ANASTROZOLE NICHE

Main information

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

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1063/028/001
  • Authorization date:
  • 27-11-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

AnastrozoleNiche1mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains1mganastrozoleasactivesubstance.

Excipients:Eachtabletcontains90.3mglactose(aslactosemonohydrate).

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

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

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofadvancedbreastcancerinpostmenopausalwomen.

Efficacyhasnotbeendemonstratedinoestrogenreceptor-negativepatientsunlesstheyhadapreviouspositiveclinical

responsetotamoxifen.

4.2Posologyandmethodofadministration

4.3Contraindications

Anastrozoleiscontraindicatedin:

-premenopausalwomen.

-pregnantorlactatingwomen.

-patientswithsevererenalimpairment(creatinineclearancelessthan20ml/min)

-patientswithmoderateorseverehepaticdisease

-patientswithhypersensitivitytoanastrozoleortoanyoftheexcipientsasreferencedinsection6.1.

Oestrogen-containingtherapiesshouldnotbeco-administeredwithanastrozoleastheywouldnegateits

pharmacologicalaction.

Concurrenttamoxifentherapy(seesection4.5)

4.4Specialwarningsandprecautionsforuse

Anastrozoleisnotrecommendedforuseinchildrenassafetyandefficacyhavenotbeenestablishedinthisgroupof

patients.

Themenopauseshouldbedefinedbiochemicallyinanypatientwherethereisdoubtabouthormonalstatus.

Adultsincludingtheelderly: One1mgtablettobetakenorallyonceaday.

Children: Notrecommendedforuseinchildren.

Renalimpairment: Nodosechangeisrecommendedinpatientswithmildor

moderaterenalimpairment.

Hepaticimpairment: Nodosechangeisrecommendedinpatientswithmild

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 27/06/2011 CRN 2099015 page number: 1

patientswithsevereimpairmentofrenalfunction(creatinineclearancelessthan20ml/min).

Womenwithosteoporosisoratriskofosteoporosis,shouldhavetheirbonemineraldensityformallyassessedbybone

densitometrye.g.DEXAscanningatthecommencementoftreatmentandatregularintervalsthereafter.Treatmentor

prophylaxisforosteoporosisshouldbeinitiatedasappropriateandcarefullymonitored.

TherearenodataavailablefortheuseofanastrozolewithLHRHanalogues.Thiscombinationshouldnotbeused

outsideclinicaltrials.

Asanastrozolelowerscirculatingoestrogenlevelsitmaycauseareductioninbonemineraldensity.Adequatedatato

showtheeffectofbisphosphonatesonbonemineraldensitylosscausedbyanastrozole,ortheirutilitywhenused

prophylactically,arenotcurrentlyavailable.

Thisproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactase

deficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

AnastrozoleinhibitedcytochromeP4501A2,2C8/9and3A4invitro.Aclinicalinteractionstudyindicatedthat

anastrozoleata1mgdosedoesnotsignificantlyalterthepharmacokineticsofwarfarin,aCYP2C9substrate.

Noclinicallysignificantinteractionsbetweenanastrozoleandbisphosphonateshavebeenidentified.

Antipyrineandcimetidineclinicalinteractionstudiesindicatethatco-administrationofanastrozolewithotherdrugsis

unlikelytoresultinclinicallysignificantdruginteractionsmediatedbycytochromeP450.

Areviewoftheclinicaltrialsafetydatatbasedidnotrevealevidenceofclinicallysignificantinteractioninpatients

treatedwithanastrozolewhoalsoreceivedothercommonlyprescribeddrugs.

Tamoxifenshouldnotbeco-administeredwithanastrozole,asthismaydiminishitspharmacologicalaction(see

section4.3).

4.6Fertility,pregnancyandlactation

Anastrozoleiscontraindicatedinpregnantorlactatingwomen.

Pregnancy

Therearenodataontheuseofanastrozoleinpregnantpatients.Studiesinanimalshaveshownreproductivetoxicity

(seesection5.3).Thepotentialriskforhumansisunknown.Anastrozole1mgshouldnotbeusedinpregnancy.

Lactation

Itisunknownwhetheranastrozoleisexcretedinhumanmilk.Anastrozole1mgshouldnotbeusedduringbreast-

feeding.

