ANASTROZOLE HIKMA

Main information

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

Documents

Localization

  • Available in:
  • ANASTROZOLE HIKMA
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1217/004/001
  • Authorization date:
  • 02-10-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

AnastrozoleHikma1mgFilmCoatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains1mganastrozole.

Excipient(s):Eachtabletcontains65mgofLactosemonohydrate

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

White,roundfilm-coatedtablet.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofadvancedbreastcancerinpostmenopausalwomen.Theefficacyofanastrozolehasnotbeendemonstrated

inoestrogen-receptornegativepatients,unlesstheyhavehadapreviouspositiveclinicalresponsetotamoxifen.

4.2Posologyandmethodofadministration

Adultsincludingtheelderly:

Onefilm-coatedtablet(1mg)tobetakenorallyonceaday.

Paediatricpopulation:

Notrecommendedforuseinchildrenduetoinsufficientdataonsafetyandefficacy(seesections4.4and5.1).

Renalimpairment:Nodosechangeisrecommendedinpatientswithmildormoderaterenalimpairment.

Hepaticimpairment:Nodosechangeisrecommendedinpatientswithmildhepaticdisease.

4.3Contraindications

Anastrozoleiscontraindicatedin:

-premenopausalwomen.

-pregnantorlactatingwomen.

-patientswithsevererenalimpairment(creatinineclearancelessthan20ml/min).

-patientswithmoderateorseverehepaticdisease.

-patientswithhypersensitivitytoanastrozoleortoanyoftheexcipientsasreferencedinsection6.1.

Oestrogen-containingtherapiesshouldnotbeco-administeredwithanastrozoleastheywouldnegateits

pharmacologicalaction.

Concurrenttamoxifentherapy(seesection4.5).

4.4Specialwarningsandprecautionsforuse

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 30/09/2011 CRN 2098638 page number: 1

groupofpatients(seesection5.1).

Anastrozoleshouldnotbeusedinboyswithgrowthhormonedeficiencyinadditiontogrowthhormonetreatment.In

thepivotalclinicaltrial,efficacywasnotdemonstratedandsafetywasnotestablished(seesection5.1).Since

anastrozolereducesoestradiollevels,itmustnotbeusedingirlswithgrowthhormonedeficiencyinadditiontogrowth

hormonetreatment.Long-termsafetydatainchildrenandadolescentsarenotavailable.

Theonsetofthemenopausemustbeconfirmedbiochemicallyifthehormonalstatusofthepatientcannotbe

establishedwithclinicalmethods.

Therearenodatatosupportthesafeuseofanastrozoleinpatientswithmoderateorseverehepaticimpairment,or

patientswithsevereimpairmentofrenalfunction(creatinineclearancebelow20ml/min).

Womenwithosteoporosisoratriskofthatdisease,shouldhavetheirbonemineraldensityformallyassessedbybone

densitometrye.g.DEXAscanningatthecommencementoftreatmentandatregularintervalsthereafter.Treatmentor

prophylaxisforosteoporosisshouldbeinitiatedasappropriateandcarefullymonitored.

TherearenodataareavailablefortheuseofanastrozolewithLHRHanalogues;therefore,thiscombinationis

restrictedforuseonlyinclinicalstudies.

Asanastrozolelowerscirculatingoestrogenlevelsitmaycauseareductioninbonemineraldensity.Adequatedatato

showtheeffectofbisphosphonatesonbonemineraldensitylosscausedbyanastrozole,ortheirutilitywhenused

prophylactically,arenotcurrentlyavailable

Oestrogen-containingtherapiesshouldnotbeco-administeredwithAnastrozoleastheywouldnegateits

pharmacologicalaction.

Thisproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactase

deficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

AnastrozoleinhibitedcytochromeP4501A2,2C8/9and3A4invitro,butaclinicalinteractionstudywithwarfarin

indicatedthatanastrozoleata1mgdosedoesnotsignificantlyinhibitthemetabolismofsubstancesthatare

metabolisedviacytochromeP450.

Noclinicallysignificantinteractionsbetweenanastrozoleandbiphosphonateshavebeenidentified.

Tamoxifenshouldnotbeco-administeredwithanastrozole,asthismaydiminishitspharmacologicalaction(see

section4.3).

4.6Fertility,pregnancyandlactation

Anastrozoleiscontraindicatedinpregnantandlactatingwomen(seesection4.3).

Pregnancy

Therearenodataontheuseofanastrozoleinpregnantpatients.Studiesinanimalshaveshownreproductivetoxicity

(seesection5.3).Thepotentialriskforhumansisunknown.Anastrozoleiscontraindicatedinpregnantwomen.

