ARKOLAMYL 5 Milligram Orodispersible Tablet

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
OLANZAPINE
Available from:
McDermott Laboratories Ltd t/a Gerard Laboratories
ATC code:
N05AH03
INN (International Name):
OLANZAPINE
Dosage:
5 Milligram
Pharmaceutical form:
Orodispersible Tablet
Prescription type:
Product subject to prescription which may not be renewed (A)
Therapeutic area:
Antipsychotics
Authorization status:
Authorised
Authorization number:
PA0577/114/001
Authorization date:
2010-07-16

Packageleaflet:Informationforthepatient

Arkolamyl5mgOrodispersibleTablets

Arkolamyl10mgOrodispersibleTablets

Arkolamyl15mgOrodispersibleTablets

Arkolamyl20mgOrodispersibleTablets

olanzapine

Readallofthisleafletcarefullybeforeyoustarttakingthismedicinebecauseitcontainsimportant

informationforyou.

- Keepthisleaflet.Youmayneedtoreaditagain.

- Ifyouhaveanyfurtherquestions,askyourdoctororpharmacist.

- Thismedicinehasbeenprescribedforyouonly.Donotpassitontoothers.Itmayharmthem,evenif

theirsignsofillnessarethesameasyours.

- Ifyougetanysideeffects,talktoyourdoctororpharmacist.Thisincludesanypossiblesideeffects

notlistedinthisleaflet.Seesection4.

Whatisinthisleaflet

1.WhatArkolamylisandwhatitisusedfor

2.WhatyouneedtoknowbeforeyoutakeArkolamyl

3.HowtotakeArkolamyl

4.Possiblesideeffects

5.HowtostoreArkolamyl

6.Contentsofthepackandotherinformation

1.WhatArkolamylisandwhatitisusedfor

Arkolamylcontainstheactivesubstanceolanzapine.Olanzapinebelongstoagroupofmedicinescalled

antipsychoticsandisusedtotreatthefollowingmentalhealthconditions:

Schizophrenia,aconditionwithsymptomssuchashearing,seeingorsensingthingswhicharenot

there,mistakenbeliefs,unusualsuspiciousness,andbecomingwithdrawn.Peoplewiththis

conditionmayalsofeeldepressed,anxiousortense.

Moderatetoseveremanicepisodes,aconditionwithsymptomsofexcitementoreuphoria.

Arkolamylhasbeenshowntopreventrecurrenceofthesesymptomsinpatientswithbipolardisorder

whosemanicepisodehasrespondedtoolanzapinetreatment.

2.WhatyouneedtoknowbeforeyoutakeArkolamyl

DonottakeArkolamyl

- Ifyouareallergictoolanzapineoranyoftheotheringredientsofthismedicine(listedinsection

6).Anallergicreactionmayberecognisedasarash,itching,aswollenface,swollenlips,tongue

orthroat,difficultybreathingorshortnessofbreath.Ifthishashappenedtoyou,tellyourdoctor.

- Ifyouhavebeenpreviouslydiagnosedwitheyeproblemssuchascertainkindsofglaucoma

(increasedpressureintheeye).

Warningsandprecautions

TalktoyourdoctororpharmacistbeforetakingArkolamylif:

youareelderlywithdementiaasyoumaygetserioussideeffects.

youorsomeoneinyourfamilyhasahistoryofbloodclots,asmedicineslikethishavebeen

associatedwithformationofbloodclots.

youhavehadastrokeor“mini”stroke(temporarysymptomsofstroke)

youhaveParkinson’sdiseaseasyoursignsofillnessmaygetworse

youhaveanenlargedprostateproblems

youhaveablockedintestine(paralyticileus)

youhaveproblemswithyourliverorkidneys

youhaveproblemswithyourbloodcells

youhaveheartdisease

youhaveproblemswiththeelectricalactivityoftheheart

youhavelowlevelsofpotassiumormagnesiumintheblood

youhavediabetes

youhaveahistoryoffitsorseizures(epilepsy)

youareasmoker

Duringtreatment

Ifyouexperienceacombinationofaveryhighfever,fasterbreathing,excessivesweating,achangein

mood,musclestiffness,highbloodpressureanddrowsinessorsleepiness,speaktoyourdoctorasyour

doctormaydecidetodiscontinueArkolamyl.

Ifyouexperienceuncontrollablemovementsofthefaceortongue,speaktoyourdoctorasyourdoctor

mayconsidertoreducethedoseordiscontinueArkolamyl.

Weightgainhasbeenseeninpatientstakingolanzapine.Youandyourdoctorshouldcheckyourweight

regularly.Considerreferraltoadieticianorhelpwithadietplanifnecessary.

YourdoctormayalsowishtoperformbloodtestsbeforeyoustarttakingArkolamylandregularlyduring

treatmenttomonitorbloodsugarandfatlevels.

Asaroutineprecaution,ifyouareover65yearsyourbloodpressuremaybemonitoredbyyourdoctor.

Childrenandadolescents

Arkolamylisnotrecommendedforpatientswhoareunder18years.

OthermedicinesandArkolamyl

OnlytakeothermedicineswhileyouareonArkolamylifyourdoctortellsyouthatyoucan.

Tellyourdoctororpharmacistifyouaretaking,haverecentlytakenormighttakeanyothermedicines,

includingmedicinesobtainedwithoutaprescription,especiallyanyofthefollowing:

antidepressantsormedicinestakenforanxietyortohelpyousleep(tranquillisers)asyoumayfeel

drowsy.

medicinesforParkinson’sdisease.

carbamazepine(ananti-epilepticandmoodstabiliser).

fluvoxamine(anantidepressant).

ciprofloxacin(anantibiotic).

activatedcharcoal.YoushouldtakethisatleasttwohoursbeforeorafteryoutakeArkolamyl.

Arkolamylwithalcohol

DonotdrinkanyalcoholifyouhavebeengivenArkolamylastogetherwithalcoholitmaymakeyoufeel

drowsy.

Pregnancyandbreast-feeding

Ifyouarepregnantorbreast-feeding,thinkyoumaybepregnantorareplanningtohaveababy,askyour

doctororpharmacistforadvicebeforetakingthismedicine.Yourdoctorwilldiscusswithyouwhether

youshouldtakethismedicinewhenpregnant.

Youshouldnottakethismedicinewhenbreast-feeding,assmallamountsofArkolamylcanpassinto

breastmilk.

Thefollowingsymptomsmayoccurinnewbornbabies,ofmothersthathaveusedArkolamylinthelast

trimester(lastthreemonthsoftheirpregnancy):shaking,musclestiffnessand/orweakness,sleepiness,

agitation,breathingproblems,anddifficultyinfeeding.Ifyourbabydevelopsanyofthesesymptomsyou

mayneedtocontactyourdoctor.

Drivingandusingmachines

ThereisariskoffeelingdrowsyordizzywhenyouaregivenArkolamyl.Ifthishappensdonotdriveor

operateanytoolsormachines.Tellyourdoctor.

Arkolamylcontainslactose

Ifyouhavebeentoldbyyourdoctorthatyouhaveanintolerancetosomesugars,contactyourdoctor

beforetakingthismedicine.

3.HowtotakeArkolamyl

Alwaystakethismedicineexactlyasyourdoctororpharmacisthastoldyou.Checkwithyourdoctoror

pharmacistifyouarenotsure.

YourdoctorwilltellyouhowmanyArkolamyltabletstotakeandhowlongyoushouldcontinuetotake

them.TherecommendeddailydoseofArkolamylisbetween5and20mg.Consultyourdoctorifyour

symptomsreturnbutdonotstoptakingArkolamylunlessyourdoctortellsyouto.

YoushouldtakeyourArkolamylorodispersibletabletsonceadayfollowingtheadviceofyourdoctor.

Trytotakeyourtabletsatthesametimeeachday.Itdoesnotmatterwhetheryoutakethemwithor

withoutfood.

Arkolamylorodispersibletabletsbreakeasily,soyoushouldhandlethetabletscarefully.Donothandle

thetabletswithwethandsasthetabletsmaybreakup.

1.Holdtheblisterstripattheedgesandseparateoneblistercellfromtherestofthestripbygentlytearing

alongtheperforationsaroundit.

2.Carefullypeeloffthebacking.

3.Gentlypushthetabletout.