4.7Effectsonabilitytodriveandusemachines

Anastrozoleisunlikelytoimpairtheabilityofpatientstodriveandoperatemachinery.However,astheniaand

somnolencehavebeenreportedwiththeuseofanastrozoleandcautionshouldbeobservedwhendrivingoroperating

machinerywhilesuchsymptomspersist.

4.8Undesirableeffects

Theassessmentofthesideeffectsisbasedonthefollowingfrequencies:

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),notknown(cannotbeestimatedfromtheavailabledata).

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 27/06/2011 CRN 2099015 page number: 2

Nervoussystemdisorders

Common: Headache,mainlymildormoderateinnature

CarpalTunnelSyndrome

Uncommon: Somnolence,mainlymildormoderateinnature

Gastrointestinaldisorders

Common: Nausea,mainlymildormoderateinnature,diarrhoea,mainlymildor

moderate

Uncommon: Vomiting,mainlymildormoderateinnature

Skinandsubcutaneoustissuedisorders

Common: Hairthinning,mainlymildormoderateinnature,Rash,mainlymildor#

moderateinnature

Veryrare: Erythemamultiforme,Stevens-Johnsonsyndrome,allergicreactions

includingangiooedema,urticariaandanaphylaxis

Musculoskeletalandconnectivetissuedisorders

Common: Jointpain/stiffness,mainlymildormoderateinnature

Metabolismandnutritiondisorders

Uncommon: Anorexia,mainlymildinnature,hypercholesterolaemia,mainlymildor

moderateinnature

Vasculardisorders

Verycommon: Hotflushes,mainlymildormoderateinnature

Generaldisordersandadministrationsiteconditions

Common: Asthenia,mainlymildormoderateinnature

Hepatobiliarydisorders

Common: Increasesinalkalinephosphatase,alanineaminotransferaseandaspartate

aminotransferase

Uncommon: Increasesingamma-GTandbilirubin,hepatitis

Reproductivesystemandbreastdisorders

Common: Vaginaldryness,mainlymildormoderateinnature

Uncommon: Vaginalbleeding,mainlymildormoderateinnature*

*Vaginalbleedinghasbeenreporteduncommonly,mainlyinpatientswithadvancedbreastcancerduringthefirstfew

weeksafterchangingfromexistinghormonaltherapytotreatmentwithanastrozole.Ifbleedingpersists,further

evaluationshouldbeconsidered.

Asanastrozolelowerscirculatingoestrogenlevels,itmaycauseareductioninbonemineraldensityplacingsome

patientsatahigherriskoffracture(seesection4.4).

Elevatedgamma-GThasbeenreporteduncommonly( ≥0.1%and<1%).Acausalrelationshipforthesethischanges

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 27/06/2011 CRN 2099015 page number: 3

Thetablebelowpresentsthefrequencyofpre-specifiedadverseeventsintheATACstudy,irrespectiveofcausality,

reportedinpatientsreceivingtrialtherapyandupto14daysaftercessationoftrialtherapy.

Fractureratesof22per1000patient-yearsand15per1000patient-yearswereobservedfortheanastrozoleand

tamoxifengroups,respectively,afteramedianfollow-upof68months.Theobservedfracturerateforanastrozoleis

similartotherangereportedinage-matchedpostmenopausalpopulations.Ithasnotbeendeterminedwhethertherates

offractureandosteoporosisseeninATACinpatientsonanastrozoletreatmentreflectaprotectiveeffectoftamoxifen,

aspecificeffectofanastrozole,orboth.Theincidenceofosteoporosiswas10.5%inpatientstreatedwithanastrozole

and7.3%inpatientstreatedwithtamoxifen.

4.9Overdose

Thereislimitedclinicalexperienceofaccidentaloverdosage.Inanimalstudies,anastrozoledemonstratedlowacute

toxicity.Clinicaltrialshavebeenconductedwithvariousdosagesofanastrozole,upto60mginasingledosegivento

healthymalevolunteersandupto10mgdailygiventopostmenopausalwomenwithadvancedbreastcancer;these

dosageswerewelltolerated.Asingledoseofanastrozolethatresultsinlife-threateningsymptomshasnotbeen

established.Thereisnospecificantidotetooverdosageandtreatmentmustbesymptomatic.

