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:
  • PA0408/078/001
  • Authorization date:
  • 23-04-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Anastrozole1mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains1mganastrozole.

Excipient(s):Eachtabletcontains65mgofLactosemonohydrate

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

White,roundfilm-coatedtabletwithadiameterof6.6mmapproximately

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofadvancedbreastcancerinpostmenopausalwomen.Efficacyhasnotbeendemonstratedinoestrogen-receptor

negativepatients,unlesstheyhavehadapreviouspositiveclinicalresponsetotamoxifen.

Adjuvanttreatmentofpostmenopausalwomenwithhormonereceptorpositiveearlyinvasivebreastcancer.

Adjuvanttreatmentofearlybreastcancerinhormonereceptorpositivepostmenopausalwomenwhohavereceived2to3yearsof

adjuvanttamoxifen.

4.2Posologyandmethodofadministration

Foradultsandelderlypatients1film-coatedtablettobetakenorallyonceaday.

Anastrozoleisnotrecommendedforuseinchildrenduetoinsufficientdataonsafetyandefficacy(seesections4.4and5.1)

Renalimpairment:Nodosechangeisrecommendedinpatientswithmildormoderaterenalimpairment.

Hepaticimpairment:Nodosechangeisrecommendedinpatientswithmildhepaticdisease.

Forearlydisease,therecommendeddurationoftreatmentshouldbe5years

4.3Contraindications

Anastrozole1mgTabletsarecontraindicatedin:

-premenopausalwomen

-pregnantorlactatingwomen.

-patientswithsevererenalimpairment(creatinineclearancelessthan

20ml/min).

-patientswithmoderateorseverehepaticdisease.

-patientswithknownhypersensitivitytoanastrozoleortoanyoftheexcipients

asreferencedinsection6.1.

Oestrogen-containingtherapiesshouldnotbeco-administeredwithAnastrozoleas

theywouldnegateitspharmacologicalaction.

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4.4Specialwarningsandprecautionsforuse

Anastrozoleisnotrecommendedforuseinchildrenassafetyandefficacyhavenotbeenestablishedinthisgroupofpatients(see

section5.1)

Anastrozoleshouldnotbeusedinboyswithgrowthhormonedeficiencyinadditiontogrowthhormonetreatment.Inthepivotal

clinicaltrial,efficacywasnotdemonstratedandsafetywasnotestablished(seesection5.1).Sinceanastrozolereducesestradiol

levels,Anastrozolemustnotbeusedingirlswithgrowthhormonedeficiencyinadditiontogrowthhormonetreatment.Long-term

safetydatainchildrenandadolescentsarenotavailable.

Themenopauseshouldbedefinedbiochemicallyinanypatientwherethereisdoubtabouthormonalstatus.

TherearenodatatosupportthesafeuseofAnastrozoleTabletsinpatientswithmoderateorseverehepaticimpairment,or

patientswithsevereimpairmentofrenalfunction(creatinineclearancelessthan20ml/min)

Womenwithosteoporosisoratriskofosteoporosis,shouldhavetheirbonemineraldensityformallyassessedbybonedensimetry

e.g.DEXAscanningatthecommencementoftreatmentandatregularintervalsthereafter.,Treatmentorprophylaxisfor

osteoporosisshouldbeinitiatedasappropriateandcarefullymonitored.

TherearenodataareavailablefortheuseofAnastrozolewithLHRHanalogues;thiscombinationshouldnotbeusedoutside

clinicaltrials.

AsAnastrozoleTabletslowercirculatingoestrogenlevelsitmaycauseareductioninbonemineraldensitywithapossible

consequentincreasedriskoffracture.theuseofbisphosphonatesmaystopfurtherbonemineraldensitylosscausedby

Anastrozoleinpostmenopausalwomenandcouldbeconsidered.

Thisproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyor

glucose-galactosemalabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Antipyrineandcimetidineclinicalinteractionstudiesindicatethattheco-administrationofAnastrozoleTabletswithotherdrugsis

unlikelytoresultinclinicallysignificantdruginteractionsmediatedbycytochromeP450.

