolutionsofessentialamino

acids,aminophylline,ascorbicacid,benzylpenicilline,carbenicilline,cefalotine,

cefalozine,dexamethasone,diazepam,glutathione,hydrogensuperoxide,

hydrocortisone-Na-succinate,methotrexate,mitomycin,nafcilline,penicilline

G, riboflavin, substances containing sulfhydryl groups, terbutaline, or thiols.

6.3 Shelf life

42 months (3,5 years).

6.4 Special precautions for storage

Store at 2 -8°C. Keep in the carton.

6.5 Nature and contents of container

Packswith1or10vialseachcontainingBleomycinsulphateequivalentto15

units (USP).

6.6 Instructions for use/handling

Thegeneralguidelinesforsafehandlingofcytotoxicdrugsshouldbefollowed.

Precautionsshouldbetakentoavoidcontactwithskin,mucousmembranes

oreyes.Intheeventofcontaminationtheaffectedpartsshouldbewashed

thoroughlywithwater.Urineproducedforupto72hoursafteradoseof

Bleomycinshould be handled by wearing protective clothing

7. DATE OF (PARTIAL) REVISION OF THE TEXT June 2010

8. MANUFACTURER

Baxter Oncology GmbH, Germany

9. REGISTRATION HOLDER

MegaPharm Ltd., P.O. Box 519, Hod Ha`Sharon 45105

The format of this leaflet was determined by the Ministry of Health and its

content was checked and approved in February 2011

BLESPC 112010P.2

Bleomycin

– Summary of Product Characteristics

Warning:

It is recommended that Bleomycin be administered under the supervision of a

qualified physician experienced in the use of cancer chemotherapeutic agents.

Appropriate management of therapy and complications is possible only when

adequate diagnostic and treatment facilities are readily available. Pulmonary

fibrosis is the most severe toxicity associated with Bleomycin. The most

frequent presentation is pneumonitis occasionally progressing to pulmonary

fibrosis. Its occurrence is higher in elderly patients and those receiving greater

than 400 units total dose, but pulmonary toxicity has been observed in young

patients and those treated with low doses.

A severe idiosyncratic reaction consisting of hypotension, mental confusion,

fever, chills and wheezing has been reported in approximately 1% of lymphoma

patients treated with Bleomycin.

1. NAME OF THE MEDICINAL PRODUCT

Bleomycin PFI

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One vial contains Bleomycin sulphate equivalent to 15 units (USP) or 15000

International Units (I.U) Bleomycin. 1 unit (USP) (corresponding to 1000 I.U.)

corresponds to 1 mg potency. Note 1 mg potency is defined by bioassay and,

therefore, is not identical to 1 mg dry weight (1 mg dry weight according USP

corresponds to 1.5 to 2.0 mg potency).

3. PHARMACEUTICAL FORM

Powder for solution for infusion, injection or instillation.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Bleomycin is useful in the management of the following neoplasms:

1) Squamous cell carcinoma affecting the mouth, nasopharynx and paranasal

sinuses, larynx, esophagus, cervix, vagina, penis and skin. Well-differentiated

tumors usually respond better than anaplastic ones.

2) Hodgkin’s

disease

other

malignant

lymphomas,

including

mycosis

fungoides.

3) Testicular carcinoma (seminoma and non-seminomas).

4) Malignant effusions of serous cavities (pleura and peritoneum).

5) Additional indications in which Bleomycin has been shown to be of some

value include metastatic malignant melanoma, carcinoma of the thyroid, lung

and bladder.

Local treatment of refractory warts.

Bleomycin can be used as a single agent, but is generally used in combination

with other cytotoxics and/or with radiation therapy.

4.2 Posology and method of administration

Bleomycin is administered parenterally as intramuscular injection, intravenous

injection/infusion,

intraarterial

injection/infusion,

subcutaneous

injection,

intratumoral injection or intracavitary instillation.

