BEXMIRT

Main information

  • Trade name:
  • BEXMIRT Orodispersible Tablet 30 Milligram
  • Dosage:
  • 30 Milligram
  • Pharmaceutical form:
  • Orodispersible Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • BEXMIRT Orodispersible Tablet 30 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0966/017/002
  • Authorization date:
  • 14-08-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Bexmirt30mgOrodispersibleTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains30mgofmirtazapine.

Excipients:includes12mgaspartame(E951)pertablet.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Orodispersibletablet.

Roundbiconvex,whiteoralmostwhite,uncoatedtabletsmarked‘M2’ononeside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofepisodesofmajordepression.

4.2Posologyandmethodofadministration

Adults:

Theeffectivedailydoseisusuallybetween15and45mg;thestartingdoseis15or30mgMirtazapinebeginstoexert

itseffectingeneralafter1-2weeksoftreatment.Treatmentwithanadequatedoseshouldresultinapositiveresponse

within2-4weeks.Withaninsufficientresponse,thedosecanbeincreaseduptothemaximumdose.Ifthereisno

responsewithinafurther2-4weeks,thentreatmentshouldbestopped.

Elderly:

Therecommendeddoseisthesameasthatforadults.Inelderlypatientsanincreaseindosingshouldbedoneunder

closesupervisiontoelicitasatisfactoryandsaferesponse.

Childrenandadolescentsundertheageof18years:

Bexmirtshouldnotbeusedinchildrenandadolescentsundertheageof18years(seesection4.4).

Renalimpairment

Theclearanceofmirtazapinemaybedecreasedinpatientswithmoderatetosevererenalimpairment(creatinine

clearance<40ml/min).ThisshouldbetakenintoaccountwhenprescribingBexmirttothiscategoryofpatients(see

section4.4).

Hepaticimpairment

Theclearanceofmirtazapinemaybedecreasedinpatientswithhepaticimpairment.Thisshouldbetakenintoaccount

whenprescribingBermirttothiscategoryofpatients,particularlywithseverehepaticimpairment,aspatientswith

severehepaticimpairmenthavenotbeeninvestigated(seesection4.4).

Mirtazapinehasaneliminationhalf-lifeof20-40hoursandthereforeBexmirtissuitableforoncedailyadministration.

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doses(onceinthemorningandonceatnight-time,thehigherdoseshouldbetakenatnight).

Thetabletsshouldbetakenorally.Thetabletwillrapidlydisintegrateandcanbeswallowedwithoutwater.

Patientswithdepressionshouldbetreatedforasufficientperiodofatleast6monthstoensurethattheyarefreefrom

symptoms.

Itisrecommendedtodiscontinuetreatmentwithmirtazapinegraduallytoavoidwithdrawalsymptoms(seesection

4.4).

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients

Concomitantuseofmirtazapinewithmonoamineoxidase(MAO)inhibitors(seesection4.5).

4.4Specialwarningsandprecautionsforuse

Useinchildrenandadolescentsunder18yearsofage:

Bexmirtshouldnotbeusedinthetreatmentofchildrenandadolescentsundertheageof18years.Suicide-related

behaviours(suicideattemptandsuicidalthoughts),andhostility(predominantlyaggression,oppositionalbehaviourand

anger)weremorefrequentlyobservedinclinicaltrialsamongchildrenandadolescentstreatedwithantidepressants

comparedtothosetreatedwithplacebo.If,basedonclinicalneed,adecisiontotreatisneverthelesstaken,thepatient

shouldbecarefullymonitoredfortheappearanceofsuicidalsymptoms.Inaddition,long-termsafetydatainchildren

andadolescentsconcerninggrowth,maturationandcognitiveandbehaviouraldevelopmentarelacking.

Suicide/suicidalthoughtsorclinicalworsening

Depressionisassociatedwithanincreasedriskofsuicidalthoughts,selfharmandsuicide(suicide-relatedevents).This

riskpersistsuntilsignificantremissionoccurs.Asimprovementmaynotoccurduringthefirstfewweeksormoreof

treatment,patientsshouldbecloselymonitoreduntilsuchimprovementoccurs.Itisgeneralclinicalexperiencethatthe

riskofsuicidemayincreaseintheearlystagesofrecovery.

