ARIMIDEX

Main information

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

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1500/069/001
  • Authorization date:
  • 29-10-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Arimidex1mgFilm-coatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains1mganastrozole.

Excipients:alsocontainslactosemonohydrate

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Film-coatedtablet.

ProductimportedfromtheUKandItaly:

White,biconvextabletwithalogoononesideandmarked'Adx1'ontheotherside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofearlybreastcancerinpostmenopausalwomenwhoarehormone-receptorpositive.

Treatmentofadvancedbreastcancerinpostmenopausalwomen.

4.2Posologyandmethodofadministration

Adultsincludestheelderly:

One1mgtablettobetakenorallyonceaday.

Children:

Arimidexisnotrecommendedforuseinchildrenduetoinsufficientdataonsafetyandefficacy(seesections4.4and

5.1).

RenalImpairment:Nodosechangeisrecommended.

HepaticImpairment:Nodosechangeisrecommended.

4.3Contraindications

Arimidexmustnotbeadministeredduringpregnancyorlactation.

PatientswithknownhypersensitivitytoanastrozoleortoanyoftheexcipientsreferencedinSection6.1.

4.4Specialwarningsandprecautionsforuse

Arimidexisnotrecommendedforuseinchildrenorinpremenopausalwomenassafetyandefficacyhavenotbeen

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Arimidexshouldnotbeusedinboyswithgrowthhormonedeficiencyinadditiontogrowthhormonetreatment.Inthe

pivotalclinicaltrial,efficacywasnotdemonstratedandsafetywasnotestablished(seesection5.1).Sinceanastrozole

reducesestradiollevels,Arimidexmustnotbeusedingirlswithgrowthhormonedeficiencyinadditiontogrowth

hormonetreatment.Long-termsafetydatainchildrenandadolescentsarenotavailable.

Arimidexhasnotbeeninvestigatedinpatientswithseverehepaticorsevererenalimpairment.Thepotential

risk/benefittosuchpatientsshouldbecarefullyconsideredbeforeadministrationofArimidex.

AsArimidexlowerscirculatingoestrogenlevels,itmaycauseareductioninbonemineraldensitywithapossible

consequentincreasedriskoffracture.Thispossibleincreasedriskshouldbemanagedaccordingtotreatmentguidelines

formanagingbonehealthinpostmenopausalwomen.

Thisproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactase

deficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Interactionwithothermedicinalproductsandotherformsofinteraction

Antipyrineandcimetidineclinicalinteractionstudiesindicatethattheco-administrationofArimidexwithotherdrugs

isunlikelytoresultinclinicallysignificantdruginteractionsmediatedbycytochromeP450.

Areviewoftheclinicaltrialsafetydatabasedidnotrevealevidenceofclinicallysignificantinteractioninpatients

treatedwithArimidexwhoalsoreceivedothercommonlyprescribeddrugs.Therewerenoclinicallysignificant

interactionswithbisphosphonates(seesection5.1).

Tamoxifenand/oroestrogen-containingtherapiesshouldnotbeco-administeredwithArimidexastheymaydiminish

itspharmacologicalaction.

4.6Fertility,pregnancyandlactation

Arimidexiscontraindicatedinpregnantorlactatingwomen.

4.7Effectsonabilitytodriveandusemachines

Arimidexisunlikelytoimpairtheabilityofpatientstodriveandoperatemachinery.However,astheniaand

somnolencehavebeenreportedwiththeuseofArimidexandcautionshouldbeobservedwhendrivingoroperating

machinerywhilesuchsymptomspersist.

4.8Undesirableeffects

Unlessspecified,thefollowingfrequencycategorieswerecalculatedfromthenumberofadverseeventsreportedina

largephaseIIIstudyconductedin9366postmenopausalwomenwithoperablebreastcancertreatedfor5yearsand

unlessspecified,noaccountwastakenofthefrequencywithinthecomparativetreatmentgrouporwhetherthe

investigatorconsideredittoberelatedtostudymedication.

