ANASTROZOLE

Main information

  • Trade name:
  • ANASTROZOLE Film Coated Tablet 1 Milligram
  • Dosage:
  • 1 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ANASTROZOLE Film Coated Tablet 1 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0585/036/001
  • Authorization date:
  • 24-07-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0585/036/001

CaseNo:2044112

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

PlivaPharmaLimited

VisionHouse,BedfordRoad,Petersfield,HampshireGU323QB,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Anastrozole1mgFilm-coatedTablets

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom24/07/2009until23/07/2014.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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Date Printed 29/07/2009 CRN 2044112 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Anastrozole1mgFilm-coatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains1mgofanastrozole

Excipient(s):

Eachtabletcontains48.94mgoflactosemonohydrate

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet

Description:

Whiteoralmostwhite,round,biconvex,film-coatedtablet,embossedwith'AA'ononesideand'1'ontheother.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofadvancedbreastcancerinpostmenopausalwomen.

Efficacyhasnotbeendemonstratedinoestrogenreceptor-negativepatientsunlesstheyhadapreviouspositiveclinical

responsetotamoxifen.

Adjuvanttreatmentofpostmenopausalwomenwithhormonereceptor-positiveearlyinvasivebreastcancer.

Adjuvanttreatmentofearlybreastcancerinhormonereceptor-positivepostmenopausalwomenwhohavereceived2to

3yearsofadjuvanttamoxifen.

4.2Posologyandmethodofadministration

Adultsincludingtheelderly:One1mgtablettobetakenorallyonceaday

Childrenandadolescents:Notrecommendedforuseinchildren

Renalimpairment:Nodosechangeisrecommendedinpatientswithmildormoderaterenalimpairment

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4.3Contraindications

Anastrozole1mgFilm-coatedTabletsarecontraindicatedin:

-patientswithknownhypersensitivitytoanastrozoleortoanyoftheexcipientsasreferencedinsection6.1.

-premenopausalwomen

-pregnantorlactatingwomen(seesection4.6)

-patientswithsevererenalimpairment(creatinineclearancelessthan20ml/min)(seesection4.4).

-patientswithmoderateorseverehepaticdisease(seesection4.4)

-oestrogen-containingtherapiesshouldnotbeco-administeredwithanastrozoleastheywouldnegateits

pharmacologicalaction

-concurrenttamoxifentherapy(seesection4.5)

4.4Specialwarningsandprecautionsforuse

Anastrozoleisnotrecommendedforuseinchildrenassafetyandefficacyhavenotbeenestablishedinthisgroupof

patients.

Themenopauseshouldbedefinedbiochemicallyinanypatientwherethereisdoubtabouthormonalstatus.

Therearenodatatosupportthesafeuseofanastrozoleinpatientswithmoderateorseverehepaticimpairment,or

patientswithsevereimpairmentofrenalfunction(creatinineclearancelessthan20ml/min)(seesection4.3).

Womenwithosteoporosisoratriskofosteoporosis,shouldhavetheirbonemineraldensitometrye.g.DEXAscanning

atthecommencementoftreatmentandatregularintervalsthereafter.Treatmentorprophylaxisforosteoporosisshould

beinitiatedasappropriateandcarefullymonitored.

TherearenodataavailablefortheuseofanastrozolewithLHRHanalogues.Thiscombinationshouldnotbeused

outsideclinicaltrials.

Asanastrozolelowerscirculatingoestrogenlevelsitmaycauseareductioninbonemineraldensity.Adequatedatato

showtheeffectofbisphosphonatesonbonemineraldensitylosscausedbyanastrozole,ortheirutilitywhenused

prophylactically,arenotcurrentlyavailable.

Thismedicinecontainslactosemonohydrate.Patientswithrarehereditaryproblemsofgalactoseintolerance,Lapp

lactasedeficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

AnastrozoleinhibitedcytochromeP450,1A2,2C8/9and3A4invitro,butaclinicalinteractionstudywithwarfarin

indicatedthatanastrozoleata1mgdosedoesnotsignificantlyinhibitthemetabolismofsubstancesthatare

metabolizedviacytochromeP450.