4.Putthetabletinyourmouth.Itwilldissolvedirectlyinyourmouth,sothatitcanbeeasilyswallowed.

Youcanalsoplacethetabletinafullglassorcupofwater,orangejuice,applejuice,milkorcoffee,and

stir.Withsomedrinks,themixturemaychangecolourandpossiblybecomecloudy.Drinkitstraight

away.

IfyoutakemoreArkolamylthanyoushould

Contactyourdoctororhospitalstraightaway.Showthedoctoryourpackoftablets.

PatientswhohavetakenmoreArkolamylthantheyshould,haveexperiencedthefollowingsymptoms:

rapidbeatingoftheheart,agitation/aggressiveness,problemswithspeech,unusualmovements(especially

ofthefaceortongue)andreducedlevelofconsciousness.Othersymptomsmaybe:acuteconfusion,

seizures(epilepsy),coma,acombinationoffever,fasterbreathing,sweating,musclestiffnessand

drowsinessorsleepiness,slowingofthebreathingrate,inhalingfluidintothewindpipeandlungs,often

afterbeingsick(aspiration),highbloodpressureorlowbloodpressure,abnormalrhythmsoftheheart.

IfyouforgettotakeArkolamyl

Takeyourtabletsassoonasyouremember.Donottakeadoubledosetomakeupforaforgottendose.

IfyoustoptakingArkolamyl

Donotstoptakingyourtabletsjustbecauseyoufeelbetter.Itisimportantthatyoucarryontaking

Arkolamylforaslongasyourdoctortellsyou.

IfyousuddenlystoptakingArkolamyl,symptomssuchassweating,difficultysleeping,shaking,anxiety

orfeelingsick(nausea)andbeingsick(vomiting)mightoccur.Yourdoctormaysuggestyoutoreduce

thedosegraduallybeforestoppingtreatment.

Ifyouhaveanyfurtherquestionsontheuseofthismedicine,askyourdoctororpharmacist.

4.Possiblesideeffects

Likeallmedicines,thismedicinecancausesideeffects,althoughnoteverybodygetsthem.

Immediatelygotothenearesthospitalemergencydepartmentorspeaktoyourdoctorifyouhave

thefollowing:

Common(mayaffectupto1in10people)

anincreaseinthenumberofinfectionsyougetcausingfever,severechills,sorethroatormouth

ulcers(thesemayindicateyouhavealownumberofwhitebloodcells).

Uncommon(mayaffectupto1in100people)

uncontrolledmovementsofthemouth,tongue,cheeksorjaws,whichmayprogresstothearms

andlegs(tardivedyskinesia).

irregularheartrate.

bloodclotsintheveinsespeciallyinthelegs(symptomsincludeswelling,pain,andrednessin

theleg),whichmaytravelthroughbloodvesselstothelungscausingchestpainanddifficultyin

breathing.

allergicreactionssuchasarash,itchingorswellingoftheface,lips,tongueorthroat,difficulty

breathingorshortnessofbreath.

diabetesortheworseningofdiabetes,occasionallyassociatedwithketoacidosis(ketonesinthe

bloodandurine)orcoma.

difficultyurinatingoremptyingthebladder.

seizures(usuallyassociatedwithahistoryofseizures(epilepsy)).

Rare(mayaffectupto1in1,000people)

acombinationofaveryhighfever,fasterbreathing,excessivesweating,changeinmood,

musclestiffness,highbloodpressureanddrowsinessorsleepiness.

shivering,coldorpaleskin(thesemaybesignsthatyourbodytemperatureislowerthan

normal).

adangerouslyfastheartbeat.

severestomachpainwhichmayradiatetoyourback(thismaybeasignofproblemswithyour

pancreas).

yellowingofyourskinorwhitesofyoureyes,darkurine,palestools,tiredness,fever,nausea,

weakness,drowsinessandabdominalpain(thesemaybesignsofproblemswithyourliver).

breakdownofmuscle,causingmusclepain,weaknessortendernessaccompaniedbydarkurine

(rhabdomyolysis).

Notknown(cannotbeestimatedfromtheavailabledata)

flu-likesymptomswitharashonthefaceandthenwithanextendedrash,hightemperature,

enlargedlymphnodes,increasedlevelsofliverenzymesseeninbloodtestsandanincreaseina

typeofwhitebloodcell(eosinophilia).ThesemaybesignsofDrugReactionwithEosinophilia

andSystemicSymptoms(DRESS).

Othersideeffectsinclude:

Verycommon(mayaffectmorethan1in10people)

weightgain.

sleepiness.

increasesinthelevelsofprolactininthebloodwhichcanbeseeninabloodtest.

intheearlystagesoftreatment,somepeoplemayfeeldizzyorfaint(withaslowheartrate),

especiallywhengettingupfromalyingorsittingposition.Thiswillusuallypassonitsownbutif

itdoesnot,tellyourdoctor.

Common(mayaffectupto1in10people)

changesinthelevelsofsomewhitebloodcells,circulatingfatsandearlyintreatment,temporary

increasesinliverenzymeswhichwouldbeseeninabloodtest.

increasesinthelevelofsugarsinthebloodandurine,whichwouldbeseeninabloodorurine

test.

increasesinlevelsofuricacidandcreatinephosphokinaseintheblood,whichwouldbeseenina

bloodtest.

feelingmorehungry.

dizziness.

restlessness.

tremor,rigidposture,slowmovement,andashuffling,unbalancedwalk(Parkinsonism).

unusualmovements(dyskinesias).

constipation.

drymouth.

rash.

unusualweakness.

extremetiredness.

waterretentionleadingtoswellingofthehands,anklesorfeet.

decreasedsexdriveinmalesandfemalesorproblemsgettingormaintaininganerectioninmales

fever.

jointpain.

Uncommon(mayaffectupto1in100people)

uncontrollablemusclestiffnessorspasmsaffectingthehead(includingeyemovements),neckor

body.

problemswithspeech.

slowheartrate.

increaseinsensitivityofskintosunlight.

bleedingfromthenose.

bloatingfeelinginyourstomach.

memorylossorforgetfulness.

inabilitytocontrolurination;difficultyinstartingtourinateormaintainingtheflow.

hairloss.

absenceordecreaseinmenstrualperiods.

increaseinbreastssizeinmalesorfemales

abnormalproductionofbreastmilkinfemales.

increaseinbilirubinlevelsinthebloodseeninabloodtest.

Rare(mayaffectupto1in1000people)

suddenunexplaineddeath.

signsofwithdrawalsuchassweating,difficultysleeping,shaking,anxiety,feelingsick(nausea)

orbeingsick(vomiting).

unexplainedbruisingandbleedingmoreeasilyorforlongerthanusual.

prolongedand/orpainfulerection.

Whiletakingolanzapine,elderlypatientswithdementiamaysufferfromstroke,pneumonia,urinary

incontinence,falls,extremetiredness,visualhallucinations,ariseinbodytemperature,rednessoftheskin

andhavetroublewalking.Somefatalcaseshavebeenreportedinthisparticulargroupofpatients.

InpatientswithParkinson'sdiseaseArkolamylmayworsenthesymptoms.

Reportingofsideeffects

Ifyougetanysideeffects,talktoyourdoctororpharmacist.Thisincludesanypossiblesideeffectsnot

listedinthisleaflet.YoucanalsoreportsideeffectsdirectlyviaHPRAPharmacovigilance,Earlsfort

Terrace,IRL-Dublin2;Tel:+35316764971;Fax:+35316762517.Website:www.hpra.ie;E-mail:

medsafety@hpra.ie.Byreportingsideeffectsyoucanhelpprovidemoreinformationonthesafetyofthis

medicine.

5.HowtostoreArkolamyl

Keepthismedicineoutofthesightandreachofchildren.

Donotusethismedicineaftertheexpirydate,whichisstatedonthecartonandblisterafter“EXP”.The

expirydatereferstothelastdayofthatmonth.

Storeintheoriginalpackageinordertoprotectfromlightandmoisture.

Donotthrowawayanymedicinesviawastewaterorhouseholdwaste.Askyourpharmacisthowtothrow

awaymedicinesyounolongeruse.Thesemeasureswillhelpprotecttheenvironment.

6.Contentsofthepackandotherinformation

WhatArkolamylcontains

Theactivesubstanceisolanzapine.EachArkolamylorodispersibletabletcontains5mg,10mg,15

mgor20mgoftheactivesubstance.