SystemOrganClass Frequency Adversereaction

Metabolismand

nutrition Common

≥1/100to<1/10) Anorexia,mainlymildinnature

Hypercholesterolaemia,mainly

mildormoderateinnature

Nervoussystem

disorders Verycommon Headache,mainlymildor

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≥1/10)

Common

≥1/100to<1/10) Somnolence,mainlymildor

moderateinnature

CarpalTunnelSyndrome*

Vasculardisorders Verycommon

≥1/10) Hotflushes,mainlymildor

moderateinnature

Gastrointestinal

disorders Verycommon

≥1/10) Nausea,mainlymildor

moderateinnature

Common

≥1/100to<1/10) Diarrhoea,mainlymildor

moderateinnature

Vomiting,mainlymildor

moderateinnature

Hepatobiliary

disorders Common

≥1/100to<1/10) Increasesinalkaline

phosphatase,alanine

aminotransferaseandaspartate

aminotransferase

Uncommon

(1/1000to<1/100) Increasesingamma-GTand

bilirubin

Hepatitis

Skinand

subcutaneous

disorders Verycommon

≥1/10) Rash,mainlymildormoderate

innature

Common

≥1/100to<1/10) Hairthinning(Alopecia),mainly

mildormoderateinnature

Allergicreactions

Uncommon

(1/1000to<1/100) Urticaria

Rare

≥1/10,000to<

1/1000) Erythemamultiforme

Anaphylactoidreaction

Cutaneousvasculitis(including

somereportsofHenoch-

Schönleinpurpura)

Notknown Stevens-Johnsonsyndrome***

Angioedema***

Musculoskeletaland

connectivetissue

disorders Verycommon

≥1/10) Arthralgia/Jointstiffness

Arthritis

Common

≥1/100to<1/10) Bonepain

Uncommon

(1/1000to<1/100) Triggerfinger

Reproductivesystem

andbreastdisorders Common

≥1/100to<1/10) Vaginaldryness,mainlymildor

moderateinnature

Vaginalbleeding,mainlymild

ormoderateinnature**

Generaldisordersand

administrationsite Verycommon Asthenia,mainlymildor

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EventsofCarpalTunnelSyndromehavebeenreportedinpatientsreceivingArimidextreatmentinclinicaltrials

ingreaternumbersthatthosereceivingtreatmentwithtamoxifen.However,themajorityoftheseeventsoccurredin

patientswithidentifiableriskfactorsforthedevelopmentofthecondition.

Vaginalbleedinghasbeenreportedcommonly,mainlyinpatientswithadvancedbreastcancer,duringthefirst

fewweeksafterchangingfromexistinghormonaltherapytotreatmentwithArimidex.Ifbleedingpersists

furtherevaluationshouldbeconsidered.

***Cannotbeestimatedfromavailabledata.

Arimidexisapotentoestrogen-loweringagent.Lackofoestrogenisknowntoresultinlossofbonemineraldensity,

osteoporosisandanincreasedriskoffractures.

At68monthsmedianfollowup,intheearlybreastcancersettingthereportedincidenceofalladverseevents

(irrespectiveofcausality)offractureswas10.2%forArimidexand6.8%fortamoxifenandtheincidenceof

osteoporosiswas10.5%inpatientstreatedwithArimidexand7.3%inpatientstreatedwithtamoxifen.

Inalargeclinicalstudy,patientswithearlybreastcancerexperiencedmorefractureswhilsttreatedwithArimidexin

comparisontopatientstreatedwithtamoxifen(theincidenceofreportedfracturesregardlessofcausalityispresented

inSection5.1“PharmacodynamicProperties”).

4.9Overdose

ThereislimitedclinicalexperienceofoverdoseofArimidex.Therearenoreportswhereapatienthastakenadose

exceeding60mg.Notoxicitywasobservedandnoclinicallyrelevantadverseeffectshavebeenseen.

Acutetoxicitywasseeninanimalsatadosegreaterthen45mg/kg(equivalentto2.7g).Clinicaltrialshavebeen

conductedwithvariousdosagesofArimidex,upto60mginasingledosegiventohealthymalevolunteersandupto

10mgdailygiventopostmenopausalwomenwithadvancedbreastcancer;thesedosageswerewelltolerated.Asingle

doseofArimidexthatresultsinlife-threateningsymptomshasnotbeenestablished.Thereisnospecificantidoteto

overdosageandtreatmentmustbesymptomatic.Inthemanagementofanoverdose,considerationshouldbegivento

thepossibilitythatmultipleagentsmayhavebeentaken.Vomitingmaybeinducedifthepatientisalert.Dialysismay

behelpfulbecauseArimidexisnothighlyproteinbound.Generalsupportivecare,includingfrequentmonitoringof

vitalsignsandcloseobservationofthepatient,isindicated.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Arimidexisapotentandhighlyselectivenon-steroidalaromataseinhibitor.Inpostmenopausalwomen,estradiolis

producedprimarilyfromtheconversionofandrostenedionetoestronethroughthearomataseenzymecomplexin

peripheraltissues.

