ANASTROZOLE DOCPHARMA 1 Milligram Film Coated Tablet

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
ANASTRAZOLE
Available from:
Docpharma BVBA
INN (International Name):
ANASTRAZOLE
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Withdrawn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:
PA1506/001/001
Authorization date:
2012-11-27

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

AnastrozoleDocpharma1mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains1mganastrozoleasactivesubstance.

Excipients:Eachtabletcontains95mgoflactosemonohydrate(seesection4.4).

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

White,round,biconvex,film-coatedtablets.Debossedwith‘1’ononesideandplainonthereverseside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Anastrozoleisindicatedforthe:

Treatmentofhormonereceptor-positiveadvancedbreastcancerinpostmenopausalwomen.

Adjuvanttreatmentofpostmenopausalwomenwithhormonereceptorpositiveearlyinvasivebreastcancer.

Adjuvanttreatmentofearlybreastcancerinhormonereceptorpositivepostmenopausalwomenwhohave

received2to3yearsofadjuvanttamoxifen.

4.2Posologyandmethodofadministration

Posology:

Adultsincludingtheelderly: Therecommendeddoseofanastrozoleisone1mgtablet

onceaday.

Forpostmenopausalwomenwithhormonereceptor-positive

earlyinvasivebreastcancer,therecommendeddurationof

adjuvantendocrinetreatmentis5years.

Specialpopulations

Paediatricpopulation: Notrecommendedforuseinchildrenandadolescentsdueto

insufficientdataonsafetyandefficacy(seesections4.4and

5.1).

Renalimpairment: Nodosechangeisrecommendedinpatientswithmildor

moderaterenalimpairment.Inpatientswithsevererenal

impairment,administrationofAnastrozoleshouldbe

performedwithcaution(seesection4.4and5.2)

Hepaticimpairment: Nodosechangeisrecommendedinpatientswithmild

hepaticdisease.Cautionisadvisedinpatientwithmoderate

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Anastrozoleshouldbetakenorally.

4.3Contraindications

Anastrozoleiscontraindicatedin:

-pregnantorbreast-feedingwomen.

-patientswithsevererenalimpairment(creatinineclearancelessthan20ml/min)

-patientswithknownhypersensitivitytoanastrozoleortoanyoftheexcipientsasreferencedinsection6.1.

4.4Specialwarningsandprecautionsforuse

General:

Anastrozoleshouldnotbeusedinpremenopausalwomen.Themenopauseshouldbedefinedbiochemically

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

doubtabouthormonalstatus.TherearenodataavailablefortheuseofanastrozolewithLHRHanalogues.

Co-administrationoftamoxifenorestrogen-containingtherapieswithanastrozoleshouldbeavoidedasthismay

diminishitspharmacologicalaction(seesection4.5and5.1)

Effectonbonemineraldensity:

Asanastrozolelowerscirculatingoestrogenlevelsitmaycauseareductioninbonemineraldensitywithapossible

consequentincreasedriskoffracture(seesection4.8).

Womenwithosteoporosisoratriskofosteoporosis,shouldhavetheirbonemineraldensityformallyassessedatthe

commencementoftreatmentandatregularintervalsthereafter.Treatmentorprophylaxisforosteoporosisshouldbe

initiatedasappropriateandcarefullymonitored.Theuseofspecifictreatmentse.g.bisphosphates,maystopfurther

boneminerallosscausedbyanastrozoleinpostmenopausalwomenandcouldbeconsidered(seesection4.8).

Hepaticimpairment:

Anastrozolehasnotbeeninvestigatedinbreastcancerpatientswithmoderateorseverehepaticimpairment.Exposure

toanastrozolecanbeincreasedinsubjectswithhepaticimpairment(seesection5.2);administrationofAnastrozolein

patientswithmoderateandseverehepaticimpairmentshouldbeperformedwithcaution(seesection4.2).Treatment

shouldbebasedonabenefit-riskevaluationfortheindividualpatient.

Renealimpairment:

Anastrozolehasnotbeeninvestigatedinbreastcancerpatientswithsevererenalimpairment.Exposuretoanastrozole

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

renalimpairment,administrationofAnastrozoleshouldbeperformedwithcaution(seesection4.2).

