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.
Tardive dyskinesia
Incomparatorstudiesofoneyearorlessduration,olanzapinewasassociatedwitha
statisticallysignificantlowerincidenceoftreatmentemergentdyskinesia.However; theriskof tardivedyskinesiaincreaseswithlong-termexposure,andtherefore ifsigns or symptomsof tardive dyskinesia appear ina patientonolanzapine, a dose reduction ordiscontinuationshouldbeconsidered.Thesesymptomscantemporallydeteriorate oreven ariseafter discontinuation oftreatment.
Postural hypotension
Posturalhypotensionwasinfrequentlyobservedintheelderlyinolanzapineclinicaltrials. It is recommended that blood pressure is measured periodicallyinpatients over 65years.
Suddencardiac death
Inpostmarketingreportswitholanzapine,theeventofsuddencardiacdeathhasbeen
reportedinpatientswitholanzapine.Inaretrospective observationalcohortstudy,the riskof presumed suddencardiac deathinpatientstreated witholanzapine was approximatelytwicetheriskinpatientsnotusing antipsychotics.Inthestudy,therisk of olanzapine wascomparable tothe riskof atypicalantipsychoticsincluded ina pooled analysis.
Paediatric population
Olanzapineisnotindicatedforuseinthetreatmentofchildrenandadolescents.
Studiesinpatients aged13-17yearsshowedvariousadversereactions,including weightgain,changesinmetabolicparameters andincreasesinprolactinlevels.(seesections 4.8 and 5.1).
Lactose
OlanzapineAccordfilm-coatedtabletscontainlactose.Patientswithrare hereditary problemsofgalactoseintolerance,theLapplactasedeficiency,orglucose- galactose malabsorption should not takethis medicine.
4.5 Interactionswith othermedicinal products andotherforms ofinteraction
Interaction studieshaveonlybeen performed in adults.
Potential InteractionsAffecting olanzapine
SinceolanzapineismetabolisedbyCYP1A2,substancesthatcanspecificallyinduce orinhibitthis isoenzymemayaffect thepharmacokinetics ofOlanzapine.
InductionofCYP1A2
Themetabolismofolanzapinemay beinducedby smoking and carbamazepine, which maylead to reduced olanzapineconcentrations. Only slighttomoderateincreaseinolanzapineclearancehasbeenobserved.Theclinical consequencesarelikely tobelimited,butclinicalmonitoringisrecommendedandan increaseof olanzapine dose maybeconsidered ifnecessary(seesection 4.2).
InhibitionofCYP1A2
Fluvoxamine,aspecificCYP1A2inhibitor,hasbeenshown to significantly inhibit the metabolism of olanzapine. The mean increase in olanzapineCmaxfollowingfluvoxaminewas54%infemalenon-smokersand77%in male smokers.The meanincrease inolanzapineAUCwas52%and108%, respectively.Alowerstartingdoseofolanzapine shouldbeconsideredinpatients whoareusingfluvoxamineorany otherCYP1A2inhibitors,suchasciprofloxacin.A decrease inthe dose of olanzapine shouldbe consideredif treatmentwithaninhibitor ofCYP1A2 is initiated.
Decreasedbioavailability
Activatedcharcoalreducesthebioavailability oforal Olanzapineby 50to60%andshouldbetakenatleast2hoursbeforeorafter olanzapine.
Fluoxetine(a CYP2D6inhibitor),singledosesofantacid(aluminium,magnesium)or cimetidinehavenotbeenfoundtosignificantly affectthepharmacokineticsof olanzapine.
Potential forolanzapineto affect othermedicinal products
Olanzapine mayantagonisethe effects of direct and indirect dopamine agonists.
OlanzapinedoesnotinhibitthemainCYP450isoenzymesinvitro(eg,1A2,2D6,2C9,2C19,3A4).Thus,noparticular interactionisexpected,asverifiedthroughin vivostudies,wherenoinhibitionofmetabolismofthefollowingactivesubstances wasfound:tricyclicantidepressant(representingmostly CYP2D6pathway),warfarin (CYP2C9), theophylline(CYP1A2), or diazepam(CYP3A4 and 2C19).
