BICALUTAMIDE FARMAPROJECTS

Main information

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

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1391/001/001
  • Authorization date:
  • 04-07-2008
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

BicalutamideFarmaprojects50mg,film-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains50mgofbicalutamide.

Eachtabletcontains56mgoflactosemonohydrateasanexcipient.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

White,round,biconvex,film-coatedtablet.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofadvancedprostatecancerincombinationwithluteinisinghormone-releasinghormone(LHRH)analogue

therapyorsurgicalcastration.

4.2Posologyandmethodofadministration

Adultmalesincludingtheelderly:onetabletoncedailyatthesametimeeachday(usuallyinthemorningorinthe

evening),withorwithoutfood.

Treatmentwithbicalutamideshouldbestartedatleast3dayspriortotheadministrationofanLHRHanalogueoratthe

sametimeassurgicalcastration.

Childrenandadolescents:Thereisnorelevantindicationfortheuseofbicalutamideinchildrenandadolescents.

Renalimpairment:nodosageadjustmentisnecessaryforpatientswithrenalimpairment.Thereisnoexperiencewith

theuseofbicalutamideinpatientswithsevererenalimpairment(creatinineclearance<30ml/min).(Seesection4.4.)

Hepaticimpairment:nodosageadjustmentisnecessaryforpatientswithmildhepaticimpairment.

Increasedaccumulationmayoccurinpatientswithmoderatetoseverehepaticimpairment(seeSection4.4).

4.3Contraindications

Bicalutamideiscontraindicatedinfemalesandchildren.

Bicalutamideiscontraindicatedinpatientswithhypersensitivitytotheactivesubstanceoranyoftheexcipients(see

section4.4).

Concomitantadministrationofterfenadine,astemizoleorcisapridewithBicalutamideiscontraindicated(seesection

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4.4Specialwarningsandprecautionsforuse

Initiationoftreatmentshouldbeunderthedirectsupervisionofaspecialist.

Bicalutamideisextensivelymetabolisedintheliver.Datasuggestthatitseliminationmaybeslowerinsubjectswith

severehepaticimpairmentandthiscouldleadtoincreasedaccumulationofbicalutamide.Therefore,Bicalutamide

shouldbeusedwithcautioninpatientswithmoderatetoseverehepaticimpairment.

Periodicliverfunctiontestingshouldbeconsideredduetothepossibilityofhepaticchanges.Themajorityofcasesare

expectedtooccurwithinthefirst6monthsofbicalutamidetherapy.

Severehepaticchangeshavebeenobservedrarelywithbicalutamideandfataloutcomeshavebeenreported(see

section4.8).Bicalutamidetherapyshouldbediscontinuedifchangesaresevere.

AreductioninglucosetolerancehasbeenobservedinmalesreceivingLHRHagonists.Thismaymanifestasdiabetes

orlossofglycaemiccontrolinthosewithpre-existingdiabetes.Considerationshouldthereforebegiventomonitoring

bloodglucoseinpatientsreceivingbicalutamidincombinationwithLHRHagonists.

Asthereisnoexperiencewiththeuseofbicalutamideinpatientswithsevererenalimpairment(creatinineclearance<

30ml/min),bicalutamideshouldonlybeusedwithcautioninthesepatients.

BicalutamidehasbeenshowntoinhibitcytochromeP450(CYP3A4),assuch,cautionshouldbeexercisedwhenco-

administeredwithdrugsmetabolisedpredominantlybyCYP3A4(seesections4.3and4.5).

Theproductcontainslactosemonohydrate.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapp

lactasedeficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

ThereisnoevidenceofanypharmacodynamicorpharmacokineticinteractionsbetweenbicalutamideandLHRH

analogues.

InvitrostudieshaveshownthatR-bicalutamideisaninhibitorofCYP3A4,withlesserinhibitoryeffectsonCYP2C9,

2C19and2D6activity.

AlthoughclinicalstudiesusingantipyrineasamarkerofcytochromeP450(CYP)activityshowednoevidenceofa

druginteractionpotentialwithbicalutamide,meanmidazolamexposure(AUC)wasincreasedbyupto80%,afterco-

administrationofbicalutamidefor28days.Fordrugswithanarrowtherapeuticindexsuchanincreasecouldbeof

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

cautionshouldbeexercisedwiththeco-administrationofbicalutamidewithcompoundssuchasciclosporinand

calciumchannelblockers.

