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:
  • PA0585/033/002
  • 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)

PA0585/033/002

CaseNo:2041277

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

PlivaPharmaLimited

VisionHouse,BedfordRoad,Petersfield,HampshireGU323QB,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Bicalutamide150mgFilm-CoatedTablets

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

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

SignedonbehalfoftheIrishMedicinesBoardthis

________________

Irish Medicines Board

______________________________________________________________________________________________________________________

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

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Bicalutamide150mgFilm-CoatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains150mgofbicalutamide

Excipients:

Eachtabletcontains3.1mgoflactose(aslactosemonohydrate)

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet

Whitetoalmostwhiteround,biconvex,film-coatedtablet,imprintedwith‘BC’ononesideand‘150’ontheotherside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Bicalutamide150mgisindicatedeitheraloneorasadjuvanttoradicalprostatectomyorradiotherapyinpatientswith

locallyadvancedprostatecancerathighriskfordiseaseprogression.(seesection5.1).

4.2Posologyandmethodofadministration

Adultmalesincludingtheelderly:onetablet(150mg)tobetakenorallyonceaday.

Route:oral

Thetabletsshouldbeswallowedwholewithliquid.

Bicalutamide150mgshouldbetakencontinuouslyforatleast2yearsoruntildiseaseprogression.

Childrenandadolescents:Bicalutamideisnotindicatedinchildrenandadolescents.

Renalimpairment:nodoseadjustmentisnecessaryforpatientswithrenalimpairment.Thereisnoexperiencewiththe

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

Hepaticimpairment:nodoseadjustmentisnecessaryforpatientswithmildhepaticimpairment.

Themedicinalproductmayaccumulateinpatientswithmoderatetoseverehepaticimpairment(seesection4.4).

4.3Contraindications

Hypersensitivitytobicalutamideoranyoftheexcipients

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/11/2008 CRN 2041277 page number: 2

Co-administrationofterfenadine,astemizoleorcisapridewithbicalutamideiscontraindicated(seesection4.5).

4.4Specialwarningsandprecautionsforuse

Bicalutamideismetabolisedintheliver.Researchresultssuggestthatbicalutamide’seliminationmaybeslowerin

patientswithseverehepaticimpairmentandthatthiscouldleadtoincreasedaccumulationofbicalutamide.Therefore,

bicalutamideshouldbeusedwithcautioninpatientswithmoderatetoseverehepaticimpairment.

Severehepaticchangeshavebeenrarelyobservedwithbicalutamide(seesection4.8).Bicalutamidetherapyshouldbe

discontinuedifchangesaresevere.

Periodicliverfunctiontestingiswarrantedinordertofindoutaboutpossiblehepaticchanges.Themajorityofchanges

areexpectedtooccurwithinthefirst6monthsofbicalutamidetherapy.

Asthereisnoexperiencewiththeuseofbicalutamideinpatientswithsevererenalimpairment(creatinineclearance

<30ml/min),bicalutamideshouldonlybeusedwithcautioninthesepatients.

Periodicmonitoringofcardiacfunctionisadvisableinpatientswithheartdisease.

ForpatientswhohaveanobjectiveprogressionofdiseasetogetherwithelevatedPSA,cessationofbicalutamide

therapyshouldbeconsidered.

Initiationoftreatmentshouldbeunderthedirectsupervisionofaspecialistandsubsequentlypatientsshouldbekept

underregularsurveillance.

Theproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactase

deficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

InvitrostudieshaveshownthatR-bicalutamideisaninhibitorofCYP3A4,withlesserinhibitoryeffectsonCYP2C9,

2C19and2D6activity.

Althoughinvitrostudieshaveindicatedthepossibilityofbicalutamideinhibitingcytochrome3A4,anumberof

clinicalstudiesshowthatthescaleofthisinhibitionformostdrugsmetabolizedbycytochromeP450isprobablynot

clinicallysignificant.

