FLUTAMIDE

Main information

  • Trade name:
  • FLUTAMIDE Tablets 250 Milligram
  • Dosage:
  • 250 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • FLUTAMIDE Tablets 250 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0888/001/001
  • Authorization date:
  • 26-06-1998
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

FlutamideTablets250mg

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Activeingredient:Flutamide250mg

Forexcipients,see6.1.

3PHARMACEUTICALFORM

Coatedtablets

Yellow,roundcoatedtabletmarked‘F'.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Advancedprostaticcarcinoma,inwhichsuppressionoftestosteroneeffectsisindicated.

FlutamideTablets250mgmaybeusedasinitialtreatmentincombinationwithLuteinizingHormone-Releasing

Hormone(LHRH)agonists,asadjunctivetherapyinpatientsalreadyontreatmentwithanLHRHagonistandas

therapyforpatientswhohavebeensurgicallycastratedandforpatientswhohavenotrespondedtootherformsof

hormonalmanipulationorwhohavenottoleratedthem.

4.2Posologyandmethodofadministration

Therecommendeddosageis250mgthreetimesdaily,preferablyaftermeals.

DataintheliteratureshowthattheincidenceandtheseverityoftheLHRHagonistflarereactionmaybereducedby

initiatingtreatmentwithanantiandrogenbeforeratherthanconcomitantlywiththeagonist.

Forthisreason,whenflutamideisusedasinitialtreatmentincombinationwithanLHRHagonist,administration

shouldbestartedatleastthreedaysbeforetheLHRHagonistatthedosageof750mg/day(1tabletthreetimesaday)

andcontinuedthereafteratthesamedose.

AdministrationofFlutamideTablets250mgandtheLHRHagonistshouldbegin8weekspriortoradiationtherapy

andcontinuethroughthecourseofradiationtherapy(usuallyapproximately8weeks)i.e.atotalofapproximately16

weeks.

Monitoringofclinicalresponsetoflutamideduringthefirstmonthsoftreatmentisrecommendedinpatientswhohave

notreceivedmedicalorsurgicalcastration.

Flutamideadministrationtendstoelevateplasmatestosteroneandoestradiollevelsandmayinducefluidretentionin

patientswhohavenotbeenpreviouslycastrated;thereforecautionisrequiredinthepresenceofheartdisease.

Inpatientswithimpairedliverfunction,longtermtreatmentwithflutamideshouldonlybeadministeredaftercareful

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Noabnormalitiesinrenalfunctionhavebeendetectedalthoughelevatedserumcreatininelevelshavebeenreported.

Flutamideishighlyproteinboundandwillnotberemovedbydialysis.

4.3Contraindications

Flutamideiscontraindicatedinpatientswhoarehypersensitivetoflutamideoranycomponentofthispreparation.

4.4Specialwarningsandprecautionsforuse

Flutamidemaybehepatotoxicandshouldbeusedwithcautioninpatientswithpre-existinghepaticdysfunctiononly

afterconsideringthebenefitsandpotentialrisks.

Hepatotoxicity,whichmaybefatal,mayoccurafterseveralweeksormonthsoftherapy.

Hepaticfunctionshouldbemonitoredregularlybefore,duringandafterinitiationofflutamidetherapy.

Liverfunctiontestsshouldbeperformedatthefirstsignorsymptomofhepaticdysfunction(e.g.pruritus,darkurine,

persistentanorexia,jaundice,rightupperquadranttendernessorunexplained“flu-like”symptoms).

Ifthepatienthasjaundiceorlaboratoryevidenceofliverinjury,intheabsenceofbiopsy-confirmedlivermetastasis,

flutamidetherapyshouldbediscontinuedorthedosagereduced.Flutamide-inducedhepatotoxicityusuallyrecovers

withdosereductionordrugwithdrawal,butfatalitieshavebeenreported(seesection4.8).

Theincreasedriskofosteoporoticfractureshouldbeweighedcarefullyinthedecisiontoprescribeandrogen

deprivationinmenwithalowriskofdiseaseprogression.