Paediatricpopulation:

Anastrozoleisnotrecommendedforuseinchildrenassafetyandefficacyhavenotbeenestablishedinthisgroupof

patients(seesection5.1).

Anastrozoleshouldnotbeusedinboyswithgrowthhormonedeficiencyinadditiontogrowthhormonetreatment.In

thepivotalclinicaltrial,efficacywasnotdemonstratedandsafetywasnotestablished(seesection5.1).Since

anastrozolereducesestradiollevels,anastrozolemustnotbeusedingirlswithgrowthhormonedeficiencyinaddition

togrowthhormonetreatment.Long-termsafetydatainchildrenandadolescentsarenotavailable.

Hypersensitivitytolactose:

Thisproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactase

deficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

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AnastrozoleinhibitsCYPs1A2,2C8/9and3A4invitro.Clinicalstudieswithantipyrineandwarfarinshowedthat

anastrozoleata1mgdosedoesnotsignificantlyinhibitthemetabolismofantipyrineandR-andS-warfarin,indicating

thatco-administrationofanastrozolewithotherdrugsisunlikelytoresultinclinicallysignificantmedicinalproduct

interactionsmediatedbyCYPenzymes.

Theenzymesmediatingmetabolismofanastrozolehavenotbeenidentified.Cimetidine,aweak,unspecificinhibitor

ofCYPenzymes,didnotaffecttheplasmaconcentrationsofanastrozole.TheeffectofpotentCYPinhibitorsis

unknown.

Areviewoftheclinicaltrialsafetydatatbasedidnotrevealevidenceofclinicallysignificantinteractioninpatients

treatedwithanastrozolewhoalsoreceivedothercommonlyprescribedmedicinalproducts.Therewerenoclinically

significantinteractionswithbiphosphonates(seesection5.1)

Co-administrationoftamoxifenorestrogen-containingtherapieswithanastrozoleshouldbeavoidedasthismay

diminishitspharmacologicalaction(seesection4.4and5.1).

4.6Fertility,pregnancyandlactation

Pregnancy

Therearenodatafromtheuseofanastrozoleinpregnantwomen.Studiesinanimalshaveshownreproductivetoxicity

(seesection5.3).

Anastrozoleiscontraindicatedduringpregnancy(seesection4.3).

Breast-feeding

Therearenodataontheuseofanastrozoleduringlactation.Anastrozoleiscontraindicatedduringbreast-feeding(see

section4.3).

Fertility

Theeffectsofanastrozoleonfertilityinhumanshavenotbeenstudied.Studiesinanimalshaveshownreproductive

toxicity(seesection5.3).

4.7Effectsonabilitytodriveandusemachines

Anastrozolehasnoornegligibleinfluenceontheabilitytodriveandusemachines.However,astheniaandsomnolence

havebeenreportedwiththeuseofanastrozoleandcautionshouldbeobservedwhendrivingoroperatingmachinery

whilesuchsymptomspersist.

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),veryrare(<1/10,000)andnotknown(frequency

cannotbeestimatedfromtheavailabledata).Themostfrequentlyreportedadversereactionswereheadache,hot

flushes,nausea,rash,arthralgia,jointstiffness,arthritis,andastenia.

Table1AdversereactionsbySystemOrganClassandfrequency

SystemOrganClass Frequency AdverseDrugReactions

Metabolismandnutrition Common: Anorexia

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Nervoussystemdisorders Verycommon: Headache

Somnolence

CarpalTunnelSyndrome*

Vasculardisorders Verycommon: Hotflushes

Gastrointestinaldisorders Verycommon: Nausea

Common: Diarrhoea

Vomiting

Hepatobiliarydisorders Common: Increaseinalkalinephosphatase,alanineaminotransferase