Areviewoftheclinicaltrialsafetydatabasedidnotrevealevidenceofclinicallysignificantinteractioninpatientstreatedwith

AnastrozoleTabletswhoalsoreceivedothercommonlyprescribeddrugs.Therewerenoclinicallysignificantinteractionswith

bisphosphonates(seesection5.1).

Oestrogen-containingtherapiesshouldnotbeco-administeredwithAnastrozoleTabletsastheywouldnegateitspharmacological

action.Tamoxifenshouldnotbeco-administeredwithAnastrozoleTabletsasthismaydiminishitspharmacologicalaction(see

section4.3).

Tamoxifenshouldnotbeco-administeredwithAnastrozoleTablets,asthismaydiminishitspharmacologicalaction(seesection

4.3).

4.6Fertility,pregnancyandlactation

Anastrozoleiscontraindicatedinpregnantorlactatingwomen

4.7Effectsonabilitytodriveandusemachines

AnastrozoleTabletsareunlikelytoimpairtheabilityofthepatienttodriveandoperatemachinery.However,astheniaand

somnolencehavebeenreportedwiththeuseof[ProductName]andcautionshouldbeobservedwhendrivingoroperating

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4.8Undesirableeffects

Unlessspecified,thefollowingfrequencycategorieswerecalculatedfromthenumberofadverseeventsreportedinalargephase

IIIstudyconductedin9366postmenopausalwomenwithoperablebreastcancertreatedforfiveyears(ATACstudy).

SystemOrgan Frequency Adversereaction

Class

Metabolismand

nutrition Common( ≥1/100to

<1/10) Anorexia,mainlymildinnature

Hypercholesterolaemia,mainly

mildormoderateinnature

Nervoussystem

disorders Verycommon( ≥1/10) Headache,mainlymildor

moderateinnature

Common( ≥1/100to

<1/10) Somnolence,mainlymildor

moderateinnatureCarpalTunnel

Syndrome

Vasculardisorders Verycommon( ≥1/10) Hotflushes,mainlymildor

moderateinnature

Gastrointestinal

disorders Verycommon( ≥1/10) Nausea,mainlymildormoderate

innature

Common( ≥1/100to

<1/10) Diarrhoea,mainlymildor

moderateinnatureVomiting,

mainlymildormoderateinnature

Hepatobiliary

disorders Common( ≥1/100to

<1/10) Increasesinalkalinephosphatase,

alanineaminotransferaseand

aspartateaminotransferase

Uncommon( ≥1/1000to

<1/100) Increasesingamma-GTand

bilirubinHepatitis

Skinand

subcutaneous

disorders Verycommon( ≥1/10) Rash,mainlymildormoderatein

nature

Common( ≥1/100to

<1/10) Hairthinning(Alopecia),mainly

mildormoderateinnature

Allergicreactions

Uncommon Urticaria

≥1/1000to<1/100)

Rare( ≥1/10,000to

<1/1000) Erythemamultiforme

Anaphylactoidreaction

Notknown Stevens-Johnsonsyndrome**

Angioedema**

Musculoskeletaland

connectivetissue

disorders Verycommon( ≥1/10) Jointpain/stiffness,mainlymildor

moderateinnatureArthritis

Common Bonepain

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*Vaginalbleedinghasbeenreportedcommonly,mainlyinpatientswithadvancedbreastcancerduringthefirstfewweeksafter

changingfromexistinghormonaltherapytotreatmentwithAnastrozoleTablets.Ifbleedingpersists,furtherevaluationshouldbe

considered.

**Cannotbeestimatedfromtheavailabledata.

AsAnastrozoleTabletslowercirculatingoestrogenlevels,itmaycauseareductioninbonemineraldensityplacingsomepatients

atahigherriskoffracture(seesection4.4).Thetablebelowpresentsthefrequencyofpre-specifiedadverseeventsintheATAC

Uncommon Triggerfinger

≥1/1000to<1/100)

Reproductivesystem

andbreastdisorders Common( ≥1/100to

<1/10) Vaginaldryness,mainlymildor

moderateinnatureVaginal

bleeding,mainlymildormoderate

innature*

Generaldisorders

andadministration

siteconditions Verycommon( ≥1/10) Asthenia,mainlymildormoderate

innature

Adverseeffects

[ProductName]