Olanzapine showed no interaction whenco-administered with lithiumor biperiden.
Therapeuticmonitoringofvalproateplasmalevelsdidnotindicatethatvalproate dosageadjustment is required afterthe introduction ofconcomitant olanzapine.
General CNS activity
Cautionshouldbeexercisedinpatientswhoconsumealcoholorreceivemedicinal products that cancausecentral nervous system depression.
The concomitantuse ofolanzapinewithanti-Parkinsonianmedicinalproductsin patients with Parkinson'sdiseaseand dementia is not recommended(seesection 4.4).
QTcinterval
Cautionshouldbeusedifolanzapineisbeingadministeredconcomitantly with medicinal products known to increaseQTcinterval (seesection 4.4).
4.6 Fertility,pregnancy andlactation
Pregnancy
Therearenoadequateandwell-controlledstudiesinpregnantwomen.Patientsshould
beadvisedtonotify theirphysicianifthey becomepregnantorintendtobecome pregnantduringtreatmentwitholanzapine.Nevertheless,becausehumanexperience islimited,olanzapineshouldbeusedinpregnancy only ifthepotentialbenefit justifies thepotential risk to the foetus.
Neonates exposedto antipsychotics(including olanzapine) duringthe third trimester ofpregnancyareat risk ofadversereactionsincludingextrapyramidaland/or withdrawal symptoms that mayvaryin severityand duration followingdelivery. Therehavebeen reports ofagitation, hypertonia,hypotonia, tremor, somnolence, respiratorydistress, or feedingdisorder. Consequently, newborns should bemonitored carefully.
Breast-feeding
Inastudyinbreast-feeding,healthywomen,olanzapinewasexcretedinbreastmilk.
Mean infant exposure (mg/kg) at steady-state was estimated to be 1.8% of the maternalolanzapinedose (mg/kg). Patientsshouldbe advisednottobreast-feedan infant if theyaretaking olanzapine.
Fertility
Effects on fertility are unknown (see section 5.3 for preclinical information).
4.7 Effects on ability to driveandusemachines
No studies on the effects on the ability to drive and use machines have been performed.Becauseolanzapinemay causesomnolenceanddizziness,patientsshould becautionedabout operatingmachinery, includingmotorvehicles.
4.8 Undesirable effects
Summary of the safety profile
Adults
Themostfrequently(seenin 1%ofpatients)reportedadversereactionsassociated with the use of olanzapine in clinical
trials were somnolence, weight
gain, eosinophilia, elevated
prolactin,
cholesterol, glucose
and triglyceride
levels (see section4.4),glucosuria,increasedappetite,
dizziness,akathisia,parkinsonism,
leukopenia, neutropenia(see
section4.4),dyskinesia,orthostatic
hypotension,anticholinergic
effects,transient asymptomaticelevationsofhepaticaminotransferases(see section4.4),
rash,asthenia,
fatiguepyrexia, arthralgia, increased
alkaline phosphatase, high gamma glutamyltransferase, high uric
acid, high creatine phosphokinase and oedema.
Tabulated list of adverse reactions
Thefollowingtableliststheadversereactionsandlaboratory investigationsobserved
fromspontaneousreporting
andinclinicaltrials.Withineachfrequency grouping,
adversereactionsarepresentedinorderofdecreasingseriousness.Thefrequency termslistedaredefinedasfollows:Verycommon(
1/10),common( 1/100 to
<
1/10),uncommon(
1/1,000to<1/100),rare( 1/10,000 to<1/1,000),veryrare(< 1/10,000),not known (cannot be
estimated from thedata
available).