Theotheringredientsarecrospovidone,lactosemonohydrate(seesection2“Arkolamylcontains

lactose”),colloidalanhydroussilica,hydroxypropylcellulose,mintflavour(consistingof:mintoil,

terpenelessmintoil,eucalyptol,menthone,isomenthone,methyleneacetate,menthol),talcand

magnesiumstearate.

WhatArkolamyllookslikeandcontentsofthepack

Arkolamyl5mgorodispersibletabletsareyellow,roundwithtwosidesthatcurveout.

Arkolamyl10mgorodispersibletabletsareyellow,roundandflat.

Arkolamyl15mgorodispersibletabletsareyellow,roundwithtwosidesthatcurveout.

Arkolamyl20mgareyellow,roundandflatorodispersibletablets.Orodispersibletabletisthetechnical

nameforatabletwhichdissolvesdirectlyinyourmouth,sothatitcanbeeasilyswallowed.

Blisters:

Arkolamyl5mg,10mg,15mgand20mgareavailableincartonscontaining:

10,28,30,56,60,70,84,90,98,100,112orodispersibletablets

Unitdoseblisters:

Arkolamyl5mg,10mg,15mgand20mgareavailableincartonscontaining28x1orodispersible

tablets

Notallpacksizesmaybemarketed.

MarketingAuthorisationHolder

McDermottLaboratoriesLimitedt/aGerardLaboratories,35/36BaldoyleIndustrialEstate,GrangeRoad,

Dublin13,Ireland

Manufacturers

PHARMATHENS.A.,Dervenakion6,Pallini15351,AttikisGreece

McDermottLaboratoriesLimitedt/aGerardLaboratories,35/36BaldoyleIndustrialEstate,GrangeRoad,

Dublin13,Ireland

ThismedicinalproductisauthorisedintheMemberStatesoftheEEAunderthefollowingnames:

Denmark Arkolamyl

Norway Arkolamyl

Sweden Arkolamyl

UnitedKingdom Arkolamyl

France OlanzapineMylanGeneriques

Ireland Arkolamyl

Italy Arkolamyl

Netherlands Arkolamyl

Thisleafletwaslastrevisedin06/2016

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Arkolamyl5mgOrodispersibleTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachorodispersibletabletcontains5mgolanzapine.

Excipientwithknowneffect:

Eachorodispersibletabletcontains57.60mglactose.

Forthefulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Orodispersibletablet

Yellow,round,biconvex,tabletwithdiameter6.0mm±0.1mmandthickness2.6mm±0.2mm.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Adults

Olanzapineisindicatedforthetreatmentofschizophrenia.

Olanzapineiseffectiveinmaintainingtheclinicalimprovementduringcontinuationtherapyinpatientswhohave

shownaninitialtreatmentresponse.

Olanzapineisindicatedforthetreatmentofmoderatetoseveremanicepisode.

Inpatientswhosemanicepisodehasrespondedtoolanzapinetreatment,olanzapineisindicatedforthepreventionof

recurrenceinpatientswithbipolardisorder(seesection5.1).

4.2Posologyandmethodofadministration

Posology

Adults

Schizophrenia:Therecommendedstartingdoseforolanzapineis10mg/day.

Manicepisode:Thestartingdoseis15mgasasingledailydoseinmonotherapyor10mgdailyincombinationtherapy

(seesection5.1).

Preventingrecurrenceinbipolardisorder:Therecommendedstartingdoseis10mg/day.Forpatientswhohavebeen

receivingolanzapinefortreatmentofmanicepisode,continuetherapyforpreventingrecurrenceatthesamedose.Ifa

newmanic,mixed,ordepressiveepisodeoccurs,olanzapinetreatmentshouldbecontinued(withdoseoptimisationas

needed),withsupplementarytherapytotreatmoodsymptoms,asclinicallyindicated.

Duringtreatmentforschizophrenia,manicepisodeandrecurrencepreventioninbipolardisorder,dailydosagemay

subsequentlybeadjustedonthebasisofindividualclinicalstatuswithintherange5-20mg/day.Anincreasetoadose

greaterthantherecommendedstartingdoseisadvisedonlyafterappropriateclinicalreassessmentandshouldgenerally

occuratintervalsofnotlessthan24hours.Olanzapinecanbegivenwithoutregardsformealsasabsorptionisnot

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Olanzapineorodispersibletabletisbioequivalenttoolanzapinetablets,withasimilarrateandextentofabsorption.It

hasthesamedosageandfrequencyofadministrationasolanzapinetablets.Olanzapineorodispersibletabletsmaybe

usedasanalternativetoolanzapinetablets.

Specialpopulations

Elderlypatients

Alowerstartingdose(5mg/day)isnotroutinelyindicatedbutshouldbeconsideredforthose65andoverwhen

clinicalfactorswarrant(seealsosection4.4).

Patientswithrenaland/orhepaticimpairment

Alowerstartingdose(5mg)shouldbeconsideredforsuchpatients.Incasesofmoderatehepaticinsufficiency

(cirrhosis,Child-PughclassAorB),thestartingdoseshouldbe5mgandonlyincreasedwithcaution.

Smokers

Thestartingdoseanddoserangeneednotberoutinelyalteredfornon-smokersrelativetosmokers.Themetabolismof

olanzapinemaybeinducedbysmoking.Clinicalmonitoringisrecommendedandanincreaseofolanzapinedosemaybe

consideredifnecessary(seesection4.5).

Whenmorethanonefactorispresentwhichmightresultinslowermetabolism(femalegender,geriatricage,non-

smokingstatus),considerationshouldbegiventodecreasingthestartingdose.Doseescalation,whenindicated,should

beconservativeinsuchpatients.

Incaseswheredoseincrementsof2.5mgareconsiderednecessary,olanzapinecoatedtabletsshouldbeused(see

sections4.5and5.2.)

Paediatricpopulation

Olanzapineisnotrecommendedforuseinchildrenandadolescentsbelow18yearsofageduetoalackofdataon

safetyandefficacy.Agreatermagnitudeofweightgain,lipidandprolactinalterationshasbeenreportedinshortterm

studiesofadolescentpatientsthaninstudiesofadultpatients(seesections4.4,4.8,5.1and5.2).

Methodofadministration

Fororaluse

Arkolamylshouldbeplacedinthemouth,whereitwillrapidlydisperseinsaliva,soitcanbeeasilyswallowed.

Removaloftheintactorodispersibletabletfromthemouthisdifficult.Sincetheorodispersibletabletisfragile,it

shouldbetakenimmediatelyonopeningtheblister.Alternatively,itmaybedispersedinafullglassofwaterorother

suitablebeverage(orangejuice,applejuice,milkorcoffee)immediatelybeforeadministration.

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipientslistedinsection6.1.

Patientswithknownriskofnarrow-angleglaucoma.

4.4Specialwarningsandprecautionsforuse

Duringantipsychotictreatment,improvementinthepatient’sclinicalconditionmaytakeseveraldaystosomeweeks.

Patientsshouldbecloselymonitoredduringthisperiod.

Dementia-relatedpsychosisand/orbehaviouraldisturbances

Olanzapineisnotrecommendedforuseinthisparticulargroupofpatientswithdementia-relatedpsychosisand/or

behaviouraldisturbancesbecauseofanincreaseinmortalityandtheriskofcerebrovascularaccident.

Inplacebo-controlledclinicaltrials(6-12weeksduration)ofelderlypatients(meanage78years)withdementia-related

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patientscomparedtopatientstreatedwithplacebo(3.5%vs.1.5%,respectively).Thehigherincidenceofdeathwasnot

associatedwitholanzapinedose(meandailydose4.4mg)ordurationoftreatment.Riskfactorsthatmaypredispose

thispatientpopulationtoincreasedmortalityincludeage>65years,dysphagia,sedation,malnutritionanddehydration,

pulmonaryconditions(e.g.pneumonia,withorwithoutaspiration),orconcomitantuseofbenzodiazepines.However,

theincidenceofdeathwashigherinolanzapine-treatedthaninplacebo-treatedpatientsindependentoftheserisk

factors.