(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,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%)

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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Fractureratesof22per1000patient-yearsand15per1000patient-yearswereobservedfortheAnastrozoleTabletsand

tamoxifengroups,respectively,afteramedianfollow-upof68months.TheobservedfracturerateforAnastrozoleTabletsis

similartotherangereportedinage-matchedpostmenopausalpopulations.Ithasnotbeendeterminedwhethertheratesoffracture

andosteoporosisseeninATACinpatientsonanastrozoletreatmentreflectaprotectiveeffectoftamoxifen,aspecificeffectof

anastrozole,orboth.

Theincidenceofosteoporosiswas10.5%inpatientstreatedwithAnastrozoleTabletsand7.3%inpatientstreatedwith

tamoxifen.

4.9Overdose

Thereislimitedclinicalexperienceofaccidentaloverdosage.Inanimalstudies,anastrozoledemonstratedlowacutetoxicity.

Clinicaltrialshavebeenconductedwithvariousdosagesofanastrozole,upto60mginasingledosegiventohealthymale

volunteersandupto10mgdailygiventopostmenopausalwomenwithadvancedbreastcancer;thesedosageswerewelltolerated.

Asingledoseofanastrozolethatresultsinlife-threateningsymptomshasnotbeenestablished.

Thereisnospecificantidotetooverdosageandtreatmentmustbesymptomatic.

Inthemanagementofanoverdose,considerationshouldbegiventothepossibilitythatmultipleagentsmayhavebeentaken.

Vomitingmaybeinducedifthepatientisalert.

DialysismaybehelpfulbecauseAnastrozoleTabletsarenothighlyproteinbound.

Generalsupportivecare,includingfrequentmonitoringofvitalsignsandcloseobservationofthepatient,isindicated.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

ATCcode:L02BG03(EnzymeInhibitors)

Anastrozoleisapotentandhighlyselectivenon-steroidalaromataseinhibitor.Inpostmenopausalwomen,estradiolisproduced

primarilyfromtheconversionofandrostenedionetoestronethroughthearomataseenzymecomplexpresentinperipheraltissues.

Estroneissubsequentlyconvertedtoestradiol.

Reducingthelevelsofcirculatingestradiolhasbeenshowntoproduceabeneficialeffectinwomenwithbreastcancer.In

postmenopausalwomen,anastrozoleatadailydoseof1mgsuppressedestradiollevelsbymorethan80%usingahighlysensitive

assay.

AnastrozoleTabletsdoesnotpossessanyprogestogenic,androgenicoroestrogenicactivity.

DailydosesofAnastrozoleTabletsupto10mgdonothaveanyeffectoncortisoloraldosteronesecretion,measuredbeforeor

afterstandardACTHchallengetesting.Corticoidsupplementsarethereforenotneededduringitsadministration.

Primaryadjuvanttreatmentofearlybreastcancer

InalargephaseIIIstudyconductedin9366postmenopausalwomenwithoperablebreastcancertreatedfor5years,Anastrozole

Tabletswasshowntobestatisticallysuperiortotamoxifenindiseasefreesurvival.Agreatermagnitudeofbenefitwasobserved

fordiseasefreesurvivalinfavourofAnastrozoleTabletsversustamoxifenfortheprospectivelydefinedhormonereceptorpositive

population.Anastrozolewasstatisticallysuperiortotamoxifenintimetorecurrence.Thedifferencewasofevengreater

magnitudethanindiseasefreesurvivalforboththeIntentionToTreat(ITT)populationandhormonereceptorpositivepopulation

AnastrozoleTabletswasstatisticallysuperiortotamoxifenintermsoftimetodistantrecurrence.Theincidenceofcontralateral

breastcancerwasstatisticallyreducedforAnastrozolecomparedtotamoxifen.Following5yearsoftherapy,anastrozoleisat

leastaseffectiveastamoxifenintermsofoverallsurvival.However,duetolowdeathrates,additionalfollow-upisrequiredto

determinemorepreciselythelong-termsurvivalforanastrozolerelativetotamoxifen.With68monthsmedianfollow-up,patients

intheATACstudyhavenotbeenfollowedupforsufficienttimeafter5yearsoftreatment,toenableacomparisonoflong-term

