BEXZIS

Main information

  • Trade name:
  • BEXZIS Film Coated Tablet 30 Milligram
  • Dosage:
  • 30 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • BEXZIS Film Coated Tablet 30 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0966/013/001
  • Authorization date:
  • 21-10-2005
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0966/013/001

CaseNo:2043671

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

ErghaHealthcareLtd

Damastown,Mulhuddart,Dublin15,Ireland

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

BexZis30mgFilm-coatedTablets

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom15/05/2008.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

Irish Medicines Board

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Date Printed 16/03/2010 CRN 2043671 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

BexZis30mgFilm-coatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains30mgofmirtazapine.

Excipients

Eachtabletcontains226.66mglactosemonohydrate

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

Reddishbrown,roundtablets.Onesideofthetablethasascorelinewiththemarking”9”ononesideofthescoreline

andthenumber”3”ontheother.Theothersideofthetabletismarkedwiththenumber”7207”.Thetabletcanbe

dividedintoequalhalves.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofepisodesofmajordepression.

4.2Posologyandmethodofadministration

Fororaladministration.

Thetabletsshouldbeswallowedwholewithoutchewing,withasufficientamountoffluid.Thetabletscanbetaken

withorwithoutfood.

Adults:Theinitialdoseispreferably15mgor30mg,takenintheevening.Themaintenancedoseisusuallybetween

15mgand45mgperday.

Elderlypatients:Asinadults.Changes,especiallyincrementsofdosagemustbemadecautiouslyandunderclose

supervision.

Childrenandadolescents(under18yearsofage):Sincethesafetyandefficacyofmirtazapinehavenotbeen

investigatedinthesepatients,theuseisnotrecommended.Seesection4.4.

Renalorhepaticinsufficiency:Theeliminationofmirtazapinemaybeslowerinpatientswithrenalorhepatic

insufficiency.Thismustbeconsideredwhenmirtazapineisprescribedforthesepatientsortheclinicalresponsesare

interpreted.

Mirtazapinetabletscanbetakenoncedaily,sincetheeliminationhalf-lifeis20to40hours.Themedicinalproduct

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dosestakeninthemorningandatthebedtime.Thelargerdoseshouldbetakenintheevening.

Theantidepressiveeffectofmirtazapineusuallybecomesevidentafter1to2weeksuse.Treatmentwithanadequate

doseshouldresultinapositiveresponsewithin2to4weeks.Withaninsufficientresponse,thedosecanbeincreased

uptothemaximumdose.Afterhavingobtainedanoptimalclinicaleffectandthepatientisfreeofsymptoms,the

treatmentshouldbecontinuedfor4to6months,untilagradualdiscontinuationcanbeconsidered.Ifnoclinical

responseisobservedwithin2to4weeksoftreatmentwiththemaximumdose,thetreatmentshouldbegradually

discontinued.Graduallytaperingdownthedosageisnecessarytoavoidwithdrawalsymptoms.

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients.

Concomitantuseofmirtazapinewithmonoamineoxidase(MAO)inhibitors(seesection4.5).

4.4Specialwarningsandprecautionsforuse

Useinchildrenandadolescentsunder18yearsofage

Mirtazapineshouldnotbeusedinthetreatmentofchildrenandadolescentsundertheageof18years.Suicide-related

behaviours(suicideattemptandsuicidalthoughts),andhostility(predominantlyaggression,oppositionalbehaviourand

anger)weremorefrequentlyobservedinclinicaltrialsamongchildrenandadolescentstreatedwithantidepressants

comparedtothosetreatedwithplacebo.If,basedonclinicalneed,adecisiontotreatisneverthelesstaken,thepatient

shouldbecarefullymonitoredfortheappearanceofsuicidalsymptoms.Inaddition,long-termsafetydatainchildren

andadolescentsconcerninggrowth,maturationandcognitiveandbehaviouraldevelopmentarelacking.

Suicide/suicidalthoughtsorclinicalworsening

Depressionisassociatedwithanincreasedriskofsuicidalthoughts,self-harmandsuicide(suicide-relatedevents).This

riskpersistsuntilsignificantremissionoccurs.Asimprovementmaynotoccurduringthefirstfewweeksormoreof

treatment,patientsshouldbecloselymonitoreduntilsuchimprovementoccurs.Itisgeneralclinicalexperiencethatthe

riskofsuicidemayincreaseintheearlystagesofrecovery.

