FEMARA

Main information

  • Trade name:
  • FEMARA 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:
  • FEMARA Film Coated Tablet 2.5 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA0465/243/001
  • Authorization date:
  • 11-12-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Femara2.5mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Activesubstance:letrozole

Eachfilm-coatedtabletcontains2.5mgletrozole.

Excipients:containslactose.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet

ProductimportedfromtheUK:

Film-coatedtablet,darkyellow,round,slightlybiconvexwithbevelededge.Onesidebearstheimprint“FV”,theother

“CG”.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Adjuvanttreatmentofpostmenopausalwomenwithhormonereceptorpositiveearlybreastcancer.

Extendedadjuvanttreatmentofhormone-dependentearlybreastcancerinpostmenopausalwomenwhohave

receivedpriorstandardadjuvanttamoxifentherapyfor5years.

First-linetreatmentinpostmenopausalwomenwithhormone-dependentadvancedbreastcancer.

Advancedbreastcancerinwomenwithnaturalorartificiallyinducedpostmenopausalstatusafterrelapseor

diseaseprogression,whohavepreviouslybeentreatedwithanti-oestrogens.

Efficacyhasnotbeendemonstratedinpatientswithhormonereceptornegativebreastcancer.

4.2Posologyandmethodofadministration

Adultandelderlypatients

TherecommendeddoseofFemarais2.5mgoncedaily.Nodoseadjustmentisrequiredforelderlypatients.

Intheadjuvantsetting,itisrecommendedtotreatfor5yearsoruntiltumourrelapseoccurs.Intheadjuvantsetting,

clinicalexperienceisavailablefor2years(mediandurationoftreatmentwas25months).

Intheextendedadjuvantsetting,clinicalexperienceisavailablefor4years(mediandurationoftreatment).

Inpatientswithadvancedormetastaticdisease,treatmentwithFemarashouldcontinueuntiltumourprogressionis

evident.

Children

Notapplicable.

Patientswithhepaticand/orrenalimpairment

Nodosageadjustmentisrequiredforpatientswithrenalinsufficiencywithcreatinineclearancegreaterthan30ml/min.

Insufficientdataareavailableincasesofrenalinsufficiencywithcreatinineclearancelowerthan30ml/minorin

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4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients

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

Preclinicalsafetydata).

4.4Specialwarningsandprecautionsforuse

Inpatientswhosepostmenopausalstatusseemsunclear,LH,FSHand/oroestradiollevelsmustbeassessedbefore

initiatingtreatmentinordertoclearlyestablishmenopausalstatus.

RenalImpairment

Femarahasnotbeeninvestigatedinasufficientnumberofpatientswithacreatinineclearancelowerthan10ml/min.

Thepotentialrisk/benefittosuchpatientsshouldbecarefullyconsideredbeforeadministrationofFemara.

HepaticImpairment

Femarahasonlybeenstudiedinalimitednumberofnon-metastaticpatientswithvaryingdegreesofhepaticfunction:

mildtomoderate,andseverehepaticinsufficiency.Innon-cancermalevolunteerswithseverehepaticimpairment

(livercirrhosisandChild-PughscoreC),systemicexposureandterminalhalf-lifewereincreased2-3-foldcomparedto

healthyvolunteers.Thus,Femarashouldbeadministeredwithcautionandaftercarefulconsiderationofthepotential

risk/benefittosuchpatients(seesection5.2Pharmacokineticproperties).

BoneEffects

Femaraisapotentoestrogen-loweringagent.Intheadjuvantandextendedadjuvantsettingthemedianfollow-up

durationof30and49monthsrespectivelyisinsufficienttofullyassessfractureriskassociatedwithlongtermuseof

Femara.Womenwithahistoryofosteoporosisand/orfracturesorwhoareatincreasedriskofosteoporosisshouldhave

theirbonemineraldensityformallyassessedbybonedensitometrypriortothecommencementofadjuvantand

extendedadjuvanttreatmentandbemonitoredfordevelopmentofosteoporosisduringandfollowingtreatmentwith

letrozole.Treatmentorprophylaxisforosteoporosisshouldbeinitiatedasappropriateandcarefullymonitored(see

section4.8Undesirableeffects).