Posology

Adults

1.) Squamous cell carcinoma

Intramuscular or intravenous injection of 10-15 units (USP)/m². Intravenous

infusion for 6-24 hours of 10-15 units (USP)/m²/day in 4 to 7 consecutive days

every 3-4 weeks.

2.) Hodgkin’s lymphoma and non-Hodgkin’s lymphoma

Intramuscular or intravenous injection of 5-10 units (USP)/m² once or twice

a week. Because of the possibility of an anaphylactoid reaction, lymphoma

patients should be treated with 1-2 units (USP)/dose for the first two doses. If no

acute reactions occur, the regular dosage regimen can be administered.

3.) Testicular carcinoma

Intramuscular or intravenous injection of 10-15 units (USP)/m² once or twice a

week. Intravenous infusion for 6-24 hours of 15-20 units (USP)/m²/day for 5-6

consecutive days every 3-4 weeks.

4.) Malignant effusions

60 units (USP) in 100 ml physiological saline intrapleurally or intraperitoneally

as a single dose and repeated, if necessary.

5.) Refractory warts

Intralesionally injection of Bleomycin has been given as a 0.1 % solution,

usually as a 0.1 ml injection.

Improvement of Hodgkin’s disease and testicular tumors is prompt and noted

within two weeks. If no improvement is seen by this time, improvement is

unlikely. Squamous cell cancers respond more slowly, sometimes requiring as

long

weeks

before

improvement

noted.

Age in years

Total dose

Dose per week

80 and over

100 units (USP)

15 units (USP)

70-79

150-200 units (USP)

30 units (USP)

60-69

200-300 units (USP)

30-60 units (USP)

Under 60

400 units (USP)

30-60 units (USP)

Total doses of Bleomycin in patients not older than 60 years should not

exceed 400 units (USP) (approximately 225 units/m² body surface), unless an

examination of the lung function has ensured continued administration. Doses

may need to be adjusted when given in combination with other antineoplastic

agents or with radiotherapy, and in patients older than 60 years (see below).

Elderly patients

The total dose should be reduced as indicated below

Children

If administration of Bleomycin to children is indicated, the dosage should be

based on that recommended for adults and adjusted to body surface area.

Reduced renal function

In patients with reduced kidney function, doses should be reduced. If creatinine

clearance decreases to 20 ml/min, 50% of Bleomycin dose should be given.

Combination therapy

In conjunction with radiotherapy the Bleomycin dosage should be reduced. The

dose may need to be adjusted when Bleomycin is used in combination with

other cytotoxic drugs.

Method of administration/preparation of solutions

Note: For preparation of the solution dissolve the whole content of a vial (15

units) in the appropriate amount of solvent. From this solution use an aliquot

according to the units needed for treatment. Example: required dosage 8.5 units

( 5 units /m

x 1.7 m

); dissolve the content of a vial (15 units) in 5 ml solvent;

take out 2.83 ml (8.5 units) for application.

Intramuscular injection

Dissolve the contents of a vial in 1-5 ml physiological saline solvent. Since

repeated i.m. injections at the same site may cause local discomfort, it is

advisable to change the injection site. In case of undue local discomfort, a local

anaesthetic such as 1 ½ -2 ml 1% lidocaine hydrochloride can be added to the

injection solution.

Intravenous injection

Dissolve the contents of a vial in 5-10 ml of physiological saline solvent and

administer over a period of 5-10 minutes. Avoid a fast bolus injection, which will

give a high blood concentration passing through the lungs, increasing the risk

of damage to the lungs.

Intravenous infusion

Dissolve Bleomycin in 200-1000 ml of physiological saline.

Intra-arterial injection

Dissolve the contents of a vial of Bleomycin in 5 ml or more of physiological

saline and administer over a period of 5-10 minutes.