Patientswithahistoryofsuicide-relatedeventsorthoseexhibitingasignificantdegreeofsuicidalideationpriorto

commencementoftreatmentareknowntobeatgreaterriskofsuicidalthoughtsorsuicideattempts,andshouldreceive

carefulmonitoringduringtreatment.Ameta-analysisofplacebo-controlledclinicaltrialsofantidepressantsinadult

patientswithpsychiatricdisordersshowedanincreasedriskofsuicidalbehaviourwithantidepressantscomparedto

placeboinpatientslessthan25yearsold.

Closesupervisionofpatientsandinparticularthoseathighriskshouldaccompanytherapywithantidepressants

especiallyinearlytreatmentandfollowingdosechanges.Patients(andcaregiversofpatients)shouldbealertedabout

theneedtomonitorforanyclinicalworsening,suicidalbehaviourorthoughtsandunusualchangesinbehaviourandto

seekmedicaladviceimmediatelyifthesesymptomspresent.Withregardtothechanceofsuicide,inparticularatthe

beginningoftreatment,onlyalimitednumberofBexZisFilm-coatedTabletsshouldbegiventothepatient.

Bonemarrowdepression

Bonemarrowdepression,usuallypresentingasgranulocytopeniaoragranulocytosis,hasbeenreportedduring

treatmentwithmirtazapine.Reversibleagranulocytosishasbeenreportedasarareoccurrenceinclinicalstudieswith

mirtazapine.Inthepost-marketingperiodwithmirtazapineveryrarecasesofagranulocytosishavebeenreported,

mostlyreversible,butinsomecasesfatal.Fatalcasesmostlyconcernedpatientswithanageabove65.Thephysician

shouldbealertforsymptomslikefever,sorethroat,stomatitisorothersignsofinfection;whensuchsymptomsoccur,

treatmentshouldbestoppedandbloodcountstaken.

Jaundice

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Conditionswhichneedsupervision

Carefuldosingaswellasregularandclosemonitoringisnecessaryinpatientswith:

epilepsyandorganicbrainsyndrome:althoughclinicalexperienceindicatesthatepilepticseizuresarerareduring

mirtazapinetreatment,aswithotherantidepressants,mirtazapineshouldbeintroducedcautiouslyinpatientswho

haveahistoryofseizures.Treatmentshouldbediscontinuedinanypatientwhodevelopsseizures,orwherethere

isanincreaseinseizurefrequency.

hepaticimpairment:followingasingle15mgoraldoseofmirtazapine,theclearanceofmirtazapinewas

approximately35%decreasedinmildtomoderatehepaticallyimpairedpatients,comparedtosubjectswith

normalhepaticfunction.Theaverageplasmaconcentrationofmirtazapinewasabout55%increased.

renalimpairment:followingasingle15mgoraldoseofmirtazapine,inpatientswithmoderate(creatinine

clearance<40ml/min)andsevere(creatinineclearance ≤10ml/min)renalimpairmenttheclearanceof

mirtazapinewasabout30%and50%decreasedrespectively,comparedtonormalsubjects.Theaverageplasma

concentrationofmirtazapinewasabout55%and115%increasedrespectively.Nosignificantdifferenceswere

foundinpatientswithmildrenalimpairment(creatinineclearance<80ml/min)ascomparedtothecontrolgroup.

cardiacdiseaseslikeconductiondisturbances,anginapectorisandrecentmyocardialinfarction,wherenormal

precautionsshouldbetakenandconcomitantmedicinescarefullyadministered.

lowbloodpressure.

diabetesmellitus:inpatientswithdiabetes,antidepressantsmayalterglycaemiccontrol.Insulinand/ororal

hypoglycaemicdosagemayneedtobeadjustedandclosemonitoringisrecommended.

Likewithotherantidepressants,thefollowingshouldbetakenintoaccount:

Worseningofpsychoticsymptomscanoccurwhenantidepressantsareadministeredtopatientswith

schizophreniaorotherpsychoticdisturbances;paranoidthoughtscanbeintensified.