Noclinicallysignificantinteractionsbetweenanastrozoleandbisphosphonateshavebeenidentified.

Oestrogen-containingtherapiesshouldnotbeco-administeredwithanastrozoleastheywouldnegateits

pharmacologicalaction.

Tamoxifenshouldnotbeco-administeredwithanastrozole,asthismaydiminishitspharmacologicalaction(see

section4.3).

4.6Pregnancyandlactation

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Pregnancy

Therearenoadequatedataontheuseofanastrozoleinpregnantwomen.Studiesinanimalshaveshownreproductive

toxicity(seesection5.3).Thepotentialriskforhumansisunknown.

Anastrozoleiscontraindicatedinpregnantwomen.

Lactation

Itisunknownwhetheranastrozoleisexcretedinhumanmilk.Anastrozoleiscontraindicatedinlactatingwomen.

4.7Effectsonabilitytodriveandusemachines

Anastrozoleisunlikelytoimpairtheabilityofpatientstodriveandoperatemachinery.

However,astheniaandsomnolencehavebeenreportedwiththeuseofanastrozoleandcautionshouldbeobserved

whendrivingoroperatingmachinerywhilesuchsymptomspersist.

4.8Undesirableeffects

Adverseeventsobservedwithanastrozoleareclassifiedinbodysystemsandlistedbelowasverycommon( ≥1/10);

common( ≥1/100to<1/10);uncommon(≥1/1,000to<1/100);rare(≥1/10,000to<1/1,000);veryrare(<1/10,000),not

known(cannotbeestimatedfromtheavailabledata):

Nervoussystem

disorders Uncommon Somnolence,mainlymildor

moderateinnature

Common Headache,mainlymildor

moderateinnature

Carpaltunnelsyndrome

Gastrointestinal

disorders Uncommon Vomiting,mainlymildor

moderateinnature

Common Nausea,mainlymildormoderate

innature

Diarrhoea,mainlymildor

moderateinnature

Hepatobiliary

disorders Common Increasesinalkalinephosphates,

alanineaminotransferaseand

aspartateaminotransferase

Uncommon Elevatedgamma-GTandbilirubin

Hepatitis

Skinand

subcutaneoustissue

disorders Veryrare Erythemamultiforme

Stevens-Johnsonsyndrome

Allergicreactionsincluding

angioedema,urticariaand

anaphylaxis

Common Hairthinning,mainlymildor

moderateinnature

Rash,mainlymildormoderatein

nature

Musculoskeletal,

connectivetissue

andbonedisorders Common Jointpain/stiffness,mainlymild

ormoderateinnature

Metabolismand

nutritiondisorders Uncommon Anorexia,mainlymildinnature

Hypercholesterolaemia,mainly

mildormoderateinnature

Vasculardisorders Verycommon Hotflushes,mainlymildor

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*Vaginalbleedinghasbeenreporteduncommonly,mainlyinpatientswithadvancedbreastcancerduringthefirstfew

weeksafterchangingfromexistinghormonaltherapytotreatmentwithanastrozole.Ifbleedingpersists,further

evaluationshouldbeconsidered.

Asanastrozolelowerscirculatingoestrogenlevels,itmaycauseareductioninbonemineraldensityplacingsome

patientsatahigherriskoffracture(seesection4.4).

Thetablebelowpresentsthefrequencyofpre-specifiedadverseeventsintheATACstudy,irrespectiveofcausality,

reportedinpatientsreceivingtrialtherapyandupto14daysaftercessationoftrialtherapy.

