EIRFEM

Main information

  • Trade name:
  • EIRFEM Film Coated Tablet 2.5 Milligram
  • Dosage:
  • 2.5 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • EIRFEM Film Coated Tablet 2.5 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1063/050/001
  • Authorization date:
  • 01-04-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Eirfem2.5mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains:2.5mgletrozole.AlsocontainsSunsetYellowFCF(E110).

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Filmcoatedtablet

Yellow,round,biconvex,film-coated,tablets.Debossed"2.5"ononeside,plainonreverse.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Adjuvanttreatmentofpostmenopausalwomenwithhormonereceptorpositiveearlybreastcancer.

Extendedadjuvanttreatmentofhormone-dependentearlybreastcancerinpostmenopausalwomenwhohave

receivedpriorstandardadjuvanttamoxifentherapyfor5years.

First-linetreatmentinpostmenopausalwomenwithhormone-dependentadvancedbreastcancer.

Advancedbreastcancerinwomenwithnaturalorartificiallyinducedpostmenopausalstatusafterrelapseor

diseaseprogression,whohavepreviouslybeentreatedwithanti-oestrogens.

Efficacyhasnotbeendemonstratedinpatientswithhormonereceptornegativebreastcancer.

4.2Posologyandmethodofadministration

Oraluse

Adultandelderlypatients

TherecommendeddoseofEirfem2.5mgfilmcoatedtabletsis2.5mgoncedaily.Nodoseadjustmentisrequiredfor

elderlypatients.

Intheadjuvantsetting,itisrecommendedtotreatfor5yearsoruntiltumourrelapseoccurs.Intheadjuvantsetting,

clinicalexperienceisavailablefor2years(mediandurationoftreatmentwas25months).

Intheextendedadjuvantsetting,clinicalexperienceisavailablefor4years(mediandurationoftreatment).

Inpatientswithadvancedormetastaticdisease,treatmentwithEirfem2.5mgfilmcoatedtabletsshouldcontinueuntil

tumourprogressionisevident.

Children

Notapplicable.

Patientswithhepaticand/orrenalimpairment

Nodosageadjustmentisrequiredforpatientswithrenalinsufficiencywithcreatinineclearancegreaterthan

30ml/min.

Insufficientdataareavailableincasesofrenalinsufficiencywithcreatinineclearancelowerthan30ml/minorin

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4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients.

Premenopausalendocrinestatus;pregnancy;lactation(seesections4.6Pregnancyandlactationand5.3Preclinical

safetydata).

4.4Specialwarningsandprecautionsforuse

Inpatientswhosepostmenopausalstatusseemsunclear,LH,FSHand/oroestradiollevelsmustbeassessedbefore

initiatingtreatmentinordertoclearlyestablishmenopausalstatus.

RenalImpairment

Letrozolehasnotbeeninvestigatedinasufficientnumberofpatientswithacreatinineclearancelowerthan10ml/min.

Thepotentialrisk/benefittosuchpatientsshouldbecarefullyconsideredbeforeadministrationofletrozole.

HepaticImpairment

Letrozolehasonlybeenstudiedinalimitednumberofnon-metastaticpatientswithvaryingdegreesofhepatic

function:mildtomoderate,andseverehepaticinsufficiency.Innon-cancermalevolunteerswithseverehepatic

impairment(livercirrhosisandChild-PughscoreC),systemicexposureandterminalhalf-lifewereincreased2-3-fold

comparedtohealthyvolunteers.Thus,letrozoleshouldbeadministeredwithcautionandaftercarefulconsiderationof

thepotentialrisk/benefittosuchpatients(seesection5.2Pharmacokineticproperties).

BoneEffects

Letrozoleisapotentoestrogen-loweringagent.Intheadjuvantandextendedadjuvantsettingthemedianfollow-up

durationof30and49monthsrespectivelyisinsufficienttofullyassessfractureriskassociatedwithlongtermuseof

letrozole.Womenwithahistoryofosteoporosisand/orfracturesorwhoareatincreasedriskofosteoporosisshould

havetheirbonemineraldensityformallyassessedbybonedensitometrypriortothecommencementofadjuvantand

extendedadjuvanttreatmentandbemonitoredfordevelopmentofosteoporosisduringandfollowingtreatmentwith

letrozole.Treatmentorprophylaxisforosteoporosisshouldbeinitiatedasappropriateandcarefullymonitored(see

section4.8Undesirableeffects).

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Clinicalinteractionstudieswithcimetidineandwarfarinindicatedthatthecoadministrationofletrozolewiththese

drugsdoesnotresultinclinicallysignificantdruginteractions.

Additionally,areviewoftheclinicaltrialdatabaseindicatednoevidenceofclinicallyrelevantinteractionswithother

commonlyprescribeddrugs.

Thereisnoclinicalexperiencetodateontheuseofletrozoleincombinationwithotheranticanceragents.

