letrozole

DrugMonograph

DrugName|MechanismofActionandPharmacokinetics|IndicationsandStatus|AdverseEffects|Dosing|Administration
Guidelines|SpecialPrecautions|Interactions|RecommendedClinicalMonitoring|SupplementaryPublicFunding|
References|Disclaimer

A-DrugName

letrozole
SYNONYM(S):CGS20267

COMMONTRADENAME(S):Femara(Novartis)

backtotop

B-MechanismofActionandPharmacokinetics

Aromatase(estrogensynthetase)isanenzymethatcatalysesvariousstepsintheconversionof
androgentoestrogen.Letrozoleisaselectivenon-steroidalaromataseinhibitorandinhibitsthe
conversionofadrenallygeneratedandrostenedionetoestroneorestradiolbyaromatasein
peripheraltissues(e.g.,adiposetissue),aswellasintumours.Itsignificantlylowersserumestradiol
concentrationinpostmenopausalwomenandhasnodetectableeffectonthyroidfunction,formation
ofadrenalcorticosteroidsoraldosteroneandplasmaandrogenlevels.Marketingapprovalsinthe
adjuvantandextendedadjuvantsettingarebasedondisease-freesurvivalasnoimprovementin
overallsurvivalwasshowntheriskofdeathinnodenegativepatientswasincreasedcomparedto
placebo.

Absorption Rapidlyandcompletelyabsorbed(99.9%)fromthegastrointestinaltract.
Absorptionisnotsignificantlyaffectedbyfood.Steadystatelevelsare
reachedwithin2to6weeks.
Distribution Rapidlyandextensivelydistributedintotissues.

Crossbloodbrainbarrier? unknown

PPB 60%(albumin)

Metabolism Themajorrouteofeliminationisviametabolism(CYP2A6and3A4)toa
pharmacologicallyinactivecarbinolmetabolite(CGP44645),followedby
glucuronidation.Dosesabove2.5mgdailyproduceover-proportional

Anyuseoftheinformationissubject,atalltimes,toCCOsTermsandConditions.
Page1of10
CCOFormulary-August2016
 letrozole
increasesinexposure,possiblyduetoasaturationofmetabolicelimination
processes.

Activemetabolites no

Inactivemetabolites Yes(CGP44645andothers).

Elimination Letrozoleandmetabolitesareexcretedmainlyviathekidneys.

Urine 88%ofdosewithin2weeks(mostlyas
metabolites)

Feces 4%ofdosewithin2weeks

Half-life (terminal):2to5days

backtotop

C-IndicationsandStatus

HealthCanadaApprovals:

Forfirst-linetreatmentofadvancedhormone-receptorpositivebreastcancerin
postmenopausalwomen
Hormonaltreatmentofadvanced/metastatichormone-receptorpositivebreastcancerafter
relapseordiseaseprogression,inwomenwithnaturalorartificially-inducedpostmenopausal
endocrinestatus,whohavepreviouslybeentreatedwithanti-estrogens
Foradjuvanttreatmentofpostmenopausalwomenwithhormone-receptorpositiveinvasive
earlybreastcancer
Fortheextendedadjuvanttreatmentofhormone-receptorpositiveinvasiveearlybreastcancer
inpostmenopausalwomenwhohavereceivedapproximately5yearsofpriorstandard
adjuvanttamoxifentherapy.

OtherUses:

Palliativetreatmentofovariancancer

backtotop

Anyuseoftheinformationissubject,atalltimes,toCCOsTermsandConditions.
Page2of10
CCOFormulary-August2016
 letrozole
D-AdverseEffects

EmetogenicPotential:Notapplicable

ExtravasationPotential:Notapplicable

Thefollowingtablecontainsadverseeventsreportedintheextendedadjuvantbreaststudywith
incidencehigherthanplaceboaswellaspost-marketingreports.

ORGANSITE SIDEEFFECT*(%) ONSET**

Cardiovascular Arrhythmia(4%) E
Arterialthromboembolism(3%) D
Cardiotoxicity(rare) D
Hypertension(8%) E
Venousthromboembolism(1%) D
Dermatological Alopecia(6%) D
Rash(2%)(maybesevere) E
Gastrointestinal Abdominalpain(5%) E
Anorexia(8%) E
Constipation(18%) IE
Diarrhea(8%) IE
Dyspepsia(5%) I
Nausea,vomiting(18%) IE
Weightchanges(3%) E
General Edema(28%) E
Fatigue(47%) E
Hematological Leukopenia(rare) E
Hepatobiliary LFTs(rare) E
Hypersensitivity Hypersensitivity(rare) I
Metabolic/Endocrine Cholesterol(23%) D
Hyperglycemia(3%) E
Musculoskeletal Fracture(13%) D
Musculoskeletalpain(42%) E
Osteoporosis(15%) D
NervousSystem Anxiety(4%) E
Depression(7%) E
Dizziness(22%) E

