BICALUTAMIDE

Main information

  • Trade name:
  • BICALUTAMIDE Film Coated Tablet 150 Milligram
  • Dosage:
  • 150 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • BICALUTAMIDE Film Coated Tablet 150 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1330/004/002
  • Authorization date:
  • 28-11-2008
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA1330/004/002

CaseNo:2078605

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

GedeonRichterLtd

Gyomroiut19-21,1103Budapest,Hungary

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Bicalutamide150mgFilm-coatedtablets

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom22/02/2010until21/08/2013.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Bicalutamide150mgFilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Onetabletcontains150mgofbicalutamide.

Excipients:Contains193.2mglactosemonohydrate

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

Whiteoralmostwhite,round,biconvexfilm-coatedtablet,withengravedsign"X"ononeside,and"RG"ontheother

side.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Bicalutamide150mgfilm-coatedtabletisindicatedeitheraloneorasadjuvanttoradicalprostatectomyor

radiotherapyinpatientswithlocallyadvancedprostatecancerathighriskfordiseaseprogression(seesection5.1)

4.2Posologyandmethodofadministration

Adultmalesincludingtheelderly

One150mgtabletonceaday.

Route:oral

Thetabletsshouldbeswallowedwholewithliquid.

Bicalutamide150mgshouldbetakencontinuouslyforatleast2yearsoruntildiseaseprogression.

Childrenandadolescents

Bicalutamideisnotindicatedinchildrenandadolescents.

Renalimpairment

Nodoseadjustmentisnecessaryforpatientswithrenalimpairment.Thereisnoexperiencewiththeuseof

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

Hepaticimpairment

Nodoseadjustmentisnecessaryforpatientswithmildhepaticimpairment.

Themedicinalproductmayaccumulateinpatientswithmoderatetoseverehepaticimpairment(seesection4.4).

4.3Contraindications

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Bicalutamideiscontra-indicatedinwomenandchildren.

Co-administrationofterfenadine,astemizoleorcisapridewithbicalutamideiscontra-indicated(seesection4.5).

4.4Specialwarningsandprecautionsforuse

Initiationoftreatmentshouldbeunderthedirectsupervisionofaspecialistandsubsequentlypatientsshouldbekept

underregularsurveillance.

Bicalutamideismetabolisedintheliver.Researchresultssuggestthatbicalutamide’seliminationmaybeslowerin

patientswithseverehepaticimpairmentandthatthiscouldleadtoincreasedaccumulationofbicalutamide.Therefore,

bicalutamideshouldbeusedwithcautioninpatientswithmoderatetoseverehepaticimpairment.

Severehepaticdamageshavebeenrarelyobservedwithbicalutamide(seesection4.8).Bicalutamidetherapyshouldbe

discontinuedifchangesaresevere.

Periodicliverfunctiontesting iswarrantedinordertofindoutaboutpossiblehepaticchanges.Themajorityof

changesareexpectedtooccurwithinthefirst6monthsofbicalutamidetherapy.

Asthereisnoexperiencewiththeuseofbicalutamideinpatientswithsevererenalimpairment(creatinineclearance<

30ml/min),bicalutamideshouldonlybeusedwithcautioninthesepatients.

Periodicalmonitoringofcardiacfunctionisadvisableinpatientswithheartdisease.

ForpatientswhohaveanobjectiveprogressionofdiseasetogetherwithelevatedPSA,cessationofbicalutamide

therapyshouldbeconsidered.

Theproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactase

deficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

InvitrostudieshaveshownthattheR-enantiomerofbicalutamideisaninhibitorofCYP3A4,withlesserinhibitory

effectsonCYP2C9,2C19and2D6activity.Althoughinvitrostudieshaveindicatedthepossibilityofbicalutamide

inhibitingcytochrome3A4,anumberofclinicalstudiesshowthatthescaleofthisinhibitionformostdrugs

metabolisedbycytochromeP450isprobablynotclinicallysignificant.

Nonetheless,fordrugswithanarrowtherapeuticindexmetabolisedintheliver,theCYP3A4inhibitioncausedby

bicalutamidecouldbeofrelevance.Assuch,concomitantuseofterfenadine,astemizoleandcisaprideiscontra-

indicated.

Cautionshouldbeexercisedwiththeco-administrationofbicalutamidewithcompoundssuchascyclosporinand

calciumchannelblockers.Dosagereductionmayberequiredforthesedrugsparticularlyifthereisevidenceof

enhancedoradversedrugeffect.Forcyclosporin,itisrecommendedthatplasmaconcentrationsandclinicalcondition

arecloselymonitoredfollowinginitiationorcessationofbicalutamidetherapy.