Whenthedepressivephaseofbipolardisorderisbeingtreated,itcantransformintothemanicphase.Patients

withahistoryofmania/hypomaniashouldbecloselymonitored.Mirtazapineshouldbediscontinuedinany

patiententeringamanicphase.

Althoughmirtazapineisnotaddictive,post-marketingexperienceshowsthatabruptterminationoftreatmentafter

long-termadministrationmaysometimesresultinwithdrawalsymptoms.Themajorityofwithdrawalreactions

aremildandself-limiting.Amongthevariousreportedwithdrawalsymptoms,dizziness,agitation,anxiety,

headacheandnauseaarethemostfrequentlyreported.Eventhoughtheyhavebeenreportedaswithdrawal

symptoms,itshouldberealizedthatthesesymptomsmayberelatedtotheunderlyingdisease.Asadvisedin

section4.2,itisrecommendedtodiscontinuetreatmentwithmirtazapinegradually.

Careshouldbetakeninpatientswithmicturitiondisturbanceslikeprostatehypertrophyandinpatientswithacute

narrow-angleglaucomaandincreasedintra-ocularpressure(althoughthereislittlechanceofproblemswith

mirtazapinebecauseofitsveryweakanticholinergicactivity).

Akathisia/psychomotorrestlessness:theuseofantidepressantshasbeenassociatedwiththedevelopmentof

akathisia,characterisedbyasubjectivelyunpleasantordistressingrestlessnessandneedtomoveoften

accompaniedbyaninabilitytositorstandstill.Thisismostlikelytooccurwithinthefirstfewweeksof

treatment.Inpatientswhodevelopthesesymptoms,increasingthedosemaybedetrimental.

Hyponatraemia

Hyponatraemia,probablyduetoinappropriateantidiuretichormonesecretion(SIADH),hasbeenreportedveryrarely

withtheuseofmirtazapine.Cautionshouldbeexercisedinpatientsatrisk,suchaselderlypatientsorpatients

concomitantlytreatedwithagentsknowntocausehyponatraemia.

Serotoninsyndrome

Interactionwithserotonergicactivesubstances:serotoninsyndromemayoccurwhenselectiveserotoninre-uptake

inhibitors(SSRIs)areusedconcomitantlywithotherserotonergicactivesubstances(seesection4.5).Symptomsof

serotoninsyndromemaybehyperthermia,rigidity,myoclonus,autonomicinstabilitywithpossiblerapidfluctuationsof

vitalsigns,mentalstatuschangesthatincludeconfusion,irritabilityandextremeagitationprogressingtodeliriumand

coma.Frompost-marketingexperienceitappearsthatserotoninsyndromeoccursveryrarelyinpatientstreatedwith

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Elderlypatients

Elderlypatientsareoftenmoresensitive,especiallywithregardtotheundesirableeffectsofantidepressants.During

clinicalresearchwithmirtazapine,undesirableeffectshavenotbeenreportedmoreofteninelderlypatientsthanin

otheragegroups.

Lactose

Thismedicinalproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapp

lactasedeficiencyorglucose-galactosemalabsorptionshouldnottakethismedicinalproduct.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Pharmacodynamicinteractions

MirtazapineshouldnotbeadministeredconcomitantlywithMAOinhibitorsorwithintwoweeksafter

discontinuationofMAOinhibitortherapy.Intheoppositewayabouttwoweeksshouldpassbeforepatients

treatedwithmirtazapineshouldbetreatedwithMAOinhibitors(seesection4.3).Inaddition,aswithSSRIs,

co-administrationwithotherserotonergicactivesubstances(L-tryptophan,triptans,tramadol,linezolid,SSRIs,

venlafaxine,lithiumandSt.John’sWort–Hypericumperforatum–preparations)mayleadtoanincidenceof

serotonin-associatedeffects(serotoninsyndrome:seesection4.4).Cautionshouldbeadvisedandacloserclinical

monitoringisrequiredwhentheseactivesubstancesarecombinedwithmirtazapine.

Mirtazapinemayincreasethesedatingpropertiesofbenzodiazepinesandothersedatives(notablymost

antipsychotics,histamineH

antagonists,opioids).Cautionshouldbeexercisedwhenthesemedicinalproducts

areprescribedtogetherwithmirtazapine.

