Olanzapine Accord
1. NAME OF THE MEDICINAL PRODUCT
Olanzapine Accord 2.5mgfilm-coated tablets Olanzapine Accord 5 mg film-coated tablets Olanzapine Accord 7.5mgfilm-coated tablets Olanzapine Accord 10mgfilm-coated tablets Olanzapine Accord 15mgfilm-coated tablets Olanzapine Accord 20mgfilm-coated tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
For2.5 mg:
Each film-coated tablet contains 2.5 mgof Olanzapine. Excipient with known effect:Lactose 58.61 mg
Each film-coated tablet contains 5 mgof Olanzapine. Excipient with known effect: Lactose 56.24 mg
For7.5 mg:
Each film-coated tablet contains 7.5 mgof Olanzapine. Excipient with known effect:Lactose 84.36 mg
For10 mg:
Each film-coated tablet contains 10mgof Olanzapine. Excipient with known effect:Lactose 112.48 mg
For15 mg:
Each film-coated tablet contains 15 mgof Olanzapine. Excipient with known effect:Lactose 168.72 mg
For20 mg:
Each film-coated tablet contains 20 mgof Olanzapine. Excipient with known effect:Lactose 224.96 mg
Forthefull list of excipients, seesection 6.1
3. PHARMACEUTICAL FORM
Film-coated tablet
For2.5 mg:
Whiteto offwhite round, biconvex, film-coated tablets of5.6 mm,plain on both sides.
For5 mg:
Whiteto offwhite round biconvex, film coated tabletsof6.4 mm, debossed with ‘O1’
on oneside and plain onotherside.
For7.5mg:
Whiteto offwhite round biconvex, film coated tabletsof7.2 mm, debossed with ‘O2’
on oneside and plain onotherside.
For10 mg:
Whiteto offwhite round biconvex, film coated tabletsof8.0 mm, debossed with ‘O3’
on oneside and plain onotherside.
For15 mg:
Light blue coloured, round, biconvex, film coated tabletsof8.8 mm,plain on both sides.
For20 mg:
Light pink coloured,round, biconvex, film coated tabletsof9.6 mm,plain on both sides.
4. CLINICAL PARTICULARS
4.1 Therapeuticindications
Adults
Olanzapine Accord is indicated forthetreatment of schizophrenia.
Olanzapine Accord is effectivein maintainingtheclinical improvement during continuation therapyin patients who haveshownan initial treatment response.
Olanzapine Accord is indicated forthetreatment of moderate to severemanic episode.
In patients whose manicepisodehas responded toOlanzapineAccord treatment, Olanzapine Accord is indicated fortheprevention ofrecurrencein patientswith bipolar disorder (seesection 5.1).
4.2 Posologyandmethodofadministration
Adults
Schizophrenia:Therecommended startingdoseforOlanzapineAccord is10mg/day.
Manic episode:Thestartingdoseis 15mg as a single dailydosein monotherapyor
10mgdailyin combination therapy(seesection 5.1).
Preventing recurrence in bipolar disorder:The recommended starting dose is
10mg/day.For patientswhohave beenreceivingOlanzapineAccordfor treatmentof manicepisode,continuetherapy forpreventingrecurrenceatthesamedose.Ifanew manic,mixed,or depressive episode occurs,OlanzapineAccordtreatmentshouldbe continued(withdoseoptimizationasneeded),withsupplementary therapy totreat mood symptoms, as clinicallyindicated.
During treatmentforschizophrenia,manicepisode,andrecurrencepreventionin bipolardisorder,dailydosagemaysubsequentlybeadjustedonthebasisofindividual clinicalstatuswithinthe range5-20mg/day.Anincreasetoadosegreaterthanthe recommendedstarting doseisadvisedonly afterappropriateclinicalreassessmentand shouldgenerallyoccuratintervalsofnotlessthan24hours.
Olanzapine Accord can be given without regard for meals as absorption is not affected by food. Gradual tapering of the dose should be considered when discontinuing olanzapine.
Special populations
Elderly patients
Alowerstartingdose(5mg/day)isnotroutinely indicatedbutshouldbe considered for those65 and over whenclinical factors warrant (seealso section 4.4).
Patients with renaland/or hepatic impairment
A lower starting dose (5mg) should be consideredforsuchpatients.Incasesofmoderatehepaticinsufficiency (cirrhosis, Child-PughclassAorB),thestartingdoseshouldbe5mgandonlyincreasedwith caution.
Smokers
Thestartingdoseanddoserangeneednotberoutinely alteredfornon- smokers relative to smokers. The metabolism of olanzapine may be induced by smoking. Clinical monitoring is recommended and an increase of olanzapine dose may be considered if necessary (see section 4.5).