Dosagereductionmayberequiredforthesedrugsparticularlyifthereisevidenceofenhancedoradversedrugeffect.

Forciclosporin,itisrecommendedthatplasmaconcentrationsandclinicalconditionarecloselymonitoredfollowing

initiationorcessationofbicalutamidetherapy.

Cautionshouldbeexercisedwhenprescribingbicalutamidewithotherdrugswhichmayinhibitdrugoxidatione.g.

cimetidineandketoconazole.Intheory,thiscouldresultinincreasedplasmaconcentrationsofbicalutamidewhich

theoreticallycouldleadtoanincreaseinsideeffects.

Invitrostudieshaveshownthatbicalutamidecandisplacethecoumarinanticoagulant,warfarin,fromitsprotein

bindingsites.Itisthereforerecommendedthatifbicalutamideisstartedinpatientswhoarealreadyreceivingcoumarin

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4.6Fertility,pregnancyandlactation

Bicalutamideiscontraindicatedinwomen:thereforeitmustnotbegiventopregnantwomenornursingmothers.

Fertility

Reversibleimpairmentofmalefertilityhasbeenobservedinanimalstudies(seesection5.3).Aperiodofsub-fertility

orinfertilityshouldbeassumedinman.

4.7Effectsonabilitytodriveandusemachines

Bicalutamideisunlikelytoimpairtheabilityofpatientstodriveoroperatemachinery.However,itshouldbenoted

thatoccasionallydizzinessorsomnolencemayoccur(seesection4.8).Anyaffectedpatientshouldexercisecaution.

4.8Undesirableeffects

Inthissection,adverseeventsaredefinedasfollows:verycommon(1/10);common(1/100,<1/10);uncommon

(1/1,000,<1/100);rare(1/10,000,<1/1,000);veryrare(<1/10,000),notknown(cannotbeestimatedfromthe

availabledata). .

Table1:frequencyofadversereactions

SystemOrganClass Frequency Bicalutamide50mg(+LHRHanalogue)

Bloodandlymphaticsystem

disorders Verycommon Anaemia

Immunesystemdisorders Uncommon Hypersensitivityreactions(includingangioneuroticoedema

andurticaria)

Metabolismandnutrition

disorders Common Anorexia

Psychiatricdisorders Common Decreasedlibido,Depression

NervousSystemDisorders Verycommon Dizziness

Common Somnolence

Vasculardisorders Verycommon Hotflush

Respiratory,thoracicand

mediastinaldisorders Uncommon Interstitiallungdisease.Fataloutcomeshavebeenreported.

Gastrointestinaldisorders Verycommon Abdominalpain,Constipation,Nausea

Common Dyspepsia,Flatulence

Hepato-biliarydisorders Common Hepaticchanges(includingelevatedlevelsoftransaminases,

cholestasis,jaundice)/hepato-biliarydisorders a

Rare

Hepaticfailure b

.Fataloutcomeshavebeenreported.

Skinandsubcutaneous

tissuedisorders Common Alopecia,Hirsuitism/hairre-growth,Dryskin,Pruritis,Rash

Renalandurinarydisorders Verycommon Haematuria

Reproductivesystemand

breastdisorders Verycommon

Gynaecomastiaandbreasttenderness c

Common Impotence

Generaldisordersand

administrationsite

conditions Verycommon

Common Asthenia,Oedema

Chestpain

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Hepaticchangesarerarelysevereandwerefrequentlytransient,resolvingorimprovingwithcontinuedtherapyor

followingcessationoftherapy.

Hepaticfailurehasoccurredrarelyinpatientstreatedwithbicalutamide,butacausalrelationshiphasnotbeen

establishedwithcertainty.Periodicliverfunctiontestingshouldbeconsidered(seealsosection4.4)

Maybereducedbyconcomitantcastration.

Inaddition,cardiacfailurewasreportedinclinicaltrials(asapossibleadversedrugreactionintheopinionof

investigatingclinicians,withafrequencyof>1%)duringtreatmentwithbicalutamideplusanLHRHanalogue.There

isnoevidenceofacausalrelationshipwithdrugtreatment.

4.9Overdose

Nocaseofoverdosehasbeenreported.Sincebicalutamidebelongstotheanilidecompoundsthereisatheoreticalrisk

ofthedevelopmentofmethaemoglobinaemia.Methaemoglobinaemiahasbeenobservedinanimalsafteranoverdose.