Fractureratesof22per1000patient-yearsand15per1000patient-yearswereobservedfortheanastrozoleand

tamoxifengroups,respectively,afteramedianfollow-upof68months.Theobservedfracturerateforanastrozoleis

similartotherangereportedinage-matchedpostmenopausalpopulations.Ithasnotbeendeterminedwhethertherates

offractureandosteoporosisseeninATACinpatientsonanastrozoletreatmentreflectaprotectiveeffectoftamoxifen,

Generaldisorders

andadministration

siteconditions Common Asthenia,mainlymildor

moderateinnature

Reproductivesystem

andbreastdisorders Uncommon Vaginalbleeding,mainlymildor

moderateinnature*

Common Vaginaldryness,mainlymildor

moderateinnature

Adverseevents Anastrozole

(N=3092) Tamoxifen

(N=3094)

Hotflushes 1104(35.7%) 1264(40.9%)

Jointpain/stiffness 1100(35.6%) 911(29.4%)

Mooddisturbances 597(19.3%) 554(17.9%)

Fatigue/asthenia 575(18.6%) 544(17.6%)

Nauseaandvomiting 393(12.7%) 384(12.4%)

Fractures 315(10.2%) 209(6.8%)

Fracturesofthespine,hip,orwrist/Colles 133(4.3%) 91(2.9%)

Wrist/Collesfractures 67(2.2%) 50(1.6%)

Spinefractures 43(1.4%) 22(0.7%)

Hipfractures 28(0.9%) 26(0.8%)

Cataracts 182(5.9%) 213(6.9%)

Vaginalbleeding 167(5.4%) 317(10.2%)

Ischaemiccardiovasculardisease 127(4.1%) 104(3.4%)

Anginapectoris 71(2.3%) 51(1.6%)

Myocardialinfarct 37(1.2%) 34(1.1%)

Coronaryarterydisorder 25(0.8%) 23(0.7%)

Myocardialischaemia 22(0.7%) 14(0.5%)

Vaginaldischarge 109(3.5%) 408(13.2%)

Anyvenousthromboembolicevent 87(2.8%) 140(4.5%)

Deepvenousthromboembolicevents

includingPE 48(1.6%) 74(2.4%)

Ischaemiccerebrovascularevents 62(2.0%) 88(2.8%)

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Theincidenceofosteoporosiswas10.5%inpatientstreatedwithanastrozoleand7.3%inpatientstreatedwith

tamoxifen.

4.9Overdose

Thereislimitedclinicalexperienceofaccidentaloverdose.Inanimalstudies,anastrozoledemonstratedlowacute

toxicity.Clinicaltrialshavebeenconductedwithvariousdosagesofanastrozole,upto60mginasingledosegivento

healthymalevolunteersandupto10mgdailygiventopostmenopausalwomenwithadvancedbreastcancer,these

dosageswerewelltolerated.Asingledoseofanastrozolethatresultsinlife-threateningsymptomshasnotbeen

established.Thereisnospecificantidotetooverdoseandtreatmentmustbesymptomatic.

Inthemanagementofanoverdose,considerationshouldbegiventothepossibilitythatmultipleagentsmayhavebeen

taken.Vomitingmaybeinducedofthepatientisalert.Dialysismaybehelpfulbecauseanastrozoleisnothighly

proteinbound.Generalsupportivecare,includingfrequentmonitoringofvitalsignsandcloseobservationofthe

patient,isindicated.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Antineoplasticandimmunomodulatingagents-Endocrinetherapy-Hormoneantagonists

andrelatedagents-Enzymeinhibitors,ATCCode:L02BG03

Anastrozoleisapotentandhighlyselectivenon-steroidalaromataseinhibitor.Inpostmenopausalwomen,estradiolis

producedprimarilyfromtheconversionofandrostenedionetoestronethroughthearomataseenzymecomplexin

peripheraltissues.Estroneissubsequentlyconvertedtoestradiol.Reducingcirculatingestradiollevelhasbeenshown

toproduceabeneficialeffectinwomenwithbreastcancer.Inpostmenopausalwomen,anastrozoleatadailydoseof1

mgproducedestradiolsuppressionofgreaterthan80%usingahighlysensitiveassay.

Anastrozoledoesnotpossessanyprogestogenic,androgenicoroestrogenicactivity.

Dailydosesofanastrozoleupto10mgdonothaveanyeffectoncortisoloraldosteronesecretion,measuredbeforeor

afterstandardACTHchallengetesting.Corticoidsupplementsarethereforenotneeded.

