ANASTROZOLE 1 Milligram Film Coated Tablet

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
ANASTROZOLE
Available from:
Ranbaxy Ireland Limited
INN (International Name):
ANASTROZOLE
Dosage:
1 Milligram
Pharmaceutical form:
Film Coated Tablet
Prescription type:
Product subject to prescription which may not be renewed (A)
Authorization status:
Withdrawn
Authorization number:
PA0408/078/001
Authorization date:
2012-10-09

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Anastrozole1mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains1mganastrozole.

Excipient(s):Eachtabletcontains65mgofLactosemonohydrate(seesection4.4)

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

White,roundfilm-coatedtabletwithadiameterof6.6mmapproximately

4CLINICALPARTICULARS

4.1TherapeuticIndications

AnastrozoleTabletsareindicatedforthe:

Treatmentofhormonereceptor-positiveadvancedbreastcancerinpostmenopausalwomen.

4.2Posologyandmethodofadministration

Posology

TherecommendeddoseofAnastrozoleforadultsincludingtheelderlyisone1mgtabletonceaday.

Specialpopulations

Paediatricpopulation

Notrecommendedforuseinchildrenandadolescentsduetoinsufficientdataonsafetyandefficacy(seesections4.4

and5.1).

Renalimpairment

Nodosechangeisrecommendedinpatientswithmildormoderaterenalimpairment.

Inpatientswithsevererenalimpairment,administrationofAnastrozoleshouldbeperformedwithcaution(seesection

4.4and5.2).

Hepaticimpairment

Nodosechangeisrecommendedinpatientswithmildhepaticdisease.Cautionisadvisedinpatientswithmoderateto

severehepaticimpairment(seesection4.4).

Methodofadministration

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4.3Contraindications

Anastrozole1mgTabletsarecontraindicatedin:

Pregnantorbreast-feedingwomen

Patientswithknownhypersensitivitytoanastrozoleortoanyoftheexcipientsasreferencedinsection6.1

4.4Specialwarningsandprecautionsforuse

General

Anastrozoleshouldnotbeusedinpremenopausalwomen.Themenopauseshouldbedefinedbiochemically

(luteinizing-hormone[LH],folliclestimulatinghormone[FSH],and/orestradiollevels)inanypatientwherethereis

doubtaboutmenopausalstatus.TherearenodatatosupporttheuseofAnastrozolewithLHRHanalogues.

Co-administrationoftamoxifenorestrogen-containingtherapieswithAnastrozoleshouldbeavoidedasthismay

diminishitspharmacologicalaction(seesection4.5and5.1).Effectonbonemineraldensity

AsAnastrozolelowerscirculatingestrogenlevelsitmaycauseareductioninbonemineraldensitywithapossible

consequentincreasedriskoffracture(seesection4.8).

Womenwithosteoporosisoratriskofosteoporosis,shouldhavetheirbonemineraldensityformallyassessedatthe

commencementoftreatmentandatregularintervalsthereafter.Treatmentorprophylaxisforosteoporosisshouldbe

initiatedasappropriateandcarefullymonitored.Theuseofspecifictreatments,e.g.,bisphosphonates,maystopfurther

boneminerallosscausedbyAnastrozoleinpostmenopausalwomenandcouldbeconsidered(seesection4.8).

Hepaticimpairment

Anastrozole1mgTabletshasnotbeeninvestigatedinbreastcancerpatientswithmoderateorseverehepatic

impairment.Exposuretoanastrozolecanbeincreasedinsubjectswithhepaticimpairment(seesection5.2);

administrationofAnastrozoleinpatientswithmoderateandseverehepaticimpairmentshouldbeperformedwith

caution(seesection4.2).Treatmentshouldbebasedonabenefit-riskevaluationfortheindividualpatient.

Renalimpairment

Anastrozolehasnotbeeninvestigatedinbreastcancerpatientswithsevererenalimpairment.Exposuretoanastrozole

isnotincreasedinsubjectswithsevererenalimpairment(GRF<30ml/min,seesection5.2);inpatientswithsevere

renalimpairment,administrationofAnastrozoleshouldbeperformedwithcaution(seesection4.2).

Paediatricpopulation

Anastrozole1mgTabletsarenotrecommendedforuseinchildrenandadolescentsassafetyandefficacyhavenotbeen

establishedinthisgroupofpatients(seesection5.1).