Intra-arterial infusion

Dissolve Bleomycin in 200-1000 ml of physiological saline. The infusion may

be given over a few hours to several days. To prevent thrombosis at the injection

site heparin can be administered, especially if an infusion is given over a long

period of time.

Injection/infusion into the artery supplying the tumor shows a tendency for

higher efficacy than other routes of systemic administration. The toxic effects

are as with i.v. injection/infusion.

Subcutaneous injection

Absorption after subcutaneous injection is delayed and may imitate slow i.v.

infusion; this form of administration is not used so often. Care must be taken to

avoid intradermal injection.

Intratumoral injection

Bleomycin is dissolved in physiological saline to make a 1-3 units (USP)/ml

solution which is injected into the tumor and its surrounding tissues. This form

of application is rarely used.

Intracavitary instillation

Following aspiration of the pleural or peritoneal cavity, Bleomycin dissolved in

physiological saline is instilled via the needle or catheter used for aspiration. The

needle or catheter is then removed. In order to ensure the uniform dispersion

of Bleomycin within the serous cavity the patient’s posture should be changed

every 5 minutes, for 20 minutes.

Extravasal administration of Bleomycin does not usually demand extraordinary

precautions. In case of doubt (concentrated solution, sclerotic tissue, etc.)

perfusion with physiological saline may be performed.

4.3 Contra-indications

Bleomycin is contra-indicated in patients with acute pulmonary infection,

severely impaired lung function or circulatory disturbances in the lungs and in

patients who have demonstrated a hypersensitive or an idiosyncratic reaction to

the drug (Pregnancy and lactation: see item 4.6).

4.4 Special warnings and special precautions for use

Patients receiving Bleomycin chemotherapy should be carefully monitored by

experienced oncologists.

Because of the possible teratogenic effect of Bleomycin on male and female

germ cells adequate conception control should be established during, and for a

period of 6 months after treatment.

Pulmonary Reactions

Patients undergoing treatment with Bleomycin should be carefully monitored

for any sign of lung dysfunction. Pulmonary reactions are the most serious side

effects, occurring in approximately 10 % of treated patients during, or occasionally

after a course of treatment. The most frequent form is interstitial pneumonitis.

If not diagnosed and treated immediately this condition may progress to

pulmonary fibrosis. Approximately 1 % of patients treated died because of

pulmonary fibrosis. Frequent chest X-rays (preferably weekly) are advisable and

should be continued for up to 4 weeks after completion of a course of treatment.

Pulmonary toxicity of Bleomycin is both dose-related and age-related when

the total dose exceeds 400 units (USP) (approximately 225 units/m² body

surface) this may also occur when lower doses are administered, especially in

elderly patients (over 70 years of age), patients with reduced kidney function,

pre-existing lung disease, previous or concurrent radiotherapy to the chest and

in patients who need administration of oxygen. It is significantly enhanced by

thoracic radiation and by hyperoxia used during surgical anesthesia. Pulmonary

toxicity is unpredictable and has been seen occasionally in young patients

receiving low doses. Vascular changes occur in the lung, partly destroying

the elasticity of the walls of the vessel. The earliest symptom associated with

pulmonary toxicity of Bleomycin is dyspnea. Fine rales are the earliest sign.

If pulmonary changes are noted, treatment should be discontinued until it can

be determined if they are drug related. Patients should be treated with broad

spectrum antibiotics and corticosteroids.

Bleomycin sensitivity increases in old age. If breathlessness or lung infiltrates

appear, not obviously attributable to tumor or to co-existent lung disease,

administration of the drug must be stopped immediately and patients should be

treated with corticosteroid and broad-spectrum antibiotics.

Pyrexia

Like most cytotoxic agents Bleomycin can cause immediate and delayed toxic

effects. The most immediate effect is fever on the day of injection. It sometimes

occurs 2 to 6 hours after the first injection of Bleomycin. In cases of persistent

severe pyrexia it may be necessary to give antipyretics. The incidence of pyrexia

decreases with subsequent injections.

