BICALUTAMIDE AVANSOR 50MG FILM-COATED TABLETS 50 Milligram Film Coated Tablet

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
BICALUTAMIDE
Available from:
Avansor Pharma Oy
INN (International Name):
BICALUTAMIDE
Dosage:
50 Milligram
Pharmaceutical form:
Film Coated Tablet
Prescription type:
Product subject to prescription which may not be renewed (A)
Authorization status:
Authorised
Authorization number:
PA1375/001/001
Authorization date:
0000-00-00

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

BicalutamideAvansor50mgFilm-CoatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains50mgofbicalutamide

Excipientswithknowneffect:eachtabletcontains60.44mglactosemonohydrate

Forthefulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

White,round,biconvex,film-coatedtablet,debossedwithBCM50ononeside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofadvancedprostatecancerincombinationwithluteinisinghormone-releasinghormone(LHRH)analogue

therapyorsurgicalcastration.

4.2Posologyandmethodofadministration

Adultmales,includingelderlypatients:thedosageisone50mgtablettobetakenorallyonceaday.

Childrenandadolescents

Bicalutamideisnotindicatedinchildrenandadolescents.

Thetabletsshouldbeswallowedwholewithliquid.

Treatmentwithbicalutamideshouldbestartedatleast3daysbeforecommencingtreatmentwithanLHRHanalogue,

oratthesametimeassurgicalcastration.

Renalimpairment

Nodoseadjustmentisnecessaryinpatientswithrenalimpairment.Thereisnoexperiencewiththeuseofbicalutamide

inpatientswithsevererenalimpairment(creatinineclearance<30ml/min)(seesection4.4).

Hepaticimpairment

Nodoseadjustmentisnecessaryforpatientswithmildhepaticimpairment.Themedicinalproductmayaccumulatein

patientswithmoderatetoseverehepaticimpairment(seesection4.4.).

4.3Contraindications

Bicalutamideiscontraindicatedinfemalesandchildren(seesection4.6).

Bicalutamidemustnotbegiventoanypatientwhohasshownahypersensitivityreactiontotheactivesubstanceorto

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Co-administrationofterfenadine,astemizoleorcisapridewithBicalutamideiscontraindicated(seesection4.5).

4.4Specialwarningsandprecautionsforuse

Initiationoftreatmentshouldbeunderthedirectsupervisionofaspecialist.

Bicalutamideisextensivelymetabolisedintheliver.Datasuggeststhatitseliminationmaybeslowerinsubjectswith

severehepaticimpairmentandthiscouldleadtoincreasedaccumulationofbicalutamide.Therefore,bicalutamide

shouldbeusedwithcautioninpatientswithmoderatetoseverehepaticimpairment.

Periodicliverfunctiontestingshouldbeconsideredduetothepossibilityofhepaticchanges.Themajorityofchanges

areexpectedtooccurwithinthefirst6monthsofbicalutamidetherapy.

Severehepaticchangesandhepaticfailurehavebeenobservedrarelywithbicalutamideandfataloutcomeshavebeen

reported(seesection4.8).Bicalutamidetherapyshouldbediscontinuedifchangesaresevere.

AreductioninglucosetolerancehasbeenobservedinmalesreceivingLHRHagonists.Thismaymanifestasdiabetes

orlossofglycaemiccontrolinthosewithpre-existingdiabetes.Considerationshouldthereforebegiventomonitoring

bloodglucoseinpatientsreceivingbicalutamideincombinationwithLHRHagonists.

BicalutamidehasbeenshowntoinhibitCytochromeP450(CYP3A4),assuchcautionshouldbeexercisedwhenco-

administeredwithdrugsmetabolisedpredominantlybyCYP3A4,(seesections4.3and4.5).

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

malabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

ThereisnoevidenceofanypharmacodynamicorpharmacokineticinteractionsbetweenbicalutamideandLHRH

analogues.

InvitrostudieshaveshownthattheR-enantiomerofbicalutamideisaninhibitorofCYP3A4withlesserinhibitory

effectsonCYP2C9,2C19and2D6activity.