Cautionshouldbeexercisedwhenadministeringbicalutamidetopatientstakingmedicinalproductsthatinhibitthe

oxidationprocessesintheliver,e.g.cimetidineandketoconazole.Thiscouldresultinincreasedplasmaconcentrations

ofbicalutamide,whichtheoreticallycouldleadtoanincreaseinsideeffects.

Invitrostudieshaveshownthatbicalutamidecandisplacethecoumarinanticoagulant,warfarin,fromitsprotein

bindingsite.Itisthereforerecommendedthatprothrombintimeiscloselymonitoredifbicalutamideisstartedin

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4.6Pregnancyandlactation

Notapplicable,sincethismedicinalproductisnotusedinwomen.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.However,itshouldbenoted

thatoccasionallydizzinessorsomnolencemayoccur(seesection4.8).Anyaffectedpatientsshouldexercisecaution.

4.8Undesirableeffects

Verycommon( ≥1/10);common(≥1/100to<1/10);uncommon(≥1/1,000to<1/100);rare(≥1/10,000to<1/1,000);

veryrare(<1/10,000),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

Uncommon:Haematuria

Reproductivesystemandbreastdisorders

Verycommon:Breasttenderness 3

,gynaecomastia 3

Generaldisordersandadministrationsiteconditions

Verycommon:Hotflushes 3

Common:Asthenia

Hepaticchangesarerarelysevereandwerefrequentlytransient,resolvingorimprovingwithcontinuedtherapyor

followingcessationoftherapy(seesection4.4).

Hepaticfailurehasoccurredveryrarelyinpatientstreatedwithbicalutamide,butacasualrelationshiphasnotbeen

establishedwithcertainty.Periodicliverfunctiontestingshouldbeconsidered(seealsosection4.4).

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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

Uncommon:Abdominalpain,chestpain,headache,painintheback,neckpain

4.9Overdose

Nocaseofoverdosehasbeenreported.Sincebicalutamidebelongstotheanilidecompoundsthereisatheoreticalrisk

ofthedevelopmentofmethaemoglobinaemia.Methaemoglobinaemiahasbeenobservedinanimalsafteranoverdose.

Accordingly,apatientwithanacuteintoxicationcanbecyanotic.Thereisnospecificantidote;treatmentshouldbe

symptomatic.Dialysisisunlikelytobehelpful,sincebicalutamideishighlyproteinboundandisnotrecovered

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Hormoneantagonistsandrelatedagents,anti-androgens

ATCcode:L02BB03.

Bicalutamideisanon-steroidalantiandrogen,devoidofotherendocrineactivity.Itbindstoandrogenreceptorswithout

activatinggeneexpression,andthusinhibitstheandrogenstimulus.Regressionofprostatictumoursresultsfromthis

inhibition.Clinically,discontinuationofbicalutamidecanresultinantiandrogenwithdrawalsyndromeinasubsetof

patients.

Bicalutamide150mgfilm-coatedtablet(Bicalutamide)wasstudiedasatreatmentforpatientswithlocalised(T1-T2,

N0orNX,M0)orlocallyadvanced(T3-T4,anyN,M0;T1-T2,N+,M0)non-metastaticprostatecancerinacombined

analysisof3placebocontrolleddouble-blindstudiesin8113patients,wherebicalutamidewasgivenasimmediate

hormonaltherapyorasadjuvanttoradicalprostatectomyorradiotherapy,(primarilyexternalbeamradiation).At7.4

yearsmedianfollowup,27.4%and30.7%ofallbicalutamideandplacebo-treatedpatients,respectively,had

experiencedobjectivediseaseprogression.

Areductioninriskofobjectivediseaseprogressionwasseenacrossmostpatientgroupsbutwasmostevidentinthose

athighestriskofdiseaseprogression.Therefore,cliniciansmaydecidethattheoptimummedicalstrategyforapatient

atlowriskofdiseaseprogression,particularlyintheadjuvantsettingfollowingradicalprostatectomy,maybetodefer

hormonaltherapyuntilsignsthatthediseaseisprogressing.

Nooverallsurvivaldifferencewasseenat7.4yearsmedianfollowupwith22.9%mortality(HR=0.99;95%CI0.91

to1.09).However,sometrendswereapparentinexploratorysubgroupanalyses.