Nonetheless,fordrugswithanarrowtherapeuticindexmetabolizedintheliver,theCYP3A4inhibitioncausedby

bicalutamidecouldbeofrelevance.Assuch,concomitantuseofterfenadine,astemizoleandcisaprideis

contraindicated.

Cautionshouldbeexercisedwiththeco-administrationofbicalutamidewithcompoundssuchasciclosporinand

calciumchannelblockers.Dosagereductionmayberequiredforthesedrugsparticularlyifthereisevidenceof

enhancedoradversedrugeffect.Forciclosporin,itisrecommendedthatplasmaconcentrationsandclinicalcondition

arecloselymonitoredfollowinginitiationorcessationofbicalutamidetherapy.

Cautionshouldbeexercisedwhenadministeringbicalutamidetopatientstakingmedicinalproductsthatinhibitthe

oxidationprocessinthelivere.g.cimetidineandketoconazole.Thiscouldresultinincreasedplasmaconcentrationsof

bicalutamidewhichtheoreticallycouldleadtoanincreaseinsideeffects.

Invitrostudieshaveshownthatbicalutamidecandisplacethecoumarinanticoagulant,warfarin,fromitsprotein

bindingsites.Itisthereforerecommendedthatprothrombintimeiscloselymonitoredifbicalutamideisstartedin

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/11/2008 CRN 2041277 page number: 3

4.6Pregnancyandlactation

Notapplicable,sincethismedicinalproductisnotusedinwomen.

Fertility

Reversibleimpairmentofmalefertilityhasbeenobservedinanimalstudies(seesection5.3).Aperiodofsubfertilityor

infertilityshouldbeassumedinman.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.

However,itshouldbenotedthatoccasionallydizzinessorsomnolencemayoccur(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

Uncommon:Haematuria

Reproductivesystemandbreastdisorders

Verycommon:Breasttenderness 3

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/11/2008 CRN 2041277 page number: 4

Generaldisordersandadministrationsiteconditions

Verycommon:Hotflushes 3

Common:Asthenia

Hepaticchangesarerarelysevereandwerefrequentlytransient,resolvingorimprovingwithcontinuedtherapyor

followingcessationoftherapy(seesection4.4).

Hepaticfailurehasoccurredveryrarelyinpatientstreatedwithbicalutamide,butacasualrelationshiphasnotbeen

establishedwithcertainty.Periodicliverfunctiontestingshouldbeconsidered(seealsosection4.4).

Maybereducedbyconcomitantcastration.

Inaddition,thefollowingadverseexperienceswerereportedinclinicaltrialsduringtreatmentwith/withoutaLHRH

analogue:

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

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/11/2008 CRN 2041277 page number: 5

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.

BicalutamideisaracematewithitsantiandrogenactivitybeingalmostexclusivelyintheR-enantiomer.

Bicalutamide150mgwasstudiedasatreatmentforpatientswithlocalised(T1-T2,N0orNX,M0)orlocallyadvanced

(T3-T4,anyN,M0;T1-T2,N+,M0)non-metastaticprostatecancerinacombinedanalysisofthreeplacebocontrolled,

double-blindstudiesin8113patients,wherebicalutamidewasgivenasimmediatehormonaltherapyorasadjuvantto

radicalprostatectomyorradiotherapy,(primarilyexternalbeamradiation).At7.4yearsmedianfollowup,27.4%and

30.7%ofallbicalutamideandplacebo-treatedpatients,respectively,hadexperiencedobjectivediseaseprogression.

Areductioninriskofobjectivediseaseprogressionwasseenacrossmostpatientsgroupsbutwasmostevidentinthose

athighestriskofdiseaseprogression.Therefore,cliniciansmaydecidethattheoptimummedicalstrategyforapatient

atlowriskofdiseaseprogression,particularlyintheadjuvantsettingfollowingradicalprostatectomy,maybetodefer

hormonaltherapyuntilsignsthatthediseaseisprogressing.

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

to1.09).However,sometrendswereapparentinexploratorysubgroupanalyses.