Skin and mucous changes

In the event of cutaneous side effects in patients with AIDS, Bleomycin

treatment should be stopped and should not be resumed.

Induration, edema, hyperkeratosis, nail changes, bulla formation over pressure

points such as elbows, alopecia and stomatitis may occur during treatment with

Bleomycin.

These side effects are rarely serious and usually disappear after completion

of treatment. Mucosal ulceration seems to be aggravated when Bleomycin

is combined with irradiation or other drugs toxic to mucous membranes. Skin

toxicity is a relatively late manifestation correlating with the cumulative doses,

usually developing in the 2nd and 3rd week of treatment after administration of

150 to 200 units (USP) of Bleomycin.

Idiosyncratic reactions

An idiosyncratic reaction, clinically similar to anaphylaxis, has been reported

in approximately 1% of the lymphoma patients treated with Bleomycin. The

reaction may be immediate or delayed for several hours, and usually occurs

after the first or second dose. It consists of hypotension, mental confusion, fever,

chills, and wheezing. Treatment is symptomatic, including volume expansion,

pressor agents, antihistamines, and corticosteroids.

Hypersensitivity

Because of the possibility of an anaphylactoid reaction (reported in 1 % of

lymphoma patients) patients should receive initially a test dose of 1 -2 units

(USP) in total. If no acute reaction occurs the regular dosage regimen can be

administered.

Gastrointestinal

Gastrointestinal side effects such as nausea and vomiting may occur but are

more often seen in high-dose schedules. Antiemetic drugs may be of help.

Anorexia and weight loss are common and may persist for a long time after

termination of the treatment.

Others

Vascular toxicities have been reported rarely. The events are clinically

heterogeneous and may include myocardial infarction, cerebrovascular

accident, thrombotic microangiopathies like hemolytic-uremic-syndrome and

cerebral arteritis.

Like other cytotoxic agents, Bleomycin may induce tumor lysis syndrome

in patients with rapidly growing tumors. Adequate supporting treatment and

pharmacological measures may prevent or relieve such complications.

4.5

Interactions

with

other

medicinal

products

and

other

forms

of

interaction

When Bleomycin is used as one of the drugs in multiple chemotherapy

regimens the toxicity of Bleomycin should be borne in mind in the selection

and dosage of drugs with a similar toxic potential.

An increased risk of pulmonary toxicity has been described with concomitant

use of BCNU, mitomycin-C, cyclophosphamide, methotrexate and gemcitabine.

Previous or concurrent radiotherapy to the chest is an important factor in

increasing the incidence and severity of lung toxicity.

Because of the potential of Bleomycin to sensitize the lung tissue, the risk

of developing pulmonary toxicity is increased in patients who have received

Bleomycin when oxygen is being administered at surgery. A reduction in inspired

oxygen during operation and post operatively is therefore recommended.

In patients treated for testicular cancer with a combination of Bleomycin

and vinca alkaloids a syndrome has been reported corresponding to morbus

Raynaud, ischemia which may lead to necrosis of the peripheral parts of the

body (fingers, toes, nose tip).

In patients treated with a triple combination regimen of cisplatin, vinblastine

and Bleomycin, a positive correlation between GFR (glomerular filtration rate)

and pulmonary function was observed. Therefore, Bleomycin should be used

cautiously in patients with severely impaired renal function. Another study

showed that an increase of the cisplatin dose was associated with a decrease

of the creatinine clearance and the Bleomycin elimination.

The increase in neutrophil counts and the stimulation of the ability to produce

superoxide radicals after the use of granulocyte-colony stimulating factor may

potentiate lung injury.

The rate and extent of absorption of oral acetyldigoxin and of phenytoin could

be reduced by Bleomycin treatments.

4.6 Use during pregnancy and lactation

Animal

experiments

have

revealed

that

Bleomycin

teratogenic

carcinogenic potential.