Invitro,letrozoleinhibitsthecytochromeP450isoenzymes2A6and,moderately,2C19.Thus,cautionshouldbeused

intheconcomitantadministrationofdrugswhosedispositionismainlydependentontheseisoenzymesandwhose

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4.6Fertility,pregnancyandlactation

Womenofperimenopausalstatusorchild-bearingpotential

ThephysicianneedstodiscussthenecessityofapregnancytestbeforeinitiatingEirfem2.5mgfilmcoatedtabletsand

ofadequatecontraceptionwithwomenwhohavethepotentialtobecomepregnant(i.e.womenwhoare

perimenopausalorwhorecentlybecamepostmenopausal)untiltheirpostmenopausalstatusisfullyestablished(see

sections4.4Specialwarningsandprecautionsforuseand5.3Preclinicalsafetydata).

Pregnancy:

Eirfem2.5mgfilm-coatedtabletsarecontraindicatedduringpregnancy(seeSection4.3–Contraindications).

Lactation

Eirfem2.5mgfilm-coatedtabletsarecontraindicatedduringlactation(seeSection4.3–Contraindications).

4.7Effectsonabilitytodriveandusemachines

Sincefatigueanddizzinesshavebeenobservedwiththeuseofletrozoleandsomnolencehasbeenreported

uncommonly,cautionisadvisedwhendrivingorusingmachines.

4.8Undesirableeffects

Letrozoleisgenerallywelltoleratedacrossallstudiesasfirst-lineandsecond-linetreatmentforadvancedbreastcancer

andasadjuvanttreatmentofearlybreastcancer.Uptoapproximatelyonethirdofthepatientstreatedwithletrozolein

themetastaticsetting,uptoapproximately70-75%ofthepatientsintheadjuvantsetting(bothletrozoleandtamoxifen

arms),anduptoapproximately40%ofthepatientstreatedintheextendedadjuvantsetting(bothletrozoleandplacebo

arms)experiencedadversereactions.Generally,theobservedadversereactionsaremainlymildormoderateinnature.

Mostadversereactionscanbeattributedtonormalpharmacologicalconsequencesofoestrogendeprivation(e.g.hot

flushes).

Themostfrequentlyreportedadversereactionsintheclinicalstudieswerehotflushes,arthralgia,nauseaandfatigue.

Manyadversereactionscanbeattributedtothenormalpharmacologicalconsequencesofoestrogendeprivation(e.g.

hotflushes,alopeciaandvaginalbleeding).

Afterstandardadjuvanttamoxifen,basedonmedianfollow-upof28months,thefollowingadverseeventsirrespective

ofcausalitywerereportedsignificantlymoreoftenwithletrozolethanwithplacebo-hotflushes(50.7%vs.44.3%),

arthralgia/arthritis(28.5%vs.23.2%)andmyalgia(10.2%vs.7.0%).Themajorityoftheseadverseeventswere

observedduringthefirstyearoftreatment.Therewasahigherbutnonsignificantincidenceofosteoporosisandbone

fracturesinpatientswhoreceivedletrozolethaninpatientswhoreceivedplacebo(7.5%vs.6.3%and6.7%vs.5.9%,

respectively).

Inanupdatedanalysisintheextendedadjuvantsettingconductedatamediantreatmentdurationof47monthsfor

letrozoleand28monthsforplacebo,thefollowingadverseeventsirrespectiveofcausalitywerereportedsignificantly

moreoftenwithletrozolethanwithplacebo–hotflushes(60.3%vs.52.6%),arthralgia/arthritis(37.9%vs.26.8%)and

myalgia(15.8%vs.8.9%).Themajorityoftheseadverseeventswereobservedduringthefirstyearoftreatment.In

thepatientsinplaceboarmwhoswitchedtoletrozoleasimilarpatternofgeneraleventswasobserved.Therewasa

higherincidenceofosteoporosisandbonefractures,anytimeafterrandomisation,inpatientswhoreceivedletrozole

thaninpatientswhoreceivedplacebo(12.3%vs.7.4%and10.9%vs.7.2%,respectively).Inpatientswhoswitchedto

letrozole,newlydiagnosedosteoporosis,anytimeafterswitching,wasreportedin3.6%ofpatientswhilefracturewere

reportedin5.1%ofpatientsanytimeafterswitching.

Intheadjuvantsetting,irrespectiveofcausality,thefollowingadverseeventsoccurredanytimeafterrandomizationin

theletrozoleandtamoxifengroupsrespectively:thromboembolicevents(1.5%vs.3.2%,P<0.001),anginapectoris

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Thefollowingadversedrugreactions,listedinTable1,werereportedfromclinicalstudiesandfrompostmarketing

experiencewithletrozole.

Table1

Adversereactionsarerankedunderheadingsoffrequency,themostfrequentfirst,usingthefollowingconvention:

verycommon10%;

common1%to<10%;

uncommon0.1%to<1%;

rare0.01%to<0.1%;

veryrare<0.01%,includingisolatedreports.