Lactation

Itisunknownwhetheranastrozoleisexcretedinhumanmilk.Anastrozoleiscontraindicatedinlactatingwomen.

4.7Effectsonabilitytodriveandusemachines

Anastrozoleisunlikelytoimpairtheabilityofpatientstodriveandoperatemachinery.However,astheniaand

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 30/09/2011 CRN 2098638 page number: 2

machinerywhilesuchsymptomspersist.

4.8Undesirableeffects

*Vaginalbleedinghasbeenreporteduncommonly,mainlyinpatientswithadvancedbreastcancerduringthefirstfew

weeksafterchangingfromexistinghormonaltherapytotreatmentwithanastrozole.Ifbleedingpersists,further

evaluationshouldbeconsidered.

Verycommon(10%)Vascular Hotflushes,mainlymildormoderatein

nature

Common

General Asthenia,mainlymildormoderate

Musculoskeletal,connective

tissueandbone Jointpain/stiffness,mainlymildormoderate

innature

Reproductivesystemandbreast Vaginaldryness,mainlymildormoderatein

nature

Skinandsubcutaneoustissues Hairthinning,mainlymildormoderatein

nature

Rash,mainlymildormoderateinnature

Gastrointestinalsystem Nausea,mainlymildormoderateinnature

Diarrhoea,mainlymildormoderatein

nature

Nervoussystem Headache,mainlymildormoderatein

nature

carpaltunnelsyndrome

Hepatobiliarydisorders Increasesinalkalinephosphatase,alanine

aminotransferaseandaspartate

aminotransferase

Uncommon

Reproductivesystemandbreast

disorders *Vaginalbleeding,mainlymildormoderate

innature

Metabolism,nutrition Anorexia,mainlymildinnature

Hypercholesterolaemia,mainlymildor

moderateinnature

Gastrointestinalsystem

Vomiting,mainlymildormoderatein

nature

Nervoussystem Somnolence,mainlymildormoderatein

nature

Hepatobiliarydisorders Elevatedgamma-GT&bilirubin

Hepatitis

Veryrare(<0.01%) Skinandsubcutaneoustissue Erythemamultiforme,Stevens-Johnson

syndrome

Allergicreactions,includingangioedema,

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 30/09/2011 CRN 2098638 page number: 3

patientsatahigherriskoffracture(seesection4.4).

Duetothepharmacologicalactionsofanastrozole,hotflushes,vaginaldrynessandhairthinningmaydevelop.During

theuseofanastrozolegastrointestinalcomplaints(anorexia,nausea,vomitinganddiarrhoea),asthenia,joint

pain/stiffness,somnolence,headacheandmildrashesmayoccur,includingrareformsofmucodermaldisorders,such

aserythemamultiformeandStevens-Johnsonsyndrome.

Thetablebelowpresentsthefrequencyofpre-specifiedadverseeventsintheATACstudy,irrespectiveofcausality,

reportedinpatientsreceivingtrialtherapyandupto14daysaftercessationoftrialtherapy.

Fractureratesof22per1000patient-yearsand15per1000patient-yearswereobservedfortheanastrozoleand

tamoxifengroups,respectively,afteramedianfollow-upof68months.

Theobservedfracturerateforanastrozoleissimilartotherangereportedinage-matchedpostmenopausalpopulations.

IthasnotbeendeterminedwhethertheratesoffractureandosteoporosisseeninATACinpatientsonanastrozole

treatmentreflectaprotectiveeffectoftamoxifen,aspecificeffectofanastrozole,orboth.

Theincidenceofosteoporosiswas10.5%inpatientstreatedwithanastrozoleand7.3%inpatientstreatedwith

tamoxifen.

4.9Overdose

Thereislimitedclinicalexperienceofoverdoseofanastrozole.

Inanimalstudies,anastrozoledemonstratedlowacutetoxicity.

