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:
  • PA1063/031/001
  • Authorization date:
  • 27-11-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Anastrozole1mgfilm-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.

Adjuvanttreatmentofpostmenopausalwomenwithhormonereceptorpositiveearlyinvasivebreastcancer.

Adjuvanttreatmentofearlybreastcancerinhormonereceptorpositivepostmenopausalwomenwhohavereceived2to

3yearsofadjuvanttamoxifen.

4.2Posologyandmethodofadministration

Forearlydisease,therecommendeddurationoftreatmentshouldbe5years.

4.3Contraindications

Anastrozoleiscontraindicatedin:

-premenopausalwomen.

-pregnantorlactatingwomen.

-patientswithsevererenalimpairment(creatinineclearancelessthan20ml/min)

-patientswithmoderateorseverehepaticdisease

-patientswithhypersensitivitytoanastrozoleortoanyoftheexcipientsasreferencedinsection6.1.

Oestrogen-containingtherapiesshouldnotbeco-administeredwithanastrozoleastheywouldnegateits

pharmacologicalaction.

Concurrenttamoxifentherapy(seesection4.5)

Adultsincludingtheelderly: One1mgtablettobetakenorallyonceaday.

Children: Notrecommendedforuseinchildren.

Renalimpairment: Nodosechangeisrecommendedinpatientswithmildor

moderaterenalimpairment.

Hepaticimpairment: Nodosechangeisrecommendedinpatientswithmild

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Anastrozoleisnotrecommendedforuseinchildrenassafetyandefficacyhavenotbeenestablishedinthisgroupof

patients.

Themenopauseshouldbedefinedbiochemicallyinanypatientwherethereisdoubtabouthormonalstatus.

Therearenodatatosupportthesafeuseofanastrozoleinpatientswithmoderateorseverehepaticimpairment,or

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)

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Veryrare (<1/10,000),notknown(cannotbeestimatedfromtheavailabledata).

Withineachfrequencygrouping,undesirableeffectsarepresentedinorderofdecreasingseriousness.

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

hasnotbeenestablished.

Thetablebelowpresentsthefrequencyofpre-specifiedadverseeventsintheATACstudy,irrespectiveofcausality,

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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%)

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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.

Primaryadjuvanttreatmentofearlybreastcancer

InalargephaseIIIstudyconductedin9366postmenopausalwomenwithoperablebreastcancertreatedfor5years,

anastrozolewasshowntobestatisticallysuperiortotamoxifenindisease-freesurvival.Agreatermagnitudeofbenefit

wasobservedfordisease-freesurvivalinfavourofanastrozoleversustamoxifenfortheprospectivelydefinedhormone

receptorpositivepopulation.Anastrozolewasstatisticallysuperiortotamoxifenintimetorecurrence.Thedifference

wasofevengreatermagnitudethanindisease-freesurvivalforboththeIntentionToTreat(ITT)populationand

hormonereceptorpositivepopulation.Anastrozolewasstatisticallysuperiortotamoxifenintermsoftimetodistant

recurrence.Theincidenceofcontralateralbreastcancerwasstatisticallyreducedforanastrozolecomparedto

tamoxifen.

Following5yearsoftherapy,anastrozoleisatleastaseffectiveastamoxifenintermsofoverallsurvival.However,due

tolowdeathrates,additionalfollow-upisrequiredtodeterminemorepreciselythelong-termsurvivalforanastrozole

relativetotamoxifen.With68monthsmedianfollow-up,patientsintheATACstudyhavenotbeenfollowedupfor

sufficienttimeafter5yearsoftreatment,toenableacomparisonoflong-termposttreatmenteffectsofanastrozole

relativetotamoxifen.

ATACendpointsummary5-yeartreatmentcompletionanalysis

Efficacy

endpoints Numberofevents(frequency)

Intention-to-treat

population Hormone-receptor-

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

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Disease-freesurvivalincludesallrecurrenceeventsandisdefinedasthefirst

occurrenceofloco-regionalrecurrence,contralateralnewbreastcancer,distant

recurrenceordeath(foranyreason).

Distantdisease-freesurvivalisdefinedasthefirstoccurrenceofdistantrecurrenceordeath(foranyreason).

Timetorecurrenceisdefinedasthefirstoccurrenceofloco-regionalrecurrence,contralateralnewbreastcancer,

distantrecurrenceordeathduetobreastcancer.

Timetodistantrecurrenceisdefinedasthefirstoccurrenceofdistantrecurrenceordeathduetobreastcancer.

Number(%)ofpatientswhohaddied.

Aswithalltreatmentdecisions,womenwithbreastcancerandtheirphysicianshouldassesstherelativebenefitsand

risksofthetreatment.

Whenanastrozoleandtamoxifenwereco-administered,theefficacyandsafetyweresimilartotamoxifenwhengiven

alone,irrespectiveofhormonereceptorstatus.Theexactmechanismofthisisnotyetclear.Itisnotbelievedtobedue

toareductioninthedegreeofestradiolsuppressionproducedbyanastrozole.

Adjuvanttreatmentofearlybreastcancerforpatientsbeingtreatedwithadjuvant

tamoxifen

InaphaseIIItrial(ABCSG8)conductedin2579postmenopausalwomenwithhormonereceptorpositiveearlybreast

cancerwhohadreceivedsurgerywithorwithoutradiotherapyandnochemotherapy,switchingtoanastrozoleafter2

yearsadjuvanttreatmentwithtamoxifenwasstatisticallysuperiorindisease-freesurvivalwhencomparedtoremaining

ontamoxifen,afteramedianfollow-upof24months.

Timetoanyrecurrence,timetolocalordistantrecurrenceandtimetodistantrecurrenceconfirmedastatistical

advantageforanastrozole,consistentwiththeresultsofdisease-freesurvival.Theincidenceofcontralateralbreast

cancerwasverylowinthetwotreatmentarmswithanumericaladvantageforanastrozole.Overallsurvivalwassimilar

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

ABCSG8trialendpointandresultsummary

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(frequency)

Anastrozole

(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

TimetolocalordistantRecurrence 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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Twofurthersimilartrials(GABG/ARNO95andITA),inoneofwhichpatientshadreceivedsurgeryand

chemotherapy,aswellasacombinedanalysisofABCSG8andGABG/ARNO95,supportedtheseresults.Thesafety

profileinthese3studieswasconsistentwiththeknownsafetyprofileestablishedinpostmenopausalwomenwith

hormonereceptorpositiveearlybreastcancer.

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

unaccompaniedbysignificanttoxicordegenerativechanges.

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

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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

2years

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions

6.5Natureandcontentsofcontainer

PVC/PVDCaluminiumblisters.

Packsizes:

28film-coatedtablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

NicheGenericsLimited

1TheCamCentre

WilburyWay

Hitchin

HertsSG40TW

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8MARKETINGAUTHORISATIONNUMBER

PA1063/31/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:27thNovember2009

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