BICALUTAMIDE

Main information

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

Documents

Localization

  • Available in:
  • BICALUTAMIDE Film Coated Tablet 50 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0585/033/001
  • Authorization date:
  • 14-11-2008
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0585/033/001

CaseNo:2041277

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

PlivaPharmaLimited

VisionHouse,BedfordRoad,Petersfield,HampshireGU323QB,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Bicalutamide50mgFilm-CoatedTablets

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom14/11/2008until13/11/2013.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

Irish Medicines Board

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Date Printed 18/11/2008 CRN 2041277 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Bicalutamide50mgFilm-CoatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains50mgofbicalutamide

Excipients:

Eachtabletcontains1.04mgoflactose(aslactosemonohydrate)

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet

Whiteoralmostwhiteround,biconvex,film-coatedtablet,imprintedwith‘BC’ononesideand‘50’ontheotherside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofadvancedprostatecancerincombinationwithluteinisinghormone-releasinghormone(LHRH)analogue

therapyorsurgicalcastration.

4.2Posologyandmethodofadministration

Adultmalesincludingtheelderly:onetablet(50mg)tobetakenorallyonceaday.

Route:oral

Thetabletsshouldbeswallowedwholewithliquid.

Treatmentwithbicalutamideshouldbestartedatleast3daysbeforecommencingtreatmentwithanLHRHanalogue,

oratthesametimeassurgicalcastration.

Childrenandadolescents:Bicalutamideisnotindicatedinchildrenandadolescents.

Renalimpairment:nodoseadjustmentisnecessaryforpatientswithrenalimpairment.Thereisnoexperiencewiththe

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

Hepaticimpairment:nodoseadjustmentisnecessaryforpatientswithmildhepaticimpairment.Themedicinalproduct

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4.3Contraindications

Hypersensitivitytobicalutamideoranyoftheexcipients.

Bicalutamideiscontraindicatedinwomenandchildren.

Co-administrationofterfenadine,astemizoleorcisapridewithbicalutamideiscontraindicated(seesection4.5).

4.4Specialwarningsandprecautionsforuse

Bicalutamideismetabolisedintheliver.Researchresultssuggestthatbicalutamide’seliminationmaybeslowerin

patientswithseverehepaticimpairmentandthiscouldleadtoincreasedaccumulationofbicalutamide.Therefore,

bicalutamideshouldbeusedwithcautioninpatientswithmoderatetoseverehepaticimpairment.

Severehepaticdamageshavebeenrarelyobservedwithbicalutamide(seesection4.8).Bicalutamidetherapyshouldbe

discontinuedifchangesaresevere.

Periodicliverfunctiontestingiswarrantedinordertofindoutaboutpossiblehepaticchanges.Themajorityofchanges

areexpectedtooccurwithinthefirst6monthsofbicalutamidetherapy.

Asthereisnoexperiencewiththeuseofbicalutamideinpatientswithsevererenalimpairment(creatinineclearance<

30ml/min),bicalutamideshouldonlybeusedwithcautioninthesepatients.

Periodicalmonitoringofcardiacfunctionisadvisableinpatientswithheartdisease.

Initiationoftreatmentshouldbeunderthedirectsupervisionofaspecialistandsubsequentlypatientsshouldbekept

underregularsurveillance.

Theproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactase

deficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

NopharmacodynamicorpharmacokineticinteractionshavebeendemonstratedbetweenbicalutamideandLHRH

analogues.

InvitrostudieshaveshownthatR-enantiomerofbicalutamideisaninhibitorofCYP3A4,withlesserinhibitoryeffects

onCYP2C9,2C19and2D6activity.

Althoughinvitrostudieshaveindicatedthepossibilityofbicalutamideinhibitingcytochrome3A4,anumberof

clinicalstudiesshowthatthescaleofthisinhibitionformostdrugsmetabolisedbycytochromeP450isprobablynot

clinicallysignificant.

Nonetheless,fordrugswithanarrowtherapeuticindexmetabolisedintheliver,theCYP3A4inhibitioncausedby

bicalutamidecouldbeofrelevance.Assuch,concomitantuseofterfenadine,astemizoleandcisaprideis

contraindicated.Cautionshouldbeexercisedwiththeco-administrationofbicalutamidewithcompoundssuchas

ciclosporinandcalciumchannelblockers.Dosagereductionmayberequiredforthesedrugsparticularlyifthereis

evidenceofenhancedoradversedrugeffect.Forciclosporin,itisrecommendedthatplasmaconcentrationsandclinical

conditionarecloselymonitoredfollowinginitiationorcessationofbicalutamidetherapy.