Anyuseoftheinformationissubject,atalltimes,toCCOsTermsandConditions.
Page3of10
CCOFormulary-August2016
 letrozole
Headache(32%) E
Insomnia(9%) E
Memoryimpairment(2%) E
Ophthalmic Cataract(<1%) D
Eyedisorders(Blurredvision,eyeirritation D
rare)
Reproductiveandbreast Estrogendeprivationsymptoms(upto61%) E
disorders
Vaginaldryness(8%) E
Respiratory Cough,dyspnea(9%) E

*"Incidence"mayrefertoanabsolutevalueorthehighervaluefromareportedrange.
"Rare"mayrefertoeventswith<1%incidence,reportedinpost-marketing,phase1studies,
isolateddataoranecdotalreports.
Dose-limitingsideeffectsareunderlined.

**I=immediate(onsetinhourstodays)E=early(daystoweeks)
D=delayed(weekstomonths)L=late(monthstoyears)

Themajorityoftheadverseeventsseemedtobemildtomoderateinseverity,andmanywere
expectedeffectsofestrogenwithdrawal.Themostcommonlyreportedeventsassociatedwith
letrozoleincludedhotflashes,asthenia,increasedsweating,headache,musculoskeletal
pain,hypercholesterolemia,edema,dizziness,osteoporosis,constipationand
nausea/vomiting.

Letrozole,whenusedinthemetastaticsetting,isassociatedwithaloweroverallincidenceof
thromboemboliceventsascomparedtotamoxifen.Whencomparedtomegestrol,lowerweightgain
andvaginalbleedinghavebeenobservedwithletrozole,buthigherincidencesofhotflashes,
headache,rash,nausea,musculoskeletalpain,othergastrointestinaleffectsandperipheraledema
werereportedwithletrozole.

Intheadjuvantearlybreastcancertrial,therewerehigherratesofosteoporosis,fractures,
hypercholesterolemia,arthralgia,myalgia,MIandCHFwhencomparedtotamoxifen,butreduced
incidencesofthromboembolicevents,uterinepolyps,vaginalhemorrhageandendometrial
hyperplasia.

Intheextendedadjuvantstudy(mediantreatmentdurationof60months),significantlyhigherratesof
cardiovascularevents(includingarterialorvenousthromboembolism)wereobservedintheletrozole
group(9.8%),ascomparedtoplacebo(7%mediantreatmentduration28months).Asignificantly
higherincidenceofosteoporosiswasobservedinthepatientswhoreceivedletrozole(14.5%)than
thosewhoreceivedplacebo(7.8%).

Anyuseoftheinformationissubject,atalltimes,toCCOsTermsandConditions.
Page4of10
CCOFormulary-August2016
 letrozole
Patientswithosteoporosisoratriskofosteoporosisshouldbecarefullymonitoredandtreated
appropriately.ConsidercalciumandvitaminDsupplementsinpatientswhohavenohistoryof
hypercalcemia,especiallyinpatientsreceivingadjuvantletrozole.Formoreinformationaboutbone
healthviadietaryandlifestylemeasures,seepamphleton"BoneHealthinPostMenopausal
Women".

backtotop

E-Dosing

Refertoprotocolbywhichpatientisbeingtreated.

Foradjuvantandextendedadjuvantuse,durationoftreatmentis5years.Forextended
adjuvanttherapy,startwithin3monthsofcompletionofapproximately5yearsoftamoxifen.In
firstandsecond-lineadvancedbreastcancer,continuetreatmentuntilfurtherdisease
progression.

ConsidercalciumandvitaminDsupplementsinpatientswithadvancedbreastcancerwho
havenohistoryofhypercalcemia.Patientsreceivingadjuvantletrozoleshouldensure
adequatecalciumintake(withsupplementationasneeded)andvitaminDsupplementation.

Adults:

Therecommendeddoseis2.5mgoncedaily.

DosagewithToxicity:

Dosageinmyelosuppression:Nodosageadjustmentrequired.

DosagewithHepaticImpairment:

HepaticImpairment Dose
Mildtomoderate Nodoseadjustmentneeded,although
exposuremayby37%
Severe Nodata.Monitorpatientscloselyand

Anyuseoftheinformationissubject,atalltimes,toCCOsTermsandConditions.
Page5of10
CCOFormulary-August2016
 letrozole
considerdosemodification.

DosagewithRenalImpairment:

Creatinineclearance Dose
10mL/min Nodoseadjustmentneeded
Severe Nodata.Considerpotentialbenefit-
riskcarefully.

Dosageintheelderly:

Nodosageadjustmentrequired.Olderpatientshaveanincreasedriskofosteoporosisand
fracture.