Progression-freesurvivalandoverallsurvivaldataforpatientswithlocallyadvanceddiseasearesummarisedinthe

followingtables:

Progression-freesurvivalinlocallyadvanceddiseasebytherapysub-group

Analysis

population Events(%)in

Bicalutamide

patients Events(%)in

placebo

patients Hazardratio

(95%CI)

Watchfulwaiting 193/335(57.6) 222/322(68.9) 0.60(0.49to

0.73)

Radiotherapy 66/161(41.0) 86/144(59.7) 0.56(0.40to

0.78)

Radical

prostatectomy 179/870(20.6) 213/849(25.1) 0.75(0.61to

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/11/2008 CRN 2041277 page number: 6

Overallsurvivalinlocallyadvanceddiseasebytherapysub-group

Forpatientswithlocaliseddiseasereceivingbicalutamidealone,therewasnosignificantdifferenceinprogressionfree

survival.Inthesepatientstherewasalsoatrendtowarddecreasedsurvivalcomparedwithplacebopatients(HR=1.16;

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

thisgroupofpatients.

5.2Pharmacokineticproperties

Bicalutamideiswellabsorbedfollowingoraladministration.Thereisnoevidenceofanyclinicallyrelevanteffectof

foodonbioavailability.

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

about1week.

Followingalong-termadministrationofbicalutamidethepeakconcentrationofthe(R)-enantiomerintheplasmais

about10-fold,ascomparedtothelevelsmeasuredafterasingledoseof50mgofbicalutamide.

Adosingschemeof150mgbicalutamidedailywillresultinasteady-stateconcentrationoftheR-enantiomerof22

µg/mlandasaconsequenceofitslonghalf-life,steadystateisreachedafterapproximately1monthoftherapy.

Thepharmacokineticsofthe(R)-enantiomerareunaffectedbyage,renalimpairmentormildtomoderatehepatic

impairment.Thereisevidencethatthe(R)-enantiomerismoreslowlyeliminatedfromplasmainpatientswithsevere

hepaticimpairment,.

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

oxidationandglucuronidation).Itsmetabolitesareeliminatedviathekidneysandbileinapproximatelyequal

proportions.

Inaclinicalstudythemeanconcentrationof(R)-enantiomerofbicalutamideinsemenofmenreceivingbicalutamide

150mgwas4.9microgram/ml.Theamountofbicalutamidepotentiallydeliveredtoafemalepartnerduringintercourse

islowandequatestoapproximately0.3microgram/kg.Thisisbelowthatrequiredtoinducechangesinoffspringof

laboratoryanimals.

5.3Preclinicalsafetydata

Bicalutamideisapureandpotentandrogenreceptorantagonistinexperimentalanimalsandhumans.Themain

secondarypharmacologicalactionisinductionofCYP450dependentmixedfunctionoxidasesintheliver.Enzyme

inductionhasnotbeenobservedinhumans.Targetorganchangesinanimalsareclearlyrelatedtotheprimaryand

secondarypharmacologicalactionofbicalutamide.Thesecompriseinvolutionofandrogen-dependenttissues;thyroid

follicularadenomas,hepaticandLeydigcellhyperplasiasandneoplasiasorcancer;disturbanceofmaleoffspring

Analysis

population Deaths(%)in

Bicalutamide

patients Deaths(%)in

placebo

patients Hazardratio

(95%CI)

Watchfulwaiting 164/335(49.0) 183/322(56.8) 0.81(0.66to

1.01)

Radiotherapy 49/161(30.4) 61/144(42.4) 0.65(0.44to

0.95)

Radical

prostatectomy 137/870(15.7) 122/849(14.4) 1.09(0.85to

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/11/2008 CRN 2041277 page number: 7

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

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/11/2008 CRN 2041277 page number: 8

7MARKETINGAUTHORISATIONHOLDER

PlivaPharmaLimited.

VisionHouse

BedfordRoad

Petersfield

Hampshire

GU323QB

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA585/33/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:14 th

November2008

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/11/2008 CRN 2041277 page number: 9