Infectionsandinfestations

Uncommon: Urinarytractinfection

Neoplasms,benign,malignantandunspecified(includingcystsandpolyps)

Uncommon: Tumourpain(notapplicableintheadjuvantand

extendedadjuvantsetting)

Bloodandthelymphaticsystemdisorders

Uncommon: Leukopenia

Metabolismandnutritiondisorders

Common: Anorexia,appetiteincrease,

hypercholesterolaemia

Uncommon: Generaloedema

Psychiatricdisorders

Common: Depression

Uncommon: Anxietyincludingnervousness,irritability

Nervoussystemdisorders

Common: Headache,dizziness

Uncommon: Somnolence,insomnia,memoryimpairment,

dysaesthesiaincludingparesthesia,hypoesthesia,

tastedisturbance,cerebrovascularaccident

Eyedisorders

Uncommon: Cataract,eyeirritation,blurredvision

Cardiacdisorders

Uncommon: Palpitations,tachycardia

Vasculardisorders

Uncommon: Thrombophlebitisincludingsuperficialanddeep

thrombophlebitis,hypertension,ischemiccardiac

events

Rare: Pulmonaryembolism,arterialthrombosis,

cerebrovascularinfarction

Respiratory,thoracicandmediastinaldisorders

Uncommon: Dyspnoea,cough

Gastrointestinaldisorders

Common: Nausea,vomiting,dyspepsia,constipation,

diarrhoea

Uncommon: Abdominalpain,stomatitis,drymouth

Hepatobiliarydisorders

Uncommon: Increasedhepaticenzymes

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4.9Overdose

Isolatedcasesofoverdosagewithletrozolehasbeenreported.

Nospecifictreatmentforoverdosageisknown;treatmentshouldbesymptomaticandsupportive.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup: Enzymeinhibitor.Non-steroidalaromataseinhibitor(inhibitorofoestrogen

biosynthesis);antineoplasticagent,ATCcode:L02BG04

Pharmacodynamiceffects:

Theeliminationofoestrogen-mediatedgrowthstimulationisaprerequisitefortumourresponseincaseswherethe

growthoftumourtissuedependsonthepresenceofoestrogensandendocrinetherapyisused.Inpostmenopausal

women,oestrogensaremainlyderivedfromtheactionofthearomataseenzyme,whichconvertsadrenalandrogens-

primarilyandrostenedioneandtestosterone-tooestroneandoestradiol.Thesuppressionofoestrogenbiosynthesisin

peripheraltissuesandthecancertissueitselfcanthereforebeachievedbyspecificallyinhibitingthearomataseenzyme.

Letrozoleisanon-steroidalaromataseinhibitor.Itinhibitsthearomataseenzymebycompetitivelybindingtothehaem

ofthearomatasecytochromeP450,resultinginareductionofoestrogenbiosynthesisinalltissueswherepresent.

Inhealthypostmenopausalwomen,singledosesof0.1,0.5,and2.5mgletrozolesuppressserumoestroneand

Verycommon: Increasedsweating

Common: Alopecia,rashincludingerythematous,

maculopapular,psoriaform,andvesicularrash

Uncommon: Pruritus,dryskin,urticaria

Notknown: Angioedema,anaphylacticreaction

Musculoskeletalandconnectivetissuedisorders

Verycommon: Arthralgia

Common: Myalgia,bonepain,osteoporosis,bonefractures

Uncommon: Arthritis

Renalandurinarydisorders

Uncommon: Increasedurinaryfrequency

Reproductivesystemandbreastdisorders

Uncommon: Vaginalbleeding,vaginaldischarge,vaginal

dryness,breastpain

Generaldisordersandadministrationsiteconditions

Verycommon: shes,fatigueincludingasthenia

Common: Malaise,peripheraloedema

Uncommon: Pyrexia,mucosaldryness,thirst

Investigations

Common: Weightincrease

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Inpostmenopausalpatientswithadvancedbreastcancer,dailydosesof0.1to5mgsuppressplasmaconcentrationof

oestradiol,oestrone,andoestronesulphateby75-95%frombaselineinallpatientstreated.Withdosesof0.5mgand

higher,manyvaluesofoestroneandoestronesulphatearebelowthelimitofdetectionintheassays,indicatingthat

higheroestrogensuppressionisachievedwiththesedoses.Oestrogensuppressionwasmaintainedthroughout

treatmentinallthesepatients.

Letrozoleishighlyspecificininhibitingaromataseactivity.Impairmentofadrenalsteroidogenesishasnotbeen

observed.Noclinicallyrelevantchangeswerefoundintheplasmaconcentrationsofcortisol,aldosterone,11-

deoxycortisol,17-hydroxyprogesterone,andACTHorinplasmareninactivityamongpostmenopausalpatientstreated

withadailydoseofletrozole0.1to5mg.TheACTHstimulationtestperformedafter6and12weeksoftreatment

withdailydosesof0.1,0.25,0.5,1,2.5,and5mgdidnotindicateanyattenuationofaldosteroneorcortisol

production.Thus,glucocorticoidandmineralocorticoidsupplementationisnotnecessary.