Inthesameclinicaltrials,cerebrovascularadverseevents(CVAEe.g.stroke,transientischaemicattack),including

fatalities,werereported.Therewasa3-foldincreaseinCVAEinpatientstreatedwitholanzapinecomparedtopatients

treatedwithplacebo(1.3%vs.0.4%,respectively).Allolanzapine-andplacebo-treatedpatientswhoexperienceda

cerebrovasculareventhadpre-existingriskfactors.Age>75yearsandvascular/mixedtypedementiawereidentified

asriskfactorsforCVAEinassociationwitholanzapinetreatment.Theefficacyofolanzapinewasnotestablishedin

thesetrials.

Parkinson’sdisease

TheuseofolanzapineinthetreatmentofdopamineagonistassociatedpsychosisinpatientswithParkinson’sdiseaseis

notrecommended.Inclinicaltrials,worseningofParkinsoniansymptomatologyandhallucinationswerereportedvery

commonlyandmorefrequentlythanwithplacebo(seesection4.8),andolanzapinewasnotmoreeffectivethanplacebo

inthetreatmentofpsychoticsymptoms.Inthesetrials,patientswereinitiallyrequiredtobestableonthelowest

effectivedoseofanti-Parkinsonianmedicinalproducts(dopamineagonist)andtoremainonthesameanti-

Parkinsonianmedicinalproductsanddosagesthroughoutthestudy.Olanzapinewasstartedat2.5mg/dayandtitrated

toamaximumof15mg/daybasedoninvestigatorjudgement.

NeurolepticMalignantSyndrome(NMS)

NMSisapotentiallylife-threateningconditionassociatedwithantipsychoticmedicinalproducts.Rarecasesreported

asNMShavealsobeenreceivedinassociationwitholanzapine.ClinicalmanifestationsofNMSarehyperpyrexia,

musclerigidity,alteredmentalstatus,andevidenceofautonomicinstability(irregularpulseorbloodpressure,

tachycardia,diaphoresis,andcardiacdysrhythmia).Additionalsignsmayincludeelevatedcreatinephosphokinase,

myoglobinuria(rhabdomyolysis),andacuterenalfailure.IfapatientdevelopssignsandsymptomsindicativeofNMS,

orpresentswithunexplainedhighfeverwithoutadditionalclinicalmanifestationsofNMS,allantipsychoticmedicines,

includingolanzapinemustbediscontinued.

Hyperglycaemiaanddiabetes

Hyperglycaemiaand/ordevelopmentorexacerbationofdiabetesoccasionallyassociatedwithketoacidosisorcomahas

beenreporteduncommonly,includingsomefatalcases(seesection4.8).Insomecases,apriorincreaseinbodyweight

hasbeenreportedwhichmaybeapredisposingfactor.Appropriateclinicalmonitoringisadvisableinaccordancewith

utilisedantipsychoticguidelinese.g.measuringofbloodglucoseatbaseline,12weeksafterstartingolanzapine

treatmentandannuallythereafter.Patientstreatedwithanyantipsychoticagents,includingolanzapine,shouldbe

observedforsignsandsymptomsofhyperglycaemia(suchaspolydipsia,polyuria,polyphagia,andweakness)and

patientswithdiabetesmellitusorwithriskfactorsfordiabetesmellitusshouldbemonitoredregularlyforworseningof

glucosecontrol.Weightshouldbemonitoredregularlye.g.atbaseline,4,8and12weeksafterstartingolanzapine

treatmentandquarterlythereafter.

Lipidalterations

Undesirablealterationsinlipidshavebeenobservedinolanzapine-treatedpatientsinplacebo-controlledclinicaltrials

(seesection4.8).Lipidalterationsshouldbemanagedasclinicallyappropriate,particularlyindyslipidemicpatients

andinpatientswithriskfactorsforthedevelopmentoflipidsdisorders.Patientstreatedwithanyantipsychotic

medicines,includingolanzapine,shouldbemonitoredregularlyforlipidsinaccordancewithutilisedantipsychotic

guidelinese.g.atbaseline,12weeksafterstartingolanzapinetreatmentandevery5yearsthereafter.

Anticholinergicactivity

Whileolanzapinedemonstratedanticholinergicactivityinvitro,experienceduringtheclinicaltrialsrevealedalow

incidenceofrelatedevents.However,asclinicalexperiencewitholanzapineinpatientswithconcomitantillnessis

limited,cautionisadvisedwhenprescribingforpatientswithprostatichypertrophy,orparalyticileusandrelated

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Hepaticfunction

Transient,asymptomaticelevationsofhepaticaminotransferases,alaninetransferase(ALT),aspartatetransferase

(AST)havebeenseencommonly,especiallyinearlytreatment.Cautionshouldbeexercisedandfollow-uporganised

inpatientswithelevatedALTand/orAST,inpatientswithsignsandsymptomsofhepaticimpairment,inpatientswith

pre-existingconditionsassociatedwithlimitedhepaticfunctionalreserve,andinpatientswhoarebeingtreatedwith

potentiallyhepatotoxicmedicines.Incaseswherehepatitis(includinghepatocellular,cholestaticormixedliverinjury)has

beendiagnosed,olanzapinetreatmentshouldbediscontinued.

Neutropenia

Cautionshouldbeexercisedinpatientswithlowleucocyteand/orneutrophilcountsforanyreason,inpatients

receivingmedicinesknowntocauseneutropenia,inpatientswithahistoryofdrug-inducedbonemarrow

depression/toxicity,inpatientswithbonemarrowdepressioncausedbyconcomitantillness,radiationtherapyor

chemotherapyandinpatientswithhypereosinophilicconditionsorwithmyeloproliferativedisease.Neutropeniahas

beenreportedcommonlywhenolanzapineandvalproateareusedconcomitantly(seesection4.8).

Discontinuationoftreatment

Acutesymptomssuchassweating,insomnia,tremor,anxiety,nausea,orvomitinghavebeenreportedrarely(0.01%

and<0.1%)whenolanzapineisstoppedabruptly.

QTinterval

Inclinicaltrials,clinicallymeaningfulQTcprolongations(FridericiaQTcorrection[QTcF] 500milliseconds[msec]

atanytimepostbaselineinpatientswithbaselineQTcF<500msec)wereuncommon(0.1%to1%)inpatientstreated

witholanzapine,withnosignificantdifferencesinassociatedcardiaceventscomparedtoplacebo.However,caution

shouldbeexercisedwhenolanzapineisprescribedwithmedicinesknowntoincreaseQTcinterval,especiallyinthe

elderly,inpatientswithcongenitallongQTsyndrome,congestiveheartfailure,hearthypertrophy,hypokalaemiaor

hypomagnesaemia.

Thromboembolism

Temporalassociationofolanzapinetreatmentandvenousthromboembolismhasbeenreporteduncommonly(0.1%

and<1%).Acausalrelationshipbetweentheoccurrenceofvenousthromboembolismandtreatmentwitholanzapine

hasnotbeenestablished.However,sincepatientswithschizophreniaoftenpresentwithacquiredriskfactorsfor

venousthromboembolismallpossibleriskfactorsofVTEe.g.immobilisationofpatientsshouldbeidentifiedand

preventivemeasuresundertaken.

GeneralCNSactivity

GiventheprimaryCNSeffectsofolanzapine,cautionshouldbeusedwhenitistakenincombinationwithother

centrallyactingmedicinesandalcohol.Asitexhibitsinvitrodopamineantagonism,olanzapinemayantagonisethe

effectsofdirectandindirectdopamineagonists.

Seizures

Olanzapineshouldbeusedcautiouslyinpatientswhohaveahistoryofseizuresoraresubjecttofactorswhichmay

lowertheseizurethreshold.Seizureshavebeenreportedtooccuruncommonlyinpatientswhentreatedwith

olanzapine.Inmostofthesecases,ahistoryofseizuresorriskfactorsforseizureswerereported.

Tardivedyskinesia

Incomparatorstudiesofoneyearorlessduration,olanzapinewasassociatedwithastatisticallysignificantlower

incidenceoftreatmentemergentdyskinesia.Howevertheriskoftardivedyskinesiaincreaseswithlongtermexposure,

andthereforeifsignsorsymptomsoftardivedyskinesiaappearinapatientonolanzapine,adosereductionor

discontinuationshouldbeconsidered.Thesesymptomscantemporallydeteriorateorevenariseafterdiscontinuationof

treatment.