|
Very common |
Common |
Uncommon |
Rare |
Not known |
|
Blood and the lymphatic system disorders |
||||
|
|
Eosinophilia Leukopenia10 Neutropenia10 |
|
Thrombocytopenia11 |
|
|
Immune system disorders |
||||
|
|
|
Hypersensitivity11 |
|
|
|
Metabolism and nutrition disorders |
||||
|
Weight gain1 |
Elevated cholesterol levels2,3 Elevated glucose levels4 Elevated triglyceride levels2,5 Glucosuria Increased appetite |
Development or exacerbation of diabetes occasionally associated with ketoacidosis or coma, including some fatal cases (see section 4.4)11 |
Hypothermia12 |
|
|
Nervous system disorders |
||||
|
Somnolence |
Dizziness Akathisia6 Parkinsonism6 Dyskinesia6 |
Seizures where in most cases a history of seizures or risk factors for seizures were reported11 Dystonia (including oculogyration)11 Tardive dyskinesia 11 Amnesia 9 Dysarthria |
Neuroleptic malignant syndrome (see section 4.4)12 Discontinuation symptoms7,12 |
|
|
Cardiac disorders |
||||
|
|
|
Bradycardia QTc prolongation (see section 4.4) |
Ventricular tachycardia/fibrillation, sudden death (see section 4.4)11 |
|
|
Vascular disorders |
||||
|
Orthostatic hypotension10 |
|
Thromboembolism (including pulmonary embolism and deep vein thrombosis) (see section 4.4) |
|
|
|
Respiratory, thoracic and mediastinal disorders |
||||
|
|
|
Epistaxis9 |
|
|
|
Gastrointestinal disorders |
||||
|
|
Mild, transient anticholinergic effects including constipation and dry mouth |
Abdominal distension9 |
Pancreatitis11 |
|
|
Hepatobiliary disorders |
||||
|
|
Transient, asymptomatic elevations of hepatic aminotransferases (ALT, AST), especially in early treatment (see section 4.4) |
|
Hepatitis (including hepatocellular, cholestatic or mixed liver injury) 11 |
|
|
Skin and subcutaneous tissue disorders |
||||
|
|
Rash |
Photosensitivity reaction, Alopecia |
|
|
|
Musculoskeletal and connective tissue disorders |
||||
|
|
Arthralgia9 |
|
Rhabdomyolysis11 |
|
|
Renal and urinary disorders |
||||
|
|
|
Urinary incontinence, urinary retention Urinary hesitation11 |
|
|
|
Pregnancy, puerperium and perinatal conditions
|
||||
|
|
|
|
|
Drug withdrawal syndrome neonatal (see section 4.6) |
|
Reproductive system and breast disorders |
||||
|
|
Erectile dysfunction in males Decreased libido in males and females |
Amenorrhea Breast enlargement Galactorrhea in females Gynaecomastia/breast enlargement in males |
Priapism12 |
|
|
General disorders and administration site conditions |
||||
|
|
Asthenia, Fatigue, Oedema Pyrexia10 |
|
|
|
|
Investigations |
||||
|
Elevated plasma prolactin levels8 |
Increased alkaline phosphatase10 High creatine phosphokinase11 High Gamma Glutamyltransferase10 High Uric Acid10 |
Increased total bilirubin |
|
|
1Clinically significantweightgainwasobservedacrossallbaselineBodyMassIndex (BMI)categories.Following shorttermtreatment(medianduration47days),weight gain≥7%ofbaselinebody weightwasvery common(22.2%),≥15%wascommon (4.2 %) and ≥ 25%wasuncommon (0.8%).Patientsgaining≥7%,≥15%and≥25%oftheirbaselinebodyweight withlong-termexposure(atleast48weeks)wereverycommon(64.4%,31.7%and 12.3 % respectively).
2Meanincreasesinfasting lipidvalues(totalcholesterol,LDL cholesterol,and triglycerides)weregreater inpatientswithoutevidenceoflipiddysregulationat baseline.
3Observedforfastingnormallevelsatbaseline(<5.17mmol/l)whichincreasedto
high( 6.2mmol/l).Changesintotalfasting cholesterollevelsfromborderlineat baseline( 5.17 -<6.2 mmol/l) to high ( 6.2 mmol/l) wereverycommon.
4Observedforfastingnormallevelsatbaseline(<5.56mmol/l)whichincreasedto high( 7mmol/l).Changesinfastingglucosefromborderlineatbaseline( 5.56-< 7 mmol/l) to high ( 7 mmol/l) wereverycommon.
5Observedforfastingnormallevelsatbaseline(<1.69mmol/l)whichincreasedto high( 2.26mmol/l).Changesinfastingtriglyceridesfromborderlineatbaseline( 1.69 mmol/l-<2.26
mmol/l) to
high
( 2.26 mmol/l) wereverycommon.