Asthetabletscontainlactose,Femaraisnotrecommendedforpatientswithrarehereditaryproblemsofgalactose

intolerance,ofseverelactasedeficiencyorofglucose-galactosemalabsorption.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

ClinicalinteractionstudieswithcimetidineandwarfarinindicatedthatthecoadministrationofFemarawiththesedrugs

doesnotresultinclinicallysignificantdruginteractions.

Additionally,areviewoftheclinicaltrialdatabaseindicatednoevidenceofclinicallyrelevantinteractionswithother

commonlyprescribeddrugs.

ThereisnoclinicalexperiencetodateontheuseofFemaraincombinationwithotheranticanceragents.

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

intheconcomitantadministrationofdrugswhosedispositionismainlydependentontheseisoenzymesandwhose

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4.6Fertility,pregnancyandlactation

Womenofperimenopausalstatusorchild-bearingpotential

ThephysicianneedstodiscussthenecessityofapregnancytestbeforeinitiatingFemaraandofadequatecontraception

withwomenwhohavethepotentialtobecomepregnant(i.e.womenwhoareperimenopausalorwhorecentlybecame

postmenopausal)untiltheirpostmenopausalstatusisfullyestablished(seesections4.4Specialwarningsand

precautionsforuseand5.3Preclinicalsafetydata).

Pregnancy

Femaraiscontraindicatedduringpregnancy(seesection4.3Contraindicationsand5.3Preclinicalsafetydata).

Lactation

Femaraiscontraindicatedduringlactation(seesection4.3Contraindications).

4.7Effectsonabilitytodriveandusemachines

SincefatigueanddizzinesshavebeenobservedwiththeuseofFemaraandsomnolencehasbeenreported

uncommonly,cautionisadvisedwhendrivingorusingmachines.

4.8Undesirableeffects

Femarawasgenerallywelltoleratedacrossallstudiesasfirst-lineandsecond-linetreatmentforadvancedbreastcancer

andasadjuvanttreatmentofearlybreastcancer.UptoapproximatelyonethirdofthepatientstreatedwithFemarain

themetastaticsetting,uptoapproximately70-75%ofthepatientsintheadjuvantsetting(bothFemaraandtamoxifen

arms),anduptoapproximately40%ofthepatientstreatedintheextendedadjuvantsetting(bothFemaraandplacebo

arms)experiencedadversereactions.Generally,theobservedadversereactionsaremainlymildormoderateinnature.

Mostadversereactionscanbeattributedtonormalpharmacologicalconsequencesofoestrogendeprivation(e.g.hot

flushes).

Themostfrequentlyreportedadversereactionsintheclinicalstudieswerehotflushes,arthralgia,nauseaandfatigue.

Manyadversereactionscanbeattributedtothenormalpharmacologicalconsequencesofoestrogendeprivation(e.g.

hotflushes,alopeciaandvaginalbleeding).

Afterstandardadjuvanttamoxifen,basedonmedianfollow-upof28months,thefollowingadverseeventsirrespective

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

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

observedduringthefirstyearoftreatment.Therewasahigherbutnonsignificantincidenceofosteoporosisandbone

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

respectively).

Inanupdatedanalysisintheextendedadjuvantsettingconductedatamediantreatmentdurationof47monthsfor

letrozoleand28monthsforplacebo,thefollowingadverseeventsirrespectiveofcausalitywerereportedsignificantly

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

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

patientsinplaceboarmwhoswitchedtoFemaraasimilarpatternofgeneraleventswasobserved.Therewasahigher

incidenceofosteoporosisandbonefractures,anytimeafterrandomisation,inpatientswhoreceivedFemarathanin

patientswhoreceivedplacebo(12.3%vs.7.4%and10.9%vs.7.2%,respectively).InpatientswhoswitchedtoFemara,

newlydiagnosedosteoporosis,anytimeafterswitching,wasreportedin3.6%ofpatientswhilefracturewerereported

in5.1%ofpatientsanytimeafterswitching.