Posturalhypotension

Posturalhypotensionwasinfrequentlyobservedintheelderlyinolanzapineclinicaltrials.Itisrecommendedthat

bloodpressureismeasuredperiodicallyinpatientsover65years.

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Inpostmarketingreportswitholanzapine,theeventofsuddencardiacdeathhasbeenreportedinpatientswith

olanzapine.Inaretrospectiveobservationalcohortstudy,theriskofpresumedsuddencardiacdeathinpatientstreated

witholanzapinewasapproximatelytwicetheriskinpatientsnotusingantipsychotics.Inthestudy,theriskof

olanzapinewascomparabletotheriskofatypicalantipsychoticsincludedinapooledanalysis.

Paediatricpopulation

Olanzapineisnotindicatedforuseinthetreatmentofchildrenandadolescents.Studiesinpatientsaged13-17years

showedvariousadversereactions,includingweightgain,changesinmetabolicparametersandincreasesinprolactin

levels(seesections4.8and5.1).

Lactose

Arkolamyltabletscontainlactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactase

deficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Interactionstudieshaveonlybeenperformedinadults.

Potentialinteractionsaffectingolanzapine

SinceolanzapineismetabolisedbyCYP1A2,substancesthatcanspecificallyinduceorinhibitthisisoenzymemay

affectthepharmacokineticsofolanzapine.

InductionofCYP1A2

Themetabolismofolanzapinemaybeinducedbysmokingandcarbamazepine,whichmayleadtoreducedolanzapine

concentrations.Onlyslighttomoderateincreaseinolanzapineclearancehasbeenobserved.Theclinicalconsequences

arelikelytobelimited,butclinicalmonitoringisrecommendedandanincreaseofolanzapinedosemaybeconsidered

ifnecessary(seesection4.2).

InhibitionofCYP1A2

Fluvoxamine,aspecificCYP1A2inhibitor,hasbeenshowntosignificantlyinhibitthemetabolismofolanzapine.The

meanincreaseinolanzapineC

followingfluvoxaminewas54%infemalenonsmokersand77%inmalesmokers.

ThemeanincreaseinolanzapineAUCwas52%and108%respectively.Alowerstartingdoseofolanzapineshould

beconsideredinpatientswhoareusingfluvoxamineoranyotherCYP1A2inhibitors,suchasciprofloxacin.A

decreaseinthedoseofolanzapineshouldbeconsiderediftreatmentwithaninhibitorofCYP1A2isinitiated.

Decreasedbioavailability

Activatedcharcoalreducesthebioavailabilityoforalolanzapineby50to60%andshouldbetakenatleast2hours

beforeorafterolanzapine.

Fluoxetine(aCYP2D6inhibitor),singledosesofantacid(aluminium,magnesium)orcimetidinehavenotbeenfound

tosignificantlyaffectthepharmacokineticsofolanzapine.

Potentialforolanzapinetoaffectothermedicinalproducts

Olanzapinemayantagonisetheeffectsofdirectandindirectdopamineagonists.

OlanzapinedoesnotinhibitthemainCYP450isoenzymesinvitro(e.g.1A2,2D6,2C9,2C19,3A4).Thusnoparticular

interactionisexpectedasverifiedthroughinvivostudieswherenoinhibitionofmetabolismofthefollowingactive

substanceswasfound:tricyclicantidepressant(representingmostlyCYP2D6pathway),warfarin(CYP2C9),

theophylline(CYP1A2)ordiazepam(CYP3A4and2C19).

Olanzapineshowednointeractionwhenco-administeredwithlithiumorbiperiden.

Therapeuticmonitoringofvalproateplasmalevelsdidnotindicatethatvalproatedosageadjustmentisrequiredafter

theintroductionofconcomitantolanzapine.

GeneralCNSactivity

Cautionshouldbeexercisedinpatientswhoconsumealcoholorreceivemedicinalproductsthatcancausecentral

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Theconcomitantuseofolanzapinewithanti-ParkinsonianmedicinalproductsinpatientswithParkinson'sdiseaseand

dementiaisnotrecommended(seesection4.4).

QTcinterval

Cautionshouldbeusedifolanzapineisbeingadministeredconcomitantlywithmedicinalproductsknowntoincrease

QTcinterval(seesection4.4).

4.6Fertility,pregnancyandlactation

Pregnancy

Therearenoadequateandwell-controlledstudiesinpregnantwomen.Patientsshouldbeadvisedtonotifytheir

physicianiftheybecomepregnantorintendtobecomepregnantduringtreatmentwitholanzapine.Nevertheless,

becausehumanexperienceislimited,olanzapineshouldbeusedinpregnancyonlyifthepotentialbenefitjustifiesthe

potentialrisktothefoetus.

Newborninfantsexposedtoantipsychotics(includingArkolamyl)duringthethirdtrimesterofpregnancyareatriskof

adversereactionsincludingextrapyramidaland/orwithdrawalsymptomsthatmayvaryinseverityandduration

followingdelivery.Therehavebeenreportsofagitation,hypertonia,hypotonia,tremor,somnolence,respiratory

distress,orfeedingdisorder.Consequently,newbornsshouldbemonitoredcarefully.

Breast-feeding

Inastudyinbreast-feeding,healthywomen,olanzapinewasexcretedinbreastmilk.Meaninfantexposure(mg/kg)at

steadystatewasestimatedtobe1.8%ofthematernalolanzapinedose(mg/kg).Patientsshouldbeadvisednotto

breast-feedaninfantiftheyaretakingolanzapine.

Fertility

Effectsonfertilityareunknown(seesection5.3forpreclinicalinformation).

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.Becauseolanzapinemaycause

somnolenceanddizziness,patientsshouldbecautionedaboutoperatingmachinery,includingmotorvehicles.

4.8Undesirableeffects

Summaryofthesafetyprofile

Adults

Themostfrequently(seenin 1%ofpatients)reportedadversereactionsassociatedwiththeuseofolanzapinein

clinicaltrialsweresomnolence,weightgain,eosinophilia,elevatedprolactin,cholesterol,glucoseandtriglyceride

levels(seesection4.4),glucosuria,increasedappetite,dizziness,akathisia,parkinsonism,leucopenia,neutropenia(see

section4.4),dyskinesia,orthostatichypotension,anticholinergiceffects,transientasymptomaticelevationsofhepatic

aminotransferases(seesection4.4),rash,asthenia,fatigue,pyrexia,arthralgia,increasedalkalinephosphatase,high

gammaglutamyltransferase,highuricacid,highcreatinephosphokinaseandoedema.

Tabulatedlistofadversereactions

Thefollowingtableliststheadversereactionsandlaboratoryinvestigationsobservedfromspontaneousreportingand

inclinicaltrials.Withineachfrequencygrouping,adversereactionsarepresentedinorderofdecreasingseriousness.

Thefrequencytermslistedaredefinedasfollows:Verycommon(1/10),common(1/100to<1/10),uncommon

(1/1,000to<1/100),rare(1/10,000to<1/1,000),veryrare(<1/10,000)andnotknown(cannotbeestimatedfrom

theavailabledata).