MirtazapinemayincreasetheCNS-depressanteffectofalcohol.Patientsshouldthereforebeadvisedtoavoid

alcoholicbeverageswhiletakingmirtazapine.

Mirtazapinedosedat30mgoncedailycausedasmallbutstatisticallysignificantincreaseintheinternational

normalizedratio(INR)insubjectstreatedwithwarfarin.Asatahigherdoseofmirtazapineamorepronounced

effectcannotbeexcluded,itisadvisabletomonitortheINRincaseofconcomitanttreatmentofwarfarinwith

mirtazapine.

Pharmacokineticinteractions

Carbamazepineandphenytoin,CYP3A4inducers,increasedmirtazapineclearanceabouttwo-fold,resultingina

decreaseinaverageplasmamirtazapineconcentrationof60%and45%,respectively.Whencarbamazepineor

anyotherinducerofhepaticmetabolism(suchasrifampicin)isaddedtomirtazapinetherapy,themirtazapine

dosemayhavetobeincreased.Iftreatmentwithsuchmedicinalproductisdiscontinued,itmaybenecessaryto

reducethemirtazapinedose.

Co-administrationofthepotentCYP3A4inhibitorketoconazoleincreasedthepeakplasmalevelsandtheAUCof

mirtazapinebyapproximately40%and50%respectively.

Whencimetidine(weakinhibitorofCYP1A2,CYP2D6andCYP3A4)isadministeredwithmirtazapine,the

meanplasmaconcentrationofmirtazapinemayincreasemorethan50%.

Cautionshouldbeexercisedandthedosemayhavetobedecreasedwhenco-administeringmirtazapinewith

potentCYP3A4inhibitors,HIVproteaseinhibitors,azoleantifungals,erythromycin,cimetidineornefazodone.

Interactionstudiesdidnotindicateanyrelevantpharmacokineticeffectsonconcurrenttreatmentofmirtazapine

withparoxetine,amitriptyline,risperidoneorlithium.

4.6Pregnancyandlactation

Limiteddataoftheuseofmirtazapineinpregnantwomendonotindicateanincreasedriskforcongenital

malformations.Studiesinanimalshavenotshownanyteratogeniceffectsofclinicalrelevance,howeverdevelopmental

toxicityhasbeenobserved(seesection5.3).Cautionshouldbeexercisedwhenprescribingtopregnantwomen.If

mirtazapineisuseduntil,orshortlybeforebirth,post-natalmonitoringofthenewbornisrecommendedtoaccountfor

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Animalstudiesandlimitedhumandatahaveshownexcretionofmirtazapineinbreastmilkonlyinverysmallamounts.

Adecisiononwhethertocontinue/discontinuebreast-feedingortocontinue/discontinuetherapywithmirtazapine

shouldbemadetakingintoaccountthebenefitofbreast-feedingtothechildandthebenefitofmirtazapinetherapyto

thewoman.

4.7Effectsonabilitytodriveandusemachines

Mirtazapinehasminorormoderateinfluenceontheabilitytodriveandusemachines.Itmayimpairconcentrationand

alertness(particularlyintheinitialphaseoftreatment).Patientsshouldavoidtheperformanceofpotentiallydangerous

tasks,whichrequirealertnessandgoodconcentration,suchasdrivingamotorvehicleoroperatingmachinery,atany

timewhenaffected.

4.8Undesirableeffects

Depressedpatientsdisplayanumberofsymptomsthatareassociatedwiththeillnessitself.Itisthereforesometimes

difficulttoascertainwhichsymptomsarearesultoftheillnessitselfandwhicharearesultoftreatmentwith

mirtazapine.

Themostcommonlyreportedadversereactions,occurringinmorethan5%ofpatientstreatedwithmirtazapinein

randomizedplacebo-controlledtrials(seebelow)aresomnolence,sedation,drymouth,weightincreased,increasein

appetite,dizzinessandfatigue.

Allrandomizedplacebo-controlledtrialsinpatients(includingindicationsotherthanmajordepressivedisorder),have

beenevaluatedforadversereactionsofmirtazapine.Themeta-analysisconsidered20trials,withaplanneddurationof

treatmentupto12weeks,with1501patients(134person-years)receivingdosesofmirtazapineupto60mgand850

patients(79person-years)receivingplacebo.Extensionphasesofthesetrialshavebeenexcludedtomaintain

comparabilitytoplacebotreatment.