andaspartateaminotransferase

Uncommon: Increaseingamma-GTandbilirubin

Skinandsubcutaneoustissuedisorders Verycommon: Rash

Common: Hairthinning(Alopecia),Allergicreactions

Uncommon: Urticaria

Rare: Erythemamultiforme,Anaphylactoidreaction,

Cutaneousvasculitis(includingsomereportsofHenoch-

Schonleinpurpura)**

Veryrare: Stevens-Johnsonsyndrome

Angiooedema

Musculoskeletalandconnectivetissuedisorders

VeryCommon: Arthralgia/jointstiffness

Arthritis

Osteoporosis

Common: Bonepain

Uncommon: Triggerfinger

Reproductivesystemandbreastdisorders

Common: Vaginaldryness

Vaginalbleeding***

Generaldisordersandadministrationsiteconditions

Verycommon: Asthenia

*EventsofCarpalTunnelSyndromehavebeenreportedinpatientsreceivingAnastrozoletreatmentinclinicaltrialsin

greaternumbersthanthosereceivingtreatmentwithtamoxifen.However,themajorityoftheseeventsoccurredin

patientswithidentifiableriskfactorsforthedevelopmentofthecondition.

**SincecutaneousvasculitisandHenoch-SchonleinpurpurawasnotobservedinATAC,thefrequencycategoryfor

theseeventscanbeconsideredas'Rare'(>0.01%and<0.1%)basedontheworstvalueofthepointestimate.

***Vaginalbleedinghasbeenreportedcommonly,mainlyinpatientswithadvancedbreastcancerduringthefirstfew

weeksafterchangingfromexistinghormonaltherapytotreatmentwithanastrozole.Ifbleedingpersists,further

evaluationshouldbeconsidered.

Table2:ATACstudypre-specifiedadverseevents

Thetablebelowpresentsthefrequencyofpre-specifiedadverseeventsintheATACstudy,irrespectiveofcausality,

reportedinpatientsreceivingtrialtherapyandupto14daysaftercessationoftrialtherapy.

Adverseevents Anastrozole

(N=3092) Tamoxifen

(N=3094)

Hotflushes 1104(35.7%) 1264(40.9%)

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Fractureratesof22per1000patient-yearsand15per1000patient-yearswereobservedfortheanastrozoleand

tamoxifengroups,respectively,afteramedianfollow-upof68months.Theobservedfracturerateforanastrozoleis

similartotherangereportedinage-matchedpostmenopausalpopulations.Ithasnotbeendeterminedwhethertherates

offractureandosteoporosisseeninATACinpatientsonanastrozoletreatmentreflectaprotectiveeffectoftamoxifen,

aspecificeffectofanastrozole,orboth.

Theincidenceofosteoporosiswas10.5%inpatientstreatedwithanastrozoleand7.3%inpatientstreatedwith

tamoxifen.

4.9Overdose

Thereislimitedclinicalexperienceofaccidentaloverdosage.Inanimalstudies,anastrozoledemonstratedlowacute

toxicity.Clinicaltrialshavebeenconductedwithvariousdosagesofanastrozole,upto60mginasingledosegivento

healthymalevolunteersandupto10mgdailygiventopostmenopausalwomenwithadvancedbreastcancer;these

dosageswerewelltolerated.Asingledoseofanastrozolethatresultsinlife-threateningsymptomshasnotbeen

established.Thereisnospecificantidotetooverdoseandtreatmentmustbesymptomatic.

Inthemanagementofanoverdose,considerationshouldbegiventothepossibilitythatmultipleagentsmayhavebeen

taken.Vomitingmaybeinducedifthepatientisalert.Dialysismaybehelpfulbecauseanastrozoleisnothighlyprotein

bound.Generalsupportivecare,includingfrequentmonitoringofvitalsignsandcloseobservationofthepatient,is

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%)

Ischaemiccardiovascular

disease 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%)

Deepvenous

thromboembolicevents

includingpulmonary

embolism 48(1.6%) 74(2.4%)

Ischaemiccerebrovascular

events 62(2.0%) 88(2.8%)

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Enzymeinhibitors

ATCcode:L02BG03

Mechanismofactionandpharmacodynamiceffects

Anastrozoleisapotentandhighlyselectivenon-steroidalaromataseinhibitor.Inpostmenopausalwomen,estradiolis

producedprimarilyfromtheconversionofandrostenedionetoestronethroughthearomataseenzymecomplexin

peripheraltissues.Estroneissubsequentlyconvertedtoestradiol.Reducingcirculatingestradiollevelshasbeenshown

toproduceabeneficialeffectinwomenwithbreastcancer.Inpostmenopausalwomen,anastrozoleatadailydoseof1

mgproducedestradiolsuppressionofgreaterthan80%usingahighlysensitiveassay.