PatientsshouldbeinformedthatFlutamideTablets250mgandthedrugusedformedicalcastrationshouldbe

administeredconcomitantly,andthattheyshouldnotinterrupttheirdosingorstoptakingthesemedicationswithout

consultingtheirphysician.

MonitoringofclinicalresponsetoFlutamideTablets250mgduringthefirstmonthsoftreatmentisrecommendedin

patientswhohavenotreceivedmedicalorsurgicalcastration.

Flutamideadministrationtendstoelevateplasmatestosteroneandoestradiollevelsandmayinducefluidretentionin

patientswhohavenotbeenpreviouslycastrated;thereforecautionisrequiredinthepresenceofheartdisease.

PatientsshouldbeinformedalsothatFlutamideTablets250mgcontainslactose,althoughtheamountofthisexcipient

isprobablynotsufficienttocauseintolerancesymptoms.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Avoidconcomitantadministrationofpotentiallyhepatotoxicdrugs.

Avoidexcessivealcoholconsumption.

Interactionsbetweenflutamideandleuprolidehavenotbeendescribed.Increasesinprothrombintimehavebeennoted

inpatientsreceivinglongtermwarfarintherapyafterflutamidewasinitiated.Thereforeclosemonitoringof

prothrombintimeisrecommendedandadjustmentoftheanticoagulantdosemaybenecessarywhenflutamideis

administeredconcomitantlywithwarfarin.

4.6Pregnancyandlactation

FlutamideTablets250mgisnotintendedforuseinwomen.

4.7Effectsonabilitytodriveandusemachines

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4.8Undesirableeffects

Monotherapy:Inclinicalstudies,themostfrequentlyreportedadversereactionstoFlutamideTablets250mgare

gynecomastiaand/orbreasttenderness,sometimesaccompaniedbygalactorrhea.Gynecomastiaoccurredin9%of

patientsreceivingflutamidetogetherwithmedicalcastration.Thesereactionsdisappearupondiscontinuationof

treatmentorreductionindosage.

FlutamideTablets250mgdemonstratealowpotentialforcardiovascularliability,andwhencomparedto

diethystilbestrolthisliabilityhasbeenshowntobesignificantlylower.

Lessfrequentadversereactions:diarrhoea,nausea,vomiting,increasedappetite,insomnia,tiredness,transient

abnormalliverfunctionandhepatitis(see:4.4SpecialwarningsandPrecautions).

Rareadversereactions:decreasedlibido,upsetstomach,anorexia,ulcer-likepain,heartburn,constipation,oedema,

ecchymoses,herpeszoster,pruritus,lupus-likesyndrome,headache,dizziness,weakness,malaise,blurredvision,

thirst,chestpain,anxiety,depression,lymphoedema.

Flutamidemayinduceaprogressiveandsignificantdecreaseinbonemineraldensityatthelumbarspineandthehip.

Reducedspermcountshavebeenreportedrarely.

Combinationtherapy:Inclinicalstudies,themostfrequentlyreportedadverseeffectsexperiencedduringcombination

therapyofFlutamideTablets250mgwithLHRHagonistwerehotflushes,decreasedlibido,impotence,diarrhoea,

nauseaandvomiting.Withtheexceptionofdiarrhoea,theseadverseexperiencesareknowntooccurwithLHRH

agonistaloneandatcomparablefrequency.

Thehighincidenceofgynaecomastiaobservedwithflutamidemonotherapywasreducedgreatlyincombination

therapy.Inclinicaltrials,nosignificantdifferenceingynaecomastiaincidencewasobservedbetweentheplaceboand

theflutamide-LHRHagonisttreatmentgroups.

Rarely,patientsexperiencedanaemia,leukopenia,unspecifiedgastro-intestinaldisorders,anorexia,injectionsite

irritationandrash,oedema,neuromuscularsymptoms,jaundice,genitourinarytractsymptoms,hypertension,central

nervoussystemadverseevents(drowsiness,depression,confusion,anxiety,nervousness)andthrombocytopenia.

Veryrarely,pulmonarysymptoms,hepatitisandphotosensitivityhaveoccured.