Estroneissubsequentlyconvertedtoestradiol.Reducingcirculatingestradiollevelshasbeenshowntoproducea

beneficialeffectinwomenwithbreastcancer.Inpostmenopausalwomen,Arimidexatadailydoseof1mgproduced

estradiolsuppressionofgreaterthan80%usingahighlysensitiveassay.

Arimidexdoesnotpossessanyprogestogenic,androgenicoroestrogenicactivity.

DailydosesofArimidexupto10mgdonothaveanyeffectoncortisoloraldosteronesecretion,measuredbeforeor

conditions

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AnextensivephaseIIIclinicalstudyprogrammeshowedthatArimidexisaneffectivetreatmentofhormone-receptor

positivebreastcancerinpostmenopausalwomen.

Primaryadjuvanttreatmentofearlybreastcancer

InalargephaseIIIstudyconductedin9366postmenopausalwomenwithoperablebreastcancerafteramedian

durationoftreatmentof60months,Arimidexwasshowntobestatisticallysuperiortotamoxifenindisease-free

survivalforpatientswithhormone-receptorpositivetumours(incidences=16.2%vs19.1%fortheArimidexand

tamoxifenarms,respectively,HR=0.83,95%CI=0.73to0.94).AbeneficialeffectofArimidexovertamoxifenin

disease-freesurvivalwasnotseeninpatientswithreceptornegativedisease.

TheincidenceofcontralateralbreastcancerswasstatisticallysignificantlyreducedforArimidexcomparedto

tamoxifenforpatientswithhormone-receptorpositivetumours(incidences=1.0%vs2.1%,OR=0.47,95%CI=0.30

to0.76).

Arimidexwasstatisticallysuperiortotamoxifenintimetorecurrence.Thedifferencewasofgreatermagnitudethanin

disease-freesurvivalforboththeIntentionToTreat(ITT)populationandhormone-receptorpositivepopulation.

Arimidexwasstatisticallysuperiortotamoxifenintermsoftimetodistantrecurrence.Therewasalsoanumerical

trendinfavourofArimidexfordistantdisease-freesurvivalbutthisresultwasnotstatisticallysignificant.

TheoverallsurvivalbenefitoftamoxifenwasmaintainedwithArimidex.Theadditionalanalysisoftimetodeath

followingrecurrenceshowedanumericaltrendinfavourofArimidexcomparedtotamoxifen,butthiswasanon-

statisticallysignificantadvantage.

Overall,Arimidexwaswelltolerated.Thefollowingadverseeventswerereportedregardlessofcausality.Patients

receivingArimidexhadadecreaseinhotflushes,vaginalbleeding,vaginaldischarge,endometrialcancer,venous

thromboemboliceventsandischaemiccerebrovasculareventscomparedwithpatientsreceivingtamoxifen.Patients

receivingArimidexhadanincreaseinjointdisorders(includingarthritis,arthrosisandarthralgia)andtheobserved

incidenceoffractureswashigherwithArimidexthanwithtamoxifen(10.2%vs6.8%,respectively),althoughthe

incidenceofhipfractures(thoseassociatedwiththegreatestdegreeofmorbidity/mortality)wassimilarbetweenthe2

groups(0.9%vs0.8%respectively).Afracturerateof22per1000patientyearswasobservedonArimidexand15per

1000patientyearswiththetamoxifengroupwithamedianfollowupof68months.ThefracturerateforArimidexfalls

withinthebroadrangeofthefractureratesreportedinanagematchedpostmenopausalpopulation.

ThecombinationofArimidexandtamoxifendidnotdemonstrateanyefficacybenefitincomparisontotamoxifen.