Intheadjuvantsetting,irrespectiveofcausality,thefollowingadverseeventsoccurredanytimeafterrandomizationin

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

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Thefollowingadversedrugreactions,listedinTable1werereportedfromclinicalstudiesandfrompostmarketing

experiencewithFemara:

Table1

Adversereactionsarerankedunderheadingsoffrequency,themostfrequentfirst,usingthefollowingconvention:very

common 10%,common1%to <

10%,uncommon 0.1%to <

1%,rare 0.01%to <

0.1%,veryrare <

0.01%,

includingisolatedreports.

Infectionsandinfestations

Uncommon: Urinarytractinfection

Neoplasms,benign,malignantandunspecified(includingcystsandpolyps)

Uncommon: Tumourpain(notapplicableintheadjuvantandextendedadjuvantsetting)

Bloodandthelymphaticsystemdisorders

Uncommon: Leukopenia

Metabolismandnutritiondisorders

Common: Anorexia,appetiteincrease,hypercholesterolaemia

Uncommon: Generaloedema

Psychiatricdisorders

Common: Depression

Uncommon: Anxietyincludingnervousness,irritability

Nervoussystemdisorders

Common: Headache,dizziness

Uncommon: Somnolence,insomnia,memoryimpairment,dysaesthesiaincluding

paresthesia,hypoesthesia,tastedisturbance,cerebrovascularaccident

Eyedisorders

Uncommon Cataract,eyeirritation,blurredvision

Cardiacdisorders

Uncommon: Palpitations,tachycardia

Vasculardisorders

Uncommon: Thrombophlebitisincludingsuperficialanddeepthrombophlebitis,

hypertension,ischemiccardiacevents

Rare: Pulmonaryembolism,arterialthrombosis,cerebrovascularinfarction

Respiratory,thoracicandmediastinaldisorders

Uncommon: Dyspnoea,cough

Gastrointestinaldisorders

Common: Nausea,vomiting,dyspepsia,constipation,diarrhoea

Uncommon: Abdominalpain,stomatitis,drymouth

Hepatobiliarydisorders

Uncommon: Increasedhepaticenzymes

Notknown: Hepatitis

Skinandsubcutaneoustissuedisorders

Verycommon: Increasedsweating

Common: Alopecia,rashincludingerythematous,maculopapular,psoriaform,and

vesicularrash

Uncommon: Pruritus,dryskin,urticaria

Notknown: Anaphylacticreaction,Angioedema,toxicepidermalnecrolysis,erythema

multiforme

Musculoskeletalandconnectivetissuedisorders

Verycommon: Arthralgia

Common: Myalgia,bonepain,osteoporosis,bonefractures

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4.9Overdose

IsolatedcasesofoverdosagewithFemarahavebeenreported.

Nospecifictreatmentforoverdosageisknown;treatmentshouldbesymptomaticandsupportive.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Enzymeinhibitor.Non-steroidalaromataseinhibitor(inhibitorofoestrogenbiosynthesis);

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

oestradiolby75-78%and78%frombaselinerespectively.Maximumsuppressionisachievedin48-78h.

Inpostmenopausalpatientswithadvancedbreastcancer,dailydosesof0.1to5mgsuppressplasmaconcentrationof

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

higher,manyvaluesofoestroneandoestronesulphatearebelowthelimitofdetectionintheassays,indicatingthat

higheroestrogensuppressionisachievedwiththesedoses.Oestrogensuppressionwasmaintainedthroughouttreatment

inallthesepatients.

Letrozoleishighlyspecificininhibitingaromataseactivity.Impairmentofadrenalsteroidogenesishasnotbeen

observed.Noclinicallyrelevantchangeswerefoundintheplasmaconcentrationsofcortisol,aldosterone,11-

deoxycortisol,17-hydroxyprogesterone,andACTHorinplasmareninactivityamongpostmenopausalpatientstreated

withadailydoseofletrozole0.1to5mg.TheACTHstimulationtestperformedafter6and12weeksoftreatmentwith

dailydosesof0.1,0.25,0.5,1,2.5,and5mgdidnotindicateanyattenuationofaldosteroneorcortisolproduction.