The use of Bleomycin should be avoided whenever possible during pregnancy

particularly during the first trimester.

In a vital indication during the first trimester of pregnancy a medical consultation

regarding abortion is absolutely necessary.

After the first trimester of pregnancy, if therapy can not be delayed and the patient

wishes to continue with her pregnancy, chemotherapy may be undertaken after

informing the patient of the minor but possible risk of teratogenic effects.

Bleomycin should not be given to mothers who are breast feeding.

Contraceptive measures:

Bleomycin

cause

congenital

anomalities.

Conception

during

months

after

treatment

advisable.

Women

should

become

pregnant

during

months

after

treatment.

4.7 Effects on ability to drive and use machines

Potential side effects of the chemotherapy with Bleomycin, like nausea and

vomiting may indirectly impair the patient’s ability to drive or to use machines.

4.8 Undesirable Effects

NEOPLASMS, BENIGN AND MALIGNANT AND UNSPECIFIED (INCLUDING

CYSTS AND POLYPS): Tumor pain, Tumor lysis syndrome

BLOOD AND LYMPHATIC SYSTEM DISORDERS:

Febrile

neutropenia,

Neutropenia,

Thrombocytopenia,

Hemolytic

uremic

syndrome, Thrombotic microangiopathy, Granulocytopenia, Leukopenia

METABOLISM AND NUTRITION DISORDERS:

Anorexia

PSYCHIATRIC DISORDERS:

Confusional state

NERVOUS SYSTEM DISORDERS:

Cerebral arteritis, Cerebrovascular accident

CARDIAC DISORDERS:

Myocardial infarction, Pericarditis

VASCULAR DISORDERS:

Hypotension, Phlebitis, Raynaud’s phenomenon, Thrombophlebitis, Arterial

thrombosis, deep vein thrombosis.

RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS:

Respiratory failure, pulmonary embolism, Dyspnoea, Interstitial lung disease,

Pulmonary fibrosis, Pulmonary toxicity, Rales, Wheezing, Acute respiratory

distress syndrome.

GASTROINTESTINAL DISORDERS:

Nausea, Stomatitis, Vomiting

SKIN

SUBCUTANEOUS

TISSUE

DISORDERS:

Alopecia,

Blister,

Erythema, Hyperkeratosis, Nail disorder, Pruritis, Rash, Rash vesicular, Skin

hyperpigmentation, Skin striae, Skin toxicity, Dermatitis, Drug eruption.

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS:

Arthralgia, Myalgia, Scleroderma

GENERAL DISORDERS AND ADMINISTRATIVE SITE CONDITIONS:

Chest pain, Chills, Induration, Injection site pain, Local reaction, Mucosal

inflammation,

Mucosal

ulceration,

Oedema,

Oedema

peripheral,

Pyrexia,

Tenderness, Idiosyncratic drug reaction

4.9 Overdose

Observations indicate that it is difficult to eliminate Bleomycin from the body

by dialysis.The acute reaction following an overdosage of Bleomycin would

probably include hypotension, fever, rapid pulse and general symptoms of

shock. Treatment is purely symptomatic. In the event of respiratory problems the

patient should be treated with a corticosteroid and a broad-spectrum antibiotic.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ATC-code: L 01 DC 01

Bleomycin is a mixture of basic, water-soluble glucopeptide-antibiotics with

cytotoxic activity. Bleomycin acts by intercalating with both single and double-

stranded DNA (deoxyribonucleic acid) resulting in both single and double-strand

scission, leading to inhibition of cell division, of growth and of DNA synthesis; to

a lesser degree Bleomycin may influence RNA (ribonucleic acid) and protein

synthesis.

The most important factor in the tissue selectivity of Bleomycin is the difference

in intracellular inactivation. Squamous cells, with their low content of Bleomycin

hydrolase, have a high susceptibility for Bleomycin. In sensitive tissues, both

normal

neoplastic,

chromosome

aberrations

such

fragmentation,

chromatide breaks, and translocations appear to be regularly produced.