Very

common Common Uncommon Rare Notknown

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Eosinophilia

Leucopenia 10

Neutropenia 10 Thrombocytopenia 11

Immunesystemdisorders

Hypersensitivity 11

Metabolismandnutritiondisorders

Weightgain 1 Elevatedcholesterol

levels 2,3

Elevatedglucose

levels 4

Elevatedtriglyceride

levels 2,5

Glucosuria

Developmentor

exacerbationof

diabetesoccasionally

associatedwith

ketoacidosisorcoma,

includingsomefatal

cases(seesection

4.4) 11 Hypothermia 12

Nervoussystemdisorders

Somnolence Dizziness

Akathisia 6

Parkinsonism 6

Dyskinesia 6 Seizureswherein

mostcasesahistory

ofseizuresorrisk

factorsforseizures

werereported 11

Dystonia(including

oculogyration) 11

Tardivedyskinesia 11

Amnesia 9

Seizureswhereinmost

casesahistoryof

seizuresorriskfactors

forseizureswere

reported

Neurolepticmalignant

syndrome(seesection

4.4) 12

Discontinuation

symptoms 7,12

Cardiacdisorders

Bradycardia

prolongation

(seesection4.4) Ventricular

tachycardia/fibrillation,

Suddendeath(see

section4.4) 11

Vasculardisorders

Orthostatic

hypotension 10 Thromboembolism

(includingpulmonary

embolismanddeep

veinthrombosis)(see

section4.4)

Respiratory,thoracicandmediastinaldisorders

Epistaxis 9

Gastrointestinaldisorders

Mild,transient

anticholinergic

effectsincluding

constipationanddry

mouth Abdominal

distension 9 Pancreatitis 11

Hepatobiliarydisorders

Transient,

asymptomatic Hepatitis(including

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ClinicallysignificantweightgainwasobservedacrossallbaselineBodyMassIndex(BMI)categories.Following

shorttermtreatment(medianduration47days),weightgain 7%ofbaselinebodyweightwasverycommon(22.2%),

15%wascommon(4.2%)and 25%wasuncommon(0.8%).Patientsgaining 7%, 15%and 25%oftheir

baselinebodyweightwithlong-termexposure(atleast48weeks)wereverycommon(64.4%,31.7%and12.3%

elevationsofhepatic

aminotransferases

(ALT,AST),

especiallyinearly

treatment(seesection

4.4) cholestaticormixed

liverinjury) 11

Skinandsubcutaneoustissuedisorders

Rash Photosensitivity

reaction

Alopecia Drug

Reaction

with

Eosinophilia

Systemic

Symptoms

(DRESS)

Musculoskeletalandconnectivetissuedisorders

Arthralgia 9

Rhabdomyolysis 11

Renalandurinarydisorders

Urinaryincontinence,

Urinaryretention

Urinaryhesitation 11

Pregnancy,puerperiumandperinatalconditions

Drug

withdrawal

syndrome

neonatal

(seesection

4.6)

Reproductivesystemandbreastdisorders

Erectiledysfunction

inmales,Decreased

libidoinmalesand

females Amenorrhea,Breast

enlargement,

Galactorrhoeain

females,

Gynaecomastia/breast

enlargementinmales Priapism 12

Generaldisordersandadministrationsiteconditions

Asthenia

Fatigue

Oedema

Pyrexia 10

Investigations

Elevated

plasma

prolactin

levels 8 Increasedalkaline

phosphatase 10

Highcreatine

phosphokinase 11

Highgamma

glutamyltransferase 10

Highuricacid 10 Increasedtotal

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Meanincreasesinfastinglipidvalues(totalcholesterol,LDLcholesterol,andtriglycerides)weregreaterinpatients

withoutevidenceoflipiddysregulationatbaseline.

Observedforfastingnormallevelsatbaseline(<5.17mmol/l)whichincreasedtohigh(6.2mmol/l).Changesin

totalfastingcholesterollevelsfromborderlineatbaseline(5.17-<6.2mmol/l)tohigh(6.2mmol/l)werevery

common.

Observedforfastingnormallevelsatbaseline(<5.56mmol/l)whichincreasedtohigh(7mmol/l).Changesin

fastingglucosefromborderlineatbaseline(5.56-<7mmol/l)tohigh(7mmol/l)wereverycommon.

Observedforfastingnormallevelsatbaseline(<1.69mmol/l)whichincreasedtohigh(2.26mmol/l).Changesin

fastingtriglyceridesfromborderlineatbaseline(1.69mmol/l-<2.26mmol/l)tohigh(2.26mmol/l)werevery

common.

Inclinicaltrials,theincidenceofParkinsonismanddystoniainolanzapine-treatedpatientswasnumericallyhigher,

butnotstatisticallysignificantlydifferentfromplacebo.Olanzapine-treatedpatientshadalowerincidenceof

Parkinsonism,akathisiaanddystoniacomparedwithtitrateddosesofhaloperidol.Intheabsenceofdetailed

informationonthepre-existinghistoryofindividualacuteandtardiveextrapyramidalmovementdisorders,itcannot

beconcludedatpresentthatolanzapineproduceslesstardivedyskinesiaand/orothertardiveextrapyramidal

syndromes.

Acutesymptomssuchassweating,insomnia,tremor,anxiety,nauseaandvomitinghavebeenreportedwhen

olanzapineisstoppedabruptly.

Inclinicaltrialsofupto12weeks,plasmaprolactinconcentrationsexceededtheupperlimitofnormalrangein

approximately30%ofolanzapinetreatedpatientswithnormalbaselineprolactinvalue.Inthemajorityofthesepatients

theelevationsweregenerallymild,andremainedbelowtwotimestheupperlimitofnormalrange.

AdverseeventidentifiedfromclinicaltrialsintheOlanzapineIntegratedDatabase.

AsassessedbymeasuredvaluesfromclinicaltrialsintheOlanzapineIntegratedDatabase.

Adverseeventidentifiedfromspontaneouspost-marketingreportingwithfrequencydeterminedutilisingthe

OlanzapineIntegratedDatabase.

Adverseeventidentifiedfromspontaneouspost-marketingreportingwithfrequencyestimatedattheupperlimitof

the95%confidenceintervalutilisingtheOlanzapineIntegratedDatabase.

Long-termexposure(atleast48weeks)

Theproportionofpatientswhohadadverse,clinicallysignificantchangesinweightgain,glucose,total/LDL/HDL

cholesterolortriglyceridesincreasedovertime.Inadultpatientswhocompleted9-12monthsoftherapy,therateof

increaseinmeanbloodglucoseslowedafterapproximately6months.

Otherspecialpopulations

Inclinicaltrialsinelderlypatientswithdementia,olanzapinetreatmentwasassociatedwithahigherincidenceofdeath

andcerebrovascularadversereactionscomparedtoplacebo(seesection4.4).Verycommonadversereactions

associatedwiththeuseofolanzapineinthispatientgroupwereabnormalgaitandfalls.Pneumonia,increasedbody

temperature,lethargy,erythema,visualhallucinationsandurinaryincontinencewereobservedcommonly.

Inclinicaltrialsinpatientswithdrug-induced(dopamineagonist)psychosisassociatedwithParkinson’sdisease,

worseningofParkinsoniansymptomatologyandhallucinationswerereportedverycommonlyandmorefrequentlythan

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Inoneclinicaltrialinpatientswithbipolarmania,valproatecombinationtherapywitholanzapineresultedinan

incidenceofneutropeniaof4.1%;apotentialcontributingfactorcouldbehighplasmavalproatelevels.Olanzapine

administeredwithlithiumorvalproateresultedinincreasedlevels(10%)oftremor,drymouth,increasedappetite,and

weightgain.Speechdisorderwasalsoreportedcommonly.Duringtreatmentwitholanzapineincombinationwith

lithiumordivalproex,anincreaseof 7%frombaselinebodyweightoccurredin17.4%ofpatientsduringacute

treatment(upto6weeks).Long-termolanzapinetreatment(upto12months)forrecurrencepreventioninpatientswith

bipolardisorderwasassociatedwithanincreaseof7%frombaselinebodyweightin39.9%ofpatients.

Paediatricpopulation

Olanzapineisnotindicatedforthetreatmentofchildrenandadolescentpatientsbelow18years.Althoughnoclinical

studiesdesignedtocompareadolescentstoadultshavebeenconducted,datafromtheadolescenttrialswerecompared

tothoseoftheadulttrials.

Thefollowingtablesummarisestheadversereactionsreportedwithagreaterfrequencyinadolescentpatients(aged13-

17years)thaninadultpatientsoradversereactionsonlyidentifiedduringshort-termclinicaltrialsinadolescent

patients.Clinicallysignificantweightgain(7%)appearstooccurmorefrequentlyintheadolescentpopulation

comparedtoadultswithcomparableexposures.Themagnitudeofweightgainandtheproportionofadolescentpatients

whohadclinicallysignificantweightgainweregreaterwithlong-termexposure(atleast24weeks)thanwithshort-

termexposure.

Withineachfrequencygrouping,adversereactionsarepresentedinorderofdecreasingseriousness.Thefrequency

termslistedaredefinedasfollows:Verycommon( 1/10),common( 1/100to<1/10).

Followingshorttermtreatment(medianduration22days),weightgain 7%ofbaselinebodyweight(kg)wasvery

common(40.6%), 15%ofbaselinebodyweightwascommon(7.1%)and 25%wascommon(2.5%).Withlong-

termexposure(atleast24weeks),89.4%gained 7%,55.3%gained 15%and29.1%gained 25%oftheir

baselinebodyweight.