Renalandurinarydisorders

Uncommon: Increasedurinaryfrequency

Reproductivesystemandbreastdisorders

Uncommon: Vaginalbleeding,vaginaldischarge,vaginaldryness,breastpain

Generaldisordersandadministrationsiteconditions

Verycommon: Hotflushes,fatigueincludingasthenia

Common: Malaise,peripheraloedema

Uncommon: Pyrexia,mucosaldryness,thirst

Investigations

Common: Weightincrease

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Nochangeswerenotedinplasmaconcentrationsofandrogens(androstenedioneandtestosterone)amonghealthy

postmenopausalwomenafter0.1,0.5,and2.5mgsingledosesofletrozoleorinplasmaconcentrationsof

androstenedioneamongpostmenopausalpatientstreatedwithdailydosesof0.1to5mg,indicatingthattheblockadeof

oestrogenbiosynthesisdoesnotleadtoaccumulationofandrogenicprecursors.PlasmalevelsofLHandFSHarenot

affectedbyletrozoleinpatients,noristhyroidfunctionasevaluatedbyTSH,T4,andT3uptaketest.

Adjuvanttreatment

Amulticenter,double-blindstudyrandomizedover8000postmenopausalwomenwithresectedreceptor-positiveearly

breastcancer,tooneofthefollowingoption:

Option1:

tamoxifenfor5years

Femarafor5years

tamoxifenfor2yearsfollowedbyFemarafor3years

Femarafor2yearsfollowedbytamoxifenfor3years

Option2:

tamoxifenfor5years

Femarafor5years

DatainTable2reflectresultsbasedondatafromthemonotherapyarmsineachrandomizationoptionanddatafrom

thetwoswitchingarmsupto30daysafterthedateofswitch.Theanalysisofmonotherapyvssequencingofendocrine

treatmentswillbeconductedwhenthenecessarynumberofeventshasbeenachieved.

Patientshavebeenfollowedforamedianof26months,76%ofthepatientsformorethan2years,and16%(1252

patients)for5yearsorlonger.

Theprimaryendpointofthetrialwasdisease-freesurvival(DFS)whichwasassessedasthetimefromrandomization

totheearliesteventofloco-regionalordistantrecurrence(metastases)oftheprimarydisease,developmentofinvasive

contralateralbreastcancer,appearanceofasecondnon-breastprimarytumourordeathfromanycausewithoutaprior

cancerevent.Femarareducedtheriskofrecurrenceby19%comparedwithtamoxifen(hazardratio0.81;P=0.003).

The5-yearDFSrateswere84.0%forFemaraand81.4%fortamoxifen.TheimprovementinDFSwithFemaraisseen

asearlyas12monthsandismaintainedbeyond5years.Femaraalsosignificantlyreducedtheriskofrecurrence

comparedwithtamoxifenwhetherprioradjuvantchemotherapywasgiven(hazardratio0.72;P=0.018)ornot(hazard

ratio0.84;P=0.044).

Forthesecondaryendpointoverallsurvivalatotalof358deathswerereported(166onFemaraand192ontamoxifen).

Therewasnosignificantdifferencebetweentreatmentsinoverallsurvival(hazardratio0.86;P=0.15).Distantdisease-

freesurvival(distantmetastases),asurrogateforoverallsurvival,differedsignificantlyoverall(hazardratio0.73;

P=0.001)andinpre-specifiedstratificationsubsets.Femarasignificantlyreducedtheriskofsystemicfailureby17%

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

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PatientsreceivingFemara,comparedtotamoxifen,hadfewersecondmalignancies(1.9%vs2.4%).Particularlythe

incidenceofendometrialcancerwaslowerwithFemaracomparedtotamoxifen(0.2%vs0.4%).