Anastrozole1mgTabletsshouldnotbeusedinboyswithgrowthhormonedeficiencyinadditiontogrowthhormone

treatment.Inthepivotalclinicaltrial,efficacywasnotdemonstratedandsafetywasnotestablished(seesection5.1).

Sinceanastrozolereducesestradiollevels,Anastrozolemustnotbeusedingirlswithgrowthhormonedeficiencyin

additiontogrowthhormonetreatment.Long-termsafetydatainchildrenandadolescentsarenotavailable.

Hypersensitivitytolactose

Thisproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactase

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

AnastrozoleinhibitsCYPs1A2,2C8/9and3A4invitro.Clinicalstudieswithantipyrineandwarfarinshowedthat

anastrozoleata1mgdosedidnotsignificantlyinhibitthemetabolismofantipyrineandR–andS-warfarinindicating

theco-administrationofAnastrozole1mgTabletswithothermedicinalproductsisunlikelytoresultinclinically

significantmedicinalproductinteractionsmediatedbyCYPenzymes.

Theenzymesmediatingmetabolismofanastrozolehavenotbeenidentified.Cimetidine,aweak,unspecificinhibitorof

CYPenzymes,didnotaffecttheplasmaconcentrationsofanastrozole.TheeffectofpotentCYPinhibitorsisunknown.

Areviewoftheclinicaltrialsafetydatabasedidnotrevealevidenceofclinicallysignificantinteractioninpatients

treatedwithAnastrozolewhoalsoreceivedothercommonlyprescribedmedicinalproducts.Therewerenoclinically

significantinteractionswithbisphosphonates(seesection5.1).

Co-administrationoftamoxifenorestrogen-containingtherapieswithAnastrozoleshouldbeavoidedasthismay

diminishitspharmacologicalaction(seesection4.4and5.1).

4.6Fertility,pregnancyandlactation

Pregnancy

TherearenodatafromtheuseofAnastrozole1mgTabletsinpregnantwomen.Studiesinanimalshaveshown

reproductivetoxicity(seesection5.3).Anastrozoleiscontraindicatedduringpregnancy(seesection4.3).

Breast-feeding

TherearenodataontheuseofAnastrozole1mgTabletsduringlactation.Anastrozoleiscontraindicatedduringbreast-

feeding(seesection4.3).

Fertility

TheeffectsofAnastrozoleonfertilityinhumanshavenotbeenstudied.Studiesinanimalshaveshownreproductive

toxicity(seesection5.3).

4.7Effectsonabilitytodriveandusemachines

AnastrozoleTabletsHasnoornegligibleinfluenceontheabilitytodriveandusemachines.However,astheniaand

somnolencehavebeenreportedwiththeuseofAnastrozoleTabletsandcautionshouldbeobservedwhendrivingor

operatingmachinerywhilesuchsymptomspersist.

4.8Undesirableeffects

Thefollowingtablepresentsadversereactionsfromclinicaltrials,post-marketingstudiesorspontaneousreports.

Unlessspecified,thefrequencycategorieswerecalculatedfromthenumberofadverseeventsreportedinalargephase

IIIstudyconductedin9,366postmenopausalwomenwithoperablebreastcancergivenadjuvanttreatmentforfive

years(theAnastrozole,Tamoxifen,AloneorinCombination[ATAC]study).

AdversereactionslistedbelowareclassifiedaccordingtofrequencyandSystemOrganClass(SOC).Frequency

groupingsaredefinedaccordingtothefollowingconvention:verycommon(1/10),common(1/100to<1/10),

uncommon(1/1,000to<1/100),rare(1/10,000to<1/1,000),andveryrare(<1/10,000).Themostfrequently

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*EventsofCarpalTunnelSyndromehavebeenreportedinpatientsreceivingAnasrozole1mgTabletstreatmentin

clinicaltrialsingreaternumbersthanthosereceivingtreatmentwithtamoxifen.However,themajorityoftheseevents

occurredinpatientswithidentifiableriskfactorsforthedevelopmentofthecondition.

**SincecutaneousvasculitisandHenoch-SchönleinpurpurawasnotobservedinATAC,thefrequencycategoryfor

theseeventscanbeconsideredas‘Rare’(0.01%and<0.1%)basedontheworstvalueofthepointestimate.