Patientswithahistoryofsuicide-relatedevents,orthoseexhibitingasignificantdegreeofsuicidalideationpriorto

commencementoftreatmentareknowntobeatgreaterriskofsuicidalthoughtsorsuicideattempts,andshouldreceive

carefulmonitoringduringtreatment.Ameta-analysisofplacebo-controlledclinicaltrialsofantidepressantdrugsin

adultpatientswithpsychiatricdisordersshowedanincreasedriskofsuicidalbehaviourwithantidepressantscompared

toplaceboinpatientslessthan25yearsold.

Closesupervisionofpatientsandinparticularthoseathighriskshouldaccompanydrugtherapyespeciallyinearly

treatmentandfollowingdosechanges.Patients(andcaregiversofpatients)shouldbealertedabouttheneedtomonitor

foranyclinicalworsening,suicidalbehaviourorthoughtsandunusualchangesinbehaviourandtoseekmedicaladvice

immediatelyifthesesymptomspresent.

Withregardtothechanceofsuicide,inparticularatthebeginningoftreatment,onlyalimitednumberofBexmirt

orodispersibletabletsshouldbegiventothepatient.

Bonemarrowdepression

Bonemarrowdepression,usuallypresentingasgranulocytopeniaoragranulocytosis,hasbeenreportedduring

treatmentwithBexmirt.Reversibleagranulocytosishasalsobeenreportedasarareoccurrenceinclinicalstudieswith

Bexmirt.Inthepost-marketingperiodwithBexmirtveryrarelycasesofagranulocytosishavebeenreported,mostly

reversible,butinsomecasesfatal.Fatalcasesconcernedpatientswithanageabove65.Thephysicianshouldbealert

forsymptomslikefever,sorethroat,stomatitisorothersignsofinfection;whensuchsymptomsoccur,treatment

shouldbestoppedandbloodcountstaken.

Jaundice

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Conditionswhichneedsupervision

Carefuldosingaswellasregularandclosemonitoringisnecessaryinpatientswith:

epilepsyandorganicbrainsyndrome:Althoughclinicalexperienceindicatesthatepilepticseizuresarerareduring

mirtazapinetreatment,aswithotherantidepressants,Bexmirtshouldbeintroductedcautiouslyinpatientswhohave

ahistoryofseizures.Treatmentshouldbediscontinuedinanypatientwhodevelopsseizures,orwherethereisan

increaseinseizurefrequency.

hepaticimpairment:Followingasingle15mgoraldoseofmirtazapine,theclearanceofmirtazapinewas

approximately35%decreasedinmildtomoderatehepaticallyimpairedpatients,comparedtosubjectswithnormal

hepaticfunction.Theaverageplasmaconcentrationofmirtazapinewasabout55%increased.

renalimpairment:Followingasingle15mgoraldoseormirtazapine,inpatientswithmoderate(creatinine

clearance<40ml/min)andsevere(creatinineclearance<10ml/min)renalimpairmenttheclearanceofmirtazapine

wasabout30%and50%decreasedrespectively,comparedtonormalsubjects.Theaverageplasmaconcentrationof

mirtazapinewasabout55%and115%increasedrespectively.Nosignificantdifferenceswerefoundinpatients

withmildrenalimpairment(creatinineclearance<80ml/min)ascomparedtothecontrolgroup.

cardiacdiseaseslikeconductiondisturbances,anginapectorisandrecentmyocardialinfarction,wherenormal

precautionsshouldbetakenandconcomitantmedicinescarefullyadministered

lowbloodpressure.

diabetesmellitus:Inpatientswithdiabetes,antidepressantsmayalterglycaemiccontrol.Insulinand/ororal

hypoglycaemicdosagemayneedtobeadjustedandclosemonitoringisrecommended.

Likewithotherantidepressants,thefollowingshouldbetakenintoaccount:

worseningofpsychoticsymptomscanoccurwhenantidepressantsareadministeredtopatientswithschizophrenia

orotherpsychoticdisturbances;paranoidthoughtscanbeintensified

whenthedepressivephaseofbipolardisorderisbeingtreated,itcantransformintothemanicphase.Patientswitha

historyofmania/hypomaniashouldbecloselymonitored.Mirtazapineshouldbediscontinuedinanypatient

enteringamanicphase.

althoughBexmirtisnotaddictive,postmarketingexperienceshowsthatabruptterminationoftreatmentafterlong-

termadministrationmaysometimesresultinwithdrawalsymptoms.Themajorityofwithdrawalreactionsaremild

andself-limiting.Amongthevariousreportedwithdrawalsymptoms,dizziness,agitation,anxiety,headacheand

nauseaarethemostfrequentlyreported.Eventhoughtheyhavebeenreportedaswithdrawalsymptoms,itshould

berealisedthatthesesymptomsmayberelatedtotheunderlyingdisease.Asadvisedinsection4.2,itis

recommendedtodiscontinuetreatmentwithmirtazapinegradually.