6Inclinicaltrials,the incidence of parkinsonismanddystonia inolanzapine-treated patientswasnumericallyhigher,butnotstatistically significantly differentfrom placebo.Olanzapine-treated patientshada lower incidence of parkinsonism,akathisia anddystonia comparedwithtitrated doses of haloperidol.Inthe absenceof detailed informationonthepre-existinghistory ofindividualacuteandtardiveextrapyramidal movementdisorders,itcan-notbe concludedatpresentthatolanzapine producesless tardive dyskinesia and/orothertardiveextrapyramidal syndromes.
7Acute symptomssuchassweating,insomnia, tremor,anxiety,nausea andvomiting havebeen reported whenolanzapine is stopped abruptly.
8Inclinicaltrialsof upto12weeks,plasmaprolactinconcentrationsexceededthe upperlimitofnormalrangeinapproximately 30%ofolanzapinetreatedpatientswith normalbaselineprolactinvalue.Inthemajorityofthesepatientstheelevationsweregenerally mild,andremainedbelowtwotimestheupperlimitofnormalrange.
9Adverse event identified from clinical trials in the Olanzapine Integrated Database.
10As assessed by measured values from clinical trials in the Olanzapine Integrated Database.
11Adverse event identified from spontaneous post-marketing reporting with frequency determined utilising the Olanzapine Integrated Database.
12Adverse event identified from spontaneous post-marketing reporting with frequency estimated at the upper limit of the 95% confidence interval utilising the Olanzapine Integrated Database.
Long-termexposure(atleast48 weeks)
Theproportionofpatientswhohadadverse,clinicallysignificantchangesinweightgain, glucose,total/LDL/HDLcholesterolortriglyceridesincreasedovertime.In adultpatientswhocompleted9-12monthsof therapy,the rate of increase inmean blood glucoseslowed after approximately6 months.
Additional informationonspecialpopulations
In clinical trials in elderly patients with dementia, olanzapine treatment wasassociated witha higherincidence of deathandcerebrovascular adverse reactions compared to placebo (see also section 4.4). Very commonadversereactions associatedwiththeuseofolanzapineinthispatientgroupwereabnormalgaitand falls.Pneumonia, increasedbody temperature, lethargy, erythema,visual hallucinations and urinaryincontinencewereobserved commonly.
In clinical trials in patients with drug-induced (dopamine agonist) psychosis associatedwithParkinson'sdisease,worseningofParkinsoniansymptomatology and hallucinations were reported verycommonlyandmorefrequentlythan with placebo.
Inoneclinicaltrialinpatientswithbipolarmania,valproatecombinationtherapywith olanzapineresultedinanincidenceof neutropeniaof 4.1%;a
potentialcontributing factorcouldbe
highplasma valproatelevels.Olanzapine administeredwithlithiumor valproate resulted in
increased
levels ( 10%) of tremor,
dry mouth, increased appetite,and weight
gain. Speech
disorder
was also
reported
commonly. During treatmentwitholanzapineincombinationwithlithiumordivalproex,anincreaseof 7%frombaselinebody
weightoccurredin17.4%ofpatientsduringacutetreatment
(upto6weeks).Long-termolanzapinetreatment(upto12months)for recurrence
preventioninpatientswithbipolardisorderwasassociatedwithanincreaseof 7% from baselinebodyweightin 39.9% ofpatients.
Paediatric population
Olanzapineisnotindicatedforthetreatment ofchildren andadolescentpatients
below18years.Althoughnoclinicalstudiesdesignedtocompareadolescentsto adults havebeenconducted, datafromtheadolescenttrials werecomparedtothose of the adulttrials.
Thefollowing tablesummarizestheadversereactionsreportedwithagreater frequency inadolescentpatients(aged13-17years)thaninadultpatientsoradverse reactionsonly identifiedduringshort-termclinicaltrialsinadolescentpatients. Clinically significantweightgain( 7%)appearstooccurmorefrequentlyinthe adolescent population
compared
toadults
with comparableexposures.