***Vaginalbleedinghasbeenreportedcommonly,mainlyinpatientswithadvancedbreastcancerduringthefirstfew

weeksafterchangingfromexistinghormonaltherapytotreatmentwithAnastrozole1mgTablets.Ifbleedingpersists,

furtherevaluationshouldbeconsidered.

Thetablebelowpresentsthefrequencyofpre-specifiedadverseeventsintheATACstudyafteramedianfollow-upof

68months,irrespectiveofcausality,reportedinpatientsreceivingtrialtherapyandupto14daysaftercessationoftrial

AdversereactionsbySOCandfrequency

Metabolismandnutritiondisorders Common Anorexia

Hypercholesterolaemia

Nervoussystemdisorders Verycommon Headache

Common Somnolence

CarpalTunnelSyndrome*

Vasculardisorders Verycommon Hotflushes

Gastrointestinaldisorders Verycommon Nausea

Common Diarrhoea

Vomiting

Hepatobiliarydisorders Common Increasesinalkaline

phosphatase,alanine

aminotransferaseandaspartate

aminotransferase

Uncommon Increasesingamma-GTand

bilirubin

Hepatitis

Skinandsubcutaneoustissue

disorders Verycommon Rash

Common Hairthinning(alopecia)

Allergicreactions

Uncommon Urticaria

Rare Erythemamultiforme

Anaphylactoidreaction

Cutaneousvasculitis(including

somereportsofHenoch-

Schönleinpurpura)**

Veryrare Stevens-Johnsonsyndrome

Angioedema

Musculoskeletalandconnectivetissue

disorders Verycommon Arthralgia/jointstiffness

Arthritis

Osteoporosis

Common Bonepain

Uncommon Triggerfinger

Reproductivesystemandbreast

disorders Common Vaginaldryness

Vaginalbleeding***

Generaldisordersandadministration

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Table2ATACstudypre-specifiedadverseevents

Fractureratesof22per1000patient-yearsand15per1000patient-yearswere

observedfortheAnastrozole1mgfilm-coatedTabletsandtamoxifengroups,respectively,afteramedianfollow-upof

68months.TheobservedfracturerateforAnastrozoleTabletsissimilartotherangereportedinage-matched

postmenopausalpopulations.Theincidenceofosteoporosiswas10.5%inpatientstreatedwithAnastrozoleTablets

and7.3%inpatientstreatedwithtamoxifen

IthasnotbeendeterminedwhethertheratesoffractureandosteoporosisseeninATACinpatientsonanastrozole

Adverseeffects Anastrozole

(N=3,092) Tamoxifen

(N=3,094)

Hotflushes 1,104 (35.7%) 1,264 (40.9%)

Jointpain/stiffness 1,100 (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,or

wrist/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%)

Anyvenousthromboembolic

event 87(2.8%) 140(4.5%)

Deepvenousthromboembolic

eventsincludingPE

(pulmonaryembolism) 48(1.6%) 74(2.4%)

Ischaemiccerebrovascular

events 62(2.0%) 88(2.8%)

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4.9Overdose

Thereislimitedclinicalexperienceofaccidentaloverdose.Inanimalstudies,anastrozoledemonstratedlowacute

toxicity.Clinicaltrialshavebeenconductedwithvariousdosagesofanastrozole,upto60mginasingledosegivento

healthymalevolunteersandupto10mgdailygiventopostmenopausalwomenwithadvancedbreastcancer;these

dosageswerewelltolerated.Asingledoseofanastrozolethatresultsinlife-threateningsymptomshasnotbeen

established.Thereisnospecificantidotetooverdoseandtreatmentmustbesymptomatic.

Inthemanagementofanoverdose,considerationshouldbegiventothepossibilitythatmultipleagentsmayhavebeen

taken.Vomitingmaybeinducedifthepatientisalert.DialysismaybehelpfulbecauseAnastrozoleTabletsarenot

highlyproteinbound.