Nochangeswerenotedinplasmaconcentrationsofandrogens(androstenedioneandtestosterone)amonghealthy

postmenopausalwomenafter0.1,0.5,and2.5mgsingledosesofletrozoleorinplasmaconcentrationsof

androstenedioneamongpostmenopausalpatientstreatedwithdailydosesof0.1to5mg,indicatingthattheblockadeof

oestrogenbiosynthesisdoesnotleadtoaccumulationofandrogenicprecursors.

PlasmalevelsofLHandFSHarenotaffectedbyletrozoleinpatients,noristhyroidfunctionasevaluatedbyTSH,T4,

andT3uptaketest.

Adjuvanttreatment

Amulti-centre,double-blindstudyrandomisedover8000postmenopausalwomenwithresectedreceptor-positiveearly

breastcancer,tooneofthefollowingoptions:

Option1:

A.tamoxifenfor5years

B.letrozolefor5years

C.tamoxifenfor2yearsfollowedbyletrozolefor3years

D.letrozolefor2yearsfollowedbytamoxifenfor3years

Option2:

A.tamoxifenfor5years

B.letrozolefor5years

DatainTable2reflectresultsbasedondatafromthemonotherapyarmsineachrandomizationoptionanddatafrom

thetwoswitchingarmsupto30daysafterthedateofswitch.Theanalysisofmonotherapyvs.sequencingof

endocrinetreatmentswillbeconductedwhenthenecessarynumberofeventshasbeenachieved.

Patientshavebeenfollowedforamedianof26months,76%ofthepatientsformorethan2years,and16%(1252

patients)for5yearsorlonger.

Theprimaryendpointofthetrialwasdisease-freesurvival(DFS)whichwasassessedasthetimefromrandomization

totheearliesteventofloco-regionalordistantrecurrence(metastases)oftheprimarydisease,developmentofinvasive

contralateralbreastcancer,appearanceofasecondnon-breastprimarytumorordeathfromanycausewithoutaprior

cancerevent.Letrozolereducedtheriskofrecurrenceby19%comparedwithtamoxifen(hazardratio0.81;P=0.003).

The5-yearDFSrateswere84.0%forletrozoleand81.4%fortamoxifen.TheimprovementinDFSwithletrozoleis

seenasearlyas12monthsandismaintainedbeyond5years.Letrozolealsosignificantlyreducedtheriskof

recurrencecomparedwithtamoxifenwhetherprioradjuvantchemotherapywasgiven(hazardratio0.72;P=0.018)or

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Forthesecondaryendpointoverallsurvivalatotalof358deathswerereported(166onletrozoleand192on

tamoxifen).Therewasnosignificantdifferencebetweentreatmentsinoverallsurvival(hazardratio0.86;P=0.15).

Distantdisease-freesurvival(distantmetastases),asurrogateforoverallsurvival,differedsignificantlyoverall(hazard

ratio0.73;P=0.001)andinpre-specifiedstratificationsubsets.Letrozolesignificantlyreducedtheriskofsystemic

failureby17%comparedwithtamoxifen(hazardratio0.83;P=0.02)

However,althoughinfavourofletrozolenonsignificantdifferencewasobtainedinthecontralateralbreastcancer

(hazardratio0.61;P=0.09).AnexploratoryanalysisofDFSbynodalstatusshowedthatletrozolewassignificantly

superiortotamoxifeninreducingtheriskofrecurrenceinpatientswithnodepositivedisease(HR0.71;95%CI0.59,

0.85;P=0.0002)whilenosignificantdifferencebetweentreatmentswasapparentinpatientswithnodenegativedisease

(HR0.98;95%CI0.77,1.25;P=0.89).Thisreducedbenefitinnodenegativepatientswasconfirmedbyanexploratory

interactionanalysis(p=0.03).

Patientsreceivingletrozole,comparedtotamoxifen,hadfewersecondmalignancies(1.9%vs.2.4%).Particularlythe

incidenceofendometrialcancerwaslowerwithletrozolecomparedtotamoxifen(0.2%vs.0.4%).

SeeTables2and3thatsummarizetheresults.TheanalysessummarizedinTable4omitthe2sequentialarmsfrom

randomizationoption1,i.e.takeaccountonlyofthemonotherapyarms:

Table2 Disease-freeandoverallsurvival(ITTpopulation)

Table3 Disease-freeandoverallsurvivalbynodalstatusandprioradjuvantchemotherapy(ITT

Letrozole

n=4003 Tamoxifen

n=4007 Hazardratio

(95%CI) P-value 1

Disease-freesurvival

(primary)–events

(protocoldefinitiontotal) 351 428 0.81(0.70,0.93) 0.0030

Distantdisease-free

survival(metastases)

(secondary) 184 249 0.73(0.60,0.88) 0.0012

Overallsurvival

(secondary)-numberof

deaths(total) 166 192 0.86(0.70,1.06) 0.1546

Systemicdisease-free

survival(secondary) 323 383 0.83(0.72,0.97) 0.0172

Contralateralbreast

cancer(invasive)