Themagnitude ofweightgainandtheproportionofadolescentpatientswhohadclinically
significant
weightgainweregreaterwithlong-termexposure(atleast24weeks)than withshort-
term
exposure.
Within each frequency grouping,
adverse reactions
are presented
in order of decreasingseriousness.Thefrequency termslistedaredefinedasfollows:Very
common (
1/10), common (
1/100 to <1/10).
|
Metabolism and nutrition disorders Very common: Weight gain13, elevated triglyceride levels14, increased appetite. Common: Elevated cholesterol levels15 |
|
Nervous system disorders Very common: Sedation (including: hypersomnia, lethargy, somnolence). |
|
Gastro-intestinal disorders Common: Dry mouth |
|
Hepato-biliary disorders Very common: Elevations of hepatic aminotransferases (ALT/AST; see section 4.4). |
|
Investigations Very common: Decreased total bilirubin, increased GGT, elevated plasma prolactin levels16. |
13 Followingshorttermtreatment(medianduration22days),weightgain≥7%of baselinebodyweight(kg)wasverycommon(40.6%),≥15%ofbaselinebody weightwascommon(7.1%)and≥25%wascommon(2.5%).With long-term exposure (atleast24weeks),89.4%gained≥7%,55.3%gained≥15%and29.1% gained ≥ 25% oftheir baselinebodyweight.
14 Observedforfasting normallevelsatbaseline(<1.016mmol/l)whichincreasedto
high( 1.467mmol/l)and changesinfasting triglyceridesfromborderlineatbaseline
( 1.016 mmol/l-<1.467
mmol/l) to
high
( 1.467 mmol/l).
5.17 mmol/l) were observed commonly. Changes in total fasting cholesterollevelsfromborderlineatbaseline( 4.39-<5.17mmol/l)tohigh(≥
5.17 mmol/l)
wereverycommon.
16Elevated plasma prolactin levels werereported in 47.4%of adolescent patients.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V
4.9 Overdose
Signs andSymptoms
Very common symptoms in overdose (> 10% incidence) include tachycardia,agitation/aggressiveness,dysarthria, various extrapyramidalsymptoms,and reduced level of consciousnessrangingfrom sedation to coma.
Othermedically significantsequelaeofoverdoseincludedelirium,convulsion,coma, possibleneurolepticmalignantsyndrome,respiratory depression,aspiration, hypertensionor hypotension,cardiac arrhythmias(<2% of overdosecases),and cardiopulmonaryarrest.Fatal outcomes havebeen reportedforacuteoverdoses as low as450mg,butsurvivalhasalsobeenreportedfollowing acuteoverdose of approximately2gof oral olanzapine.
Management
There isnospecificantidoteforolanzapine.Inductionofemesisisnot recommended.
Standard procedures formanagement of overdosemaybeindicated (ie,gastric lavage, administrationofactivatedcharcoal).Theconcomitantadministrationofactivated charcoal was shown to reducethe oral bioavailabilityof olanzapine by50 to 60%.
Symptomatictreatmentandmonitoringofvitalorganfunctionshouldbeinstituted accordingtoclinicalpresentation,includingtreatmentofhypotensionandcirculatory collapseandsupportofrespiratoryfunction.Donotuseepinephrine,dopamine,or othersympathomimeticagentswithbeta-agonistactivity,sincebetastimulationmay worsen hypotension. Cardiovascularmonitoring is necessary to detect possible arrhythmias. Close medical supervision and monitoringshould continueuntil the patient recovers.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamicproperties
Pharmacotherapeuticgroup:psycholeptics,diazepines,oxazepines,thiazepines and oxepines.ATCcode:N05AH03.
Pharmacodynamic effects
Olanzapineisanantipsychotic,antimanicandmoodstabilising agentthat demonstrates abroad pharmacologic profileacross a number ofreceptor systems.