Inthemanagementofanoverdose,considerationshouldbegiventothepossibilitythatmultipleagentsmayhavebeen

taken.Vomitingmaybeinducedifthepatientisalert.Dialysismaybehelpfulbecauseanastrozoleisnothighlyprotein

bound.Generalsupportivecare,includingfrequentmonitoringofvitalsignsandcloseobservationofthepatient,is

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,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

includingPE 48(1.6%) 74(2.4%)

Ischaemiccerebrovascular

events 62(2.0%) 88(2.8%)

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 27/06/2011 CRN 2099015 page number: 4

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Antineoplasticandimmunomodulatingagents–Endocrinetherapy–Hormoneantagonists

andrelatedagents–Enzymeinhibitors.

ATCcode:L02BG03

Anastrozoleisapotentandhighlyselectivenon-steroidalaromataseinhibitor.Inpostmenopausalwomen,estradiolis

producedprimarilyfromtheconversionofandrostenedionetoestronethroughthearomataseenzymecomplexin

peripheraltissues.Estroneissubsequentlyconvertedtoestradiol.Reducingcirculatingestradiollevelshasbeenshown

toproduceabeneficialeffectinwomenwithbreastcancer.Inpostmenopausalwomen,anastrozoleatadailydoseof1

mgproducedestradiolsuppressionofgreaterthan80%usingahighlysensitiveassay.

Anastrozoledoesnotpossessanyprogestogenic,androgenicoroestrogenicactivity.Dailydosesofanastrozoleupto

10mgdonothaveanyeffectoncortisoloraldosteronesecretion,measuredbeforeorafterstandardACTHchallenge

testing.Corticoidsupplementsarethereforenotneeded.

AnextensivephaseIIIclinicalstudyprogrammeshowedthatanastrozoleisaneffectivetreatmentofhormone-receptor

positivebreastcancerinpostmenopausalwomen.

5.2Pharmacokineticproperties

Absorptionofanastrozoleisrapidandmaximumplasmaconcentrationstypicallyoccurwithintwohoursofdosing

(underfastedconditions).Anastrozoleiseliminatedslowlywithaplasmaeliminationhalf-lifeof40to50hours.Food

slightlydecreasestheratebutnottheextentofabsorption.Thesmallchangeintherateofabsorptionisnotexpectedto

resultinaclinicallysignificanteffectonsteady-stateplasmaconcentrationsduringoncedailydosingofanastrozole.

Approximately90to95%ofplasmaanastrozolesteady-stateconcentrationsareattainedafter7dailydoses.Thereisno

evidenceoftimeordose-dependencyofanastrozolepharmacokineticparameters.

Anastrozolepharmacokineticsareindependentofageinpostmenopausalwomen.

Pharmacokineticshavenotbeenstudiedinchildren.

Anastrozoleisonly40%boundtoplasmaproteins.

Anastrozoleisextensivelymetabolisedbypostmenopausalwomenwithlessthan10%ofthedoseexcretedintheurine

unchangedwithin72hoursofdosing.MetabolismofanastrozoleoccursbyN-dealkylation,hydroxylationand

glucuronidation.Themetabolitesareexcretedprimarilyviatheurine.Triazole,themajormetaboliteinplasma,does

notinhibitaromatase.

Theapparentoralclearanceofanastrozoleinvolunteerswithstablehepaticcirrhosisorrenalimpairmentwasinthe

rangeobservedinhealthyvolunteers.

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)wererelatedtoeitherthepharmacologicalorenzyme-inducingpropertiesofanastrozoleandwere

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 27/06/2011 CRN 2099015 page number: 5

Mutagenicity

Genetictoxicologystudieswithanastrozoleshowthatitisnotamutagenoraclastogen.

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.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

Lactosemonohydrate

Sodiumstarchglycolate(TypeA)

Magnesiumstearate

Filmcoating:

OpadryIIwhite85F18422consistingof

Poly(vinylalcohol)–partiallyhydrolysed

Titaniumdioxide

Macrogol3350

Talc

6.2Incompatibilities

Notapplicable.

6.3Shelflife

41months

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 27/06/2011 CRN 2099015 page number: 6

PVC/PVDCaluminiumblisters.

Packsizes:

20,28,30.84,98,100and300film-coatedtablets

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

NicheGenericsLimited

1TheCamCentre

WilburyWay

Hitchin

HertsSG40TW

8MARKETINGAUTHORISATIONNUMBER

PA1063/28/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:27thNovember2009

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 27/06/2011 CRN 2099015 page number: 7