Children:

Safetyandefficacynotestablished.CONTRAINDICATEDinpatientsunder18yearsofage.

backtotop

F-AdministrationGuidelines

Oralself-administrationdrugavailablebyoutpatientprescription.
Tabletsshouldbetakenwithaglassofwater,withorwithoutfood,ataroundthesametime
everyday.
Donotcrushorchewthetablets.
Misseddosesshouldbetakenassoonaspossible,butshouldbeskippedifwithinafew
hoursofthenextplanneddose.Donotdoublethedoseduetoover-proportionalityof
exposureatdosesabove2.5mgdaily.
Avoidgrapefruit,starfruit,Sevilleorangesortheirjuices/productswhileonthistreatment,since
thismayincreasesideeffects.
Storetabletsatroomtemperature(15-30C)

Anyuseoftheinformationissubject,atalltimes,toCCOsTermsandConditions.
Page6of10
CCOFormulary-August2016
 letrozole

backtotop

G-SpecialPrecautions

Contraindications:

Patientswithknownhypersensitivitytoletrozole,oranyofitscomponents,orotheraromatase
inhibitors.
Premenopausalwomen
Patientsunder18yearsofage
Inpregnancyand/orlactation
Letrozoleusageinmenwithbreastcancerhasnotbeenstudied.
Itisnotindicatedinhormone-receptornegativedisease

OtherWarnings/Precautions:

Useofletrozoleintheadjuvantsettingshouldbecarefullyconsideredforpatientswith
osteoporosisorriskfactorsforcardiovasculareventsorosteoporosis.
Somebrandscontainlactosecarefullyconsideruseinpatientswithhereditarygalactose
intolerance,severelactasedeficiencyorglucose-galactosemalabsorption.
Carefullyassessbenefit-riskbeforeusingletrozoleasextendedadjuvanttreatmentforearly
breastcancerpatientswithlowrecurrencerisk,asanincreaseindeathswasobservedin
node-negativepatientsintheletrozolearmascomparedtopatientsonplacebo.

OtherDrugProperties:

Carcinogenicity:Anincreasedincidenceofbenignovarianstromaltumourswasobservedin
animalstudies.

PregnancyandLactation:

Mutagenicity:No
Clastogenicity:No
Embryotoxicity:Yes
Fetotoxicity:Yes
Teratogenicity:Yes
Appropriatecontraceptionshouldbeusedinwomenwithpotentialtobecomepregnant,
includingwomenwhoareperimenopausalorrecentlybecomepostmenopausal.

backtotop

H-Interactions

Administrationwithcimetidinehadnosignificanteffectonletrozolespharmacokinetics,and

Anyuseoftheinformationissubject,atalltimes,toCCOsTermsandConditions.
Page7of10
CCOFormulary-August2016
 letrozole
letrozolehadnosignificanteffectonwarfarinspharmacokineticparameters.

However,letrozoleisastronginhibitorofCYP2A6andamoderateinhibitorofCYP2C19(at
doseshigherthanthoseachievedwithclinicaldoses).Cautionisadvisedwithconcomitant
administrationofdrugswithanarrowtherapeuticindex(e.g.phenytoin,clopidogrel),thataremainly
metabolizedbytheseisoenzymes.

AGENT EFFECT MECHANISM MANAGEMENT

Tamoxifen,other mayletrozoleefficacy Unknown Avoidconcomitantuse
anti-estrogensor tamoxifenletrozolelevels
estrogen- by38%onaverage
containing
therapies
CYP3A4inhibitors letrozoleconcentrationor letrozolemetabolism Cautionwithstrong
(i.e.ketoconazole, adverseeffects(theoretical) CYP3A4inhibitors
clarithromycin, (theoretical)
ritonavir,fruitor
juicefrom
grapefruit,Seville
orangesor
starfruit)
CYP2A6inhibitors letrozoleconcentrationor letrozolemetabolism Cautionwithstrong
(e.g.methoxsalen, adverseeffects(theoretical) CYP2A6inhibitors
tranylcypromine) (theoretical)
CYP3A4inducers letrozoleconcentrationor letrozolemetabolism Cautionwithstrong
(i.e.phenytoin, efficacy(theoretical) CYP3A4inducers
rifampin, (theoretical)
dexamethasone,
carbamazepine,
phenobarbital,St.
JohnsWort,etc)

backtotop

I-RecommendedClinicalMonitoring

Treatingphysiciansmaydecidetomonitormoreorlessfrequentlyforindividualpatientsbutshould
alwaysconsiderrecommendationsfromtheproductmonograph.