Additionaladverseexperiences:Inaddition,thefollowingadverseexperienceshavebeenreportedduringworld-wide

marketingofflutamide:haemolyticanaemia,macrocyticanaemia,methemoglobinemia,photosensitivityreactions-

includingerythema,ulcerations,bullouseruptions,andepidermalnecrolysis-andchangeinurinecolourtoamberor

yellow-greenappearance,whichcanbeattributedtoflutamideand/oritsmetabolites.

Hepaticreactionssuchascholestaticjaundice,hepaticencephalopathyandhepaticnecrosishavebeenreported,which

maybefatal(seesection4.4).

Tworeportsofmalignantmalebreastneoplasmsinpatientsbeingdosedwithflutamidehavebeenreported.One

involvedaggravationofapre-existingnodulewhichwasfirstdetectedthreetofourmonthsbeforeinitiationof

flutamidemonotherapyinapatientwithbenignprostatichypertrophy.Afterexcision,thiswasdiagnosedasapoorly

differentiatedductalcarcinoma.Theotherreportinvolvedgynecomastiaandanodulenotedtwoandsixmonths,

respectively,afterinitiationofflutamidemonotherapyfortreatmentofadvancedprostaticcarcinoma.Ninemonths

aftertheinitiationoftherapythenodulewasexcisedanddiagnosedasamoderatelydifferentiatedinvasiveductal

tumourstagedT4NOMO,G3,nometastaseshadadvanced.

Abnormallaboratorytestvaluesreportedincludechangesinliverfunction,elevatedbloodureanitrogen(BUN)and

rarely,elevatedserumcreatininevaluesevenifnoabnormalitiesinrenalfunctionhavebeendetected.

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4.9Overdose

Inanimalstudieswithflutamidealone,signsofoverdoseincludedhypoactivity,piloerection,slowrespiration,ataxia,

and/orlacrimation,anorexia,tranquilization,emesisandmethaemoglobinemia.

Clinicaltrialshavebeenconductedwithflutamideindosesupto1500mgperdayforperiodsupto36weekswithno

seriousadverseeffectsreported.Thoseadversereactionsreportedincludedgynaecomastia,breasttendernessandsome

increaseinSerumGlutamic-OxaloaceticTransaminase(SGOT).Thesingledoseofflutamideordinarilyassociated

withsymptomsofoverdoseorconsideredtobelife-threateninghasnotbeenestablished.

Sinceflutamideishighlyproteinbound,dialysismaynotbeofanyuseastreatmentofoverdosage.Asinthe

managementofoverdosagewithanydrug,itshouldbeborninmindthatmultipleagentsmayhavebeentaken.If

vomitingdoesnotoccurspontaneously,itshouldbeinducedifthepatientisalert.Gastriclavageandgeneral

supportivecare,includingfrequentmonitoringofthevitalsignsandcloseobservationofthepatients,isindicated.

Onepatientsurvivedaftertakingmorethan5gasasingledose–noadverseeffectswereobserved.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Inanimalstudies,flutamidedemonstratespotentantiandrogeniceffects.Itexertsitsantiandrogenicactionbyinhibiting

androgenuptakeand/orbyinhibitingnuclearbindingofandrogenintargettissuesorboth.

Mostcasesofadvancedprostaticcarcinomaareknowntobeandrogensensitiveandrespondtoflutamidetreatment.

Whenflutamideisgivenincombinationwithsurgicalormedicalcastration,suppressionofbothtesticularandadrenal

androgenactivityisachieved.

5.2Pharmacokineticproperties

Flutamideiswellabsorbedfollowingoralingestion.

Analysisofplasma,urineandfaecesfollowingasingleoral200mgdoseoftritium-labelledflutamidetohuman

volunteersshowedthatthedrugisrapidlyandcompletelyabsorbed.Itisexcretedmainlyintheurinewithonly4.2%

ofthedoseexcretedinthefaecesover72hours.

Thecompositionofplasmaradioactivityshowedthatflutamideisrapidlyandextensivelymetabolized,withflutamide

comprisingonly2.5%ofplasmaradioactivityonehourafteradministration.Atleastsixmetaboliteshavebeen

identifiedinplasma.Themajorplasmametaboliteisabiologicallyactive2-hydroxyflutamidewhichaccountsfor23%

oftheplasmatritiumonehourafterdrugadministration.