SeeTables2and3thatsummarizetheresults.TheanalysessummarizedinTable4omitthe2sequentialarmsfrom

randomizationoption1,i.e.takeaccountonlyofthemonotherapyarms:

Table2 Disease-freeandoverallsurvival(ITTpopulation)

Table3 Disease-freeandoverallsurvivalbynodalstatusandprioradjuvantchemotherapy(ITT

Femara

N=4003 Tamoxifen

N=4007 HazardRatio

(95%CI) P-Value 1

Disease-freesurvival(primary)

-events(protocoldefinition,total) 351 428 0.81(0.70,0.93) 0.0030

Distantdisease-freesurvival

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

Overallsurvival(secondary)

-numberofdeaths(total) 166 192 0.86(0.70,1.06) 0.1546

Systemicdisease-freesurvival

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

Contralateralbreastcancer(invasive)

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

CI=confidenceinterval,

Logranktest,stratifiedbyrandomizationoptionanduseofprioradjuvantchemotherapy

HazardRatio,95%CIforhazardratio

P-Value 1

Disease-freesurvival

Nodalstatus

-Positive

-Negative 0.71(0.59,0.85)

0.98(0.77,1.25) 0.0002

0.8875

Prioradjuvantchemotherapy

-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

Prioradjuvantchemotherapy

-Yes

-No 0.76(0.51,1.14)

0.90(0.71,1.15) 0.1848

0.3951

Distantdisease-freesurvival

Nodalstatus

-Positive

-Negative 0.67(0.54,0.84)

0.90(0.60,1.34) 0.0005

0.5973

Prioradjuvantchemotherapy

-Yes

-No 0.69(0.50,0.95)

0.75(0.60,0.95) 0.0242

0.0184

CI=confidenceinterval

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Table4 PrimaryCoreAnalysis:Efficacyendpointsaccordingtorandomizationoptionmonotherapyarms

(ITTpopulation)

Themediandurationoftreatment(safetypopulation)was25months,73%ofthepatientsweretreatedformorethan2

years,22%ofthepatientsformorethan4years.Themediandurationoffollow-upwas30monthsforbothletrozole

andtamoxifen.

Adverseeventssuspectedofbeingrelatedtostudydrugwerereportedfor78%ofthepatientstreatedwithletrozole

comparedwith73%ofthosetreatedwithtamoxifen.ThemostcommonadverseeventsexperiencedwithFemarawere

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

oftenwithFemarathanwithtamoxifen(20%vs13%fortamoxifen).Femaratreatmentwasassociatedwithahigher

riskofosteoporosis(2.2%vs1.2%withtamoxifen).Overall,irrespectiveofcausality,cardiovascular/cerebrovascular

eventswerereportedanytimeafterrandomizationforsimilarproportionsofpatientsinbothtreatmentarms(10.8%for

letrozole,12.2%fortamoxifen).Amongstthese,thromboemboliceventswerereportedsignificantlylessoftenwith

Femara(1.5%)thanwithtamoxifen(3.2%)(P<0.001),whilecardiacfailurewasreportedsignificantlymoreoftenwith

Femara(0.9%)thanwithtamoxifen(0.4%)(P=0.006).Amongstpatientswhohadbaselinevaluesoftotalserum

cholesterolwithinthenormalrange,increasesintotalserumcholesterolhigherthan1.5timestheULNwereobserved

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

Overall Events/n 155/2463 196/2459

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,andbyrandomizationoptionandadjuvantchemotherapyforoverall

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Extendedadjuvanttreatment

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

withreceptor-positiveorunknownprimarybreastcancer,patientswhohadremaineddisease-freeaftercompletionof

adjuvanttreatmentwithtamoxifen(4.5to6years)wererandomlyassignedeitherFemaraorplacebo.

Theprimaryanalysisconductedatamedianfollow-upofaround28months(25%patientsofthepatientsbeing

followedforatleast38months)showedthatFemarareducedtheriskofrecurrenceby42%comparedwithplacebo

(hazardratio0.58;P=0.00003).ThestatisticallysignificantbenefitinDFSinfavourofletrozolewasobserved

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

Forthesecondaryendpointoverallsurvival(OS)atotalof113deathswerereported(51Femara,62placebo).Overall,

therewasnosignificantdifferencebetweentreatmentsinOS(hazardratio0.82;P=0.29).