Careshouldbetakeninpatientswithmicturitiondisturbanceslikeprostatehypertrophyandinpatientswithacute

narrow-angleglaucomaandincreasedintro-ocularpressure(althoughthereislittlechanceofproblemswith

Bexmirtbecauseofitsveryweakanticholinergicactivity).

akathisia/psychomotorrestlessness:Theuseofantidepressantshavebeenassociatedwiththedevelopmentof

akathisia,characterizedbyasubjectivelyunpleasantordistressingrestlessnessandneedtomoveoften

accompaniedbyaninabilitytositorstandstill.Thisismostlikelytooccurwithinthefirstfewweeksoftreatment.

Inpatientswhodevelopthesesymptoms,increasingthedosemaybedetrimental.

Hyponatraemia

Hyponataemia,probablyduetoinappropriateantidiuretichormonesecretion(SIADH),hasbeenreportedveryrarely

withtheuseofmirtazapine.Cautionshouldbeexercisedinpatientsatrisk,suchaselderlypatientsorpatients

concomitantlytreatedwithmedicationsknowntocausehyponatraemia.

Serotoninsyndrome

Interactionwithsertonergicactivesubstances:serotoninsyndromemayoccurwhenselectiveserotoninreuptake

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

serotoninsyndromemaybehyperthermia,rigidity,myoclonus,autonomicinstabilitywithpossiblerapidfluctuationsof

vitalsigns,mentalstatuschangesthatincludeconfusion,irritabilityandextremeagitationprogressingtodeliriumand

coma.Frompostmarketingexperienceitappearsthatserotoninsyndromeoccursveryrarelyinpatientstreatedwith

Bexmirtalone(seesection4.8).

Elderlypatients

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clinicalresearchwithBexmirt,undesirableeffectshavenotbeenreportedmoreofteninelderlypatientsthaninother

agegroups.

Aspartame

Bexmirtcontainsaspartame,asourceofphenylalanine.Eachtabletwith15mg,30mgand45mgmirtazapine,

correspondsto3mg,6mgand9mgphenylalanine,respectively.Itmaybeharmfulforpatientswithphenylketonuria.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Pharmacodynamicinteractions

MirtazapineshouldnotbeadministeredconcomitantlywithMAOinhibitorsorwithintwoweeksafter

discontinuationofMAOinhibitortherapy.Intheoppositewayabouttwoweeksshouldpassbeforepatientstreated

withMirtazapineshouldbetreatedwithMAOinhibitors(seesection4.3).

Inaddition,aswithSSRIs,co-administrationwithotherserotonergicactivesubtances(L-tryptophan,triptans,

tramadol,linezolid,SSRIs,venlafaxine,lithiumandSt.John’sWort–Hypericumperforatum–preparations)may

leadtoanincidenceofserotoninassociatedeffects(serotoninsyndrome:seesection4.4).Cautionshouldbe

advisedandacloserclinicalmonitoringisrequiredwhentheseactivesubstancesarecombinedwithMirtazapine.

Mirtazapinemayincreasethesedatingpropertiesofbenzodiazepinesandothersedatives(notablymost

antipsychotics,antihistamineH1antagonists,opioids).Cautionshouldbeexercisedwhenthesemedicinalproducts

areprescribedtogetherwithmirtazapine.

MirtazapinemayincreasetheCNSdepressanteffectofalcohol.Patientsshouldthereforebeadvisedtoavoid

alcoholicbeverageswhiletakingmirtazapine.

Mirtazapinedosedat30mgoncedailycausedasmallbutstatisticallysignificantincreaseintheinternational

normalizedratio(INR)insubjectstreatedwithwarfarin.Asatahigherdoseofmirtazapineamorepronounced

effectcannotbeexcluded,itisadvisabletomonitortheINRincaseofconcomitanttreatmentofwarfarinwith

mirtazapine.