Table1showsthecategorizedincidenceoftheadversereactionswhichoccurredintheclinicaltrialsstatistically

significantlymorefrequentlyduringtreatmentwithmirtazapinethanwithplacebo,addedwithadversereactionsfrom

spontaneousreporting.Thefrequenciesoftheadversereactionsfromspontaneousreportingarebasedonthereporting

rateoftheseeventsintheclinicaltrials.Thefrequencyofadversereactionsfromspontaneousreportingforwhichno

casesintherandomizedplacebo-controlledpatienttrialswereobservedwithmirtazapinehasbeenclassifiedas‘not

known’.

Table1.Adversereactionsofmirtazapine

Systemorgan

class Verycommon

≥1/10) Common( ≥

1/100to<1/10) Uncommon( ≥

1/1,000to

<1/100) Rare( ≥

1/10,000to

<1/1,000) Frequencynot

known

Investigations Weight

increased 1

Bloodand

lymphatic

system

disorders Bonemarrow

depression

(granulocytopenia,

agranulocytosis,

aplastic

anaemia,

thrombocytopenia)

Eosinophilia

Nervoussystem

disorders Somnolence 1,4

Sedation 1,4

Headache 2 Lethargy 1

Dizziness

Tremor Paraesthesia 2

Restlesslegs

Syncope Myoclonus Convulsions

(insults)

Serotonin

syndrome

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Inclinicaltrialstheseeventsoccurredstatisticallysignificantlymorefrequentlyduringtreatmentwith

mirtazapinethanwithplacebo.

Inclinicaltrialstheseeventsoccurredmorefrequentlyduringtreatmentwithplacebothanwithmirtazapine,

howevernotstatisticallysignificantlymorefrequently.

Inclinicaltrialstheseeventsoccurredstatisticallysignificantlymorefrequentlyduringtreatmentwithplacebo

thanwithmirtazapine.

N.B.dosereductiongenerallydoesnotleadtolesssomnolence/sedationbutcanjeopardizeantidepressant

efficacy.

Upontreatmentwithantidepressantsingeneral,anxietyandinsomnia(whichmaybesymptomsofdepression)

candeveloporbecomeaggravated.Undermirtazapinetreatment,developmentoraggravationofanxietyand

insomniahasbeenreported.

Casesofsuicidalideationandsuicidalbehaviourshavebeenreportedduringmirtazapinetherapyorearlyafter

treatmentdiscontinuation(seesection4.4).

Inlaboratoryevaluationsinclinicaltrialstransientincreasesintransaminasesandgamma-glutamyl-transferasehave

beenobserved(howeverassociatedadverseeventshavenotbeenreportedstatisticallysignificantlymorefrequently

paraesthesesia

Gastrointestinal

disoders Drymouth

Nausea 3

Diarrhoea 2

Vomiting 2 Oral

hypoaesthesia Mouthoedema

Skinand

subcutaneous

tissuedisorders Exanthema 2

Musculoskeletal

andconnective

tissuedisorders Arthralgia

Myalgia

Backpain 1

Metabolism

andnutrition

disorders Increasein

appetite 1 Hyponatraemia

Vascular

disorders Orthostatic

hypotension Hypotension 3

General

disordersand

administration

siteconditions Oedema

peripheral 1

Fatigue

Hepatobiliary

disorders Elevationsin

serum

transaminase

levels

Psychiatric

disorders Abnormal

dreams

Confusion

Anxiety 2,5

Insomnia 3,5 Nightmares 2

Mania

Agitation 2

Hallucinations

Psychomotor

restlessness

(incl.akathisia,

hyperkinesia) Suicidal

ideation 6

Suicidal

behaviour 6

Endocrine

disorders Inappropriate

antidiuretic

hormone

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4.9Overdose

Presentexperienceconcerningoverdosewithmirtazapinealoneindicatesthatsymptomsareusuallymild.Depression

ofthecentralnervoussystemwithdisorientationandprolongedsedationhavebeenreported,togetherwithtachycardia

andmildhyper-orhypotension.However,thereisapossibilityofmoreseriousoutcomes(includingfatalities)at

dosagesmuchhigherthanthetherapeuticdose,especiallywithmixedoverdoses.Casesofoverdoseshouldreceive

appropriatesymptomaticandsupportivetherapyforvitalfunctions.Activatedcharcoalorgastriclavageshouldalsobe

considered.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Otherantidepressants