Progression-freesurvivalandoverallsurvivaldataforpatientswithlocallyadvanceddiseasearesummarisedinthe

followingtables:

Table1 Progression-freesurvivalinlocallyadvanceddiseasebytherapysub-

group

Analysispopulation Events(%)in

bicalutamidepatients Events(%)in

placebopatients Hazardratio

(95%CI)

Watchfulwaiting 193/335(57.6) 222/322(68.9) 0.60(0.49to0.73)

Radiotherapy 66/161(41.0) 86/144(59.7) 0.56(0.40to0.78)

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Forpatientswithlocaliseddiseasereceivingbicalutamidealone,therewasnosignificantdifferenceinprogressionfree

survival.Inthesepatientstherewasalsoatrendtowarddecreasedsurvivalcomparedwithplacebopatients(HR=1.16;

95%CI0.99to1.37).Inviewofthis,thebenefit-riskprofilefortheuseofbicalutamideisnotconsideredfavourable

inthisgroupofpatients.

5.2Pharmacokineticproperties

Bicalutamideiswellabsorbedfollowingoraladministration.Thereisnoevidenceofanyclinicallyrelevanteffectof

foodonbioavailability.

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

about1week.

Followingalong-termadministrationofbicalutamide,thepeakconcentrationofthe(R)-enantiomerintheplasmais

about10-fold,ascomparedtothelevelsmeasuredafterasingledoseof50mgofbicalutamide.

Adosingschemeof150mgbicalutamidedailywillresultinasteady-stateconcentrationoftheR-enantiomerof22

µg/mlandasaconsequenceofitslonghalf-life,steadystateisreachedafterapproximately1monthoftherapy.

Thepharmacokineticsofthe(R)-enantiomerareunaffectedbyage,renalimpairmentormildtomoderatehepatic

impairment.Thereisevidencethatthe(R)-enantiomerismoreslowlyeliminatedfromplasmainpatientswithsevere

hepaticimpairment.

Bicalutamideishighlyproteinbound(racemateto96%,(R)-enantiomer>99%)andextensivelymetabolised(by

oxidationandglucuronidation).Itsmetabolitesareeliminatedviathekidneysandbileinapproximatelyequal

proportions.

Inclinicalstudythemeanconcentrationof(R)-enantiomerinsemenofmenreceivingbicalutamide150mgwas4.9

µg/ml.Theamountofbicalutamidepotentiallydeliveredtoafemalepartnerduringintercourseislowandequatesto

approximately0.3µg/kg.Thisisbelowthatrequiredtoinducechangesinoffspringoflaboratoryanimals.

5.3Preclinicalsafetydata

Bicalutamideisapureandpotentandrogenreceptorantagonistinexperimentalanimalsandhumans.Themain

secondarypharmacologicalactionisinductionofCYP450dependentmixedfunctionoxidasesintheliver.Enzyme

inductionhasnotbeenobservedinhumans.Targetorganchangesinanimalsareclearlyrelatedtotheprimaryand

secondarypharmacologicalactionofbicalutamide.Thesecompriseinvolutionofandrogen-dependenttissues;thyroid

follicularadenomas,hepaticandLeydigcellhyperplasiasandneoplasiasorcancer;disturbanceofmaleoffspring

Table2 Overallsurvivalinlocallyadvanceddiseasebytherapysub-group

Analysispopulation Deaths(%)in

bicalutamidepatients Deaths(%)in

placebo

patients Hazardratio

(95%CI)

Watchfulwaiting 164/335(49.0) 183/322(56.8) 0.81(0.66to1.01)

Radiotherapy 49/161(30.4) 61/144(42.4) 0.65(0.44to0.95)

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Genotoxicitystudiesdidnotrevealanymutagenicpotentialofbicalutamide.Alladverseeffectsobservedinanimal

studiesareconsideredtohavenorelevancetothetreatmentofpatientswithadvancedprostatecancer.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

Lactosemonohydrate,

Sodiumstarchglycolate(typeA),

PovidoneK-30,

Silica,colloidalanhydrous,

Magnesiumstearate

Film-coating:

OpadryII.White33G28523(Hypromellose,Titaniumdioxide(E171),Lactosemonohydrate,Macrogol3350,

Triacetin)

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

5years.

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

10,14,20,28,30,40,50,56,80,84,90,100,140,200,280film-coatedtabletsinblisterpacks(PVC/PVDC/

aluminiumfoil)

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

GedeonRichterPlc

Gyomroiut19-21

1103Budapest

Hungary

8MARKETINGAUTHORISATIONNUMBER

PA1330/4/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:22 nd

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10DATEOFREVISIONOFTHETEXT

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