Primaryadjuvanttreatmentofearlybreastcancer

InalargephaseIIIstudyconductedin9366postmenopausalwomenwithoperablebreatcancertreatmentfor5years,

anastrozolewasshowntobestatisticallysuperiortotamoxifenindisease-freesurvival.Agreatermagnitudeofbenefit

wasobservedfordisease-freesurvivalinfavourofanastrozoleversustamoxifenfortheprospectivelydefinedhormone

receptorpositivepopulation.Anastrozolewasstatisticallysuperiortotamoxifenintimetorecurrence.Thedifference

wasofevengreatermagnitudethanindisease-freesurvivalforboththeIntentionToTreat(ITT)populationand

hormonereceptorpositivepopulation.Anastrozolewasstatisticallysuperiortotamoxifenintermsoftimetodistant

recurrence.Theincidenceofcontralateralbreastcancerwasstatisticallyreducedforanastrozolecomparedto

tamoxifen.Following5yearsoftherapy,anastrozoleisatleastaseffectiveastamoxifenintermsofoverallsurvival.

However,duetolowdeathrates,additionalfollow-upisrequiredtodeterminemorepreciselythelong-termsurvival

foranastrozolerelativetotamoxifen.With68monthsmedianfollow-up,patientsintheATACstudyhavenotbeen

followedupforsufficienttimeafter5yearsoftreatment,toenableacomparisonoflong-termposttreatmenteffectsof

anastrozolerelativetotamoxifen.

ATACendpointsummary:5-yeartreatmentcompletionanalysis

Efficacyendpoints Numberofevents(frequency)

Intention-to-treatpopulation Hormone-receptor-positive

tumourstatus

Anastrozole

(N=3125) Tamoxifen

(N=3116) Anastrozole

(N=2618) Tamoxifen

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aDisease-freesurvivalincludesallrecurrenceeventsandisdefinedasthefirstoccurenceofloco-regionalrecurrence,

contralateralnewbreastcancer,distantrecurrenceordeath(foranyreason).

bDistantdisease-freesurvivalisdefinedasthefirstoccurenceofdistantrecurrenceordeath(foranyreason).

cTimetorecurrenceisdefinedasthefirstoccurenceofloco-regionalrecurrence,contralateralnewbreastcancer,

distantrecurrenceofdeathduetobreastcancer.

dTimetodistantrecurrenceisdefinedasthefirstoccurrenceofdistantrecurrenceordeathduetobreastcancer.

Disease-freesurvival a 575(18.4) 651(20.9) 424(16.2) 497(19.1)

Hazardratio 0.87 0.83

2-sided95%CI 0.78to

0.97 0.73to

0.94

p-value 0.0127 0.0049

Distantdisease-free

survival b 500(16.0) 530(17.0) 370(14.1) 394(15.2)

Hazardratio 0.94 0.93

2-sided95%CI 0.83to

1.06 0.80to

1.07

p-value 0.2850 0.2838

Timetorecurrence c 402(12.9) 498(16.0) 282(10.8) 370(14.2)

Hazardratio 0.79 0.74

2-sided95%CI 0.70to

0.90 0.64to

0.87

p-value 0.0005 0.0002

Timetodistant

recurrence d 324(10.4) 375(12.0) 226(8.6) 265(10.2)

Hazardratio 0.86 0.84

2-sided95%CI 0.74to

0.99 0.70to

1.00

p-value 0.0427 0.0559

Contralateralbreast

primary 35(1.1) 59(1.9) 26(1.0) 54(2.1)

Oddsratio 0.59 0.47

2-sided95%CI 0.39to

0.89 0.30to

0.76

p-value 0.0131 0.0018

Overallsurvival e 411(13.2) 420(13.5) 296(11.3) 301(11.6)

Hazardratio 0.97 0.97

2-sided95%CI 0.85to

1.12 0.83to

1.14

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Aswithalltreatmentdecisions,womenwithbreastcancerandtheirphysicianshouldassesstherelativebenefitsand

risksofthetreatment.

Whenanastrozoleandtamoxifenwereco-administered,theefficacyandsafetyweresimilartotamoxifenwhengiven

alone,irrespectiveofhormonereceptorstatus.Theexactmechanismofthisisnotyetclear.Itisnotbelievedtobedue

toareductioninthedegreeofestradiolsuppressionproducedbyanastrozole.