(secondary) 19 31 0.61(0.35,1.08) 0.0910

CI=Confidenceinterval

Logranktest,stratifiedbyrandomisationoptionandadjuvantchemotherapy

HazardRatio,95%CIforhazard

ratio P-Value 1

Disease-freesurvival

Nodalstatus

-Positive

-Negative 0.71(0.59,0.85)

0.98(0.77,1.25) 0.0002

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Table4 PrimaryCoreAnalysis:Efficacyendpointsaccordingtorandomizationoptionmonotherapyarms

Prioradjuvant

chemotherapy

-Yes

-No 0.72(0.55,0.95)

0.84(0.71,1.00) 0.0178

0.0435

Overallsurvival

Nodalstatus

-Positive

-Negative 0.81(0.63,1.05)

0.88(0.59,1.30) 0.1127

0.5070

Prioradjuvant

chemotherapy

-Yes

-No 0.76(0.51,1.14)

0.90(0.71,1.15) 0.1848

0.3951

Distantdisease-free

survival

Nodalstatus

-Positive

-Negative 0.67(0.54,0.84)

0.90(0.60,1.34) 0.0005

0.5973

Prioradjuvant

chemotherapy

-Yes

-No 0.69(0.50,0.95)

0.75(0.60,0.95) 0.0242

0.0184

CI=confidenceinterval

Coxmodelsignificancelevel

Endpoint Option Statistic Letrozole Tamoxifen

DFS(Primary,protocol

definition) 1 Events/n 100/1546 137/1548

HR(95%CI),P 0.73(0.56,0.94),0.0159

Events/n 177/917 202/911

HR(95%CI),P 0.85(0.69,1.04),0.1128

Overall Events/n 277/2463 339/2459

HR(95%CI),P 0.80(0.68,0.94),0.0061

DFS(excludingsecond

malignancies) 1 Events/n 80/1546 110/1548

HR(95%CI),P 0.73(0.54,0.97),0.0285

Events/n 159/917 187/911

HR(95%CI),P 0.82(0.67,1.02),0.0753

Overall Events/n 239/2463 297/2459

HR(95%CI),P 0.79(0.66,0.93),0.0063

DistantDFS(Secondary) 1 Events/n 57/1546 72/1548

HR(95%CI),P 0.79(0.56,1.12),0.1913

Events/n 98/917 124/911

HR(95%CI),P 0.77(0.59,1.00),0.0532

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Themediandurationoftreatment(safetypopulation)was25months,73%ofthepatientsweretreatedformorethan2

years,22%ofthepatientsformorethan4years.Themediandurationoffollow-upwas30monthsforbothletrozole

andtamoxifen.

Adverseeventssuspectedofbeingrelatedtostudydrugwerereportedfor78%ofthepatientstreatedwithletrozole

comparedwith73%ofthosetreatedwithtamoxifen.Themostcommonadverseeventsexperiencedwithletrozolewere

hotflushes,nightsweats,arthralgia,weightincrease,andnausea.Ofthese,onlyarthralgiaoccurredsignificantlymore

oftenwithletrozolethanwithtamoxifen(20%vs.13%fortamoxifen).Letrozoletreatmentwasassociatedwitha

higherriskofosteoporosis(2.2%vs.1.2%withtamoxifen).Overall,irrespectiveofcausality,

cardiovascular/cerebrovasculareventswerereportedanytimeafterrandomizationforsimilarproportionsofpatientsin

bothtreatmentarms(10.8%forletrozole,12.2%fortamoxifen).Amongstthese,thromboemboliceventswerereported

significantlylessoftenwithletrozole(1.5%)thanwithtamoxifen(3.2%)(P<0.001),whilecardiacfailurewasreported

significantlymoreoftenwithletrozole(0.9%)thanwithtamoxifen(0.4%)(P=0.006).Amongstpatientswhohad

baselinevaluesoftotalserumcholesterolwithinthenormalrange,increasesintotalserumcholesterolhigherthan1.5

timestheULNwereobservedin5.4%ofthepatientsintheletrozolearm,comparedwith1.1%inthetamoxifenarm.

Extendedadjuvanttreatment

Inamulticentre,double-blind,randomised,placebo-controlledstudy,performedinover5,100postmenopausalpatients

withreceptor-positiveorunknownprimarybreastcancer,patientswhohadremaineddisease-freeaftercompletionof

adjuvanttreatmentwithtamoxifen(4.5to6years)wererandomlyassignedeitherletrozoleorplacebo.

Theprimaryanalysisconductedatamedianfollow-upofaround28months(25%patientsofthepatientsbeing

followedforatleast38months)showedthatletrozolereducedtheriskofrecurrenceby42%comparedwithplacebo

(hazardratio0.58;P=0.00003).ThestatisticallysignificantbenefitinDFSinfavourofletrozolewasobserved

regardlessofnodalstatus–nodenegative:hazardratio0.48;P=0.002;nodepositive:hazardratio0.61;P=0.002.

Forthesecondaryendpointoverallsurvival(OS)atotalof113deathswerereported(51letrozole,62placebo).

Overall,therewasnosignificantdifferencebetweentreatmentsinOS(hazardratio0.82;P=0.29).