Generalsupportivecare,includingfrequentmonitoringofvitalsignsandcloseobservationofthepatient,isindicated.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:EnzymeInhibitors,ATCcode:L02BG03

Mechanismofactionandpharmacodynamiceffects

Anastrozoleisapotentandhighlyselectivenon-steroidalaromataseinhibitor.Inpostmenopausalwomen,estradiolis

producedprimarilyfromtheconversionofandrostenedionetoestronethroughthearomataseenzymecomplexpresent

inperipheraltissues.Estroneissubsequentlyconvertedtoestradiol.Reducingcirculatingestradiollevelshasbeen

showntoproduceabeneficialeffectinwomenwithbreastcancer.Inpostmenopausalwomen,anastrozoleatadaily

doseof1mgproducedestradiolsuppressionofgreaterthan80%usingahighlysensitiveassay.

Anastrozoledoesnotpossessanyprogestogenic,androgenicorestrogenicactivity.

DailydosesofAnastrozoleTabletsupto10mgdonothaveanyeffectoncortisoloraldosteronesecretion,measured

beforeorafterstandardadrenocorticotrophichormone(ACTH)challengetesting.Corticoidsupplementsaretherefore

notneeded.

Clinicalefficacyandsafety

Advancedbreastcancer

First-linetherapyinpostmenopausalwomenwithadvancedbreastcancer

Twodouble-blind,controlledclinicalstudiesofsimilardesign(Study1033IL/0030andStudy1033IL/0027)were

conductedtoassesstheefficacyofAnastrozolecomparedwithtamoxifenasfirst-linetherapyforhormonereceptor-

positiveorhormonereceptor-unknownlocallyadvancedormetastaticbreastcancerinpostmenopausalwomen.Atotal

of1,021patientswererandomisedtoreceive1mgofAnastrozoleoncedailyor20mgoftamoxifenoncedaily.The

primaryendpointsforbothtrialsweretimetotumourprogression,objectivetumourresponserate,andsafety.

Fortheprimaryendpoints,Study1033IL/0030showedthatAnastrozolehadastatisticallysignificantadvantageover

tamoxifenfortimetotumourprogression(Hazardratio(HR)1.42,95%ConfidenceInterval(CI)[1.11,1.82],Median

timetoprogression11.1and5.6monthsforAnastrozoleandtamoxifenrespectively,p=0.006);objectivetumour

responseratesweresimilarforAnastrozoleandtamoxifen.Study1033IL/0027showedthatAnastrozoleand

tamoxifenhadsimilarobjectivetumourresponseratesandtimetotumourprogression.Resultsfromthesecondary

endpointsweresupportiveoftheresultsoftheprimaryefficacyendpoints.Thereweretoofewdeathsoccurringacross

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Second-linetherapyinpostmenopausalwomenwithadvancedbreastcancer

Anastrozolewasstudiedintwocontrolledclinicaltrials(Study0004andStudy0005)inpostmenopausalwomenwith

advancedbreastcancerwhohaddiseaseprogressionfollowingtamoxifentherapyforeitheradvancedorearlybreast

cancer.Atotalof764patientswererandomisedtoreceiveeitherasingledailydoseof1mgor10mgofAnastrozoleor

megestrolacetate40mgfourtimesaday.Timetoprogressionandobjectiveresponseratesweretheprimaryefficacy

variables.Therateofprolonged(morethan24weeks)stabledisease,therateofprogression,andsurvivalwerealso

calculated.Inbothstudiestherewerenosignificantdifferencesbetweentreatmentarmswithrespecttoanyofthe

efficacyparameters.

BoneMineralDensity(BMD)

InthephaseIII/IV(StudyofAnastrozolewiththeBisphosphonateRisedronate[SABRE]),234postmenopausal

womenwithhormonereceptor-positiveearlybreastcancerscheduledfortreatmentwithAnastrozole1mg/daywere

stratifiedtolow,moderateandhighriskgroupsaccordingtotheirexistingriskoffragilityfracture.Theprimary

efficacyparameterwastheanalysisoflumbarspinebonemassdensityusingDEXAscanning.Allpatientsreceived

treatmentwithvitaminDandcalcium.PatientsinthelowriskgroupreceivedAnastrozolealone(N=42),thoseinthe

moderategroupwererandomisedtoAnastrozoleplusrisedronate35mgonceaweek(N=77)orAnastrozoleplus

placebo(N=77)andthoseinthehighriskgroupreceivedAnastrozoleplusrisedronate35mgonceaweek(N=38).The

primaryendpointwaschangefrombaselineinlumbarspinebonemassdensityat12months.