AlthoughclinicalstudiesusingantipyrineasamarkerofcytochromeP450(CYP)activityshowednoevidenceofa

druginteractionpotentialwithbicalutamide,meanmidazolamexposure(AUC)wasincreasedbyupto80%,afterco-

administrationofbicalutamidefor28days.Fordrugswithanarrowtherapeuticindexsuchanincreasecouldbeof

relevance.Assuch,concomitantuseofterfenadine,astemizoleandcisaprideiscontraindicated(seesection4.3)and

cautionshouldbeexercisedwiththeco-administrationofbicalutamidewithcompoundssuchasciclosporinand

calciumchannelblockers.Dosagereductionmayberequiredforthesedrugsparticularlyifthereisevidenceof

enhancedoradversedrugeffect.Forciclosporin,itisrecommendedthatplasmaconcentrationsandclinicalcondition

arecloselymonitoredfollowinginitiationorcessationofbicalutamidetherapy.

Cautionshouldbeexercisedwhenprescribingbicalutamidewithotherdrugswhichmayinhibitdrugoxidatione.g.

cimetidineandketoconazole.Intheory,thiscouldresultinincreasedplasmaconcentrationsofbicalutamidewhich

theoreticallycouldleadtoanincreaseinsideeffects.

Invitrostudieshaveshownthatbicalutamidecandisplacethecoumarinanticoagulant,warfarin,fromitsprotein

bindingsite.Itisthereforerecommendedthatifbicalutamideisstartedinpatientswhoarealreadyreceivingcoumarin

anticoagulants,prothrombintimeshouldbecloselymonitored.

4.6Fertility,pregnancyandlactation

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4.7Effectsonabilitytodriveandusemachines

Bicalutamideisunlikelytoimpairtheabilityofpatientstodriveoroperatemachinery.However,itshouldbenoted

thatoccasionallysomnolencemayoccur.Anyaffectedpatientsshouldexercisecaution.

4.8Undesirableeffects

Inthissectionundesirableeffectsaredefinedasfollows:Verycommon(1/10);common(1/100to<1/10);

uncommon(1/1,000to1/100);rare(1/10,000to1/1,000);veryrare(1/10,000),notknown(cannotbeestimated

formtheavailabledata).

Table1:frequencyofadversereactions

SystemOrgan

Class Frequency Bicalutamide50mg

(+LHRHanalogue)

Bloodand

lymphatic

system

disorders Very

common Anaemia

Immunesystem

disorders Uncommon Hypersensitivity,

angioedema,and

urticaria

Metabolismand

nutrition

disorders Common Decreasedappetite

Psychiatric

disorders Common Decreasedlibido,

Depression

Cardiac

disorders Common Myocardialinfarction

(fataloutcomeshave

beenreported) a

,Cardiac

failure a

NervousSystem

Disorders Very

common Dizziness

Common Somnolence

Vascular

disorders Very

common Hotflush

Respiratory,

thoracicand

mediastinal

disorders Uncommon

Interstitiallungdisease b

(fataloutcomeshave

beenreported)

Gastrointestinal

disorders Very

common Abdominalpain,

Constipation,Nausea

Common Dyspepsia,Flatulence

Hepato-biliary

disorders Common Hepatotoxicitiy,

jaundice,

hypertransaminasaemia c

Rare

Hepaticfailure d

(fatal

outcomeshavebeen

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Observedinapharmaco-epidemiologystudyofLHRHagonistsandanti-androgensusedinthetreatmentofprostatecancer.Therisk

appearedtobeincreasedwhenBicalutamide50mgwasusedincombinationwithLHRHagonists,butnoincreaseinriskwasevident

whenBicalutamide150mgwasusedasamonotherapytotreatprostatecancer.

Listedasanadversedrugreactionfollowingreviewofpost-marketeddata.Frequencyhasbeendeterminedfromtheincidenceof

reportedadverseeventsofinterstitialpneumoniaintherandomisedtreatmentperiodofthe150mgEPCstudies.

Hepaticchangesarerarelysevereandwerefrequentlytransient,resolvingorimprovingwithcontinuedtherapyorfollowingcessation

oftherapy.

Listedasanadversedrugreactionfollowingreviewofpost-marketeddata.Frequencyhasbeendeterminedfromtheincidenceof

reportedadverseeventsofhepaticfailureinpatientsreceivingtreatmentintheopen-labelBicalutamidearmofthe150mgEPC

studies.

Maybereducedbyconcomitantcastration.