RecommendedClinicalMonitoring

MonitorType MonitorFrequency
Serumcholesterolandlipidsevaluation Baselineandregular

Anyuseoftheinformationissubject,atalltimes,toCCOsTermsandConditions.
Page8of10
CCOFormulary-August2016
 letrozole
Bonemineraldensity Baselineandregular
LH,FSHand/orestradiollevelsinpatientswhose
menopausalstatusisunclearorwhobecome
amenorrheicafterchemotherapybeforestarting
letrozoleandregularlyduringthefirst6monthsof
treatment.Onlyconfirmedpostmenopausalpatients
shouldreceiveletrozole.
Assessmentoffatigue,estrogenwithdrawalsymptoms, Ateachvisit
musculoskeletal,cardiovascular,thromboembolism,GI
andGUeffects,ophthalmic,etc.

GradetoxicityusingthecurrentNCI-CTCAE(CommonTerminologyCriteriaforAdverseEvents)
version

backtotop

J-SupplementaryPublicFunding

ODBLimitedUse(ODBFormulary)
Treatmentofmetastaticbreastcancerinhormonereceptorpositivepostmenopausalwomen
()
Asanalternativetotamoxifenfortheadjuvanttreatmentofpostmenopausalwomenwith
hormonereceptorpositiveearlybreastcancerforamaximumoffiveyears()
Treatmentofhormonereceptorpositiveearlybreastcancerinpostmenopausalwomenwho
havereceived5yearsofadjuvanttamoxifentherapy()

backtotop

K-References

McEvoyGK,editor.AHFSDrugInformation2013.Bethesda:AmericanSocietyofHealth-System
Pharmacists,p.1104-9.

ProductMonograph:Femara(letrozole).NovartisPharmaceuticalsCanada,April23,2014.

August2016addedotherindication

backtotop

Anyuseoftheinformationissubject,atalltimes,toCCOsTermsandConditions.
Page9of10
CCOFormulary-August2016
 letrozole

L-Disclaimer

RefertotheNewDrugFundingProgramorOntarioPublicDrugProgramswebsitesforthemostup-to-datepublic
fundinginformation.

Theinformationsetoutinthedrugmonographs,regimenmonographs,appendicesandsymptommanagement
information(forhealthprofessionals)containedintheDrugFormulary(the"Formulary")isintendedforhealthcare
providersandistobeusedforinformationalpurposesonly.Theinformationisnotintendedtocoverallpossibleuses,
directions,precautions,druginteractionsoradverseeffectsofaparticulardrug,norshoulditbeconstruedtoindicate
thatuseofaparticulardrugissafe,appropriateoreffectiveforagivencondition.TheinformationintheFormularyis
notintendedtoconstituteorbeasubstituteformedicaladviceandshouldnotberelieduponinanysuchregard.All
usesoftheFormularyaresubjecttoclinicaljudgmentandactualprescribingpatternsmaynotfollowtheinformation
providedintheFormulary.

Theformatandcontentofthedrugmonographs,regimenmonographs,appendicesandsymptommanagement
informationcontainedintheFormularywillchangeastheyarereviewedandrevisedonaperiodicbasis.Thedateof
lastrevisionwillbevisibleoneachpageofthemonographandregimen.Sincestandardsofusageareconstantly
evolving,itisadvisedthattheFormularynotbeusedasthesolesourceofinformation.Itisstronglyrecommended
thatoriginalreferencesorproductmonographbeconsultedpriortousingachemotherapyregimenforthefirsttime.

SomeFormularydocuments,suchasthemedicationinformationsheets,regimeninformationsheetsandsymptom
managementinformation(forpatients),areintendedforpatients.Patientsshouldalwaysconsultwiththeirhealthcare
provideriftheyhavequestionsregardinganyinformationsetoutintheFormularydocuments.

WhilecarehasbeentakeninthepreparationoftheinformationcontainedintheFormulary,suchinformationis
providedonanas-isbasis,withoutanyrepresentation,warranty,orcondition,whetherexpress,orimplied,statutory
orotherwise,astotheinformationsquality,accuracy,currency,completeness,orreliability.

CCOandtheFormularyscontentprovidersshallhavenoliability,whetherdirect,indirect,consequential,contingent,
special,orincidental,relatedtoorarisingfromtheinformationintheFormularyoritsusethereof,whetherbasedon
breachofcontractortort(includingnegligence),andevenifadvisedofthepossibilitythereof.Anyoneusingthe
informationintheFormularydoessoathisorherownrisk,andbyusingsuchinformation,agreestoindemnifyCCO
anditscontentprovidersfromanyandallliability,loss,damages,costsandexpenses(includinglegalfeesand
expenses)arisingfromsuchpersonsuseoftheinformationintheFormulary.

backtotop

Anyuseoftheinformationissubject,atalltimes,toCCOsTermsandConditions.
Page10of10
CCOFormulary-August2016