The12-monthmainanalysishasshownthatpatientsalreadyatmoderatetohighriskoffragilityfractureshowedno

decreaseintheirbonemassdensity(assessedbylumbarspinebonemineraldensityusingDEXAscanning)when

managedbyusingAnastrozole1mg/dayincombinationwithrisedronate35mgonceaweek.Inaddition,adecreasein

BMDwhichwasnotstatisticallysignificantwasseeninthelowriskgrouptreatedwithAnastrozole1mg/dayalone.

ThesefindingsweremirroredinthesecondaryefficacyvariableofchangefrombaselineintotalhipBMDat12

months.

Thisstudyprovidesevidencethattheuseofbisphosphonatescouldbeconsideredinthemanagementofpossiblebone

minerallossinpostmenopausalwomenwithearlybreastcancerscheduledtobetreatedwithAnastrozole.

Paediatricspopulation

AnastrozoleTabletsisnotindicatedforuseinchildrenandadolescents.Efficacyhasnotbeenestablishedinthe

paediatricpopulationsstudied(seebelow).Thenumberofchildrentreatedwastoolimitedtodrawanyreliable

conclusionsonsafety.Nodataonthepotentiallong-termeffectsofanastrozoletreatmentinchildrenandadolescents

areavailable(seealsosection5.3).

TheEuropeanMedicinesAgencyhaswaivedtheobligationtosubmittheresultsofstudieswithAnastrozoleTabletsin

oneorseveralsubsetsofthepaediatricpopulationinshortstatureduetogrowthhormonedeficiency(GHD),

testotoxicosis,gynaecomastia,andMcCune-Albrightsyndrome(seesection4.2).

ShortstatureduetoGrowthHormoneDeficiency

Arandomised,double-blind,multi-centrestudyevaluated52pubertalboys(aged11to16yearsinclusive)withGHD

treatedfor12to36monthswithAnastrozoleTablets1mg/dayorplaceboincombinationwithgrowthhormone.Only

14subjectsonanastrozolecompleted36months.

Nostatisticallysignificantdifferencewithplacebowasobservedforthegrowthrelatedparametersofpredictedadult

height,height,heightSDS(standarddeviationscore),andheightvelocity.Finalheightdatawerenotavailable.While

thenumberofchildrentreatedwastoolimitedtodrawanyreliableconclusionsonsafety,therewasanincreased

fracturerateandatrendtowardsreducedbonemineraldensityintheanastrozolearmcomparedtoplacebo.

Testotoxicosis

Anopen-label,non-comparative,multi-centrestudyevaluated14malepatients(aged2to9)withfamilialmale-limited

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primaryobjectivewastoassesstheefficacyandsafetyofthiscombinationregimenover12months.Thirteenoutofthe

14patientsenrolledcompleted12monthsofcombinationtreatment(onepatientwaslosttofollow-up).Therewasno

significantdifferenceingrowthrateafter12monthsoftreatment,relativetothegrowthrateduringthe6monthsprior

toenteringthestudy.

Gynaecomastiastudies

Trial0006wasarandomised,double-blind,multi-centrestudyof82pubertalboys(aged11-18yearsinclusive)with

gynaecomastiaofgreaterthan12monthsdurationtreatedwithanastrozole1mg/dayorplacebodailyforupto6

months.Nosignificantdifferenceinthenumberofpatientswhohada50%orgreaterreductionintotalbreastvolume

after6monthsoftreatmentwasobservedbetweentheanastrozole1mgtreatedgroupandtheplacebogroup.

Trial0001wasanopen-label,multiple-dosepharmacokineticstudyofanastrozole1mg/dayin36pubertalboyswith

gynaecomastiaoflessthan12monthsduration.Thesecondaryobjectivesweretoevaluatetheproportionofpatients

withreductionsfrombaselineinthecalculatedvolumeofgynaecomastiaofbothbreastscombinedofatleast50%

betweenday1andafter6monthsofstudytreatment,andpatienttolerabilityandsafety.Adecreasein50%ormoreof

totalbreastvolumewasseenin56%(20/36)oftheboysafter6months.