Anastrozoledoesnotpossessanyprogestogenic,androgenicoroestrogenicactivity.Dailydosesofanastrozoleupto10

mgdonothaveanyeffectoncortisoloraldosteronesecretion,measuredbeforeorafterstandardadrenocorticotrophic

hormone(ACTH)challengetesting.Corticoidsupplementsarethereforenotneeded.

Clinicalefficacyandsafety

Advancedbreastcancer

First-linetherapyinpostmenopausalwomenwithadvancedbreastcancer

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

conductedtoassesstheefficacyofanastrozolecomparedwithtamoxifenasfirst-linetherapyforhormonereceptor-

positiveorhormonereceptor-unknownlocallyadvancedormetastaticbreastcancerinpostmenopausalwomen.Atotal

of1,021patientswererandomisedtoreceive1mgofanastrozoleoncedailyor20mgoftamoxifenoncedaily.The

primaryendpointsforbothtrialsweretimetotumourprogression,objectivetumourresponserate,andsafety.

Fortheprimaryendpoints,Study11033IL/0030showedthatanastrozolehadastatisticallysignificantadvantageover

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

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

responseratesweresimilarforanastrozoleandtamoxifen.Study1033IL/0027showedthatanastrozoleandtamoxifen

hadsimilarobjectivetumourresponseratesandtimetotumourprogression.Resultsfromthesecondaryendpoints

weresupportiveoftheresultsoftheprimaryefficacyendpoints.Thereweretoofewdeathsoccurringacrosstreatment

groupsofbothtrialstodrawconclusionsonoverallsurvivaldifferences.

Second-linetherapyinpostmenopausalwomenwithadvancedbreastcancer

Anastrozolewasstudiedintwocontrolledclinicaltrials(Study0004andStudy0005)inpostmenopausalwomenwith

advancedbreastcancerwhohaddiseaseprogressionfollowingtamoxifentherapyforeitheradvancedorearlybreast

cancer.Atotalof764patientswererandomisedtoreceiveeitherasingledoseof1mgor10mgofanastrozoleor

megestrolacetate40mgfourtimesaday.Timetoprogressionandobjectiveresponseratesweretheprimaryefficacy

variables.Therateofprolonged(morethan24weeks)stabledisease,therateofprogression,andsurvivalwerealso

calculated.Inbothstudiestherewerenosignificantdifferencesbetweentreatmentarmswithrespecttoanyofthe

efficacyparameters.

Adjuvanttreatmentofearlyinvasivebreastcancerforhormonereceptor-positivepatients

InalargephaseIIIstudyconductedin9366postmenopausalwomenwithoperablebreastcancertreatedfor5

years(seebelow),anastrozolewasshowntobestatisticallysuperiortotamoxifenindisease-freesurvival.Agreater

magnitudeofbenefitwasobservedfordisease-freesurvivalinfavourofanastrozoleversustamoxifenforthe

prospectivelydefinedhormonereceptorpositivepopulation.

Table3:ATACendpointsummary5-yeartreatmentcompletionanalysis

Efficacy

endpoints Numberofevents(frequency)

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population positivetumourstatus

Anastrozole

(N=3125) Tamofixen

(N=3116) Anastrozole

(N=2618) Tamoxifen

(N=2598)

Disease-free

survival a 575(18.4) 651(20.9) 424(16.2) 497(19.1)

Hazardratio 0.87 0.83

2-sided95%CI 0.78to0.97 0.73to0.94

p-value 0.0127 0.0049

Distantdisease-

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

Hazardratio 0.94 0.93

2-sided95%CI 0.83to1.06 0.80to1.07

p-value 0.2850 0.2838

Timeto

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

Hazardratio 0.79 0.74

2-sided95%CI 0.70to0.90 0.64to0.87

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 0.74to0.99 0.70to1.00

p-value 0.0427 0.0559

Contralateral

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

OddsRatio 0.59 0.47

2-sided95%CI 0.39to0.89 0.30to0.76

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 0.85to1.12 0.83to1.14

p-value 0.7142 0.7339

ATACendpointsummary5-yeartreatmentcompletionanalysis

Efficacy

endpoints Numberofevents(frequency)