Afterwardsthestudycontinuedinanunblindedfashionandpatientsintheplaceboarmcouldswitchtoletrozole,if

theywishedtodoso.Afterthestudyunblinding,over60%ofthepatientsintheplaceboarmeligibletoswitchopted

toswitchtoletrozole(i.e.,lateextendedadjuvantpopulation).Patientswhoswitchedtoletrozolefromplacebohad

beenoffadjuvanttamoxifenforamedian31months(range14to79months).

Updatedintent-to-treatanalyseswereconductedatamedianfollow-upof49months.Intheletrozolearmatleast30%

ofthepatientshadcompleted5yearsand59%hadcompletedatleast4yearsoffollow-up.Intheupdatedanalysisof

DFS,letrozolesignificantlyreducedtheriskofbreastcancerrecurrencecomparedwithplacebo(hazardratio0.68;

95%CI0.55,0.83;P=0.0001).Letrozolealsosignificantlyreducedtheoddsofanewinvasivecontralateralcancerby

41%comparedwithplacebo(oddsratio0.59;95%CI0.36,0.96;P=0.03).Therewasnosignificantdifferencein

HR(95%CI),P 0.78(0.63,0.96),0.0195

Overallsurvival

(Secondary) 1 Events/n 41/1546 48/1548

HR(95%CI),P 0.86(0.56,1.30),0.4617

Events/n 98/917 116/911

HR(95%CI),P 0.84(0.64,1.10),0.1907

Overall Events/n 139/2463 164/2459

HR(95%CI),P 0.84(0.67,1.06),0.1340

P-valuegivenisbasedonlogranktest,stratifiedbyadjuvantchemotherapyforeach

randomizationoption,andbyrandomizationoptionandadjuvantchemotherapyfor

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Updatedresults(mediandurationoffollow-upwas40months)fromthebonemineraldensity(BMD)substudy(226

patientsenrolled)demonstratedthat,at2years,comparedtobaseline,patientsreceivingletrozolewereassociatedwith

greaterdecreasesinBMDinthetotalhip(mediandecreaseof3.8%inhipBMDcomparedtoamediandecreaseof

2.0%intheplacebogroup(P=0.012,adjustedforbisphosphonateuse,P=0.018).Patientsreceivingletrozolewere

associatedwithagreaterdecreaseinlumbarspineBMDalthoughnotsignificantlydifferent.

ConcomitantcalciumandvitaminDsupplementationwasmandatoryintheBMDsubstudy.

Updatedresults(mediandurationoffollow-upwas50months)fromtheLipidsubstudy(347patientsenrolled)show

nosignificantdifferencesbetweentheletrozoleandplaceboarmsintotalcholesterolorinanylipidfraction.

Intheupdatedanalysisofthecorestudy11.1%ofpatientsintheletrozolearmreportedcardiovascularadverseevents

duringtreatmentcomparedwith8.6%intheplaceboarmuntilswitch.Theseeventsincludedmyocardialinfarction

(letrozole1.3%,placebo0.9%);anginarequiringsurgicalintervention(letrozole1.0%,placebo0.8%),newor

worseningangina(letrozole1.7%vs.placebo1.2%),thromboembolicevents(letrozole1.0%,placebo0.6%)and

cerebrovascularaccident(letrozole1.7%vs.placebo1.3%).

Nosignificantdifferenceswereobservedonglobalphysicalandmentalsummaryscores,suggestingthatoverall,

letrozoledidnotworsenqualityofliferelativetoplacebo.Treatmentdifferencesinfavourofplacebowereobservedin

patients`assessmentswithparticularlythemeasuresofphysicalfunctioning,bodilypain,vitality,sexualandvasomotor

items.Althoughstatisticallysignificantthesedifferenceswerenotconsideredclinicallyrelevant.

First-linetreatment

Onecontrolleddouble-blindtrialwasconductedcomparingletrozole2.5mgtotamoxifen20mgasfirst-linetherapyin

postmenopausalwomenwithadvancedbreastcancer.In907women,letrozolewassuperiortotamoxifenintimeto

progression(primaryendpoint)andinoverallobjectiveresponse,timetotreatmentfailureandclinicalbenefit.

Table5Resultsatamedianfollow-upof32months

Variable Statistic Letrozole

n=453 Tamoxifen

n=454

Timetoprogression Median 9.4months 6.0months

(95%CIformedian) (8.9,11.6months) (5.4,6.3months)

Hazardratio(HR) 0.72

(95%CIforHR) (0.62,0.83)

P <0.0001

Objectiveresponse

rate(ORR) CR+PR 145(32%) 95(21%)

(95%CIforrate) (28,36%) (17,25%)

Oddsratio 1.78

(95%CIforodds

ratio) (1.32,2.40)

P 0.0002

Overallclinical

benefitrate CR+PR+NC24

weeks 226(50%) 173(38%)

Oddsratio 1.62

(95%CIforodds

ratio) (1.24,2.11)