In preclinical studies, olanzapine exhibited a range of receptor affinities (Ki<100nM)forserotonin5HT2A/2C,5HT3,5HT6;dopamineD1,D2, D3,D4,D5; cholinergicmuscarinicreceptorsM1-M5;α1 adrenergic;andhistamineH1 receptors. Animal behavioural studies with olanzapine indicated 5HT, dopamine, and cholinergicantagonism,consistentwiththereceptor-binding profile.Olanzapine demonstrated a greater in vitro affinity for serotonin 5HT2 than dopamine D2 receptorsandgreater5HT2 thanD2 activityininvivomodels.Electrophysiological studiesdemonstratedthatolanzapineselectivelyreducedthefiring ofmesolimbic (A10)dopaminergicneurons,whilehaving littleeffectonthestriatal(A9)pathways involvedinmotor function.Olanzapinereduceda conditionedavoidanceresponse,a testindicativeofantipsychoticactivity,atdosesbelowthoseproducing catalepsy,an effectindicative ofmotorside-effects.Unlikesomeother antipsychoticagents, olanzapine increases respondingin an'anxiolytic' test.
Inasingleoraldose(10mg)PositronEmissionTomography (PET)studyinhealthy volunteers, Olanzapineproduceda higher 5HT2Athan dopamineD2receptor occupancy.Inaddition,aSingle Photon Emission Computed Tomography (SPECT)imagingstudyinschizophrenicpatientsrevealed thatOlanzapine-responsivepatientshadlowerstriatalD2occupancythansomeother antipsychotic-andrisperidone-responsivepatients,whilebeing comparableto clozapine-responsivepatients.
Clinical efficacy
Intwoof twoplaceboandtwoof three comparator-controlledtrialswithover 2,900 schizophrenicpatientspresenting withbothpositiveandnegativesymptoms, Olanzapinewasassociatedwithstatistically significantlygreaterimprovementsin negativeas wellas positivesymptoms.
Inamultinational,double-blind,comparativestudy ofschizophrenia,schizoaffective and related disorders, which included 1,481 patients with varying degrees of associated depressive symptoms(baseline meanof 16.6onthe Montgomery-Asberg DepressionRating Scale),aprospectivesecondary analysisofbaselinetoendpoint moodscorechangedemonstratedastatistically significantimprovement(P=0.001) favouringolanzapine (-6.0) versus haloperidol (-3.1).
Inpatientswithamanicormixedepisode ofbipolardisorder,Olanzapine demonstratedsuperiorefficacy toplaceboandvalproatesemisodium(divalproex)in reduction of manic symptoms over 3 weeks. Olanzapine also demonstrated comparableefficacy resultstohaloperidolintermsoftheproportionofpatientsin symptomatic remissionfrom mania anddepressionat6and12weeks.Inaco-therapy study ofpatientstreatedwithlithiumorvalproateforaminimumof2weeks,the additionofolanzapine10mg(co-therapy withlithiumorvalproate)resultedina greaterreductioninsymptomsofmaniathanlithiumorvalproatemonotherapyafter6 weeks.
Ina12-monthrecurrencepreventionstudyinmanicepisodepatientswhoachieved remissiononolanzapineandwere thenrandomisedtoolanzapineorplacebo, olanzapinedemonstratedstatistically significantsuperiorityoverplaceboonthe primary endpointofbipolarrecurrence.olanzapinealsoshowedastatistically significantadvantage over placebointermsof preventingeither recurrence intomania orrecurrenceinto depression.
Inasecond12-monthrecurrencepreventionstudy inmanicepisodepatientswho achievedremissionwith acombinationofolanzapineandlithium andwere then randomisedtoolanzapineorlithiumalone,olanzapinewasstatisticallynon-inferior tolithiumontheprimaryendpointofbipolarrecurrence(olanzapine30.0%,lithium 38.3%; p =0.055).
Inan18-monthco-therapy study inmanicormixedepisodepatientsstabilisedwith olanzapineplusamoodstabiliser (lithiumorvalproate),long-termolanzapineco-therapy withlithiumorvalproatewasnotstatistically significantly superiortolithium orvalproatealoneindelaying bipolarrecurrence,definedaccordingtosyndromic (diagnostic) criteria.