Intention-to-treat

population Hormone-receptor-

positivetumourstatus

Anastrozole

(N=3125) Tamoxifen

(N=3116) Anastrozole

(N=2618) Tamoxifen

(N=2598)

Disease-free

survival a 575(18.4) 651(20.9) 424(16.2) 497(19.1)

Hazardratio 0.87 0.83

2-sided95%CI 0.78to0.97 0.73to0.94

p-value 0.0127 0.0049

Distantdisease-

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

Hazardratio 0.94 0.93

2-sided95%CI 0.83to1.06 0.80to1.07

p-value 0.2850 0.2838

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Disease-freesurvivalincludesallrecurrenceeventsandisdefinedasthefirst

occurrenceofloco-regionalrecurrence,contralateralnewbreastcancer,distant

recurrenceordeath(foranyreason).

Distantdisease-freesurvivalisdefinedasthefirstoccurrenceofdistantrecurrenceordeath(foranyreason).

Timetorecurrenceisdefinedasthefirstoccurrenceofloco-regionalrecurrence,contralateralnewbreastcancer,

distantrecurrenceordeathduetobreastcancer.

Timetodistantrecurrenceisdefinedasthefirstoccurrenceofdistantrecurrenceordeathduetobreastcancer.

Number(%)ofpatientswhohaddied.

Thecombinationofanastrozoleandtamoxifendidnotdemonstrateanyefficacybenefitsincomparisonwithtamoxifen

inallpatientsaswellasinthehormonereceptor-positivepopulation.Thistreatmentarmwasdiscontinuedfromthe

study.Withanupdatedfollow-upatamedianof10years,longtermcomparisonofthetreatmenteffectsofanastrozole

relativetotamoxifenwereshowntobeconsistentwithpreviousanalyses.

Adjuvanttreatmentofearlyinvasivebreastcancerforhormonereceptor-positivepatientsbeingtreatedwithadjuvant

tamoxifen

InaphaseIIItrial(AustrianBreastandColorectalCancerStudyGroup[ABCSG8]conductedin2579postmenopausal

womenwithhormonereceptorpositiveearlybreastcancerwhohadreceivedsurgerywithorwithoutradiotherapyand

nochemotherapy,(seebelow)switchingtoanastrozoleafter2yearsadjuvanttreatmentwithtamoxifenwasstatistically

superiorindisease-freesurvivalwhencomparedtoremainingontamoxifen,afteramedianfollow-upof24months.

Timetoanyrecurrence,timetolocalordistantrecurrenceandtimetodistantrecurrenceconfirmedastatistical

advantageforanastrozole,consistentwiththeresultsofdisease-freesurvival.Theincidenceofcontralateralbreast

cancerwasverylowinthetwotreatmentarmswithanumericaladvantageforanastrozole.Overallsurvivalwassimilar

recurrence c

Hazardratio 0.79 0.74

2-sided95%CI 0.70to0.90 0.64to0.87

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 0.74to0.99 0.70to1.00

p-value 0.0427 0.0559

Contralateral

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

OddsRatio 0.59 0.47

2-sided95%CI 0.39to0.89 0.30to0.76

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 0.85to1.12 0.83to1.14

p-value 0.7142 0.7339

Table4:ABCSG8trialendpointandresultsummary

Efficacyendpoints Numberofevents

(frequency)

Anastrozole

(N=1297) Tamoxifen

(N=1282)

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Twofurthersimilartrials(GABG/ARNO95andITA),inoneofwhichpatientshadreceivedsurgeryand

chemotherapy,aswellasacombinedanalysisofABCSG8andGABG/ARNO95,supportedtheseresults.The

anastrozolesafetyprofileinthese3studieswasconsistentwiththeknownsafetyprofileestablishedinpostmenopausal

womenwithhormonereceptorpositiveearlybreastcancer.