Accordingly,apatientwithanacuteintoxicationcanbycyanotic.

Thereisnospecificantidote;treatmentshouldbesymptomatic.Dialysismaynotbehelpful,sincebicalutamideis

highlyproteinboundandisnotrecoveredunchangedintheurine.Generalsupportivecare,includingfrequent

monitoringofvitalsigns,isindicated.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Hormoneantagonistsandrelatedagents,anti-androgens

ATCcodeL02BB03.

Bicalutamideisanon-steroidalantiandrogen,devoidofotherendocrineactivity.Itbindstoandrogenreceptorswithout

activatinggeneexpression,andthusinhibitstheandrogenstimulus.Regressionofprostatictumoursresultsfromthis

inhibition.Clinically,discontinuationofBicalutamidecanresultinantiandrogenwithdrawalsyndromeinasubsetof

patients.

Bicalutamideisaracematewithitsantiandrogenicactivitybeingalmostexclusivelyinthe(R)-enantiomer.

5.2Pharmacokineticproperties

Bicalutamideiswellabsorbedfollowingoraladministration.Thereisnoevidenceofanyclinicallyrelevanteffectof

foodonbioavailability.

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

about1week.

OndailyadministrationofBicalutamide,the(R)-enantiomeraccumulatesabout10-foldcomparedtothe(S)-

enantiomerinplasmaasaconsequenceofitslongeliminationhalf-life.

Steadystateplasmaconcentrationsofthe(R)-enantiomer,ofapproximately9micrograms/mlareobservedduringdaily

administrationofBicalutamide50mg.Atsteadystate,thepredominantlyactive(R)-enantiomeraccountsfor99%of

thetotalcirculatingenantiomers.

Thepharmacokineticsofthe(R)-enantiomerareunaffectedbyage,renalimpairmentormildtomoderatehepatic

impairment.Thereisevidencethatforsubjectswithseverehepaticimpairment,the(R)-enantiomerismoreslowly

eliminatedfromplasma.

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

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InaclinicalstudythemeanconcentrationofR-bicalutamideinsemenofmenreceivingbicalutamide150mgwas4.9

microgram/ml.Theamountofbicalutamidepotentiallydeliveredtoafemalepartnerduringintercourseislowand

equatestoapproximately0.3microgram/kg.Thisisbelowthatrequiredtoinducechangesinoffspringoflaboratory

animals.

5.3Preclinicalsafetydata

Bicalutamideisapureandpotentandrogenreceptorantagonistinexperimentalanimalsandhumans.Themain

secondarypharmacologicalactionisinductionofCYP

dependentmixedfunctionoxidasesintheliver.Enzyme

inductionhasnotbeenobservedinhumans.Targetorganchangesinanimalsareclearlyrelatedtotheprimaryand

secondarypharmacologicalactionofbicalutamideandcompriseinvolutionofandrogen-dependenttissues,thyroid,

hepaticandLeydigcellhyperplasiasandneoplasiasorcancer;disturbanceofmaleoffspringsexualdifferentiation;

reversibleimpairmentoffertilityinmales.Atrophyofseminiferoustubulesisapredictedclasseffectwith

antiandrogensandhasbeenobservedforallspeciesexamined.Fullreversaloftesticularatrophywas24weeksaftera

12monthrepeateddosetoxicitystudyinrats,althoughfunctionalreversalwasevidentinreproductionstudies7weeks

aftertheendofan11weekdosingperiod.Aperiodofsubfertilityorinfertilityshouldbeassumedinman.

Genotoxicitystudiesdidnotrevealanymutagenicpotentialofbicalutamide.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

TabletCore

Lactosemonohydrate

SodiumstarchglycolatetypeA

Povidone

CrospovidonetypeB

Magnesiumstearate

Film-coating

Hypromellose

Macrogol300

Titaniumdioxide(E171)

6.2Incompatibilities

Notapplicable.

6.3Shelflife

3years.

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

PVC/aluminiumblisters.

Packsizes:28,30and90tablets.

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6.6Specialprecautionsfordisposal

Anyunusedproductofwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

FarmaprojectsSA

Ava.SantaEulalia240-242

08902L’HospitaletdeLlobregat

Barcelona

Spain

8MARKETINGAUTHORISATIONNUMBER

PA1391/001/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:4thJuly2008

Dateoflastrenewal:3rdNovember2011

10DATEOFREVISIONOFTHETEXT

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