Pharmacokineticinteractions

Carbamazepineandphenytoin,CYP3A4inducers,increasedMirtazapineclearanceabouttwofold,resultingina

decreaseinaverageplasmaMirtazapineconcentrationof60%and45%respectively.Whencarbamazepineorany

otherinducerofhepaticmetabolism(suchasrifampicin)isaddedtomirtazapinetherapy,themirtazapinedosemay

havetobeincreased.Iftreatmentwithsuchmedicinalproductisdiscontinued,itmaybenecessarytoreducethe

mirtazapinedose.

Co-administrationofthepotentCYP3A4inhibitorketoconazoleincreasedthepeakplasmalevelsandtheAUCof

mirtazapinebyapproximately40%and50%respectively.

Whencimetidine(weakinhibitorofCYP1A2,CYP2D6andCYP3A4)isadministeredwithmirtazapine,themean

plasmaconcentrationofmirtazapinemayincreasemorethan50%.Cautionshouldbeexercisedandthedosemay

havetobedecreasedwhenco-administeringmirtazapinewithpotentCYP3A4inhibitors,azoleantifungals,

erythromycin,cimetidineornefazodone.

Interactionstudiesdidnotindicateanyrelevantpharmacokineticeffectsonconcurrenttreatmentofmirtazapine

withparoxetine,amitriptylin,risperidoneorlithium.

4.6Pregnancyandlactation

Limiteddataoftheuseofmirtazapineinpregnantwomendonotindicateanincreasedriskforcongenital

malformations.Studiesinanimalshavenotshownanyteratogeniceffectsofclinicalrelevancehoweverdevelopmental

toxicityhasbeenobserved(seesection5.3).Cautionshouldbeexercisedwhenprescribingtopregnantwomen.If

Bexmirtisuseduntil,orshortlybeforebirth,postnatal,monitoringofthenewbornisrecommendedtoaccountfor

possiblediscontinuationeffects.

EpidemiologydatahavesuggestedthattheuseofSSRIsinpregnancy,particularinlatepregnancy,mayincreasethe

riskofpersistentpulmonaryhypertensioninthenewborn(PPHN).Althoughthereisnoevidencefortheassociationof

PPHNtoSNRItreatment,thispotentialriskcannotberuledoutwithmirtazepinetakingintoaccounttherelated

mechanismsofaction(increaseinserotoninconcentrations).

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Adecisiononwhethertocontinue/discontinuebreast-feedingortocontinue/discontinuetherapywithBexmirtshould

bemadetakingintoaccountthebenefitofbreast-feedingtothechildandthebenefitofBexmirttherapytothewoman.

4.7Effectsonabilitytodriveandusemachines

Bexmirthasminortomoderateinfluenceontheabilitytodriveandusemachines.Bexmirtmayimpairconcentration

andalertness(particularlyintheinitialphaseoftreatment).Patientsshouldavoidtheperformanceofpotentially

dangeroustasks,whichrequirealertnessandgoodconcentration,suchasdrivingamotorvehicleoroperating

machinery,atanytimewhenaffected.

4.8Undesirableeffects

Depressedpatientsdisplayanumberofsymptomsthatareassociatedwiththeillnessitself.Itisthereforesometimes

difficulttoascertainwhichsymptomsarearesultoftheillnessitselfandwhicharearesultoftreatmentwithBexmirt.

Themostcommonlyreportedadversereactions,occurringinmorethan5%ofpatientstreatedwithBexmirtin

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

appetite,dizzinessandfatigue.

Allrandomizedplacebo-controlledtrialsinpatients(includingindicationsotherthanmajordepressivedisorder),have

beenevaluatedforadversereactionsofBexmirt.Themeta-analysisconsidered20trials,withaplanneddurationof

treatmentupto12weeks,with1501patients(134personyears)receivingdosesofmirtazapineupto60mgand850

patients(79personyears)receivingplacebo.Extensionphasesofthesetrialshavebeenexcludedtomaintain

comparabilitytoplacebotreatment.

Table1showsthecategorizedincidenceoftheadversereactions,whichoccurredintheclinicaltrialsstatistically

significantlymorefrequentlyduringtreatmentwithBexmirtthanwithplacebo,addedwithadversereactionsfrom

spontaneousreporting.Thefrequenciesoftheadversereactionsfromspontaneousreportingarebasedonthereporting

rateoftheseeventsintheclinicaltrials.Thefrequencyofadversereactionsfromspontaneousreportingforwhichno

casesintherandomizedplacebo-controlledpatienttrialswereobservedwithmirtazapinehasbeenclassifiedas‘not

known’.