When morethanone factor is present which might result in slower metabolism (femalegender,geriatricage,non-smoking status),considerationshouldbegivento decreasing thestarting dose.Doseescalation,whenindicated,shouldbeconservative in suchpatients.
(Seesection 4.5 and section 5.2.).
Paediatric population
Olanzapineisnotrecommendedforuseinchildrenandadolescentsbelow18 yearsofageduetoalackofdataonsafetyandefficacy.Agreatermagnitudeof weightgain, lipid and prolactin alterations has been reported in short-termstudies of adolescent patients than in studies ofadultpatients (seesections 4.4, 4.8, 5.1 and 5.2).
4.3 Contraindications
Hypersensitivity totheactivesubstanceortoany oftheexcipients listed in section 6.1.Patientswith known risk fornarrow-angleglaucoma.
4.4 Special warnings and precautions for use
Duringantipsychotictreatment,improvementinthepatient'sclinicalconditionmay takeseveraldaystosomeweeks.Patientsshouldbeclosely monitoredduringthis period.
Dementia-relatedpsychosis and/or behaviouraldisturbances
Olanzapineisnotrecommendedforuse inpatientswithdementia-related psychosis and/orbehavioural disturbancesbecauseofanincreaseinmortalityandtheriskofcerebrovascularaccident. Inplacebo-controlledclinicaltrials(6-12weeksduration)ofelderlypatients(mean age78years)withdementia-relatedpsychosisand/ordisturbedbehaviours,therewas a 2-foldincrease intheincidence of deathinolanzapinetreatedpatientscomparedto patientstreatedwithplacebo(3.5% vs.1.5%,respectively).Thehigherincidenceof deathwasnotassociatedwitholanzapinedose(meandailydose4.4mg)orduration oftreatment.Riskfactorsthatmaypredisposethispatientpopulationtoincreasemortality includeage>65years,dysphagia,sedation,malnutritionanddehydration, pulmonaryconditions(e.g.,pneumonia,withorwithoutaspiration),orconcomitant useofbenzodiazepines.However,theincidenceofdeathwashigherinolanzapine- treated than in placebo-treated patients independent of theserisk factors.
In the same clinical trials, cerebrovascular adverse events (CVAE e.g., stroke, transientischaemic attack),includingfatalities,werereported.Therewasa3-fold increaseinCVAEinpatientstreatedwitholanzapinecomparedtopatientstreated withplacebo(1.3% vs.0.4%,respectively).Allolanzapine-andplacebo-treated patientswhoexperiencedacerebrovasculareventhadpre-existingriskfactors.Age>75yearsandvascular/mixedtypedementiawereidentifiedasriskfactorsforCVAE inassociationwitholanzapinetreatment.Theefficacy ofolanzapinewasnot establishedin thesetrials.
Parkinson's disease
Theuseofolanzapineinthetreatmentofdopamineagonistassociatedpsychosisin
patientswithParkinson'sdiseaseisnotrecommended.Inclinicaltrials,worsening of Parkinsoniansymptomatology andhallucinationswerereportedvery commonly and morefrequently thanwithplacebo(seesection4.8),andolanzapinewasnotmore effectivethanplacebointhetreatmentofpsychoticsymptoms.Inthese trials,patients wereinitially requiredtobestableonthelowesteffectivedoseofanti-Parkinsonian medicinalproducts(dopamine agonist)andtoremainonthesameanti-Parkinsonian medicinalproductsanddosagesthroughoutthe study.Olanzapine wasstarted at2.5 mg/dayand titrated to amaximum of 15 mg/daybased on investigator judgement.
NeurolepticMalignant Syndrome(NMS)
NMS is a potentially life-threatening condition associated with antipsychotic medicinal products.Rarecasesreported asNMS havealso beenreceived inassociation witholanzapine.ClinicalmanifestationsofNMSare hyperpyrexia,musclerigidity, alteredmentalstatus,andevidenceofautonomicinstability (irregularpulseorblood pressure,tachycardia,diaphoresis,andcardiac dysrhythmia).Additionalsignsmay include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acuterenalfailure.If apatientdevelopssignsandsymptomsindicative of NMS,or presentswithunexplainedhighfever withoutadditionalclinicalmanifestationsof NMS, allantipsychoticmedicines, includingolanzapine must bediscontinued.
Hyperglycaemiaanddiabetes
Hyperglycaemia and/or development or exacerbation of diabetes, occasionally
associated withketoacidosisor coma, hasbeen reported uncommonly, including some fatal cases(seesection4.8).Insomecases,apriorincreaseinbody weighthasbeen reported, which maybeapredisposingfactor.