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aDisease-freesurvivalincludesallrecurrenceeventsandisdefinedasthefirstoccurrenceofloco-regionalrecurrence,

contralateralnewbreastcancer,distantrecurrenceordeath(foranyreason).

bDistantdisease-freesurvivalisdefinedasthefirstoccurrenceofdistantrecurrenceordeath(foranyreason).

cTimetorecurrenceisdefinedasthefirstoccurrenceofloco-regionalrecurrence,contralateralnewbreastcancer,distant

recurrenceordeathduetobreastcancer.

dTimetodistantrecurrenceisdefinedasthefirstoccurrenceofdistantrecurrenceordeathduetobreastcancer.

eNumber(%)ofpatientswhohaddied.

Aswithalltreatmentdecisions,womenwithbreastcancerandtheirphysicianshouldassesstherelativebenefitsandrisksofthe

treatment.

WhenAnastrozoleTabletsandtamoxifenwereco-administered,theefficacyandsafetyweresimilartotamoxifenwhengiven

alone,irrespectiveofhormonereceptorstatus.Theexactmechanismofthisisnotyetclear.Itisnotbelievedtobeduetoa

ATACendpointsummary:5-yeartreatmentcompletionanalysis

Efficacyendpoints Numberofevents(frequency)

Intention-to-treat

population Hormone-receptor-

positivetumourstatus

Anastrozole

Tablets

(N=3125) Tamoxifen

(N=3116) Anastrozole

Tablets

(N=2618) Tamoxifen

(N=2598)

Disease-freesurvival 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-free

survival 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

Timetorecurrence 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

Contralateralbreast

primary 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

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Adjuvanttreatmentofearlybreastcancerforpatientsbeingtreatedwithadjuvanttamoxifen

InaphaseIIItrial(ABCSG8)conductedin2579postmenopausalwomenwithhormonereceptorpositiveearlybreastcancerwho

hadreceivedsurgerywithorwithoutradiotherapyandnochemotherapy,switchingtoAnastrozoleafter2yearsadjuvanttreatment

withtamoxifenwasstatisticallysuperiorindisease-freesurvivalwhencomparedtoremainingontamoxifen,afteramedian

follow-upof24months.

Timetoanyrecurrence,timetolocalordistantrecurrenceandtimetodistantrecurrenceconfirmedastatisticaladvantagefor

Anastrozole,consistentwiththeresultsofdisease-freesurvival.Theincidenceofcontralateralbreastcancerwasverylowinthe

twotreatmentarmswithanumericaladvantageforAnastrozole.Overallsurvivalwassimilarforthetwotreatmentgroups.

Twofurthersimilartrials(GABG/ARNO95andITA),inoneofwhichpatientshadreceivedsurgeryandchemotherapy,aswell

asacombinedanalysisofABCSG8andGABG/ARNO95,supportedtheseresults.

TheAnastrozoleTabletssafetyprofileinthese3studieswasconsistentwiththeknownsafetyprofileestablishedin

ABCSG8trialendpointandresultssummary

Efficacyendpoints Numberofevents(frequency)

AnastrozoleTablets

(N=1297) Tamoxifen

(N=1282)

Disease-freesurvival 65(5.0) 93(7.3)

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

Timetolocalordistant

recurrence 29(2.2) 51(4.0)

Hazardratio 0.55

2-sided95%CI 0.35to0.87

p-value 0.011

Timetodistant

recurrence 22(1.7) 41(3.2)

Hazardratio 0.52

2-sided95%CI 0.31to0.88

p-value 0.015

Newcontralateralbreast

cancer 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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Studyofanastrozolewiththebisphosphonaterisedronate(SABRE)

BoneMineralDensity(BMD)

InthephaseIII/IVSABREstudy,234postmenopausalwomenwithhormonereceptorpositiveearlybreastcancerscheduledfor

treatmentwithAnastrozoleTablets1mg/daywerestratifiedtolow,moderateandhighriskgroupsaccordingtotheirexistingrisk

offragilityfracture.TheprimaryefficacyparameterwastheanalysisoflumbarspinebonemassdensityusingDEXAscanning.