Bonemineraldensity(BMD)

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

womenwithhormonereceptor-positiveearlybreastcancerscheduledfortreatmentwithanastrozole1mg/daywere

stratifiedtolow,moderateandhighriskgroupsaccordingtotheirexistingriskoffragilityfracture.Theprimaryefficacy

parameterwastheanalysisoflumbarspinebonemassdensityusingDEXAscanning.Allpatientsreceivedtreatment

withvitaminDandcalcium.Patientsinthelowriskgroupreceivedanastrozolealone(N=42),thoseinthemoderate

group

Hazardratio 0.67

2-sided95%CI 0.49to0.92

p-value 0.014

Timetoanyrecurrence 36(2.8) 66(5.1)

Hazardratio 0.53

2-sided95%CI 0.35to0.79

p-value 0.002

TimetodistantRecurrence 29(2.2) 51(4.0)

HazardRatio 0.55

2-sided95%CI 0.35to0.87

p-value 0.011

Timetodistantrecurrence 22(1.7) 41(3.2)

Hazardratio 0.52

2-sided95%CI 0.31to0.88

p-value 0.015

Newcontralateralbreastcancer 7(0.5) 15(1.2)

Oddsratio 0.46

2-sided95%CI 0.19to1.13

p-value 0.090

Overallsurvival 43(3.3) 45(3.5)

Hazardratio 0.96

2-sided95%CI 0.63to1.46

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thoseinthehighriskgroupreceivedanastrozoleplusrisedronate35mgonceaweek(N=38).Theprimaryendpointwas

changefrombaselineinlumbarspinebonemassdensityat12months.

The12-monthmainanalysishasshownthatpatientsalreadyatmoderatetohighriskoffragilityfractureshowedno

decreaseintheirbonemassdensity(assessedbylumbarspinebonemineraldensityusingDEXAscanning)when

managedbyusinganastrozole1mg/dayincombinationwithrisedronate35mgonceaweek.

Inaddition,adecreaseinBMDwhichwasnotstatisticallysignificantwasseeninthelowriskgrouptreatedwith

anastrozole1mg/dayalone.Thesefindingsweremirroredinthesecondaryefficacyvariableofchangefrombaselinein

totalhipBMDat12

months.

Thisstudyprovidesevidencethattheuseofbisphosphonatescouldbeconsideredinthemanagementofpossiblebone

minerallossinpostmenopausalwomenwithearlybreastcancerscheduledtobetreatedwithAnastrozole.

Paediatricpopulation

Anastrozoleisnotindicatedforuseinchildrenandadolescents.Efficacyhasnotbeenestablishedinthepaediatric

populationsstudied(seebelow).Thenumberofchildrentreatedwastoolimitedtodrawanyreliableconclusionson

safety.Nodataonthepotentiallong-termeffectsofanastrozoletreatmentinchildrenandadolescentsareavailable(see

alsosection5.3).TheEuropeanMedicinesAgencyhaswaivedtheobligationtosubmittheresultsofstudieswith

anastrozoleinoneorseveralsubsetsofthepaediatricpopulationinshortstatureduetogrowthhormonedeficiency

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

ShortstatureduetoGrowthHormoneDeficiency

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

treatedfor12to36monthswithanastrozole1mg/dayorplaceboincombinationwithgrowthhormone.Only14

subjectsonanastrozolecompleted36months.

Nostatisticallysignificantdifferencefromplacebowasobservedforthegrowthrelatedparametersofpredictedadult

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

thenumberofchildrentreatedwastoolimitedtodrawanyreliableconclusionsonsafety,therewasanincreased

fracturerateandatrendtowardsreducedbonemineraldensityintheanastrozolearmcomparedtoplacebo.

Testotoxicosis

Anopen-label,non-comparative,multi-centrestudyevaluated14malepatients(aged2to9years)withfamilialmale-

limitedprecociouspuberty,alsoknownastestotoxicosis,treatedwithcombinationofanastrozoleandbicalutamide.