Afterwardsthestudycontinuedinanunblendedfashionandpatientsintheplaceboarmcouldswitchtofemara,ifthey

wishedtodoso.Afterthestudyunblinding,over60%ofthepatientsintheplaceboarmeligibletoswitchoptedto

switchtoFemara(i.e.,lateextendedadjuvantpopulation).Patientswhoswitchedtofemarafromplacebohadbeenoff

adjuvanttamoxifenforamedian31months(range14to79months).

Updatedintent-to-treatanalyseswereconductedatamedianfollow-upof49months.IntheFemaraarmatleast30%of

thepatientshadcompleted5yearsand59%hadcompletedatleast4yearsoffollow-up.Intheupdatedanalysisof

DFS,Femarasignificantlyreducedtheriskofbreastcancerrecurrencecompared

withplacebo(hazardratio0.68;95%CI0.55,0.83;P=0.0001).Femaraalsosignificantlyreducedtheoddsofanew

invasivecontralateralcancerby41%comparedwithplacebo(oddsratio0.59;95%CI0.36,0.96;P=0.03).Therewas

nosignificantdifferenceindistantdisease-freesurvivaloroverallsurvival.

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

nosignificantdifferencesbetweentheFemaraandplaceboarmsintotalcholesterolorinanylipidfraction.

Intheupdatedanalysisofthecorestudy11.1%ofpatientsintheFemaraarmreportedcardiovascularadverseevents

duringtreatmentcomparedwith8.6%intheplaceboarmuntilswitch.Theseeventsincludedmyocardialinfarction

(Femara1.3%,placebo0.9%);anginarequiringsurgicalintervention(Femara1.0%,placebo0.8%),neworworsening

angina(Femara1.7%vsplacebo1.2%),thromboembolicevents(Femara1.0%,placebo0.6%)andcerebrovascular

accident(Femara1.7%vsplacebo1.3%).

Nosignificantdifferenceswereobservedonglobalphysicalandmentalsummaryscores,suggestingthatoverall,

letrozoledidnotworsenqualityofliferelativetoplacebo.Treatmentdifferencesinfavourofplacebowereobservedin

patients`assessmentswithparticularlythemeasuresofphysicalfunctioning,bodilypain,vitality,sexualandvasomotor

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First-linetreatment:

Onecontrolleddouble-blindtrialwasconductedcomparingFemara(letrozole)2.5mgtotamoxifen20mgasfirst-line

therapyinpostmenopausalwomenwithadvancedbreastcancer.In907women,letrozolewassuperiortotamoxifenin

timetoprogression(primaryendpoint)andinoverallobjectiveresponse,timetotreatmentfailureandclinicalbenefit.

TheresultsaresummarizedinTable5:

Table5 Resultsatamedianfollow-upof32months

Timetoprogressionwassignificantlylonger,andresponseratewassignificantlyhigherforletrozolethanfor

tamoxifeninpatientswithtumoursofunknownreceptorstatusaswellaswithpositivereceptorstatus.Similarly,time

toprogressionwassignificantlylonger,andresponseratesignificantlyhigherforletrozoleirrespectiveofwhether

adjuvantanti-oestrogentherapyhadbeengivenornot.Timetoprogressionwassignificantlylongerforletrozole

irrespectiveofdominantsiteofdisease.MediantimetoprogressionwasalmosttwiceaslongforFemarainpatients

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

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

Femarainpatientswithsofttissuediseaseonly(50%vs34%forFemaraandtamoxifenrespectively),andforpatients

withvisceralmetastases(28%Femaravs17%tamoxifen).

Studydesignallowedpatientstocrossoveruponprogressiontotheothertherapyordiscontinuefromthestudy.