AllpatientsreceivedtreatmentwithvitaminDandcalcium.PatientsinthelowriskgroupreceivedAnastrozoleTabletsalone

(N=42),thoseinthemoderategroupwererandomisedtoAnastrozoleplusrisedronate35mgonceaweek(N=77)orAnastrozole

Tabletsplusplacebo(N=77)andthoseinthehighriskgroupreceived[ProductName]plusrisedronate35mgonceaweek

(N=38).Theprimaryendpointwaschangefrombaselineinlumbarspinebonemassdensityat12months.

The12-monthmainanalysishasshownthatpatientsalreadyatmoderatetohighriskoffragilityfractureshowednodecreasein

theirbonemassdensity(assessedbylumbarspinebonemineraldensityusingDEXAscanning)whenmanagedbyusing

AnastrozoleTablets1mg/dayincombinationwithrisedronate35mgonceaweek.Inaddition,adecreaseinBMDwhichwasnot

statisticallysignificantwasseeninthelowriskgrouptreatedwithAnastrozoleTablets1mg/dayalone.Thesefindingswere

mirroredinthesecondaryefficacyvariableofchangefrombaselineintotalhipBMDat12months.

Thisstudyprovidesevidencethattheuseofbisphosphonatesshouldbeconsideredinthemanagementofpossiblebonemineral

lossinpostmenopausalwomenwithearlybreastcancerscheduledtobetreatedwithAnastrozoleTablets.

Lipids

IntheSABREstudytherewasaneutraleffectonplasmalipidsinthosepatientstreatedwithAnastrozoleplusrisedronate.

Paediatrics

AnastrozoleTabletsarenotindicatedforuseinchildren.Efficacyhasnotbeenestablishedinthepaediatricpopulationsstudied

(seebelow).Thenumberofchildrentreatedwastoolimitedtodrawanyreliableconclusionsonsafety.Nodataonthepotential

long-termeffectsofanastrozoletreatmentinchildrenareavailable(seealsosection5.3).

TheEuropeanMedicinesAgencyhaswaivedtheobligationtosubmittheresultsofstudieswithAnastrozoleTabletsinoneor

severalsubsetsofthepaediatricpopulationinshortstatureduetogrowthhormonedeficiency(GHD),testotoxicosis,

gynaecomastia,andMcCune-Albrightsyndrome.

ShortstatureduetoGrowthHormoneDeficiency

Arandomised,double-blind,multi-centrestudyevaluated52pubertalboys(aged11-16yearsinclusive)withGHDtreatedfor12

to36monthswithAnastrozoleTablets1mg/dayorplaceboincombinationwithgrowthhormone.Only14subjectson

anastrozolecompleted36months.

After3yearsanastrozolewasfoundtostatisticallysignificantlyslowbonematurationinpubertalboysongrowthhormone

therapy.Nostatisticallysignificantdifferencewithplacebowasobservedforthegrowthrelatedparametersofpredictedadult

height,height,heightSDS,andheightvelocity.Finalheightdatawerenotavailable.Whilethenumberofchildrentreatedwastoo

limitedtodrawanyreliableconclusionsonsafety,therewasanincreasedfracturerateandatrendtowardsreducedbonemineral

densityintheanastrozolearmcomparedtoplacebo.

Testotoxicosis

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

puberty,alsoknownastestotoxicosis,treatedwithcombinationofAnastrozoleandbicalutamide.Theprimaryobjectivewasto

assesstheefficacyandsafetyofthiscombinationregimenover12months.Thirteenoutofthe14patientsenrolledcompleted12

monthsofcombinationtreatment(onepatientwaslosttofollow-up).Therewasnosignificantdifferenceingrowthrateafter12

monthsoftreatment,relativetothegrowthrateduringthe6monthspriortoenteringthestudy.