Paediatric population
Controlled efficacy datainadolescents(ages13to17years)arelimitedtoshort-termstudiesinschizophrenia(6weeks)andmaniaassociatedwithbipolar Idisorder(3 weeks),involvinglessthan200adolescents.olanzapine wasusedasaflexible dose starting with2.5andranging upto20 mg/day.During treatmentwitholanzapine, adolescentsgainedsignificantlymoreweightcomparedwithadults.Themagnitudeof changesin fasting total cholesterol,LDL cholesterol, triglycerides, andprolactin (see sections4.4and4.8) weregreater inadolescentsthaninadults.Therearenocontrolled dataon maintenanceof effectorlong-term safety(seesections 4.4 and 4.8). Information on long term safety is primarily limited to open-label, uncontrolled data.
5.2 Pharmacokineticproperties
Absorption
Olanzapineiswellabsorbedafteroraladministration,reaching peakplasma concentrationswithin5to8hours.Theabsorptionisnotaffectedby food.Absolute oral bioavailabilityrelativeto intravenous administration has not been determined.
Distribution
The plasma protein binding of olanzapine was about 93 % over the concentration range of about 7 to about 1000 ng/ml. Olanzapine is bound predominantly to albumin and 1-acid-glycoprotein.
Biotransformation
Olanzapineismetabolisedintheliverby conjugativeandoxidativepathways.The majorcirculating metaboliteisthe10-N-glucuronide,whichdoesnotpasstheblood brainbarrier.CytochromesP450-CYP1A2andP450-CYP2D6contribute tothe formationof the N-desmethyland 2-hydroxymethylmetabolites;both exhibited significantly lessinvivopharmacologicalactivitythanOlanzapineinanimalstudies. Thepredominantpharmacologicactivity isfromtheparent,Olanzapine.
Elimination
Afteroral administration,the meanterminaleliminationhalf-lifeofOlanzapineinhealthy subjects varied on thebasisof ageandgender.
Inhealthyelderly(65andover)versusnon-elderlysubjects,themeanelimination half-life wasprolonged(51.8versus33.8hours)andtheclearancewasreduced(17.5 versus18.2l/hr).Thepharmacokineticvariabilityobservedintheelderlyiswithinthe rangefor thenon-elderly.In44patientswithschizophrenia>65yearsofage,dosing from5to20mg/day wasnotassociatedwithanydistinguishingprofileofadverse events.
Infemaleversusmalesubjects,themeaneliminationhalf-life wassomewhat prolonged(36.7versus32.3hours) andtheclearance wasreduced(18.9versus27.3 l/hr).However,olanzapine(5-20mg)demonstratedacomparablesafety profilein female(n=467)as in male patients (n =869).
Renal impairment
Inrenally impairedpatients(creatinineclearance<10ml/min)versushealthy subjects, therewasnosignificantdifferenceinmeaneliminationhalf-life (37.7versus32.4 hours)orclearance(21.2versus25.0 l/hr).Amassbalancestudy showedthat approximately 57%ofradiolabelledolanzapineappearedinurine,principallyas metabolites.
Smokers
Insmoking subjectswithmildhepaticdysfunction,meaneliminationhalf-life (39.3 hours) was prolonged and clearance (18.0 l/hr) was reduced analogous to non- smokinghealthysubjects(48.8 hours and14.1 l/hr, respectively).
Innon-smoking versussmoking subjects(malesandfemales),themeanelimination half-life wasprolonged(38.6versus30.4hours)andtheclearancewasreduced(18.6 versus 27.7 l/hr).
Theplasmaclearanceofolanzapineislowerinelderly versusyoungsubjects,in femalesversusmales,andinnon-smokersversussmokers.However,themagnitude oftheimpactofage,gender,orsmokingonolanzapineclearanceandhalf-lifeis small in comparison to theoverallvariabilitybetween individuals.
Inastudy ofCaucasians,Japanese,andChinesesubjects,therewerenodifferencesin the pharmacokineticparameters amongthe threepopulations.
Paediatric population
Adolescents(ages13to17years):Thepharmacokineticsofolanzapinearesimilar betweenadolescentsandadults.Inclinicalstudies,the averageolanzapine exposure wasapproximately 27%higherinadolescents.Demographicdifferencesbetweenthe adolescentsandadultsincludealoweraveragebody weightandfeweradolescents weresmokers.Suchfactorspossibly contributetothehigheraverageexposure observed in adolescents.