Adjuvanttreatmentofearlybreastcancerforpatientsbeingtreatedwithadjuvanttamoxifen

InaphaseIIItrial(ABCSG8)conductedin2579postmenopausalwomenwithhormonereceptorpositiveearlybreast

cancerwhohadreceivedsurgerywithorwithoutradiotherapyandnochemotherapy,switchingtoanastrozoleafter2

yearsadjuvanttreatmentwithtamoxifenwasstatisticallysuperiorindisease-freesurvivalwhencomparedtoremaining

ontamoxifen,afteramedianfollow-upof24months.

Timetoanyrecurrence,timetolocalordistantrecurrenceandtimetodistantrecurrenceconfirmedastatistical

advantageforanastrozole,consistentwiththeresultsofdisease-freesurvival.Theincidenceofcontralateralbreast

cancerwasverylowinthetwotreatmentarmswithanumericaladvantageforanastrozole.Overallsurvivalwassimilar

forthetwotreatmentgroups.

ABCSG8trialendpointandresultssummary

Efficacyendpoints Numberofevents(frequency)

Anastrozole

(N=1297) Tamoxifen

(N=1282)

Disease-freesurvival 65(5.0) 93(7.3)

Hazardratio 067

2-sided95%CI 0.49to

0.92

p-value 0.014

Timetoanyrecurrence 36(2.8) 66(5.1)

Hazardratio 0.53

2-sided95%CI 0.35

0.79

p-value 0.002

Timetolocalordistantrecurrence 29(2.2) 51(4.0)

Hazardratio 0.55

2-sided95%CI 0.35

0.87

p-value 0.011

Timetodistantrecurrence 22(1.7) 41(3.2)

Hazardratio 0.52

2-sided95%CI 0.31

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Twofurthersimilartrials(GABG/ARNO95andITA),inoneofwhichpatientshadreceivedsurgeryand

chemotherapy,aswellasacombinedanalysisofABCSG8andGABG/ARNO95,supportedtheseresults.

Theanastrozolesafetyprofileinthese3studieswasconsistentwiththeknownsafetyprofileestablishedin

postmenopausalwomenwithhormonereceptorpositiveearlybreastcancer.

5.2Pharmacokineticproperties

Absorptionofanastrozoleisrapidandmaximumplasmaconcentrationstypicallyoccurwithintwohoursofdosing

(underfastedconditions).Anastrozoleiseliminatedslowlywithaplasmaeliminationhalf-lifeof40to50hours.Food

slightlydecreasestheratebutnottheextentofabsorption.Thesmallchangeintherateofabsorptionisnotexpectedto

resultinaclinicallysignificanteffectonsteady-stateplasmaconcentrationsduringoncedailydosingofanastrozole

tablets.Approximately90to95%ofplasmaanastrozolesteady-stateconcentrationsareattainedafter7dailydoses.

Thereisnoevidenceoftimeordose-dependencyofanastrozolepharmacokineticparameters.

Anastrozolepharmacokineticsareindependentofageinpostomenopausalwomen.

Pharmacokineticshavenotbeenstudiedinchildren.

Anastrozoleisonly40%boundtoplasmaproteins.

Anastrozoleisextensivelymetabolisedbypostmenopausalwomenwithlessthan10%ofthedoseexcretedintheurine

unchangedwithin72hoursofdosing.MetabolismofanastrozoleoccursbyN-dealkylation,hydroxylationand

glucuronidation.Themetabolitesareexcretedprimarilyviatheurine.Triazole,themajormetaboliteinplasma,does

notinhibitaromatase.

Theapparentoralclearanceofanastrozoleinvolunteerswithstablehepaticcirrhosisorrenalimpairmentwasinthe

rangeobservedinhealthyvolunteers.