Observedforfastingnormallevelsatbaseline(<1.016mmol/l)whichincreasedtohigh(1.467mmol/l)and

changesinfastingtriglyceridesfromborderlineatbaseline(1.016mmol/l-<1.467mmol/l)tohigh(1.467

mmol/l).

Changesintotalfastingcholesterollevelsfromnormalatbaseline(<4.39mmol/l)tohigh(5.17mmol/l)were

observedcommonly.Changesintotalfastingcholesterollevelsfromborderlineatbaseline(4.39-<5.17mmol/l)to

high(5.17mmol/l)wereverycommon.

Elevatedplasmaprolactinlevelswerereportedin47.4%ofadolescentpatients.

Reportingofsuspectedadversereactions

Reportingsuspectedadversereactionsafterauthorisationofthemedicinalproductisimportant.Itallowscontinued

Metabolismandnutritiondisorders

Verycommon:Weightgain 13

,elevatedtriglyceridelevels 14

,increasedappetite.

Common:Elevatedcholesterollevels 15

Nervoussystemdisorders

Verycommon:Sedation(including:hypersomnia,lethargy,somnolence).

Gastrointestinaldisorders

Common:Drymouth

Hepatobiliarydisorders

Verycommon:Elevationsofhepaticaminotransferases(ALT/AST;seesection4.4).

Investigations

Verycommon:Decreasedtotalbilirubin,increasedGGT,elevatedplasmaprolactin

levels 16

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suspectedadversereactionsviaHPRAPharmacovigilance,EarlsfortTerrace,IRL-Dublin2;Tel:+35316764971;

Fax:+35316762517.Website:www.hpra.ie;E-mail: medsafety@hpra.ie .

4.9Overdose

Signsandsymptoms

Verycommonsymptomsinoverdose(>10%incidence)includetachycardia,agitation/aggressiveness,dysarthria,

variousextrapyramidalsymptoms,andreducedlevelofconsciousnessrangingfromsedationtocoma.

Othermedicallysignificantsequelaeofoverdoseincludedelirium,convulsion,coma,possibleneurolepticmalignant

syndrome,respiratorydepression,aspiration,hypertensionorhypotension,cardiacarrhythmias(<2%ofoverdose

cases)andcardiopulmonaryarrest.Fataloutcomeshavebeenreportedforacuteoverdosesaslowas450mgbut

survivalhasalsobeenreportedfollowingacuteoverdoseofapproximately2goforalolanzapine.

Management

Thereisnospecificantidoteforolanzapine.Inductionofemesisisnotrecommended.Standardproceduresfor

managementofoverdosemaybeindicated(i.e.gastriclavage,administrationofactivatedcharcoal).Theconcomitant

administrationofactivatedcharcoalwasshowntoreducetheoralbioavailabilityofolanzapineby50to60%.

Symptomatictreatmentandmonitoringofvitalorganfunctionshouldbeinstitutedaccordingtoclinicalpresentation,

includingtreatmentofhypotensionandcirculatorycollapseandsupportofrespiratoryfunction.Donotuse

epinephrine,dopamine,orothersympathomimeticagentswithbeta-agonistactivitysincebetastimulationmayworsen

hypotension.Cardiovascularmonitoringisnecessarytodetectpossiblearrhythmias.Closemedicalsupervisionand

monitoringshouldcontinueuntilthepatientrecovers.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Antipsychotics;diazepines,oxazepines,thiazepinesandoxepines,ATCcode:N05AH03.

Mechanismofaction

Olanzapineisanantipsychotic,antimanicandmoodstabilisingagentthatdemonstratesabroadpharmacologicprofile

acrossanumberofreceptorsystems.Inpreclinicalstudies,olanzapineexhibitedarangeofreceptoraffinities(Ki;<

100nM)forserotonin5HT

2A/2C ,5HT

,5HT

;dopamineD

,D

,D

,D

,D

;cholinergicmuscarinicreceptorsM

;1adrenergic;andhistamineH

receptors.Animalbehaviouralstudieswitholanzapineindicated5HT,dopamine,

andcholinergicantagonism,consistentwiththereceptor-bindingprofile.Olanzapinedemonstratedagreaterin-vitro

affinityforserotonin5HT

thandopamineD

receptorsandgreater5HT

thanD

activityinvivo,models.

Pharmacodynamiceffects

Electrophysiologicalstudiesdemonstratedthatolanzapineselectivelyreducedthefiringofmesolimbic(A10)

dopaminergicneurons,whilehavinglittleeffectonthestriatal(A9)pathwaysinvolvedinmotorfunction.Olanzapine

reducedaconditionedavoidanceresponse,atestindicativeofantipsychoticactivity,atdosesbelowthoseproducing

catalepsy,aneffectindicativeofmotorside-effects.Unlikesomeotherantipsychoticagents,olanzapineincreases

respondinginan“anxiolytic”test.

Inasingleoraldose(10mg)PositronEmissionTomography(PET)studyinhealthyvolunteers,olanzapineproduceda

higher5HT2AthandopamineD2receptoroccupancy.Inaddition,aSinglePhotonEmissionComputedTomography

(SPECT)imagingstudyinschizophrenicpatientsrevealedthatolanzapine-responsivepatientshadlowerstriatalD2

occupancythansomeotherantipsychotic-andrisperidone-responsivepatients,whilebeingcomparabletoclozapine-

responsivepatients.

Clinicalefficacyandsafety

Intwooftwoplaceboandtwoofthreecomparatorcontrolledtrialswithover2,900schizophrenicpatientspresenting

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improvementsinnegativeaswellaspositivesymptoms.

Inamultinational,double-blind,comparativestudyofschizophrenia,schizoaffective,andrelateddisorderswhich

included1,481patientswithvaryingdegreesofassociateddepressivesymptoms(baselinemeanof16.6onthe

Montgomery-AsbergDepressionRatingScale),aprospectivesecondaryanalysisofbaselinetoendpointmoodscore

changedemonstratedastatisticallysignificantimprovement(p=0.001)favouringolanzapine(-6.0)versushaloperidol(-

3.1).

Inpatientswithamanicormixedepisodeofbipolardisorder,olanzapinedemonstratedsuperiorefficacytoplaceboand

valproatesemisodium(divalproex)inreductionofmanicsymptomsover3weeks.Olanzapinealsodemonstrated

comparableefficacyresultstohaloperidolintermsoftheproportionofpatientsinsymptomaticremissionfrommania

anddepressionat6and12weeks.Inaco-therapystudyofpatientstreatedwithlithiumorvalproateforaminimumof

2weeks,theadditionofolanzapine10mg(co-therapywithlithiumorvalproate)resultedinagreaterreductionin

symptomsofmaniathanlithiumorvalproatemonotherapyafter6weeks.

Ina12-monthrecurrencepreventionstudyinmanicepisodepatientswhoachievedremissiononolanzapineandwere

thenrandomisedtoolanzapineorplacebo,olanzapinedemonstratedstatisticallysignificantsuperiorityoverplaceboon

theprimaryendpointofbipolarrecurrence.Olanzapinealsoshowedastatisticallysignificantadvantageoverplaceboin

termsofpreventingeitherrecurrenceintomaniaorrecurrenceintodepression.

Inasecond12-monthrecurrencepreventionstudyinmanicepisodepatientswhoachievedremissionwitha

combinationofolanzapineandlithiumandwerethenrandomisedtoolanzapineorlithiumalone,olanzapinewas

statisticallynon-inferiortolithiumontheprimaryendpointofbipolarrecurrence(olanzapine30.0%,lithium38.3%;p

=0.055).

Inan18-monthco-therapystudyinmanicormixedepisodepatientsstabilisedwitholanzapineplusamoodstabiliser

(lithiumorvalproate),long-termolanzapineco-therapywithlithiumorvalproatewasnotstatisticallysignificantly

superiortolithiumorvalproatealoneindelayingbipolarrecurrence,definedaccordingtosyndromic(diagnostic)

criteria.