Table1.AdversereactionsofBexmirt

Systemorgan

class Verycommon

(>1/10) Common

(>1/100to

<1/10) Uncommon

(>1/1,000to

<1/100) Rare

(>1/10,000to

<1/1,1000) Frequencynot

known

Bloodandthe

lymphatic

systemdisorders Bonemarrow

depression

(granulocytopenia,

agranulocytosis,

aplasticanaemia

thrombocytopenia

Eosinophilia

Metabolismand

nutrition

disorders Increasein

appetite 1

Psychiatric

disorders Abnormal

dreams

Confusion

Anxiety 2,5

Insomnia 3,5 Nightmares 2

Mania

Agitation 2

Hallucinations

Psychomotor

restlessness

(incl.akathisia, Suicidal

ideation 6

Suicidal

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1.Inclinicaltrialstheseeventsoccurredstatisticallysignificantlymorefrequentlyduringtreatmentduringtreatment

withBexmirtthanwithplacebo.

2.InclinicaltrialstheseeventsoccurredmorefrequentlyduringtreatmentwithplacebothanwithBexmirt,however

notstatisticallysignificantlymorefrequently.

3.Inclinicaltrialstheseeventsoccurredstatisticallysignificantlymorefrequentlyduringtreatmentwithplacebothan

withBexmirt

4.N.B.dosereductiongenerallydoesnotleadtolesssomnolence/sedationbutcanjeopardizeantidepressantefficacy.

5.Upontreatmentwithantidepressantsingeneral,anxietyandinsomnia(whichmaybesymptomsofdepression)can

hyperkinesia)

Nervoussystem

disorders Somnolence 1,4

Sedation 1,4

Headache 2 Lethargy 1

Dizziness

Tremor Paraesthesia 2

Restlesslegs

Syncope Myoclonus Convulsions

(insults)

Serotonin

syndrome

Oral

paraesthesia

Vascular

disorders (Orthostatic)

hypotension Hypotension 2

Gastrointestinal

disorders Drymouth Nausea 3

Diarrhea 2

Vomiting 2 Oral

hypoaesthesia Mouthoedema

Hepato-biliary

disorders Elevationsin

serum

transaminase

activities

Skinand

subcutaneous

tissuedisorders Exanthema 2

Musculoskeletal,

connectivetissue

andbone

disorders Arthralgia

Myalgia

Backpain 1

General

disordersand

administration

sitedisorders Oedema

peripheral 1

Fatigue

Investigations Weight

increased 1

Endocrine

disorders Inappropriate

antidiuretic

hormone

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hasbeenreported.

6.CasesofsuicidalideationandsuicidalbehaviourshavebeenreportedduringMirtazapinetherapyorearlyafter

treatmentdiscontinuation(seesection4.4).

Inlaboratoryevaluationsinclinicaltrialstransientincreasesintransaminasesandgamma-glutamyltransferasehave

beenobserved(howeverassociatedadverseeventshavenotbeenreportedstatisticallysignificantlymorefrequently

withBexmirtthanwithplacebo).

4.9Overdose

PresentexperienceconcerningoverdosewithBexmirtaloneindicatesthatsymptomsareusuallymild.Depressionof

thecentralnervoussystemwithdisorientationandprolongedsedationhasbeenreported,togetherwithtachycardiaand

mildhyper-orhypotension.However,thereisapossibilityofmoreseriousoutcomes(includingfatalities)atdosages

muchhigherthanthetherapeuticdose,especiallywithmixedoverdosages.

Casesofoverdoseshouldbetreatedbygastriclavagewithappropriatesymptomaticandsupportivetherapyforvital

functions.Activatedcharcoalorgastriclavageshouldalsobeconsidered.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:otherantidepressantATCcode:NO6AX11.

Mirtazapineisacentrallyactivepresynaptic

-antagonist,whichincreasescentralnoradrenergicandserotonergic

neurotransmission.Theenhancementofserotonergicneurotransmissionisspecificallymediatedvia5-HT

receptors,

because5-HT

and5-HT

receptorsareblockedbymirtazapine.Bothenantiomersofmirtazapinearepresumedto

contributetotheantidepressantactivity,theS(+)enantiomerbyblocking

and5-HT

receptorsandtheR(-)

enantiomerbyblocking5-HT

receptors.

ThehistamineH

-antagonisticactivityofmirtazapineisresponsibleforitssedativeproperties.Ithaspracticallyno

anticholinergicactivityand,attherapeuticdoses,haspracticallynoeffectonthecardiovascularsystem.