P 0.0004

Timetotreatment

failure Median 9.1months 5.7months

(95%formedian) (8.6,9.7months) (3.7,6.1months)

Hazardratio 0.73

(95%CIforHR) (0.64,0.84)

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Timetoprogressionwassignificantlylonger,andresponseratewassignificantlyhigherforletrozolethanfor

tamoxifeninpatientswithtumoursofunknownreceptorstatusaswellaswithpositivereceptorstatus.Similarly,time

toprogressionwassignificantlylonger,andresponseratesignificantlyhigherforletrozoleirrespectiveofwhether

adjuvantanti-oestrogentherapyhadbeengivenornot.Timetoprogressionwassignificantlylongerforletrozole

irrespectiveofdominantsiteofdisease.Mediantimetoprogressionwasalmosttwiceaslongforletrozoleinpatients

withsofttissuediseaseonly(median12.1monthsforletrozole,6.4monthsfortamoxifen),andinpatientswithvisceral

metastases(median8.3monthsforletrozole,4.6monthsfortamoxifen).Responseratewassignificantlyhigherfor

letrozoleinpatientswithsofttissuediseaseonly(50%vs.34%forletrozoleandtamoxifenrespectively),andfor

patientswithvisceralmetastases(28%letrozolevs.17%tamoxifen).

Studydesignallowedpatientstocrossoveruponprogressiontotheothertherapyordiscontinuefromthestudy.

Approximately50%ofpatientscrossedovertotheoppositetreatmentarmandcrossoverwasvirtuallycompletedby

36months.Themediantimetocrossoverwas17months(letrozoletotamoxifen)and13months(tamoxifento

letrozole).

Letrozoletreatmentinthefirst-linetherapyofadvancedbreastcancerresultedinamedianoverallsurvivalof34

monthscomparedwith30monthsfortamoxifen(logranktestP=0.53,notsignificant).Bettersurvivalwasassociated

withletrozoleuptoatleast24months.Thesurvivalrateat24monthswas64%fortheletrozoletreatmentgroup

versus58%forthetamoxifentreatmentgroup.Theabsenceofanadvantageforletrozoleonoverallsurvivalcouldbe

explainedbythecrossoverdesignofthestudy.

Thetotaldurationofendocrinetherapy(timetochemotherapy)wassignificantlylongerforletrozole(median16.3

months,95%CI15to18months)thanfortamoxifen(median9.3months,95%CI8to12months)(logrank

P=0.0047).

Second-linetreatment:

Twowell-controlledclinicaltrialswereconductedcomparingtwoletrozoledoses(0.5mgand2.5mg)tomegestrol

acetateandtoaminoglutethimide,respectively,inpostmenopausalwomenwithadvancedbreastcancerpreviously

treatedwithanti-oestrogens.

Timetoprogressionwasnotsignificantlydifferentbetweenletrozole2.5mgandmegestrolacetate(P=0.07).

Statisticallysignificantdifferenceswereobservedinfavourofletrozole2.5mgcomparedtomegestrolacetatein

overallobjectivetumourresponserate(24%vs.16%,P=0.04),andintimetotreatmentfailure(P=0.04).Overall

survivalwasnotsignificantlydifferentbetweenthe2arms(P=0.2).

Inthesecondstudy,theresponseratewasnotsignificantlydifferentbetweenletrozole2.5mgandaminoglutethimide

(P=0.06).Letrozole2.5mgwasstatisticallysuperiortoaminoglutethimidefortimetoprogression(P=0.008),timeto

Variable Statistic Letrozole

n=453 Tamoxifen

n=454

Hazardratio 0.73

(95%CIforHR) (0.64,0.84)

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5.2Pharmacokineticproperties

Absorption

Letrozoleisrapidlyandcompletelyabsorbedfromthegastrointestinaltract(meanabsolutebioavailability:99.9%).

Foodslightlydecreasestherateofabsorption(mediantmax:1hourfastedversus2hoursfed;andmeanCmax:129±

20.3nmol/litrefastedversus98.7±18.6nmol/litrefed)buttheextentofabsorption(AUC)isnotchanged.Theminor

effectontheabsorptionrateisnotconsideredtobeofclinicalrelevanceandthereforeletrozolemaybetakenwithout

regardtomealtimes.

Distribution

Plasmaproteinbindingofletrozoleisapproximately60%,mainlytoalbumin(55%).Theconcentrationofletrozolein

erythrocytesisabout80%ofthatinplasma.Afteradministrationof2.5mg14C-labelledletrozole,approximately82%

oftheradioactivityinplasmawasunchangedcompound.Systemicexposuretometabolitesisthereforelow.Letrozole

israpidlyandextensivelydistributedtotissues.Itsapparentvolumeofdistributionatsteadystateisabout1.87±0.47

L/kg

MetabolismandElimination

Metabolicclearancetoapharmacologicallyinactivecarbinolmetaboliteisthemajoreliminationpathwayofletrozole

(CLm=2.1L/h)butisrelativelyslowwhencomparedtohepaticbloodflow(about90L/h).ThecytochromeP450

isoenzymes3A4and2A6werefoundtobecapableofconvertingletrozoletothismetabolite.