Approximately50%ofpatientscrossedovertotheoppositetreatmentarmandcrossoverwasvirtuallycompletedby

36months.Themediantimetocrossoverwas17months(Femaratotamoxifen)and13months(tamoxifentoFemara).

Femaratreatmentinthefirst-linetherapyofadvancedbreastcancerresultedinamedianoverallsurvivalof34months

comparedwith30monthsfortamoxifen(logranktestP=0.53,notsignificant).Bettersurvivalwasassociatedwith

Femarauptoatleast24months.Thesurvivalrateat24monthswas64%fortheFemaratreatmentgroupversus58%

forthetamoxifentreatmentgroup.TheabsenceofanadvantageforFemaraonoverallsurvivalcouldbeexplainedby

thecrossoverdesignofthestudy.

Thetotaldurationofendocrinetherapy(timetochemotherapy)wassignificantlylongerforFemara(median16.3

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

Variable Statistic Femara

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%CIforoddsratio) (1.32,2.40)

P 0.0002

Overallclinical

benefitrate CR+PR+NC ≥24weeks226(50%)

173(38%)

Oddsratio 1.62

(95%CIforoddsratio) (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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Second-linetreatment:

Twowell-controlledclinicaltrialswereconductedcomparingtwoletrozoledoses(0.5mgand2.5mg)tomegestrol

acetateandtoaminoglutethimide,respectively,inpostmenopausalwomenwithadvancedbreastcancerpreviously

treatedwithanti-oestrogens.

Timetoprogressionwasnotsignificantlydifferentbetweenletrozole2.5mgandmegestrolacetate(P=0.07).

Statisticallysignificantdifferenceswereobservedinfavourofletrozole2.5mgcomparedtomegestrolacetatein

overallobjectivetumourresponserate(24%vs16%,P=0.04),andintimetotreatmentfailure(P=0.04).Overall

survivalwasnotsignificantlydifferentbetweenthe2arms(P=0.2).

Inthesecondstudy,theresponseratewasnotsignificantlydifferentbetweenletrozole2.5mgandaminoglutethimide

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

treatmentfailure(P=0.003)andoverallsurvival(P=0.002).

5.2Pharmacokineticproperties

Absorption

Letrozoleisrapidlyandcompletelyabsorbedfromthegastrointestinaltract(meanabsolutebioavailability:99.9%).

Foodslightlydecreasestherateofabsorption(mediant

1hourfastedversus2hoursfed;andmeanC

129±20.3

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

ontheabsorptionrateisnotconsideredtobeofclinicalrelevance,andthereforeletrozolemaybetakenwithoutregard

tomealtimes.

Distribution

Plasmaproteinbindingofletrozoleisapproximately60%,mainlytoalbumin(55%).Theconcentrationofletrozolein

erythrocytesisabout80%ofthatinplasma.Afteradministrationof2.5mg 14

C-labelledletrozole,approximately82%

oftheradioactivityinplasmawasunchangedcompound.Systemicexposuretometabolitesisthereforelow.Letrozole

israpidlyandextensivelydistributedtotissues.Itsapparentvolumeofdistributionatsteadystateisabout1.870.47

l/kg.

Metabolismandelimination

Metabolicclearancetoapharmacologicallyinactivecarbinolmetaboliteisthemajoreliminationpathwayofletrozole

=2.1l/h)butisrelativelyslowwhencomparedtohepaticbloodflow(about90l/h).ThecytochromeP450

isoenzymes3A4and2A6werefoundtobecapableofconvertingletrozoletothismetabolite.Formationofminor

unidentifiedmetabolitesanddirectrenalandfaecalexcretionplayonlyaminorroleintheoveralleliminationof

letrozole.Within2weeksafteradministrationof2.5mg 14

C-labelledletrozoletohealthypostmenopausalvolunteers,

88.2±7.6%oftheradioactivitywasrecoveredinurineand3.8±0.9%infaeces.Atleast75%oftheradioactivity

recoveredinurineupto216hours(84.7±7.8%ofthedose)wasattributedtoatheglucuronideofthecarbinol

metabolite,about9%totwounidentifiedmetabolites,and6%tounchangedletrozole.