Bleomycin is pyrogenic.

Bleomycin causes little or no bone-marrow toxicity and no immunosuppression.

Bleomycin can be used alone, in combination with radiotherapy and together

with other cytotoxic drugs.

5.2 Pharmacokinetic properties

Absorption

Bleomycin is administered parenterally. After intravenous administration of a

bolus dose of 15 units (USP)/m² body surface peak concentrations of 1 to 10 mU/

ml are achieved in plasma. Following the i.m. injection of 15 units peak plasma

concentrations of about 1 mU/ml are achieved after 30 minutes. Continuous

infusion of 30 units (USP) of Bleomycin daily for 4 to 5 days resulted in an

average steady state plasma concentration of 100-300 µU/ml.

Distribution

Bleomycin is rapidly distributed to body tissues with highest concentrations in

skin, lungs, peritoneum and lymphatic tissue. Low concentrations are seen in

the bone marrow.

Bleomycin could not be detected in cerebrospinal fluid after intravenous

injection. Bleomycin appears to cross the placental barrier. The apparent

volume of distribution (Vd)ß is about 0.27+0.09 L/kg. Bleomycin is bound to

plasma proteins only to a slight extent.

Biotransformation

The biotransformation of Bleomycin is not fully mapped out. Inactivation takes

place during enzymatic break down by Bleomycin hydrolase which is localized

primarily in plasma, liver, spleen, intestine and bone marrow and to a much

lesser extent in skin and lungs.

Elimination

The elimination half-life (T ½ ß) of Bleomycin is about 3 hours. After continuous

i.v. infusion the elimination half-life may be increased to about 9 hours. The

systemic plasma clearance (Cls) is about 1.1 ml/min x kg. About two thirds of the

administered drug is excreted unchanged in the urine, probably by glomerular

filtration. Approximately 50 % is recovered in the urine in 24 hours after an i.v.

or i.m. injection. Therefore, the rate of excretion is highly influenced by renal

function; concentrations in plasma are significantly elevated if usual doses are

given to patients with renal impairment with only up to 20 % excreted in 24

hours. Observations indicate that it is difficult to eliminate Bleomycin from the

body by dialysis.

5.3 Preclinical safety data

Animal

experiences

have

revealed

that

Bleomycin

teratogenic

carcinogenic potential.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

None.

6.2 Incompatibilities

Bleomycin solution should not be mixed with solutions of essential amino

acids, aminophylline, ascorbic acid, benzylpenicilline, carbenicilline, cefalotine,

cefalozine,

dexamethasone,

diazepam,

glutathione,

hydrogen

superoxide,

hydrocortisone-Na -succinate, methotrexate, mitomycin, nafcilline, penicilline

G, riboflavin, substances containing sulfhydryl groups, terbutaline, or thiols.

6.3 Shelf life

42 months (3,5 years).

6.4 Special precautions for storage

Store at 2 -8°C. Keep in the carton.

6.5 Nature and contents of container

Packs with 1 or 10 vials each containing Bleomycin sulphate equivalent to 15

units (USP).

6.6 Instructions for use/handling

The general guidelines for safe handling of cytotoxic drugs should be followed.

Precautions should be taken to avoid contact with skin, mucous membranes

or eyes. In the event of contamination the affected parts should be washed

thoroughly with water. Urine produced for up to 72 hours after a dose of

Bleomycin should be handled by wearing protective clothing

7. DATE OF (PARTIAL) REVISION OF THE TEXT June 2010

8. MANUFACTURER

Baxter Oncology GmbH, Germany

9. REGISTRATION HOLDER

MegaPharm Ltd., P.O. Box 519, Hod Ha`Sharon 45105

The format of this leaflet was determined by the Ministry of Health and its

content was checked and approved in February 2011

BLESPC 112010 P.2