Adjuvanttreatmentofearlybreastcancerforpatientsbeingtreatedwithadjuvanttamoxifen

InaphaseIIItrial(ABCSG8)conductedin2579postmenopausalwomenwithhormonereceptorpositiveearlybreast

cancerbeingtreatedwithadjuvanttamoxifen,patientshadasuperiordisease-freesurvivalwhenswitchedtoArimidex

comparedwiththosecontinuingontamoxifen,afteramedianfollow-upof24months.

Timetoanyrecurrence,timetolocalordistantrecurrenceandtimetodistantrecurrenceconfirmedastatistical

advantageforArimidex,consistentwiththeresultsofdiseasefreesurvival.Theincidenceofcontralateralbreastcancer

wasverylowinthetwotreatmentarmswithanumericaladvantageforArimidex.Overallsurvivalwassimilarforthe

twotreatmentgroups.

Twofurthersimilartrials(GABG/ARNO95andITA)withArimidex,aswellasacombinedanalysisofABCSG8and

GABG/ARNO95,supportedtheseresults.

TheArimidexsafetyprofileinthese3studieswasconsistentwiththeknownsafetyprofileestablishedin

postmenopausalwomenwithhormonereceptorpositiveearlybreastcancer.

Studyofanastrozolewiththebisphosphonaterisedronate(SABRE)

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InthephaseIII/IVSABREstudy,234postmenopausalwomenwithhormonereceptorpositiveearlybreastcancer

scheduledfortreatmentwithArimidexwerestratifiedtolow,moderateandhighriskgroupsaccordingtotheirexisting

riskoffragilityfracture.AllpatientsreceivedtreatmentwithvitaminDandcalcium.Patientsinthelowriskgroup

receivedArimidexalone,thoseinthemoderategroupwererandomisedtoArimidexplusbisphosphonateorArimidex

plusplaceboandthoseinthehighriskgroupreceivedArimidexplusbisphosphonate.

The12-monthmainanalysishasshownthatpatientsalreadyatmoderatetohighriskoffragilityfracturehadtheirbone

health(assessedbybonemineraldensityandboneformationandresorptionmarkers)successfullymanagedbyusing

Arimidexincombinationwithabisphosphonate.

Inaddition,nochangesinBMDwereseeninthelowriskgrouptreatedwithArimidexaloneandgivenvitaminDand

calcium.ThesefindingsweremirroredinthesecondaryefficacyvariableofchangefrombaselineintotalhipBMDat

12months.

Thisstudyprovidesevidencethatpostmenopausalwomenwithearlybreastcancerscheduledtobetreatedwith

Arimidexshouldhavetheirbonestatusmanagedaccordingtotreatmentguidelinesalreadyavailablefor

postmenopausalwomenatsimilarriskoffragilityfracture.

Lipids

IntheSABREstudy,therewasaneutraleffectonplasmalipidsbothinthosepatientstreatedwithArimidexalone,and

inthosetreatedwithArimidexplusabisphosphonate.

Paediatrics

Arimidexisnotindicatedforuseinchildren.Efficacyhasnotbeenestablishedinthepaediatricpopulationsstudied

(seebelow).Thenumberofchildrentreatedwastoolimitedtodrawanyreliableconclusionsonsafety.Nodataonthe

potentiallong-termeffectsofanastrozoletreatmentinchildrenareavailable(seealsosection5.3).

TheEuropeanMedicinesAgencyhaswaivedtheobligationtosubmittheresultsofstudieswithArimidexinoneor

severalsubsetsofthepaediatricpopulationinshortstatureduetogrowthhormonedeficiency(GHD),testotoxicosis,

gynaecomastia,andMcCune-Albrightsyndrome.

ShortstatureduetoGrowthHormoneDeficiency

Arandomised,double-blind,multi-centrestudyevaluated52pubertalboys(aged11-16yearsinclusive)withGHD

treatedfor12to36monthswithArimidex1mg/dayorplaceboincombinationwithgrowthhormone.Only14subjects

onanastrozolecompleted36months.

After3yearsanastrozolewasfoundtostatisticallysignificantlyslowbonematurationinpubertalboysongrowth

hormonetherapy.Nostatisticallysignificantdifferencewithplacebowasobservedforthegrowthrelatedparametersof

predictedadultheight,height,heightSDS,andheightvelocity.Finalheightdatawerenotavailable.Whilethenumber

ofchildrentreatedwastoolimitedtodrawanyreliableconclusionsonsafety,therewasanincreasedfracturerateanda

trendtowardsreducedbonemineraldensityintheanastrozolearmcomparedtoplacebo.