Clinicaltrialshavebeenconductedwithvariousdosagesofanastrozole,upto60mginasingledosegiventohealthy

malevolunteersandupto10mgdailygiventopostmenopausalwomenwithadvancedbreastcancer;thesedosages

Adverseeffects Anastrozole

(N=3092) Tamoxifen

(N=3094)

Hotflushes 1104(35.7%) 1264(40.9%)

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

Mooddisturbances 597(19.3%) 554(17.9%)

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

Nauseaandvomiting 393(12.7%) 384(12.4%)

Fractures 315(10.2%) 209(6.8%)

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

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

Spinefractures 43(1.4%) 22(0.7%)

Hipfractures 28(0.9%) 26(0.8%)

Cataracts 182(5.9%) 213(6.9%)

Vaginalbleeding 167(5.4%) 317(10.2%)

Ischaemiccardiovasculardisease 127(4.1%) 104(3.4%)

Anginapectoris 71(2.3%) 51(1.6%)

Myocardialinfarct 37(1.2%) 34(1.1%)

Coronaryarterydisorder 25(0.8%) 23(0.7%)

Myocardialischaemia 22(0.7%) 14(0.5%)

Vaginaldischarge 109(3.5%) 408(13.2%)

Anyvenousthromboembolicevent 87(2.8%) 140(4.5%)

Deepvenousthromboembolicevents

includingPE 48(1.6%) 74(2.4%)

Ischaemiccerebrovascularevents 62(2.0%) 88(2.8%)

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 30/09/2011 CRN 2098638 page number: 4

Thereisnospecificantidotetoanoverdoseandtreatmentmustbesymptomatic.

Absorptionmaybepreventedbygastriclavagefollowedbyadministrationofactivatedcharcoal(adsorbant)or

activatedcharcoalalone.

Inthemanagementofanoverdose,considerationshouldbegiventothepossibilitythatmultipleagentsmayhavebeen

takensimultaneously.Ifthepatientisalert,itisrecommendedtoinducevomiting.

Dialysismaybehelpfulfortheeliminationofthemedicinethathasbeenabsorbedalreadybecauseanastrozoleisnot

highlyproteinbound.

Generalsupportivecare,includingfrequentmonitoringofvitalsignsandcloseobservationofthepatient,is

recommended.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:EnzymeInhibitors,ATCcode:L02BG03

Anastrozoleisapotentandhighlyselectivenon-steroidalaromataseinhibitor.Inpostmenopausalwomen,estradiolis

producedprimarilyfromtheconversionofandrostenedionetoestronethroughthearomataseenzymecomplexpresent

inperipheraltissues.Estroneissubsequentlyconvertedtoestradiol.

Reducingthelevelsofcirculatingestradiolhasbeenshowntoproduceabeneficialeffectinwomenwithbreastcancer.

Inpostmenopausalwomen,anastrozoleatadailydoseof1mgsuppressedestradiollevelsbymorethan80%.

Anastrozoledoesnotpossessanyprogestogenic,androgenicoroestrogenicactivity.

Regulardailydosesofanastrozoleupto10mgdidnothaveanyeffectoncortisoloraldosteronesecretion,measured

beforeorafterstandardACTHchallengetesting.Corticoidsupplementsarethereforenotneededduringits

administration.

Aswithalltreatmentdecisions,womenwithbreastcancerandtheirphysicianshouldassesstherelativebenefitsand

risksofthetreatment.

Whenanastrozoleandtamoxifenwereco-administered,theefficacyandsafetyweresimilartotamoxifenwhengiven

alone,irrespectiveofhormonereceptorstatus.Theexactmechanismofthisisnotyetclear.Itisnotbelievedtobedue

toareductioninthedegreeofestradiolsuppressionproducedbyanastrozole.

Paediatricpopulation:

Anastrozoleisnotindicatedforuseinchildren.Efficacyhasnotbeenestablishedinthepaediatricpopulationsstudied

(seebelow).Thenumberofchildrentreatedwastoolimitedtodrawanyreliableconclusionsonsafety.Nodataonthe

potentiallong-termeffectsofanastrozoletreatmentinchildrenareavailable(seealsosection5.3).

TheEuropeanMedicinesAgencyhaswaivedtheobligationtosubmittheresultsofstudieswithanastrozoleinoneor

severalsubsetsofthepaediatricpopulationinshortstatureduetogrowthhormonedeficiency(GHD),testotoxicosis,

gynaecomastia,andMcCune-Albrightsyndrome.

Shortstatureduetogrowthhormonedeficiency

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

treatedfor12to36monthswithanastrozole1mg/dayorplaceboincombinationwithgrowthhormone.Only14

subjectsonanastrozolecompleted36months.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 30/09/2011 CRN 2098638 page number: 5

hormonetherapy.Nostatisticallysignificantdifferencewithplacebowasobservedforthegrowthrelatedparametersof

predictedadultheight,height,heightSDS,andheightvelocity.Finalheightdatawerenotavailable.Whilethenumber

ofchildrentreatedwastoolimitedtodrawanyreliableconclusionsonsafety,therewasanincreasedfracturerateanda

trendtowardsreducedbonemineraldensityintheanastrozolearmcomparedtoplacebo.