5.3 Preclinical safety data
Acute(Single-Dose) Toxicity
Signsoforaltoxicityinrodentswerecharacteristicofpotentneurolepticcompounds: hypoactivity, coma,tremors,clonicconvulsions,salivation,anddepressedweight gain.Themedianlethaldoseswereapproximately210mg/kg(mice)and175mg/kg (rats).Dogstoleratedsingleoraldosesupto100mg/kg withoutmortality.Clinical signsincludedsedation,ataxia, tremors,increasedheartrate, labouredrespiration, miosis,andanorexia.Inmonkeys,single oraldoses upto100mg/kgresultedin prostration and, at higherdoses, semi-consciousness.
Repeated-DoseToxicity
Instudiesupto3monthsdurationinmiceandupto1yearinratsanddogs,the
predominanteffectswere CNSdepression,anticholinergiceffects,andperipheral haematologicaldisorders.Tolerance developedtothe CNSdepression.Growth parameters weredecreasedathighdoses.Reversible effectsconsistentwithelevated prolactininratsincludeddecreasedweightsofovariesanduterus andmorphologic changes in vaginalepithelium and in mammarygland.
Haematologic toxicity
Effectsonhaematologyparameterswere foundineachspecies,includingdose-related
reductions in circulating leukocytes in miceand non-specificreductions ofcirculating leukocytesinrats;however,noevidenceofbonemarrowcytotoxicity wasfound. Reversible neutropenia, thrombocytopenia, or anaemia developed in a few dogs treatedwith8or10mg/kg/day (totalolanzapineexposure[areaunderthecurve- AUC]is12-to15-fold greaterthanthatofamangivena12mg dose).Incytopenic dogs,therewerenoadverseeffectsonprogenitorandproliferating cellsinthebone marrow.
ReproductiveToxicity
Olanzapinehadnoteratogeniceffects.Sedationaffectedmatingperformanceofmale rats. Estrous cycles were affected at dosesof 1.1 mg/kg(3times the maximum humandose)andreproductionparameterswere influencedinratsgiven3mg/kg (9timesthemaximumhumandose).Inthe offspringof ratsgiven olanzapine,delaysin foetal developmentand transient decreases in offspringactivitylevels wereseen.
Mutagenicity
Olanzapinewasnotmutagenicorclastogenicinafullrangeofstandardtests,which included bacterial mutation testsand in vitroand in vivomammalian tests.
Carcinogenicity
Basedontheresultsofstudiesinmiceandrats,itwasconcludedthatolanzapineis
not carcinogenic.
6. PHARMACEUTICALPARTICULARS
6.1 List ofexcipients
Tablet Core:
Lactose monohydrate Cellulose microcrystalline Crospovidone Hydroxypropylcellulose Magnesiumstearate
Tablet coating:
For2.5 mg, 5 mg, 7.5 mg, 10 mg:Hypromellose (E464)
Macrogol
Titanium dioxide (E171) Polysorbate 80(E433)
For15 mg:Hypromellose (E464) Macrogol
Titanium dioxide (E171) Polysorbate 80(E433)
Indigo carminealuminumlake(E132)
For20 mg:Hypromellose (E464) Macrogol
Titanium dioxide(E171) Polysorbate 80(E433) Iron oxide red (E172)
6.2 Incompatibilities
Not applicable
6.3 Shelflife
2years
6.4 Specialprecautionsforstorage
Do not storeabove30°C.
6.5 Natureandcontents ofcontainer
“2.5 mg, 5 mg, 10 mg and 15 mg: Alu/Alu blister of 15, 28, 30, 35, 56 or 70 tablets.
7.5 mg and 20 mg: Alu/Alu blister of 28, 30, 35, 56 or 70 tablets.”
Not allpack sizes maybemarketed
6.6 Specialprecautionsfordisposalandotherhandling
Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocal requirements.
7 MARKETING AUTHORISATION HOLDER
AccordHealthcare Limited
SageHouse
319, PinnerRoad North Harrow MiddlesexHA1 4 HF United Kingdom
8 MARKETING AUTHORISATIONNUMBER
To becompleted nationally.
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
To becompleted nationally.
10. DATE OF REVISION OF THE TEXT
2016-05-11