McCune-AlbrightSyndromestudy

Trial0046wasaninternational,multi-centre,open-labelexploratorytrialofAnastrozolin28girls(aged2to 10

years)withMcCune-AlbrightSyndrome(MAS).Theprimaryobjectivewastoevaluatethesafetyandefficacyof

anastrozole1mg/dayinpatientswithMAS.Theefficacyofstudytreatmentwasbasedontheproportionofpatients

fulfillingdefinedcriteriarelatingtovaginalbleeding,boneage,andgrowthvelocity.

Nostatisticallysignificantchangeinthefrequencyofvaginalbleedingdaysontreatmentwasobserved.Therewereno

clinicallysignificantchangesinTannerstaging,meanovarianvolume,ormeanuterinevolume.Nostatistically

significantchangeintherateofincreaseinboneageontreatmentcomparedtotherateduringbaselinewasobserved.

Growthrate(incm/year)wassignificantlyreduced(p<0.05)frompre-treatmentthroughmonth0tomonth12,and

frompre-treatmenttothesecond6months(month7tomonth12).

5.2Pharmacokineticproperties

Absorptionofanastrozoleisrapidandmaximumplasmaconcentrationstypicallyoccurwithintwohoursofdosing

(underfastedconditions)Foodslightlydecreasetheratebutnotintheextentofabsorption.Thesmallchangeinthe

rateofabsorptionisnotexpectedtoresultinaclinicallysignificanteffectonthesteady-stateplasmaconcentrations

duringoncedailydosingofAnastrozoletablets.Approximately90to95%ofplasmaanastrozolesteady-state

concentrationsareattainedafter7dailydoses,andaccumulationis3-to4-fold..Thereisnoevidenceofatimeordose-

dependencyofthepharmacokineticparametersofanastrozole.

Anastrozolepharmacokineticsareindependentofageinpostmenopausalwomen.

Anastrozoleisonly40%boundtoplasmaproteins.

Anastrozoleiseliminatedslowlywithaplasmaeliminationhalf-lifeof40to50hours.Anastrozoleisextensively

metabolisedbypostmenopausalwomenwithlessthan10%ofthedoseexcretedintheurineunchangedwithin72hours

ofdosing.MetabolismofanastrozoleoccursbyN-dealkylation,hydroxylationandglucuronidation.Themetabolites

areexcretedprimarilyviatheurine.Triazole,themajormetaboliteinplasma,doesnotinhibitaromatase.

Renalorhepaticimpairment

Theapparentclearance(CL/F)ofanastrozole,followingoraladministration,wasapproximately30%lowerin

volunteerswithstablehepaticcirrhosisthaninmatchedcontrols(Study1033IL/0014).However,plasmaanastrozole

concentrationsinthevolunteerswithhepaticcirrhosiswerewithintherangeofconcentrationsseeninnormalsubjects

inothertrials.Plasmaanastrozoleconcentrationsobservedduringlong-termefficacytrialsinpatientswithhepatic

impairmentwerewithintherangeofplasmaanastrozoleconcentrationsseeninpatientswithouthepaticimpairment.

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renalimpairment(GFR<30ml/min)inStudy1033IL/0018,consistentwiththefactthatanastrozoleiseliminated

primarilybymetabolism.Plasmaanastrozoleconcentrationsobservedduringlong-termefficacytrialsinpatientswith

renalimpairmentwerewithintherangeofplasmaanastrozoleconcentrationsseeninpatientswithoutrenalimpairment.

Inpatientswithsevererenalimpairment,administrationofArimidexshouldbeperformedwithcaution(seesection4.2

and4.4).

Paediatricpopulation

Inboyswithpubertalgynaecomastia(10-17years),anastrozolewasrapidlyabsorbed,waswidelydistributed,andwas

eliminatedslowlywithahalf-lifeofapproximately2days.Clearanceofanastrozolewasloweringirls(3-10years)

thanintheolderboysandexposurehigher.Anastrozoleingirlswaswidelydistributedandslowlyeliminated.

5.3Preclinicalsafetydata

Non-clinicaldatarevealnospecialhazardforhumansbasedonconventionalstudiesofsafetypharmacology,repeated

dosetoxicity,genotoxicity,carcinogenicpotential,toxicitytoreproductionfortheindicatedpopulation.