Gynaecomastiastudies

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

gynaecomastiaofgreaterthan12monthsdurationtreatedwithanastrozole1mg/dayorplacebodailyforupto6months.No

significantdifferenceinthenumberofpatientswhohada50%orgreaterreductionintotalbreastvolumeafter6monthsof

treatmentwasobservedbetweentheanastrozole1mgtreatedgroupandtheplacebogroup.

Trial0001wasanopen-label.Multiple-dosepharmacokineticstudyofanastrozole1mg/dayin36pubertalboyswith

gynaecomastiaoflessthan12monthsduration.Thesecondaryobjectivesweretoevaluatetheproportionofpatientswith

reductionsfrombaselineinthecalculatedvolumeofgynaecomastiaofbothbreastscombinedofatleast50%betweenday1and

after6monthsofstudytreatmentandpatienttolerabilityandsafety.

Apharmacodynamicsubpopulationof25boyswasselectedinthisstudytoexplorethepontentialbenefitsofanastrozole.Itwas

notedadecreaseintotalbreastvolumeof50%orgreaterat6monthswasseenin55.6%(asmeasuredbyultrasound)and77.8%

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McCune-AlbrightSyndromestudy

Trial0046wasaninternational,multi-centre,open-labelexploratorytrialofanastrozolein28girls(aged2to ≤10years)with

McCune-AlbrightSyndrome(MAS).Theefficacyofstudytreatmentwasbasedontheproportionofpatientsfulfillingdefined

criteriarelatingtovaginalbleeding,boneageandgrowthvelocity.

Nostatisticallysignificantchangeinthefrequencyofvaginalbleedingdaysontreatmentwasobserved.Therewerenoclinically

significantchangesinTannerstaging,meanovarianvolumeormeanuterinevolume.Nostatisticallysignificantchangeintherate

duringbaselinewasobserved.Growthrate(incm/year)wassignificantlyreduced(p<0.05)frompre-treatmentthroughmonth0to

month12,andfrompre-treatmenttothesecond6months(month7tomonth12).Ofthepatientswithbaselinevaginalbleeding,

28%experienceda ≥50%reductioninthefrequencyofbleedingdaysontreatment;40%experiencedacessationovera6-month

period,and12%experiencedacessationovera12-monthperiod.

Theoverallassessmentoftheadverseeventsinchildrenlessthan18yearsofageraisednosafetyortolerabilityconcerns.

5.2Pharmacokineticproperties

Absorptionofanastrozole,theactivesubstanceofAnastrozoleTablets,israpid.Maximumplasmaconcentrationstypicallyoccur

withintwohoursofdosingifthemedicineisgivenunderfastingconditions.Foodcausesaslightdecreaseintheratebutnotin

theextentofabsorption.Thesmallchangeintherateofabsorptionisnotexpectedtoresultinaclinicallysignificanteffectonthe

steady-stateplasmaconcentrationsduringoncedailydosingofAnastrozoletablets.After7dailydoses,theplasmaanastrozole

concentrationsattainedare90-95%ofthesteady-stateconcentration.Thereisnoevidenceofatimeordose-dependencyofthe

pharmacokineticparametersofanastrozole.

Anastrozolepharmacokineticsareindependentofageinpostmenopausalwomen.

Inboyswithpubertalgynaecomastia,anastrozolewasrapidlyabsorbed,waswidelydistributedandwaseliminatedslowlywitha

half-lifeofapproximately2days.Clearanceofanastrozolewasloweringirlsthaninboysandexposurehigher.Anastrzoleingirls

waswidelydistributedandslowlyeliminatedwithanestimatedhalf-lifeofapproximately0.8days.

Anastrozoleisonly40%boundtoplasmaproteins.

Anastrozoleisextensivelymetabolisedbypostmenopausalwomen,withlessthan10%ofthedoseexcretedunchangedinthe

urinewithin72hoursofdosing.MetabolismofanastrozoleoccursbyN-dealkylation,hydroxylationandglucuronidation.The

metabolitesareexcretedprimarilyviatheurine.Triazole,themajormetaboliteofanastrozoleinplasma,doesnotinhibitthe

aromatase.

Involunteerswithstablehepaticcirrhosisorrenalimpairment,theoralclearanceofanastrozoleremainedintherangeobservedin

healthyvolunteers.