Cautionshouldbeexercisedwhenadministeringbicalutamidetopatientstakingmedicinalproductsthatinhibitthe

oxidationprocessinthelivere.g.cimetidineandketoconazole.Thiscouldresultinincreasedplasmaconcentrationsof

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Invitrostudieshaveshownthatbicalutamidecandisplacethecoumarinanticoagulant,warfarin,fromitsprotein

bindingsites.Itisthereforerecommendedthatprothrombintimeiscloselymonitoredifbicalutamideisstartedin

patientswhoarealreadyreceivingcoumarinanticoagulants.

4.6Pregnancyandlactation

Notapplicable,sincethismedicinalproductisnotusedinwomen.

Fertility

Reversibleimpairmentofmalefertilityhasbeenobservedinanimalstudies(seesection5.3).Aperiodofsubfertilityor

infertilityshouldbeassumedinman.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.

However,itshouldbenotedthatoccasionallydizzinessandsomnolencemayoccur(seesection4.8).Anyaffected

patientsshouldexercisecaution.

4.8Undesirableeffects

Adverseeventsobservedwithbicalutamideareclassifiedinbodysystemsandlistedbelowas:

Verycommon( ≥1/10)

Common( ≥1/100to<1/10)

Uncommon( ≥1/1000to<1/100)

Rare( ≥1/10000to<1/1000)

Veryrare(<1/10000),notknown(cannotbeestimatedfromtheavailabledata).

Immunesystemdisorders

Uncommon:Hypersensitivityreactions,includingangio-oedemaandurticaria

Psychiatricdisorders

Uncommon:Depression

Respiratory,thoracicandmediastinaldisorders

Uncommon:Interstitiallungdisease

Gastrointestinaldisorders

Common:Diarrhoea,nausea

Rare:Vomiting

Hepatobiliarydisorders

Common:Hepaticchanges(elevatedlevelsoftransaminases,cholestasisandjaundice) 1

Veryrare:Hepaticfailure 2

Skinandsubcutaneoustissuedisorders

Common:Pruritus

Rare:Dryskin

Renalandurinarydisorders

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Reproductivesystemandbreastdisorders

Verycommon:Breasttenderness 3

,gynaecomastia 3

Generaldisordersandadministrationsiteconditions

Verycommon:Hotflushes 3

Common:Asthenia

Hepaticchangesarerarelysevereandwerefrequentlytransient,resolvingorimprovingwithcontinuedtherapyor

followingcessationoftherapy(seesection4.4).

Hepaticfailurehasoccurredveryrarelyinpatientstreatedwithbicalutamide,butacasualrelationshiphasnotbeen

establishedwithcertainty.Periodicliverfunctiontestingshouldbeconsidered(seealsosection4.4).

Maybereducedbyconcomitantcastration.

Inaddition,thefollowingadverseexperienceswerereportedinclinicaltrialsduringtreatmentwithbicalutamide

with/withoutaLHRHanalogue:

Bloodandlymphaticsystemdisorders

Common:Anaemia

Veryrare:Thrombocytopenia

Metabolismandnutritiondisorders

Common:Diabetesmellitus,weightgain

Uncommon:Anorexia,hyperglycaemia,weightloss

Nervoussystemdisorders

Common:Dizziness,insomnia

Uncommon:Somnolence

Cardiacdisorders

Veryrare:Heartfailure,angina,conductiondefectsincludingPRandQTintervalprolongations,arrhythmiasandnon-

specificECGchanges

Respiratory,thoracicandmediastinaldisorders

Uncommon:Dyspnoea

Gastrointestinaldisorders

Common:Constipation

Uncommon:Drymouth,dyspepsia,flatulence

Skinandsubcutaneoustissuedisorders

Common:Rash,sweating,hirsutism

Uncommon:Alopecia

Renalandurinarydisorders

Uncommon:Nocturia

Reproductivesystemandbreastdisorders

Verycommon:Decreasedlibido,erectiledysfunction,impotence

Generaldisordersandadministrationsiteconditions

Common:Oedema,generalpain,pelvicpain,chills

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4.9Overdose

Nocaseofoverdosehasbeenreported.Sincebicalutamidebelongstotheanilidecompoundsthereisatheoreticalrisk

ofthedevelopmentofmethaemoglobinaemia.Methaemoglobinaemiahasbeenobservedinanimalsafteranoverdose.