Formationofminorunidentifiedmetabolitesanddirectrenalandfaecalexcretionplayonlyaminorroleintheoverall

eliminationofletrozole.Within2weeksafteradministrationof2.5mg14C-labelledletrozoletohealthy

postmenopausalvolunteers,88.2±7.6%oftheradioactivitywasrecoveredinurineand3.8±0.9%infaeces.Atleast

75%oftheradioactivityrecoveredinurineupto216hours(84.7±7.8%ofthedose)wasattributedtoaglucuronideof

thecarbinolmetabolite,about9%totwounidentifiedmetabolites,and6%tounchangedletrozole.

Theapparentterminaleliminationhalf-lifeinplasmaisabout2days.Afterdailyadministrationof2.5mgsteady-state

levelsarereachedwithin2to6weeks.Plasmaconcentrationsatsteadystateareapproximately7timeshigherthan

concentrationsmeasuredafterasingledoseof2.5mg,whiletheyare1.5to2timeshigherthanthesteady-statevalues

predictedfromtheconcentrationsmeasuredafterasingledose,indicatingaslightnon-linearityinthepharmacokinetics

ofletrozoleupondailyadministrationof2.5mg.Sincesteady-statelevelsaremaintainedovertime,itcanbe

concludedthatnocontinuousaccumulationofletrozoleoccurs.

Agehadnoeffectonthepharmacokineticsofletrozole.

Specialpopulations

Inastudyinvolving19volunteerswithvaryingdegreesofrenalfunction(24hourcreatinineclearance9-116mL/min)

noeffectonthepharmacokineticsofletrozolewasfoundafterasingledoseof2.5mg.Inasimilarstudyinvolving

subjectswithvaryingdegreesofhepaticfunction,themeanAUCvaluesofthevolunteerswithmoderatehepatic

impairment(Child-PughscoreB)was37%higherthaninnormalsubjects,butstillwithintherangeseeninsubjects

withoutimpairedfunction.

Inastudycomparingthepharmacokineticsofletrozoleafterasingleoraldoseineightmalesubjectswithliver

cirrhosisandseverehepaticimpairment(Child-PughscoreC)tothoseinhealthyvolunteers(N=8),AUCandt

increasedby95and187%,respectively.ThusEirfem2.5mgfilmcoatedtabletsshouldbeadministeredwithcaution

andafterconsiderationofthepotentialrisk/benefittosuchpatients.

5.3Preclinicalsafetydata

Inavarietyofpreclinicalsafetystudiesconductedinstandardanimalspecies,therewasnoevidenceofsystemicor

targetorgantoxicity.

Letrozoleshowedalowdegreeofacutetoxicityinrodentsexposedupto2000mg/kg.Indogsletrozolecausedsigns

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Inrepeated-dosetoxicitystudiesinratsanddogsupto12months,themainfindingsobservedcanbeattributedtothe

pharmacologicalactionofthecompound.Theno-adverse-effectlevelwas0.3mg/kginbothspecies.

Bothinvitroandinvivoinvestigationsonletrozole'smutagenicpotentialrevealednoindicationsofanygenotoxicity.

Ina104-weekratcarcinogenicitystudy,notreatment-relatedtumourswerenotedinmalerats.Infemalerats,a

reducedincidenceofbenignandmalignantmammarytumoursatallthedosesofletrozolewasfound.

Oraladministrationofletrozoletogravidratsresultedinaslightincreaseintheincidenceoffoetalmalformation

amongtheanimalstreated.However,itwasnotpossibletoshowwhetherthiswasanindirectconsequenceofthe

pharmacologicalproperties(inhibitionofoestrogenbiosynthesis)oradirecteffectofletrozoleinitsownright(see

recommendationinsections4.3Contraindicationsand4.6Pregnancyandlactation).

Preclinicalobservationswereconfinedtothoseassociatedwiththerecognisedpharmacologicalaction,whichisthe

onlysafetyconcernforhumanusederivedfromanimalstudies.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore

Microcrystallinecellulose

Anhydrouscolloidalsilica

Sodiumstarchglycollate(TypeA)

Magnesiumstearate

Tabletcoating

OpadryIIYellow85F38026consistingof

PolyvinylAlcohol

PolyethyleneGlycol

TitaniumDioxide(E171)

Talc

YellowIronOxide(E172)

SunsetYellowFCF(E110)

6.2Incompatibilities

Notapplicable.

6.3Shelflife

24months.

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

BlisterofPVC/PVdCandhardtemperedAluminiumfoil.Cartonsof10,14,28,30,100tablets.Notallpacksizes

maybemarketed

6.6Specialprecautionsfordisposal

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7MARKETINGAUTHORISATIONHOLDER

NicheGenericsLtd

1TheCamCentre

WilburyWay

HitchinSG40TW

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA1063/50/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:28thAugust2009

10DATEOFREVISIONOFTHETEXT

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Date Printed 08/11/2011 CRN 2103917 page number: 14