ATCcode:N06AX11

Mirtazapineisacentrally-activepresynaptic

-antagonist,whichincreasescentralnoradrenergicandserotonergic

neurotransmission.Theenhancementofserotonergicneurotransmissionisspecificallymediatedvia5-HT

receptors,

because5-HT

and5-HT

receptorsareblockedbymirtazapine.Bothenantiomersofmirtazapinearepresumedto

contributetotheantidepressantactivity,theS(+)enantiomerbyblocking

and5-HT

receptorsandtheR(-)

enantiomerbyblocking5-HT

receptors.

ThehistamineH

-antagonisticactivityofmirtazapineisassociatedwithitssedativeproperties.Ithaspracticallyno

anticholinergicactivityand,attherapeuticdoses,haspracticallynoeffectonthecardiovascularsystem.

5.2Pharmacokineticproperties

Afteroraladministration,theactivesubstancemirtazapineisrapidlyandwellabsorbed(bioavailability 50%),

reachingpeakplasmalevelsafterapprox.twohours.Bindingofmirtazapinetoplasmaproteinsisapprox.85%.The

meanhalf-lifeofeliminationis20-40hours;longerhalf-lives,upto65hours,haveoccasionallybeenrecordedand

shorterhalf-liveshavebeenseeninyoungmen.Thehalf-lifeofeliminationissufficienttojustifyonce-a-daydosing.

Steadystateisreachedafter3-4days,afterwhichthereisnofurtheraccumulation.Mirtazapinedisplayslinear

pharmacokineticswithintherecommendeddoserange.Foodintakehasnoinfluenceonthepharmacokineticsof

mirtazapine.

Mirtazapineisextensivelymetabolizedandeliminatedviatheurineandfaeceswithinafewdays.Majorpathwaysof

biotransformationaredemethylationandoxidation,followedbyconjugation.Invitrodatafromhumanliver

microsomesindicatethatcytochromeP450enzymesCYP2D6andCYP1A2areinvolvedintheformationofthe

8-hydroxymetaboliteofmirtazapine,whereasCYP3A4isconsideredtoberesponsiblefortheformationofthe

N-demethylandN-oxidemetabolites.Thedemethylmetaboliteispharmacologicallyactiveandappearstohavethe

samepharmacokineticprofileastheparentcompound.

Theclearanceofmirtazapinemaybedecreasedasaresultofrenalorhepaticimpairment.

5.3Preclinicalsafetydata

Preclinicaldatarevealnospecialhazardforhumansbasedonconventionalstudiesofsafetypharmacology,

repeated-dosetoxicity,carcinogenicityorgenotoxicity.

Inreproductivetoxicitystudiesinratsandrabbitsnoteratogeniceffectswereobserved.Attwo-foldsystemicexposure

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pupbirthweights,andreductioninpupsurvivalduringthefirstthreedaysoflactationinrats.

MirtazapinewasnotgenotoxicinaseriesoftestsforgenemutationandchromosomalandDNAdamage.Thyroid

glandtumoursfoundinaratcarcinogenicitystudyandhepatocellularneoplasmsfoundinamousecarcinogenicity

studyareconsideredtobespecies-specific,non-genotoxicresponsesassociatedwithlong-termtreatmentwithhigh

dosesofhepaticenzymeinducers.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore

Lactosemonohydrate

Maizestarch

PovidoneK-30

Anhydrouscolloidalsilica

Magnesiumstearate.

Coating

Hypromellose

Titaniumdioxide(E171)

Macrogol400

Macrogol6000

Yellowironoxide(E172)

Redironoxide(E172)

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

2years.

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

Blisters:transparentorwhiteopaque(PVC/PVdC/Al).

Packsizes:14,20,28,30,50,60,100and200(2x100)tablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

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ErghaHealthcareLtd.

Damastown

Mulhuddart

Dublin15

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA966/13/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:21October2005

Dateoflastrenewal:15May2008

10DATEOFREVISIONOFTHETEXT

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