5.3Preclinicalsafetydata

Acutetoxicity

Inacutetoxicitystudiesinrodents,themedianlethaldoseofanastrozolewasgreaterthan100mg/kg/daybytheoralrouteand

greaterthan50mg/kg/daybytheintraperitonealroute.Inoralacutetoxicitystudyinthedog,themedianlethaldosewasgreater

than45mg/kg/day.

Chronictoxicity

Multipledosetoxicitystudiesutilizedratsanddogs.Nono-effectlevelswereestablishedforanastrozoleinthetoxicitystudies,

butthoseeffectsthatwereobservedatthelowdoses(1mg/kg/day)andmiddoses(dog3mg/kg/day;rat5mg/kg/day)were

relatedtoeitherthepharmacologicalorenzyme-inducingpropertiesofanastrozoleandwereunaccompaniedbysignificanttoxic

ordegenerativechanges.

Mutagenicity

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Reproductivetoxicology

Inafertilitystudyweanlingmaleratsweredosedorallywith50or400mg/lanastrozoleviatheirdrinkingwaterfor10weeks.

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

affectedinbothdosegroups,whilstareductioninfertilitywasevidentonlyatthe400mg/ldoselevel.Thereductionwas

transientasallmatingandfertilityparametersweresimilartocontrolgroupvaluesfollowinga9weektreatment-freerecovery

period.

Oraladministrationofanastrozoletofemaleratsproducedahighincidenceofinfertilityat1mg/kg/dayandincreasedpre-

implantationlossat0.02mg/kg/day.Theseeffectsoccurredatclinicallyrelevantdoses.Aneffectinmancannotbeexcluded.

Theseeffectswererelatedtothepharmacologyofthecompoundandwerecompletelyreversedaftera5-weekcompound

withdrawalperiod.

Oraladministrationofanastrozoletopregnantratsandrabbitscausednoteratogeniceffectsatdosesupto1.0and0.2mg/kg/day

respectively.Thoseeffectsthatwereseen(plancentalenlargementinratsandpregnancyfailureinrabbits)wererelatedtothe

pharmacologyofthecompound.

Thesurvivaloflittersborntoratsgivenanastrozoleat0.02mg/kg/dayandabove(fromday17ofpregnancytoday22post-

partum)wascompromised.Theseeffectswererelatedtothepharmacologicaleffectsofthecompoundonparturition.Therewere

noadverseeffectsonbehaviourorreproductiveperformanceofthefirstgenerationoffspringattributabletomaternaltreatment

withanastrozole.

Carcinogenicity

ATwoyearratoncogenicitystudyresultedinanincreasesinincidenceofhepaticneoplasmsanduterinestromalpolypsin

femalesandthyroidadenomasinmalesatthehighdose(25mg/kg/day)only.Thesechangesoccurredatadosewhichrepresents

100-foldgreaterexposurethanoccursathumantherapeuticdoses.Thesechangesareconsiderednottobeclinicallyrelevantto

thetreatmentofpatientswithanastrozole.

Atwo-yearmouseoncogenicitystudyresultedintheinductionofbenignovariantumoursandadisturbanceintheincidenceof

lymphoreticularneoplasms(fewerhistiocyticsarcomasinfemalesandmoredeathsasaresultoflymphomas).Thesechangesare

consideredtobemouse-specificeffectsofaromataseinhibitionandnotclinicallyrelevanttothetreatmentofpatientswith

anastrozole.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

Lactosemonohydrate

Maizestarch

PovidoneK-30

CellulosemicrocrystallinepH102

SodiumstarchglycolateTypeA

Silicacolloidalanhydrous

Magnesiumstearate(E572)

Talc

Film-coating:

Hypromellose5cp(E464)

Macrogol400

Titaniumdioxide(E171)

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6.2Incompatibilities

Notapplicable.

6.3ShelfLife

3years

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

PVC/Aluminiumblisters.

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

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

RanbaxyIreland

Spafield

CorkRoad

Cashel

Co.Tipperary

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA408/78/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:23rdApril2010

10DATEOFREVISIONOFTHETEXT

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Date Printed 15/02/2011 CRN 2093433 page number: 11