5.3Preclinicalsafetydata

Acutetoxicity

Inacutetoxicitystudiesinrodents,themedianlethaldoseofanastrozolewasgreaterthan100mg/kg/daybytheoral

routeandgreaterthan50mg/kg/daybytheintraperitonealroute.Inanoralacutetoxicitystudyinthedog,themedian

p-value 0.015

Newcontralateralbreastcancer 7(0.5) 15(1.2)

Oddsratio 0.46

2-sided95%CI 0.19to

1.13

p-value 0.090

Overallsurvival 43(3.3) 45(3.5)

Hazardratio 0.96

2-sided95%CI 0.63to

1.46

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Chronictoxicity

Multipledosetoxicitystudiesutilizedratsanddogs.Nono-effectlevelswereestablishedforanastrozoleinthetoxicity

studies,butthoseeffectsthatwereobservedatthelowdoses(1mg/kg/day)andmiddoses(dog3mg/kg/day;rat5

mg/kg/day)wererelatedtoeitherthepharmacologicalorenzyme-inducingpropertiesofanastrozoleandwere

unaccompaniedbysignificanttoxicordegenerativechanges.

Mutagenicity

Genetictoxicologystudieswithanastrozoleshowthatitisnotamutagenoraclastogen.

Reproductivetoxicology

Oraladministrationofanastrozoletofemaleratsproducedahighincidenceofinfertilityat1mg/kg/dayandincreased

pre-implantationlossat0.02mg/kg/day.Theseeffectswererelatedtothepharmacologyofthecompoundandwere

completelyreversedaftera5-weekcompoundwithdrawalperiod.

Oraladministrationofanastrozoletopregnantratsandrabbitscausednoteratogeniceffectsatdosesupto1.0and0.2

mg/kg/dayrespectively.Thoseeffectsthatwereseen(placentalenlargementinratsandpregnancyfailureinrabbits)

wererelatedtothepharmacologyofthecompound.

Thesurvivaloflittersborntoratsgivenanastrozoleat0.02mg/kg/dayandabove(fromday17ofpregnancytoday22

post-partum)wascompromised.Theseeffectswererelatedtothepharmacologicaleffectsofthecompoundon

parturition.Therewerenoadverseeffectsonbehaviourorreproductiveperformanceofthefirstgenerationoffspring

attributabletomaternaltreatmentwithanastrozole.

Carcinogenicity

Atwoyearratoncogenicitystudyresultedinanincreaseinincidenceofhepaticneoplasmsanduterinestromalpolyps

infemalesandthyroidadenomasinmalesatthehighdose(25mg/kg/day)only.Thesechangesoccuredatadose

whichrepresents100-foldgreaterexposurethanoccursathumantherapeuticdoses,andareconsiderednottobe

clinicallyrelevanttothetreatmentofpatientswithanastrozole.

Atwoyearmouseoncogenicitystudyresultedintheinductionofbenignovariantumoursandadisturbanceinthe

incidenceoflymphoreticularneoplasms(fewerhistiocyticsarcomasinfemalesandmoredeathsasaresultof

lymphomas).Thesechangesareconsideredtobemouse-specificeffectsofaromataseinhibitionandnotclinically

relevanttothetreatmentofpatientswithanastrozole.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

Microcrystallinecellulose

Lactosemonohydrate

PovidoneK25

Sodiumlaurilsulfate

Silica,colloidalanhydrous

Starch,Pregelatinized(maizestarch)

Croscarmellosesodium

Magensiumstearate

Coating:

HypromelloseE464

Lactosemonohydrate

TitaniumdioxideE171

Marcogol4000

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6.2Incompatibilities

Notapplicable

6.3ShelfLife

2years

6.4Specialprecautionsforstorage

Storebelow25°C

6.5Natureandcontentsofcontainer

PVC/PVdC/Alblister

Packsizes:28,30,100andhospitalpacksof3x28and3x30

Notallpacksizesmaybemarketed

6.6Specialprecautionsfordisposal

Nospecialrequirements

7MARKETINGAUTHORISATIONHOLDER

PlivaPharmaLimited

VisionHouse

BedfordRoad

Petersfield

Hampshire

GU323QB

8MARKETINGAUTHORISATIONNUMBER

PA585/36/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:24 th

July2009

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