Acutetoxicity

Inanimalstudiestoxicitywasonlyseenathighdoses.Inacutetoxicitystudiesinrodents,themedianlethaldoseof

anastrozolewasgreaterthan100mg/kg/daybytheoralrouteandgreaterthan50mg/kg/daybytheintraperitoneal

route.Inanoralacutetoxicitystudyinthedog,themedianlethaldosewasgreaterthan45mg/kg/day.

Chronictoxicity

Inanimalstudiesadverseeffectswereonlyseenathighdoses.Multipledosetoxicitystudiesutilizedratsanddogs.No

no-effectlevelswereestablishedforanastrozoleinthetoxicitystudies,butthoseeffectsthatwereobservedatthelow

doses(1mg/kg/day)andmiddoses(dog3mg/kg/day;rat5mg/kg/day)wererelatedtoeitherthepharmacologicalor

enzymeinducingpropertiesofanastrozoleandwereunaccompaniedbysignificanttoxicordegenerativechanges.

Mutagenicity

Genetictoxicologystudiesperformedwithanastrozoleshowedthatitisneitheramutagennoraclastogen.

Reproductivetoxicology

Inafertilitystudyweanlingmaleratsweredosedorallywith50or400mg/lanastrozoleviatheirdrinkingwaterfor10

weeks.Measuredmeanplasmaconcentrationswere44.4(±14.7)ng/mland165(±90)ng/mlrespectively.Mating

indiceswereadverselyaffectedinbothdosegroups,whilstareductioninfertilitywasevidentonlyatthe400mg/l

doselevel.Thereductionwastransientasallmatingandfertilityparametersweresimilartocontrolgroupvalues

followinga9weektreatment-freerecoveryperiod.

Oraladministrationofanastrozoletofemaleratsproducedahighincidenceofinfertilityat1mg/kg/dayandincreased

pre-implantationlossat0.02mg/kg/day.Theseeffectsoccurredatclinicallyrelevantdoses.Aneffectinmancannotbe

excluded.Theseeffectswererelatedtothepharmacologyofthecompoundandwerecompletelyreversedaftera5-

weekcompoundwithdrawalperiod.

Oraladministrationofanastrozoletopregnantratsandrabbitscausednoteratogeniceffectsatdosesupto1.0and0.2

mg/kg/dayrespectively.Thoseeffectsthatwereseen(plancentalenlargementinratsandpregnancyfailureinrabbits)

wererelatedtothepharmacologyofthecompound.

Thesurvivaloflittersborntoratsgivenanastrozoleat0.02mg/kg/dayandabove(fromDay17ofpregnancytoDay22

post-partum)wascompromised.Theseeffectswererelatedtothepharmacologicaleffectsofthecompoundon

parturition.Therewerenoadverseeffectsonbehaviourorreproductiveperformanceofthefirstgenerationoffspring

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Carcinogenicity

Atwoyearratoncogenicitystudyresultedinanincreasesinincidenceofhepaticneoplasmsanduterinestromalpolyps

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

whichrepresents100-foldgreaterexposurethanoccursathumantherapeuticdosesandareconsiderednottobe

clinicallyrelevanttothetreatmentofpatientswithanastrozole.

Atwo-yearmouseoncogenicitystudyresultedintheinductionofbenignovariantumoursandadisturbanceinthe

incidenceoflymphoreticularneoplasms(fewerhistiocyticsarcomasinfemalesandmoredeathsasaresultof

lymphomas).Thesechangesareconsideredtobemouse-specificeffectsofaromataseinhibitionandnotclinically

relevanttothetreatmentofpatientswithanastrozole.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

Lactosemonohydrate

Maizestarch

PovidoneK-30

CellulosemicrocrystallinepH102

SodiumstarchglycolateTypeA

Silicacolloidalanhydrous

Magnesiumstearate(E572)

Talc

Film-coating:

Hypromellose5cp(E464)

Macrogol400

Titaniumdioxide(E171)

Talc

6.2Incompatibilities

Notapplicable.

6.3Shelflife

3years

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

PVC/Aluminiumblisters.

Packsizes:20,28,30,50,84,98,100and300tabletscontainedinacarton.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 26/07/2012 CRN 2103768 page number: 10

7MARKETINGAUTHORISATIONHOLDER

RanbaxyIreland

Spafield

CorkRoad

Cashel

Co.Tipperary

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA408/78/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:23rdApril2010

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 26/07/2012 CRN 2103768 page number: 11

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