Accordingly,apatientwithanacuteintoxicationcanbecyanotic.Thereisnospecificantidote;treatmentshouldbe

symptomatic.Dialysisisunlikelytobehelpful,sincebicalutamideishighlyproteinboundandisnotrecovered

unchangedintheurine.Generalsupportivecare,includingfrequentmonitoringofvitalsigns,isindicated.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Anti-androgens,ATCCode:L02BB03

Bicalutamideisanon-steroidalantiandrogen,devoidofotherendocrineactivity.Itbindstoandrogenreceptorswithout

activatinggeneexpression,andthusinhibitstheandrogenstimulus.Regressionofprostatictumoursresultsfromthis

inhibition.Clinically,discontinuationofbicalutamidecanresultinantiandrogenwithdrawalsyndromeinasubsetof

patients.

Bicalutamideisaracematewithitsantiandrogenicactivitybeingalmostexclusivelyinthe(R)-enantiomer.

5.2Pharmacokineticproperties

Bicalutamideiswellabsorbedfollowingoraladministration.Thereisnoevidenceofanyclinicallyrelevanteffectof

foodonbioavailability.

The(S)-enantiomerisrapidlyclearedrelativetothe(R)-enantiomer,thelatterhavingaplasmaeliminationhalf-lifeof

about1week.

Followingalong-termadministrationofbicalutamide,thepeakconcentrationofthe(R)-enantiomerintheplasmais

about10fold,ascomparedtothelevelsmeasuredafterasingledoseof50mgbicalutamide.

Adosingschemeof50mgbicalutamidedailywillresultinasteady-stateconcentrationoftheR-enantiomerof9µg/ml

andasaconsequenceofitslonghalf-life,steadystateisreachedafterapproximately1monthoftherapy.

Thepharmacokineticsofthe(R)-enantiomerareunaffectedbyage,renalimpairmentormildtomoderatehepatic

impairment.Thereisevidencethatthe(R)-enantiomerismoreslowlyeliminatedfromplasmainpatientswithsevere

hepaticimpairment.

Bicalutamideishighlyproteinbound(racemate96%,(R)-enantiomer>99%)andextensivelymetabolised(by

oxidationandglucuronidation):Itsmetabolitesareeliminatedviathekidneysandbileinapproximatelyequal

proportions.

5.3Preclinicalsafetydata

Bicalutamideisapureandpotentandrogenreceptorantagonistinexperimentalanimalsandhumans.Themain

secondarypharmacologicalactionisinductionofCYP450dependentmixedfunctionoxidasesintheliver.Enzyme

inductionhasnotbeenobservedinhumans.Targetorganchangesinanimalsareclearlyrelatedtotheprimaryand

secondarypharmacologicalactionofbicalutamide.Thesecompriseinvolutionofandrogen-dependenttissues;thyroid

follicularadenomas,hepaticandLeydigcellhyperplasiasandneoplasiasorcancer;disturbanceofmaleoffspring

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Atrophyofseminiferoustubulesisapredictedclasseffectwithantiandrogensandhasbeenobservedforallspecies

examined.Fullreversaloftesticularatrophywas24weeksaftera12-monthrepeateddosetoxicitystudyinrats,

althoughfunctionalreversalwasevidentinreproductionstudies7weeksaftertheendofan11weekdosingperiod.A

periodofsubfertilityorinfertilityshouldbeassumedinman.

Genotoxicitystudiesdidnotrevealanymutagenicpotentialofbicalutamide.

Alladverseeffectsobservedinanimalstudiesareconsideredtohavenorelevancetothetreatmentofpatientswith

advancedprostatecancer.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

Cellulose,Microcrystalline

Povidone

Sodiumlaurilsulfate

Croscarmellosesodium

Sodiumstarchglycolate(TypeC)

Magnesiumstearate

Coating:

OpadryII31F58914white

Contains HypromelloseE464

Lactosemonohydrate

TitaniumdioxideE171

Macrogol4000

SodiumcitratedihydrateE331(c)

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

2years

6.4Specialprecautionsforstorage

Storebelow30°C.

6.5Natureandcontentsofcontainer

PVC//Aluminiumblister

Packsizes: 28,30,40,90

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6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements

7MARKETINGAUTHORISATIONHOLDER

PlivaPharmaLimited.

VisionHouse

BedfordRoad

Petersfield

Hampshire

GU323QB

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA585/33/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:14 th

November2008

Irish Medicines Board

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