Themajorurinarymetaboliteis2-amino-5-nitro-4-(trifluoromethyl)phenol.

Followingasingle250mgoraldosetonormaladultvolunteers,lowplasmalevelsofvaryingamountsofflutamide

weredetected.Thebiologicallyactivemetabolite2-hydroxyflutamidereachesmaximumplasmalevelsinabouttwo

hours,indicatingthatitisrapidlyformedfromflutamide.Theplasmahalf-lifeforthismetaboliteisabout6hours.

Followingmultipleoraldosingof250mgthreetimesdailyinnormalgeriatricvolunteers,flutamideanditsactive

metaboliteapproachedsteady-stateplasmalevels(basedonpharmacokineticsimulations)afterthefourthflutamide

dose.Thehalf-lifeoftheactivemetaboliteingeriatricvolunteersafterasingleflutamidedoseisabout8hoursandat

steady-stateis9.6hours.

Flutamide,invivo,atsteady-stateplasmaconcentrationsof24to78ng/mlis94%to96%boundtoplasmaproteins.

Theactivemetaboliteofflutamide,invivo,atsteady-stateplasmaconcentrationsof1556to2284ng/ml,is92%to94%

boundtoplasmaproteins.

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afteranoral5mg/kgdoseof 14

C-Flutamide.Totaldruglevelswerehighest6hoursafterdrugadministrationinall

tissues.Levelsdeclinedatroughlysimilarratestolowlevelsat18hours.Themajormetabolitewaspresentathigher

concentrationsthanflutamideinalltissuesstudied.

5.3Preclinicalsafetydata

AcutetoxicitystudiesinratshaveshownthattheLD

offlutamidefollowingoraladministrationisequivalentto1078

mg/kginmalesandto787mg/kginfemales,whereastheLD

PerOs(P.O.)indogsisabove2.000mg/kg.

Treatmentofratsanddogsforoneyearwithdosesupto75mg/kg(7.5timesthehumandose)wasnotassociatedwith

anyimportanteffectsotherthanthoseonthegenitalorgans(atrophyofepididymides,seminalvesicles,prostateandthe

seminiferoustubulesofthetestesassociatedwithreducedspermatogenesis,hyperplasiaofthepituitary),closelyrelated

tothemechanismofactionofthecompound.

Slightalterationsofbiochemicalandhaematologicalparametersreturnedtonormalafterdiscontinuationoftreatment.

Reproductionstudiesinadultmaleratshavedemonstratedthatthegenitalatrophyinducedbyflutamidediminishes

fertility.

FlutamidedidnotdemonstrateDNAmodifyingactivityintheAMESSalmonella/microsomeMutagenesisAssay.

Dominantlethaltestsinratswerealsonegative.

Nocarcinogenesisstudieshavebeenperformedwithflutamide.However,longterm(1year)treatmentintoxicity

studies,inratanddogs,withdosesupto75mg/kg/daywasnotassociatedwiththedevelopmentoftumoursindogsbut

andincreasedincidenceoftesticularfollicularcelladenomaswasobservedinratstreatedwithdosesequaltoorgreater

than7.5mg/kg/day(7.5timesthehumandose).

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactosemonohydrate

Maizestarch

Povidone

Crospovidone

Sodiumlaurilsulfate

Magnesiumstearate

Hypromellose

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

2years.

6.4Specialprecautionsforstorage

Storebelow25 o

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6.5Natureandcontentsofcontainer

A1/PVDCgreenstrips(blisters)ofcoatedtablets.

BlisterstripofPVC250µ/PVDC40g–Aluminium20µ

2stripsof15tabletsarecontainedinanoutercardboardcarton(30tablets).

4stripsof21tabletsarecontainedinanoutercardboardcarton(84tablets).

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialprecautionsrequired.

7MARKETINGAUTHORISATIONHOLDER

PH&TSpA

ViaAriosto,34

20145Milano

Italy

8MARKETINGAUTHORISATIONNUMBER

PA888/1/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:26June1998

Dateoflastrenewal:26June2003

10DATEOFREVISIONOFTHETEXT

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