Theapparentterminaleliminationhalf-lifeinplasmaisabout2days.Afterdailyadministrationof2.5mgsteady-state

levelsarereachedwithin2to6weeks.Plasmaconcentrationsatsteadystateareapproximately7timeshigherthan

concentrationsmeasuredafterasingledoseof2.5mg,whiletheyare1.5to2timeshigherthanthesteady-statevalues

predictedfromtheconcentrationsmeasuredafterasingledose,indicatingaslightnon-linearityinthepharmacokinetics

ofletrozoleupondailyadministrationof2.5mg.Sincesteady-statelevelsaremaintainedovertime,itcanbeconcluded

thatnocontinuousaccumulationofletrozoleoccurs.

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Specialpopulations

Inastudyinvolving19volunteerswithvaryingdegreesofrenalfunction(24-hourcreatinineclearance9-116ml/min)

noeffectonthepharmacokineticsofletrozolewasfoundafterasingledoseof2.5mg.Inasimilarstudyinvolving

subjectswithvaryingdegreesofhepaticfunction,themeanAUCvaluesofthevolunteerswithmoderatehepatic

impairment(Child-PughscoreB)was37%higherthaninnormalsubjects,butstillwithintherangeseeninsubjects

withoutimpairedfunction.Inastudycomparingthepharmacokineticsofletrozoleafterasingleoraldoseineightmale

subjectswithlivercirrhosisandseverehepaticimpairment(Child-PughscoreC)tothoseinhealthyvolunteers(N=8),

AUCandt

increasedby95and187%,respectively.ThusFemarashouldbeadministeredwithcautionandafter

considerationofthepotentialrisk/benefittosuchpatients.

5.3Preclinicalsafetydata

Inavarietyofpreclinicalsafetystudiesconductedinstandardanimalspecies,therewasnoevidenceofsystemicor

targetorgantoxicity.

Letrozoleshowedalowdegreeofacutetoxicityinrodentsexposedupto2000mg/kg.Indogsletrozolecausedsignsof

moderatetoxicityat100mg/kg.

Inrepeated-dosetoxicitystudiesinratsanddogsupto12months,themainfindingsobservedcanbeattributedtothe

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

Bothinvitroandinvivoinvestigationsonletrozole'smutagenicpotentialrevealednoindicationsofanygenotoxicity.

Ina104-weekratcarcinogenicitystudy,notreatment-relatedtumourswerenotedinmalerats.Infemalerats,areduced

incidenceofbenignandmalignantmammarytumoursatallthedosesofletrozolewasfound.

Oraladministrationofletrozoletogravidratsresultedinaslightincreaseintheincidenceoffoetalmalformation

amongtheanimalstreated.However,itwasnotpossibletoshowwhetherthiswasanindirectconsequenceofthe

pharmacologicalproperties(inhibitionofoestrogenbiosynthesis)oradirecteffectofletrozoleinitsownright(see

recommendationinsections4.3Contraindicationsand4.6Pregnancyandlactation).

Preclinicalobservationswereconfinedtothoseassociatedwiththerecognisedpharmacologicalaction,whichisthe

onlysafetyconcernforhumanusederivedfromanimalstudies.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactose

Cellulose

Maizestarch

Sodiumstarchglycolate

Magnesiumstearate

Silicaaerogel

Hypromellose

Talc

Macrogol

Titaniumdioxide(E171)

Ironoxideyellow(E172)

6.2Incompatibilities

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6.3ShelfLife

Theshelf-lifeexpirydateofthisproductisthedateshownonthecontainerandouterpackageoftheproductonthe

marketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove30 °

Storeintheoriginalpackageinordertoprotectfrommoisture.

6.5Natureandcontentsofcontainer

Blisterstripsof14tabletsinanover-labelledoutercarton.

Packsize:28tablets.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

PCOManufacturing

Unit10,AshbourneBusinessPark

Rath

Ashbourne

Co.Meath

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA465/243/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:11thDecember2009

10DATEOFREVISIONOFTHETEXT

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