Testotoxicosis

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

precociouspuberty,alsoknownastestotoxicosis,treatedwithcombinationofanastrozoleandbicalutamide.The

primaryobjectivewastoassesstheefficacyandsafetyofthiscombinationregimenover12months.Thirteenoutofthe

14patientsenrolledcompleted12monthsofcombinationtreatment(onepatientwaslosttofollow-up).Therewasno

significantdifferenceingrowthrateafter12monthsoftreatment,relativetothegrowthrateduringthe6monthsprior

toenteringthestudy.

5.2Pharmacokineticproperties

Absorptionofanastrozole,theactivesubstanceofAnastrozoleHikma1mgfilm-coatedtablets,israpid.Maximum

plasmaconcentrationstypicallyoccurwithintwohoursofdosingifthemedicineifgivenunderfastingconditions.

Anastrozoleiseliminatedslowlywithaplasmaeliminationhalf-lifeof40-50hours.Foodcausesaslightdecreasein

theratebutnotintheextentofabsorption.Thesmallchangeintherateofabsorptionisnotexpectedtoresultina

clinicallysignificanteffectonthesteady-stateplasmaconcentrationsduringoncedailydosingofAnastrozoleHikma

1mgfilm-coatedtablets.

After7dailydoses,theplasmaanastrozoleconcentrationsattainedare90-95%ofthesteady-stateconcentration.

Thereisnoevidenceofatimeordose-dependencyofthepharmacokineticparametersofanastrozole.

Thepharmacokineticsofanastrozoleareindependentofageinpostmenopausalwomen.

Pharmacokineticshavenotbeenstudiedinchildren.

Anastrozoleis40%boundtoplasmaproteins.

Anastrozoleisextensivelymetabolisedbypostmenopausalwomen,withlessthan10%ofthedoseexcretedunchanged

intheurinewithin72hoursofdosing.MetabolismofanastrozoleoccursbyN-dealkylation,hydroxylationand

glucuronidation.Themetabolitesareexcretedprimarilyviatheurine.

Triazole,themajormetaboliteofanastrozoleinplasma,doesnotinhibitthearomataseenzyme.

Involunteerswithstablehepaticcirrhosisorrenalimpairment,theoralclearanceofanastrozoleremainedintherange

observedinhealthyvolunteers.

5.3Preclinicalsafetydata

Acutetoxicity

Inacutetoxicitystudiesinrodents,themedianlethaldoseofanastrozolewasgreaterthan100mg/kg/daybytheoral

routeandgreaterthan50mg/kg/daybytheintraperitonealroute.Inanoralacutetoxicitystudyinthedog,themedian

lethaldosewasgreaterthan45mg/kg/day.

Chronictoxicity

Multipledosetoxicitystudiesutilizedratsanddogs.Nono-effectlevelswereestablishedforanastrozoleinthetoxicity

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

mg/kg/day)wererelatedtoeitherthepharmacologicalorenzymeinducingpropertiesofanastrozoleandwere

unaccompaniedbysignificanttoxicordegenerativechanges.

Mutagenicity

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 30/09/2011 CRN 2098638 page number: 6

Reproductivetoxicology

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.

Inafertilitystudyweanlingmaleratsweredosedorallywith50or400mg/lanastrozoleviatheirdrinkingwaterfor10

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

indiceswereadverselyaffectedinbothdosegroups,whilstareductioninfertilitywasevidentonlyatthe400mg/l

doselevel.Thereductionwastransientasallmatingandfertilityparametersweresimilartocontrolgroupvalues

followinga9-weektreatment-freerecoveryperiod.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

Lactosemonohydrate

Maizestarch

Povidone

Microcrystallinecellulose

SodiumstarchglycolateTypeA

Colloidalanhydroussilica

Magnesiumstearate

Talc

Film-coating:

Hypromellose

Macrogol

Titaniumdioxide(E171)

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 30/09/2011 CRN 2098638 page number: 7

6.2Incompatibilities

Notapplicable.

6.3Shelflife

36months

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions

6.5Natureandcontentsofcontainer

PVC/Aluminiumblistersof10,14,20,28,30,98or100film-coatedtablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

HikmaFarmacêutica(Portugal)S.A.

EstradadoRiodaMó,n°8,8Ae8B

Fervença

2705-906TerrugemSNT

Portugal

8MARKETINGAUTHORISATIONNUMBER

PA1217/4/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:2October2009

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 30/09/2011 CRN 2098638 page number: 8