Paediatricpopulation

Controlledefficacydatainadolescents(ages13to17years)arelimitedtoshorttermstudiesinschizophrenia(6

weeks)andmaniaassociatedwithbipolarIdisorder(3weeks),involvinglessthan200adolescents.Olanzapinewas

usedasaflexibledosestartingwith2.5andrangingupto20mg/day.Duringtreatmentwitholanzapine,adolescents

gainedsignificantlymoreweightcomparedwithadults.Themagnitudeofchangesinfastingtotalcholesterol,LDL

cholesterol,triglycerides,andprolactin(seesections4.4and4.8)weregreaterinadolescentsthaninadults.Thereare

nocontrolleddataonmaintenanceofeffectoronlongtermsafety(seesections4.4and4.8).Informationonlongterm

safetyisprimarilylimitedtoopenlabel,uncontrolleddata.

5.2Pharmacokineticproperties

Olanzapineorodispersibletabletisbioequivalenttoolanzapinetablets,withasimilarrateandextentofabsorption.

Olanzapineorodispersibletabletsmaybeusedasanalternativetoolanzapinetablets.

Absorption

Olanzapineiswellabsorbedafteroraladministration,reachingpeakplasmaconcentrationswithin5to8hours.The

absorptionisnotaffectedbyfood.Absoluteoralbioavailabilityrelativetointravenousadministrationhasnotbeen

determined.

Distribution

Theplasmaproteinbindingofolanzapinewasabout93%overtheconcentrationrangeofabout7toabout1000ng/ml.

Olanzapineisboundpredominantlytoalbuminand

-acid-glycoprotein.

Biotransformation

Olanzapineismetabolisedintheliverbyconjugativeandoxidativepathways.Themajorcirculatingmetaboliteisthe

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contributetotheformationoftheN-desmethyland2-hydroxymethylmetabolites,bothexhibitedsignificantlylessin

vivopharmacologicalactivitythanolanzapineinanimalstudies.Thepredominantpharmacologicactivityisfromthe

parentolanzapine.

Elimination

Afteroraladministration,themeanterminaleliminationhalf-lifeofolanzapineinhealthysubjectsvariedonthebasis

ofageandgender.Inhealthyelderly(65andover)versusnon-elderlysubjects,themeaneliminationhalf-lifewas

prolonged(51.8versus33.8hr)andtheclearancewasreduced(17.5versus18.2l/hr).Thepharmacokineticvariability

observedintheelderlyiswithintherangeforthenon-elderly.In44patientswithschizophrenia>65yearsofage,

dosingfrom5to20mg/daywasnotassociatedwithanydistinguishingprofileofadverseevents.

Infemaleversusmalesubjectsthemeaneliminationhalf-lifewassomewhatprolonged(36.7versus32.3hrs)andthe

clearancewasreduced(18.9versus27.3l/hr).However,olanzapine(5-20mg)demonstratedacomparablesafety

profileinfemale(n=467)asinmalepatients(n=869).

Renalimpairment

Inrenallyimpairedpatients(creatinineclearance<10ml/min)versushealthysubjects,therewasnosignificant

differenceinmeaneliminationhalf-life(37.7versus32.4hr)orclearance(21.2versus25.0l/hr).Amassbalancestudy

showedthatapproximately57%ofradiolabelledolanzapineappearedinurine,principallyasmetabolites.

Insmokingsubjectswithmildhepaticdysfunction,meaneliminationhalf-life(39.3hr)wasprolongedandclearance

(18.0l/hr)wasreducedanalogoustonon-smokinghealthysubjects(48.8hrand14.1l/hr,respectively).

Smokers

Innon-smokingversussmokingsubjects(malesandfemales)themeaneliminationhalf-lifewasprolonged(38.6

versus30.4hr)andtheclearancewasreduced(18.6versus27.7l/hr).

Theplasmaclearanceofolanzapineislowerinelderlyversusyoungsubjects,infemalesversusmales,andinnon-

smokersversussmokers.However,themagnitudeoftheimpactofage,gender,orsmokingonolanzapineclearance

andhalf-lifeissmallincomparisontotheoverallvariabilitybetweenindividuals.

InastudyofCaucasians,Japanese,andChinesesubjects,therewerenodifferencesinthepharmacokineticparameters

amongthethreepopulations.

Paediatricpopulation

Adolescents(ages13to17years):Thepharmacokineticsofolanzapinearesimilarbetweenadolescentsandadults.In

clinicalstudies,theaverageolanzapineexposurewasapproximately27%higherinadolescents.Demographic

differencesbetweentheadolescentsandadultsincludealoweraveragebodyweightandfeweradolescentswere

smokers.Suchfactorspossiblycontributetothehigheraverageexposureobservedinadolescents.

5.3Preclinicalsafetydata

Acute(single-dose)toxicity

Signsoforaltoxicityinrodentswerecharacteristicofpotentneurolepticcompounds:hypoactivity,coma,tremors,

clonicconvulsions,salivation,anddepressedweightgain.Themedianlethaldoseswereapproximately210mg/kg

(mice)and175mg/kg(rats).Dogstoleratedsingleoraldosesupto100mg/kgwithoutmortality.Clinicalsigns

includedsedation,ataxia,tremors,increasedheartrate,labouredrespiration,miosis,andanorexia.Inmonkeys,single

oraldosesupto100mg/kgresultedinprostrationand,athigherdoses,semi-consciousness.

Repeated-dosetoxicity

Instudiesupto3monthsdurationinmiceandupto1yearinratsanddogs,thepredominanteffectswereCNS

depression,anticholinergiceffects,andperipheralhaematologicaldisorders.TolerancedevelopedtotheCNS

depression.Growthparametersweredecreasedathighdoses.Reversibleeffectsconsistentwithelevatedprolactinin

ratsincludeddecreasedweightsofovariesanduterusandmorphologicchangesinvaginalepitheliumandinmammary

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Haematologictoxicity

Effectsonhaematologyparameterswerefoundineachspecies,includingdose-relatedreductionsincirculating

leucocytesinmiceandnon-specificreductionsofcirculatingleucocytesinrats;however,noevidenceofbonemarrow

cytotoxicitywasfound.Reversibleneutropenia,thrombocytopenia,oranaemiadevelopedinafewdogstreatedwith8

or10mg/kg/day(totalolanzapineexposure[AUC]is12-to15-foldgreaterthanthatofamangivena12-mgdose).In

cytopenicdogs,therewerenoadverseeffectsonprogenitorandproliferatingcellsinthebonemarrow.

Reproductivetoxicity

Olanzapinehadnoteratogeniceffects.Sedationaffectedmatingperformanceofmalerats.Estrouscycleswereaffected

atdosesof1.1mg/kg(3timesthemaximumhumandose)andreproductionparameterswereinfluencedinratsgiven3

mg/kg(9timesthemaximumhumandose).Intheoffspringofratsgivenolanzapine,delaysinfoetaldevelopmentand

transientdecreasesinoffspringactivitylevelswereseen.

Mutagenicity

Olanzapinewasnotmutagenicorclastogenicinafullrangeofstandardtests,whichincludedbacterialmutationtests

andinvitroandinvivomammaliantests.

Carcinogenicity

Basedontheresultsofstudiesinmiceandrats,itwasconcludedthatolanzapineisnotcarcinogenic.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Crospovidone

Lactosemonohydrate

Silica,colloidalanhydrous

Hydroxypropylcellulose

Talc

Magnesiumstearate

Mintflavourconsistingof:

MintOil

TerpenelessMintOil

Eucalyptol

Menthone

Isomenthone

MethyleneAcetate

Menthol

6.2Incompatibilities

Notapplicable.

6.3Shelflife

2years

6.4Specialprecautionsforstorage

Storeintheoriginalpackageinordertoprotectfromlightandmoisture.

6.5Natureandcontentsofcontainer

Health Products Regulatory Authority

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CardboardboxcontainingPA/Al/PVC–Aluminiumfoilblisterswith:

10,28,30,56,60,70,84,90,98,100,112orodispersibletablets

UnitDoseBlisters:

Cardboardboxcontaining28x1orodispersibletabletsinPA/Al/PVC–Aluminiumperforatedunitdoseblisters

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

McDermottLaboratoriesLtd.

T/AGerardLaboratories

35-36BaldoyleIndustrialEstate

GrangeRoad

Dublin13

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA0577/114/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:16thJuly2010

10DATEOFREVISIONOFTHETEXT

Health Products Regulatory Authority

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Date Printed 21/09/2016 CRN 2183152 page number: 15

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