BICALUTAMIDE SYNTHON

Main information

  • Trade name:
  • BICALUTAMIDE SYNTHON
  • Dosage:
  • 50 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • BICALUTAMIDE SYNTHON
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0840/006/001
  • Authorization date:
  • 10-08-2007
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

BicalutamideSynthon50mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains50mgofbicalutamide.

Excipient:eachtabletcontains60.44mglactosemonohydrate

Forafulllistofexcipients,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.

Bicalutamidemustnotbegiventoanypatientwhohasshownahypersensitivityreactiontoitsuse.

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4.4Specialwarningsandprecautionsforuse

Initiationoftreatmentshouldbeunderthedirectsupervisionofaspecialist.

Bicalutamideisextensivelymetabolisedintheliver.Datasuggeststhatitseliminationmaybeslowerinsubjectswith

severehepaticimpairmentandthiscouldleadtoincreasedaccumulationofbicalutamide.Therefore,bicalutamide

shouldbeusedwithcautioninpatientswithmoderatetoseverehepaticimpairment.

Periodicliverfunctiontestingiswarrantedinordertofindoutaboutpossiblehepaticchanges.Themajorityofchanges

areexpectedtooccurwithinthefirst6monthsofbicalutamidetherapy.

Severehepaticdamageshavebeenrarelyobservedwithbicalutamide(seesection4.8).Bicalutamidetherapyshouldbe

discontinuedifchangesaresevere.

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

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4.6Fertility,pregnancyandlactation

Bicalutamideiscontraindicatedinfemalesandmustnotbegiventopregnantwomenornursingmothers.

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

lymphaticsystem

disorders Common Anaemia

Immunesystem

disorders Uncommon Hypersensitivity

reactions(including

angioneuroticoedema

andurticaria)

Metabolismand

nutrition

disorders Common Anorexia

Psychiatric

disorders Common Decreasedlibido,

Depression

NervousSystem

Disorders Verycommon Dizziness

Common Somnolence

Vascular

disorders Verycommon Hotflush

Respiratory,

thoracicand

mediastinal

disorders Uncommon Interstitiallungdisease

Gastrointestinal

disorders Verycommon Abdominalpain,

Constipation,Nausea

Common Dyspepsia,Flatulence

Hepato-biliary

disorders Common Hepaticchanges

(includingelevated

levelsoftransaminases,

jaundice)/hepato-biliary

disorders a

Rare

Hepaticfailure b

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Hepaticchangesarerarelysevereandwerefrequentlytransient,resolvingorimprovingwithcontinuedtherapyorfollowingcessationof

therapy.

Hepaticfailurehasoccurredrarelyinpatientstreatedwithbicalutamide,butacausalrelationshiphasnotbeenestablishediwhtcertainty.

Periodicliverfunctiontestingshouldbeconsidered(seealsosection4.4)

Maybereducedbyconcomitantcastration.

Inaddition,cardiacfailurewasreportedinclinicaltrials(asapossibleadversedrugreactionintheopinionof

investigatingclinicians,withafrequencyof>1%)duringtreatmentwithbicalutamideplusanLHRHanalogue.There

isnoevidenceofacausalrelationshipwithdrugtreatment.

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

foodonbioavailability.

S-enantiomerisrapidlyclearedincomparisontotheR-enantiomer,whichhalf-lifeofplasmateliminationis

subcutaneous

tissuedisorders hairre-growth,Dry

skin,Pruritis,Rash

Renalandurinary

disorders Verycommon Haematuria

Reproductive

systemandbreast

disorders Verycommon Gynaecomastiaand

breasttenderness c

Common Impotence

Generaldisorders

administration

siteconditions Verycommon Asthenia,Chestpain,

Oedema

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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

Notapplicable.

6.3Shelflife

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6.4Specialprecautionsforstorage

Thismedicinalproductrequiresnospecialconditionsforstorage.

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

SynthonBV

Microweg22

6545CMNijmegen

TheNetherlands

8MARKETINGAUTHORISATIONNUMBER

PA840/6/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:10 th

August2007

Dateoflastrenewal:21 st

April2011

10DATEOFREVISIONOFTHETEXT

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