Testotoxicosis

Anopen-label,non-comparative,multi-centrestudyevaluated14malepatients(aged2-9)withfamilialmale-limited

precociouspuberty,alsoknownastestotoxicosis,treatedwithcombinationofArimidexandbicalutamide.Theprimary

objectivewastoassesstheefficacyandsafetyofthiscombinationregimenover12months.Thirteenoutofthe14

patientsenrolledcompleted12monthsofcombinationtreatment(onepatientwaslosttofollow-up).Therewasno

significantdifferenceingrowthrateafter12monthsoftreatment,relativetothegrowthrateduringthe6monthsprior

toenteringthestudy.

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Trial0006wasarandomised,double-blind,multi-centrestudyof80pubertalboys(aged11-18yearsinclusive)with

gynaecomastiaofgreaterthan12monthsdurationtreatedwithArimidex1mg/dayorplacebodailyforupto6months.

Adecreaseof ≥50%intotalbreastvolumemeasuredbyultrasoundwasseenin38.5%(15/39)oftheArimidexand

31.4%(11/35)oftheplacebotreatedgroup(oddsratio=1.513,95%CI0.496to4.844,p=0.4687).

Trial0001wasanopenlabel,multiple-dosepharmacokinetic(PK)studyofArimidex1mg/dayin36pubertalboys

withgynaecomastiaoflessthan12monthsduration.Adecreaseintotalbreastvolumeof50%orgreaterat6months

wasseenin55.6%(20/36)oftheboys.

McCune-AlbrightSyndromestudy

Trial0046wasaninternational,multi-centre,openlabelexploratorytrialofArimidexin28girls(aged2to ≤10years)

withMcCune-AlbrightSyndrome.Nostatisticallysignificantchangeinthefrequencyofvaginalbleedingdayson

treatmentwasobserved.Ofthepatientswithbaselinevaginalbleeding,28%experienceda ≥50%reductioninthe

frequencyofbleedingdaysontreatment;40%experiencedacessationovera6monthperiodand12%experienceda

cessationovera12monthperiod.TherewerenoclinicallysignificantchangesinTannerstaging,meanovarianvolume

ormeanuterinevolume.Nostatisticallysignificantchangeintherateofincreaseinboneageontreatmentcomparedto

therateduringbaselinewasobserved.Growthrate(incm/year)wassignificantlyreduced(p<0.05)frompre-treatment

throughmonth0tomonth12andfrompre-treatmenttothesecond6months(month7tomonth12).

Theoverallassessmentoftheadverseeventsinchildrenlessthan18yearsofageraisednosafetyandtolerability

concerns.

5.2Pharmacokineticproperties

Absorptionofanastrozoleisrapidandmaximumplasmaconcentrationstypicallyoccurwithintwohoursofdosing

(underfastedconditions).Anastrozoleiseliminatedslowlywithaplasmaeliminationhalf-lifeof40to50hours.Food

slightlydecreasestheratebutnottheextentofabsorption.Thesmallchangeintherateofabsorptionisnotexpectedto

resultinaclinicallysignificanteffectonsteady-stateplasmaconcentrationsduringoncedailydosingofArimidex

tablets.Approximately90to95%ofplasmaanastrozolesteady-stateconcentrationsareattainedafter7dailydoses.

Thereisnoevidenceoftimeordose-dependencyofanastrozolepharmacokineticparameters.

Anastrozolepharmacokineticsareindependentofageinpostmenopausalwomen.

Inboyswithpubertalgynaecomastia,anastrozolewasrapidlyabsorbed,waswidelydistributedandwaseliminated

slowlywithahalf-lifeofapproximately2days.Pharmacokineticparametersinboyswerecomparabletothoseof

postmenopausalwomen.Clearanceofanastrozolewasloweringirlsthaninboysandexposurehigher.Anastrozolein

girlswaswidelydistributedandslowlyeliminated,withanestimatedhalf-lifeofapproximately0.8days.

Anastrozoleisonly40%boundtoplasmaproteins.