5.2Pharmacokineticproperties

AfteroraladministrationofBexmirt,theactiveconstituentmirtazapineisrapidlyandwellabsorbed(bioavailability ≈

50%),reachingpeakplasmalevelsafterabout2hours.Bindingofmirtazapinetoplasmaproteinsisapprox.85%.The

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

shorterhalf-liveshavebeenseeninyoungmen.

Thehalf-lifeofeliminationissufficienttojustifyonce-a-daydosing.Steadystateisreachedafter3-4days,afterwhich

thereisnofurtheraccumulation.Mirtazapinedisplayslinearpharmacokineticswithintherecommendeddoserange.

Foodintakehasnoinfluenceonthepharmacokineticsofmirtazapine.

Mirtazapineisextensivelymetabolizedandeliminatedviatheurineandfaeceswithinafewdays.Majorpathwaysof

biotransformationaredemethylationandoxidation,followedbyconjugation.Invitrodatafromhumanliver

microsomesindicatethatcytochromeP450enzymesCYP2D6andCYP1A2areinvolvedintheformationofthe8-

hydroxymetaboliteofmirtazapine,whereasCYP3A4isconsideredtoberesponsiblefortheformationoftheN-

demethylandN-oxidemetabolites.Thedemethylmetaboliteispharmacologicallyactiveandappearstohavethesame

pharmacokineticprofileastheparentcompound.

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5.3Preclinicalsafetydata

Preclinicaldatarevealnospecialhazardforhumansbasedonconventionalstudiesofsafetypharmacology,repeated

dosetoxicity,carcinogenicityorgenotoxicity.Inreproductivetoxicitystudiesinratsandrabbitsnoteratogeniceffects

wereobserved.Attwo-foldsystemicexposurecomparedtomaximumhumantherapeuticexposure,therewasan

increaseinpost-implantationloss,decreaseinpupbirthweights,andreductioninpupsurvivalduringthefirstthree

daysoflactationinrats.

MirtazapinewasnotgenotoxicinaseriesoftestsforgenemutationandchromosomalandDNAdamage.Thyroid

glandtumoursfoundinaratcarcinogenicitystudyandhepatocellularneoplasmsfoundinamousecarcinogenicity

studyareconsideredtobespecies-specific,non-genotoxicresponsesassociatedwithlong-termtreatmentwithhigh

dosesofhepaticenzymeinducers.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Mannitol(E421)

Microcrystallinecellulose

Magnesiumcarbonate

Hydroxypropylcelluloselowsubstituted

Crospovidone

Silicacolloidalanhydrous

L-Methionine

Microcrystallinecelluloseandguargum

Aspartame(E951)

Magnesiumstearate

Orangeflavoursilesia(Naturalflavouringingredients,maltodextrin,gumarabicandtriacetin(E1518))

6.2Incompatibilities

Notapplicable

6.3ShelfLife

2years.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.

Storeinoriginalpackageinordertoprotectfrommoisture.

6.5Natureandcontentsofcontainer

Plasticcontainer(PP-containerorHDPE)withdesiccant.

Al-OPA-PVC/Alpushthroughblisterpacks.

-Peel-to-openblisters:Childresistant,peeltoopen,rigidstrip,formedfromalaminateofaluminiumfoilandplastic

filmssealedtoapaper-basedlaminateofaluminiumfoilcoatedwithaheatseallacquer.Tabletpocketsinthestripare

separatedbyperforations.

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-Packssizes:6,18,30,48,90,96and180tablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Inordertopreventcrushingthetablet,donotpushagainstthetabletpocket(Figure1).Eachstripcontainssixtablet

pockets,whichareseparatedbyperforations.Tearoffonetabletpocketalongthedottedlines(Figure2).

Carefullypeelofftheliddingfoil,startinginthecornerindicatedbythearrow(Figures3and4).

Takeoutthetabletwithdryhandsandplaceitonthetongue(Figure5).Thetabletwillrapidlydisintegrateandcanbe

swallowedwithorwithoutwater.

Fig.1

Fig.2

Fig.3

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Fig.5

7MARKETINGAUTHORISATIONHOLDER

ErghaHealthcareLtd

Damastown

Mulhuddart

Dublin15

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA966/17/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:14 th

August2009

10DATEOFREVISIONOFTHETEXT

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