Theprimaryobjectivewastoassesstheefficacyandsafetyofthiscombinationregimenover12months.Thirteenout

ofthe14patientsenrolledcompleted12monthsofcombinationtreatment(onepatientwaslosttofollow-up).There

wasnosignificantdifferenceingrowthrateafter12monthsoftreatment,relativetothegrowthrateduringthe6

monthspriortoenteringthestudy.

Gynaecomastiastudies

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

gynaecomastiaofgreaterthan12monthsdurationtreatedwithanastrozole1mg/dayorplacebodailyforupto6

months.Nosignificantdifferenceinthenumberofpatientswhohada50%orgreaterreductionintotalbreastvolume

after6monthsoftreatmentwasobservedbetweentheanastrozole1mgtreatedgroupandtheplacebogroup.Trial

0001wasanopen-label,multiple-dosepharmacokineticstudyofanastrozole1mg/dayin36pubertalboyswith

gynaecomastiaoflessthan12monthsduration.Thesecondaryobjectivesweretoevaluatetheproportionofpatients

withreductionsfrombaselineinthecalculatedvolumeofgynaecomastiaofbothbreastscombinedofatleast50%

betweenday1andafter6monthsofstudytreatment,andpatienttolerabilityandsafety.Adecreasein50%ormoreof

totalbreastvolumewasseenin56%(20/36)oftheboysafter6months.

McCune-AlbrightSyndromestudy

Trial0046wasaninternational,multi-centre,open-labelexploratorytrialofanastrozolein28girls(aged2to 10

years)withMcCune-AlbrightSyndrome(MAS).Theprimaryobjectivewastoevaluatethesafetyandefficacyof

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fulfillingdefinedcriteriarelatingtovaginalbleeding,boneage,andgrowthvelocity.Nostatisticallysignificantchange

inthefrequencyofvaginalbleedingdaysontreatmentwasobserved.Therewerenoclinicallysignificantchangesin

Tannerstaging,meanovarianvolume,ormeanuterinevolume.Nostatisticallysignificantchangeintherateof

increaseinboneageontreatmentcomparedtotherateduringbaselinewasobserved.Growthrate(incm/year)was

significantlyreduced(p<0.05)frompre-treatmentthroughmonth0tomonth12,andfrompre-treatmenttothesecond

6months(month7tomonth12).

5.2Pharmacokineticproperties

Absorptionofanastrozoleisrapidandmaximumplasmaconcentrationstypicallyoccurwithintwohoursofdosing

(underfastedconditions).Foodslightlydecreasestheratebutnottheextentofabsorption.Thesmallchangeintherate

ofabsorptionisnotexpectedtoresultinaclinicallysignificanteffectonsteady-stateplasmaconcentrationsduring

oncedailydosingofanastrozole.Approximately90to95%ofplasmaanastrozolesteady-stateconcentrationsare

attainedafter7dailydoses,andaccumulationis3-to4-fold.Thereisnoevidenceoftimeordose-dependencyof

anastrozolepharmacokineticparameters.

Anastrozolepharmacokineticsareindependentofageinpostmenopausalwomen.

Anastrozoleisonly40%boundtoplasmaproteins.

Anastrozoleiseliminatedslowlywithaplasmaeliminationhalf-lifeof40to50hours.

Anastrozoleisextensivelymetabolisedbypostmenopausalwomenwithlessthan10%ofthedoseexcretedintheurine

unchangedwithin72hoursofdosing.MetabolismofanastrozoleoccursbyN-dealkylation,hydroxylationand

glucuronidation.Themetabolitesareexcretedprimarilyviatheurine.Triazole,themajormetaboliteinplasma,does

notinhibitaromatase.

Renalorhepaticimpairment

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

volunteerswithstablehepaticcirrhosisthaninmatchedcontrols(Study1033IL/0014).However,plasmaanastrozole

concentrationsinthevolunteerswithhepaticcirrhosiswerewithintherangeofconcentrationsseeninnormalsubjects

inothertrials.Plasmaanastrozoleconcentrationsobservedduringlong-termefficacytrialsinpatientswithhepatic

impairmentwerewithintherangeofplasmaanastrozoleconcentrationsseeninpatientswithouthepaticimpairment.