Anastrozoleisextensivelymetabolisedbypostmenopausalwomenwithlessthan10%ofthedoseexcretedintheurine

unchangedwithin72hoursofdosing.MetabolismofanastrozoleoccursbyN-dealkylation,hydroxylationand

glucuronidation.Themetabolitesareexcretedprimarilyviatheurine.Triazole,amajormetaboliteinplasmaandurine,

doesnotinhibitaromatase.

Theapparentoralclearanceofanastrozoleinvolunteerswithstablehepaticcirrhosisorrenalimpairmentwasinthe

rangeobservedinhealthyvolunteers.

5.3Preclinicalsafetydata

AcuteToxicity

Inacutetoxicitystudiesinrodentsthemedianlethaldoseofanastrozolewasgreaterthan100mg/kg/daybytheoral

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lethaldosewasgreaterthan45mg/kg/day.

ChronicToxicity

Multipledosetoxicitystudiesutilisedratsanddogs.Nono-effectlevelswereestablishedforanastrozoleinthetoxicity

studies,butthoseeffectsthatwereobservedatthelowdoses(1mg/kg/day)andmid-doses(dog3mg/kg/day;rat

5mg/kg/day)wererelatedtoeitherthepharmacologicalorenzyme-inducingpropertiesofanastrozoleandwere

unaccompaniedbysignificanttoxicordegenerativechanges.

Mutagenicity

Genetictoxicologystudieswithanastrozoleshowthatitisnotamutagenoraclastogen.

ReproductiveToxicology

Inafertilitystudyweanlingmaleratsweredosedorallywith50or400mg/lanastrozoleviatheirdrinkingwaterfor10

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

indiceswereadverselyaffectedinbothdosegroups,whilstareductioninfertilitywasevidentonlyatthe400mg/ldose

level.Thereductionwastransientasallmatingandfertilityparametersweresimilartocontrolgroupvaluesfollowing

a9-weektreatmentfreerecoveryperiod.

Oraladministrationofanastrozoletopregnantratsandrabbitscausednoteratogeniceffectsatdosesupto1and0.2

mg/kg/dayrespectively.Thoseeffectsthatwereseen(placentalenlargementinratsandpregnancyfailuresinrabbits)

wererelatedtothepharmacologyofthecompound.

Oraladministrationofanastrozoletofemaleratsproducedahighincidenceofinfertilityat1mg/kg/dayandincreased

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

completelyreversedaftera5-weekcompoundwithdrawalperiod.

Thesurvivaloflittersborntoratsgivenanastrozoleat0.02mg/kg/dayandabove(fromday17ofpregnancytoday22

post-partum)wascompromised.Theseeffectswererelatedtothepharmacologicaleffectsofthecompoundon

parturition.Therewerenoadverseeffectsonthebehaviourorreproductiveperformanceofthefirstgeneration

offspringattributabletomaternaltreatmentwithanastrozole.

Carcinogenicity

Atwoyearratoncogenicitystudyresultedinanincreaseinincidenceofhepaticneoplasmsanduterinestromalpolyps

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

whichrepresents100-foldgreaterexposurethanoccursathumantherapeuticdoses,andareconsiderednottobe

clinicallyrelevanttothetreatmentofpatientswithanastrozole.

Atwoyearmouseoncogenicitystudyresultedintheinductionofbenignovariantumoursandadisturbanceinthe

incidenceoflymphoreticularneoplasms(fewerhistiocyticsarcomasinfemalesandmoredeathsasaresultof

lymphomas).Thesechangesareconsideredtobemouse-specificeffectsofaromataseinhibitionandnotclinically

relevanttothetreatmentofpatientswithanastrozole.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactosemonohydrate

Povidone

SodiumStarchGlycolate

MagnesiumStearate

Hypromellose

Macrogol

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6.2Incompatibilities

Notapplicable.

6.3Shelflife

Theshelflifeexpirydateofthisproductisthedateshownontheblisterstripsandoutercartonoftheproductas

marketedinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove30°C.

Storeinoriginalpackage.

6.5Natureandcontentsofcontainer

Over-labelledcardboardcartoncontainingtwoPVC/aluminiumblisterstrips(14tabletsperblister).

Packsize:28tablets

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

ProfindWholesaleLtd

Unit625,KilshaneAvenue

NorthwestBusinessPark

Dublin15

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1500/69/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:29thofOctober2010

10DATEOFREVISIONOFTHETEXT

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