Appropriateclinicalmonitoring isadvisableinaccordancewithutilisedantipsychotic guidelines, e.g.measuringofbloodglucoseatbaseline,12weeksafterstarting olanzapine treatment andannuallythereafter. Patientstreatedwithany antipsychoticmedicines,includingOlanzapine Accord,shouldbe observedfor signsandsymptomsof hyperglycaemia (suchaspolydipsia,polyuria, polyphagia,and weakness) and patientswithdiabetes mellitusor withrisk factorsfor diabetesmellitusshould bemonitoredregularly forworsening ofglucosecontrol. Weightshouldbemonitoredregularly,e.g.at baseline,4,8 and12 weeksafter startingolanzapine treatment and quarterlythereafter.
Lipidalterations
Undesirablealterationsinlipidshavebeenobservedinolanzapine-treatedpatientsin placebo-controlled clinical trials (see section 4.8). Lipid alterations should be managedasclinically appropriate,particularly indyslipidemicpatientsandinpatients withriskfactorsforthedevelopmentoflipids disorders.Patientstreatedwithany antipsychoticmedicines,including Olanzapine Accord,shouldbemonitoredregularly forlipidsin accordance withutilisedantipsychoticguidelines,e.g.atbaseline,12weeksafter startingolanzapine treatment and every5years thereafter.
Anticholinergic activity
Whileolanzapinedemonstratedanticholinergicactivityinvitro,experienceduring the
clinicaltrialsrevealeda lowincidence ofrelatedevents.However,asclinical experiencewitholanzapine inpatientswithconcomitantillnessislimited,cautionis advisedwhenprescribingforpatientswithprostatichypertrophy,orparalyticileus and relatedconditions.
Hepaticfunction
Transient,asymptomaticelevationsofhepaticaminotransferases,ALT,ASThave beenseencommonly,especially inearly treatment.Cautionshouldbeexercisedand follow-uporganizedinpatientswithelevatedALT and/orAST,inpatientswithsigns andsymptomsof hepatic impairment,inpatientswithpre-existingconditions associatedwithlimitedhepaticfunctionalreserve,andinpatientswhoarebeing treatedwithpotentiallyhepatotoxicmedicines.Incaseswhere hepatitis(including hepatocellular,cholestatic or mixedliver injury)hasbeendiagnosed,olanzapine treatment should be discontinued.
Neutropenia
Cautionshouldbeexercisedinpatientswithlowleukocyteand/orneutrophilcounts for any reason, in patients receiving medicines known to cause neutropenia, in patientswithahistory ofdrug-inducedbonemarrowdepression/toxicity,inpatients withbonemarrowdepressioncausedby concomitantillness,radiationtherapy or chemotherapy andinpatientswithhypereosinophilicconditionsorwith myeloproliferativedisease.Neutropeniahas beenreported commonlywhen olanzapine and valproateareusedconcomitantly(seesection 4.8).
Discontinuationoftreatment
Acutesymptomssuchassweating,insomnia,tremor,anxiety,nausea,orvomiting
havebeen
reported
rarely(
0.01% and <0.1%)
when olanzapine is
stopped
abruptly.
QTinterval
Inclinicaltrials,clinicallymeaningfulQTcprolongations(FridericiaQTcorrection
[QTcF] ≥500milliseconds[msec]atanytimepostbaselineinpatientswithbaseline QTcF < 500msec)wereuncommon(0.1% to1%)inpatientstreatedwitholanzapine, withnosignificantdifferencesinassociated cardiac eventscomparedtoplacebo. However,cautionshouldbeexercisedwhenolanzapine isprescribedwithmedicinesknowntoincreaseQTcinterval,especiallyintheelderly, inpatientswith congenitallong QTsyndrome,congestiveheartfailure,heart hypertrophy, hypokalaemiaor hypomagnesaemia.
Thromboembolism
Temporal association ofolanzapine treatmentandvenous thromboembolism has been
reporteduncommonly (≥0.1% and< 1%).A causalrelationshipbetweenthe occurrence ofvenousthromboembolismandtreatmentwitholanzapinehasnotbeen established.However,sincepatientswithschizophreniaoftenpresentwithacquired riskfactorsfor venousthromboembolismallpossible riskfactorsofVTEe.g., immobilisation ofpatients, should beidentified and preventivemeasures undertaken.
General CNS activity
Giventheprimary CNSeffectsofolanzapine,cautionshouldbeusedwhenitistaken incombinationwithothercentrallyactingmedicinesandalcohol.Asitexhibitsin vitrodopamineantagonism,olanzapinemay antagonisetheeffectsofdirectand indirect dopamine agonists.
Seizures
Olanzapineshouldbeusedcautiouslyinpatientswhohaveahistory ofseizuresorare
subjecttofactorswhichmay lowertheseizurethreshold.Seizureshavebeenreported tooccuruncommonly inpatientswhentreatedwitholanzapine.Inmostofthesecases,a historyof seizures or riskfactors for seizures were reported.