Theapparentclearance(CL/F)ofanastrozole,followingoraladministration,wasnotalteredinvolunteerswithsevere

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

primarilybymetabolism.Plasmaanastrozoleconcentrationsobservedduringlong-termefficacytrialsinpatientswith

renalimpairmentwerewithintherangeofplasmaanastrozoleconcentrationsseeninpatientswithoutrenalimpairment.

Inpatientswithsevererenalimpairment,administrationofanastrozoleshouldbeperformedwithcaution(see

section4.2and4.4).

Paediatricpopulation

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

eliminatedslowlywithahalf-lifeofapproximately2days.Clearanceofanastrozolewasloweringirls(3-10years)

thanintheolderboysandexposurehigher.Anastrozoleingirlswaswidelydistributedandslowlyeliminated.

5.3Preclinicalsafetydata

Non-clinicaldatarevealnospecialhazardforhumansbasedonconventionalstudiesofsafetypharmacology,repeated

dosetoxicity,genotoxicity,carcinogenicpotential,toxicitytoreproductionfortheindicatedpopulation.

Acutetoxicity

Inanimalstudiesadverseeffectswereonlyseenathighdoses.Inacutetoxicitystudiesinrodents,themedianlethal

doseofanastrozolewasgreaterthan100mg/kg/daybytheoralrouteandgreaterthan50mg/kg/daybythe

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Chronictoxicity

Inanimalstudiesadverseeffectswereonlyseenathighdoses.Multipledosetoxicitystudiesutilizedratsanddogs.No

no-effectlevelswereestablishedforanastrozoleinthetoxicitystudies,butthoseeffectsthatwereobservedatthelow

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

enzyme-inducingpropertiesofanastrozoleandwereunaccompaniedbysignificanttoxicordegenerativechanges.

Mutagenicity

Genetictoxicologystudieswithanastrozoleshowthatitisnotamutagenoraclastogen.

Reproductivetoxicology

Inafertilitystudyweanlingmaleratsweredosedorallywith50or400mg/lanastrozoleviatheirdrinkingwaterfor10

weeks.Measuredmeanplasma

concentrationswere44.4(±14.7)ng/mland165(±90)ng/mlrespectively.Matingindiceswereadverselyaffectedin

bothdosegroups,whilstareductioninfertilitywasevidentonlyatthe400mg/ldoselevel.Thereductionwastransient

asallmatingandfertilityparametersweresimilartocontrolgroupvaluesfollowinga9weektreatment-freerecovery

period.

Oraladministrationofanastrozoletofemaleratsproducedahighincidenceofinfertilityat1mg/kg/dayandincreased

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

excluded.Theseeffectswererelatedtothepharmacologyofthecompoundandwerecompletelyreversedaftera5-

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.Thesechangesoccurredatadose

whichrepresents100-foldgreaterexposurethanoccursathumantherapeuticdoses,andareconsiderednottobe

clinicallyrelevanttothetreatmentofpatientswithanastrozole.

Atwoyearmouseoncogenicitystudyresultedintheinductionofbenignovariantumoursandadisturbanceinthe

incidenceoflymphoreticularneoplasms(fewerhistiocyticsarcomasinfemalesandmoredeathsasaresultof

lymphomas).Thesechangesareconsideredtobemouse-specificeffectsofaromataseinhibitionandnotclinically

relevanttothetreatmentofpatientswithanastrozole.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

Lactosemonohydrate

Sodiumstarchglycolate(TypeA)

Magnesiumstearate

Filmcoating:

OpadryIIwhite85F18422consistingof

Poly(vinylalcohol)–partiallyhydrolysed

Titaniumdioxide

Macrogol3350

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6.2Incompatibilities

Notapplicable.

6.3Shelflife

2years

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions

6.5Natureandcontentsofcontainer

PVC/PVDCaluminiumblisters.

Packsizes:

20,28,30,84,98,100and300film-coatedtablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

DOCPHARMABVBA

Terhulpsesteenweg6A

1560Hoeilaart

Belgium

8MARKETINGAUTHORISATIONNUMBER

PA1506/1/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:22ndDecember2009

10DATEOFREVISIONOFTHETEXT

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Date Printed 16/11/2012 CRN 2121625 page number: 13

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