4.9Overdose

Thereisnohumanexperienceofoverdosage.Thereisnospecificantidote;treatmentshouldbesymptomatic.Dialysis

maynotbehelpful,sincebicalutamideishighlyproteinboundandisnotrecoveredunchangedintheurine.General

supportivecare,includingfrequentmonitoringofvitalsigns,isindicated.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:anti-androgens,ATC-code:L02BB03

Bicalutamideisanon-steroidanti-androgen;ithasnoadditionalendocrineactivity.Itisboundtoandrogenreceptors

withoutactivatinggeneexpressionandtherebyinhibitsandrogenstimulation.Theresultofthisinhibitionisregression

ofprostatetumours.Fromtheclinicalpointofviewinterruptionoftherapyinsomepatientscouldresultin

manifestationoftheanti-androgenwithdrawalsyndrome.

Bicalutamideisaracematewithananti-androgeneffect,whichispresentalmostexclusivelyinitsR-enantiomer.

5.2Pharmacokineticproperties

Bicalutamideiswellabsorbedfollowingoraladministration.Thereisnoevidenceofanyclinicallyrelevanteffectof

Skinand

subcutaneous

tissuedisorders Common Alopecia,Hirsuitism/

hairre-growth,Dryskin,

Pruritis,Rash

Renaland

urinary

disorders Very

common Haematuria

Reproductive

systemand

breastdisorders Very

common Gynaecomastiaand

breasttenderness e

Common Erectiledysfunction

General

disordersand

administration

siteconditions Very

common

Common Asthenia,Oedema

Chestpain

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S-enantiomerisrapidlyclearedincomparisontotheR-enantiomer,whichhalf-lifeofplasmateliminationis

approximately1week.

WithregulardailyadministrationofbicalutamidetheconcentrationoftheR-enantiomerinplasmaincomparisonwith

S-enantiomerisapproximatelyten-fold,whichiscausedbyitslengthyeliminationhalf-life.

TheplasmaconcentrationsofR-enantiomerreachapproximately9microgram/mlinthecaseofadailydoseof50mg

ofbicalutamide.Fromthetotalnumberofenantiomerspresentinplasmainthesteadystatethereis99%ofR-

enantiomer,whichhasadominantshareinthetherapeuticeffect.

PharmacokineticsofR-enantiomerarenotaffectedbyage,renalimpairmentormildtomoderatehepaticimpairment.It

hasbeenshownthatinpatientswithsevereliverimpairmenttheR-enantiomeriseliminatedslowerfromplasma.

Bicalutamideishighlyproteinbound(racemate96%,R-Bicalutamide99.6%)andisextensivelymetabolised(by

oxidationandglucuronidation):itsmetabolitesareeliminatedviathekidneysandbileinapproximatelyequal

proportions.Afterexcretingtobile,hydrolysisofglucuronidesoccurs.

5.3Preclinicalsafetydata

Bicalutamideisapureandpotentandrogenreceptorantagonistinexperimentalanimalsandhumans.Themain

secondarypharmacologicalactionisinductionofCYP450dependentmixedfunctionoxidasesinliver.Enzyme

inductionhasnotbeenobservedinhumans.Targetorganchangesinanimalsareclearlyrelatedtotheprimaryand

secondarypharmacologicalactionofbicalutamidecomprisedofinvolutionofandrogen-dependenttissues;thyroid

gland,hepaticandLeydigcellhyperplasiasandneoplasiasorcancer;disturbanceofmaleoffspringsexual

differentiation;reversibleimpairmentoffertilityinmales.Genotoxicitystudiesdidnotrevealanymutagenicpotential

ofbicalutamide.Alladverseeffectsobservedinanimalstudiesareconsideredtobespecies-specific,havingno

relevanceforhumansintheindicatedclinicalsetting.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore

Lactosemonohydrate

PovidoneK-29/32

Crospovidone

Sodiumlaurilsulfate

MagnesiumStearate

Coating

Lactosemonohydrate

Hypromellose

Titaniumdioxide(E171)

Macrogol4,000

6.2Incompatibilities

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6.3Shelflife

5years

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

PVC/PE/PVDC/Alblister,box.

Thepackagingcontains5,7,10,14,20,28,30,40,50,56,80,84,90,98,100,140,200,or280film-coatedtablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

AvansorPharmaOy

Tekniikantie14

02150Espoo

Finland

8MARKETINGAUTHORISATIONNUMBER

PA1375/1/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:10 th

August2007

Dateoflastrenewal:31 st

March2006

10DATEOFREVISIONOFTHETEXT

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Date Printed 28/09/2012 CRN 2119558 page number: 6

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