EFEXOR XL

Main information

  • Trade name:
  • EFEXOR XL
  • Dosage:
  • 150 Milligram
  • Pharmaceutical form:
  • Prolonged Release Capsules
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • EFEXOR XL
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1659/004/002
  • Authorization date:
  • 19-11-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

EfexorXL150mgProlonged-releasecapsules,hard

2QUALITATIVEANDQUANTITATIVECOMPOSITION

EachEfexorXL150mgprolonged-releasehardcapsulecontains150mgofvenlafaxineasvenlafaxinehydrochloride.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Prolonged-releasecapsule,hard

ProductimportedfromtheUnitedKingdom:

Opaquedarkorangecapsulesprintedinwhitewith‘W’and’150’.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofmajordepressiveepisodes.

Forpreventionofrecurrenceofmajordepressiveepisodes.

Treatmentofgeneralisedanxietydisorder.

Treatmentofsocialanxietydisorder.

Treatmentofpanicdisorder,withorwithoutagoraphobia.

4.2Posologyandmethodofadministration

Majordepressiveepisodes

Therecommendedstartingdoseforprolonged-releasevenlafaxineis75mggivenoncedaily.Patientsnotresponding

totheinitial75mg/daydosemaybenefitfromdoseincreasesuptoamaximumdoseof375mg/day.Dosageincreases

canbemadeatintervalsof2weeksormore.Ifclinicallywarrantedduetosymptomseverity,doseincreasescanbe

madeatmorefrequentintervals,butnotlessthan4days.

Becauseoftheriskofdose-relatedadverseeffects,doseincrementsshouldbemadeonlyafteraclinicalevaluation(see

section4.4).Thelowesteffectivedoseshouldbemaintained.

Patientsshouldbetreatedforasufficientperiodoftime,usuallyseveralmonthsorlonger.Treatmentshouldbe

reassessedregularlyonacase-by-casebasis.Longer-termtreatmentmayalsobeappropriateforpreventionof

recurrenceofmajordepressiveepisodes(MDE).Inmostofthecases,therecommendeddoseinpreventionof

recurrenceofMDEisthesameastheoneusedduringthecurrentepisode.

Antidepressivemedicinalproductsshouldcontinueforatleastsixmonthsfollowingremission.

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Therecommendedstartingdoseforprolonged-releasevenlafaxineis75mggivenoncedaily.Patientsnotresponding

totheinitial75mg/daydosemaybenefitfromdoseincreasesuptoamaximumdoseof225mg/day.Dosageincreases

canbemadeatintervalsof2weeksormore.

Becauseoftheriskofdose-relatedadverseeffects,doseincrementsshouldbemadeonlyafteraclinicalevaluation(see

section4.4).Thelowesteffectivedoseshouldbemaintained.

Patientsshouldbetreatedforasufficientperiodoftime,usuallyseveralmonthsorlonger.Treatmentshouldbe

reassessedregularly,onacase-by-casebasis.

Socialanxietydisorder

Therecommendeddoseforprolonged-releasevenlafaxineis75mggivenoncedaily.Thereisnoevidencethathigher

dosesconferanyadditionalbenefit.

However,inindividualpatientsnotrespondingtotheinitial75mg/day,increasesuptoamaximumdoseof

225mg/daymaybeconsidered.Dosageincreasescanbemadeatintervalsof2weeksormore.

Becauseoftheriskofdose-relatedadverseeffects,doseincrementsshouldbemadeonlyafteraclinicalevaluation(see

section4.4).Thelowesteffectivedoseshouldbemaintained.

Patientsshouldbetreatedforasufficientperiodoftime,usuallyseveralmonthsorlonger.Treatmentshouldbe

reassessedregularly,onacase-by-casebasis.

Panicdisorder

Itisrecommendedthatadoseof37.5mg/dayofprolonged-releasevenlafaxinebeusedfor7days.Dosageshouldthen

beincreasedto75mg/day.Patientsnotrespondingtothe75mg/daydosemaybenefitfromdoseincreasesuptoa

maximumdoseof225mg/day.Dosageincreasescanbemadeatintervalsof2weeksormore.

Becauseoftheriskofdose-relatedadverseeffects,doseincrementsshouldbemadeonlyafteraclinicalevaluation(see

section4.4).Thelowesteffectivedoseshouldbemaintained.

Patientsshouldbetreatedforasufficientperiodoftime,usuallyseveralmonthsorlonger.Treatmentshouldbe

reassessedregularly,onacase-by-casebasis.

Useinelderlypatients

Nospecificdoseadjustmentsofvenlafaxineareconsiderednecessarybasedonpatientagealone.However,caution

shouldbeexercisedintreatingtheelderly(e.g.,duetothepossibilityofrenalimpairment,thepotentialforchangesin

neurotransmittersensitivityandaffinityoccurringwithaging).Thelowesteffectivedoseshouldalwaysbeused,and

patientsshouldbecarefullymonitoredwhenanincreaseinthedoseisrequired.

Useinchildrenandadolescentsundertheageof18years

Venlafaxineisnotrecommendedforuseinchildrenandadolescents.

Controlledclinicalstudiesinchildrenandadolescentswithmajordepressivedisorderfailedtodemonstrateefficacy

anddonotsupporttheuseofvenlafaxineinthesepatients(seesections4.4and4.8).

Theefficacyandsafetyofvenlafaxineforotherindicationsinchildrenandadolescentsundertheageof18havenot

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Useinpatientswithhepaticimpairment

Inpatientswithmildandmoderatehepaticimpairment,ingenerala50%dosereductionshouldbeconsidered.

However,duetointer-individualvariabilityinclearance,individualisationofdosagemaybedesirable.

Therearelimiteddatainpatientswithseverehepaticimpairment.Cautionisadvised,andadosereductionbymore

than50%shouldbeconsidered.Thepotentialbenefitshouldbeweighedagainsttheriskinthetreatmentofpatients

withseverehepaticimpairment.

Useinpatientswithrenalimpairment

Althoughnochangeindosageisnecessaryforpatientswithglomerularfiltrationrate(GFR)between

-70ml/minute,cautionisadvised.Forpatientsthatrequirehaemodialysisandinpatientswithsevererenal

impairment(GFR<30ml/min),thedoseshouldbereducedby50%.Becauseofinter -individualvariabilityin

clearanceinthesepatients,individualisationofdosagemaybedesirable.

Withdrawalsymptomsseenondiscontinuationofvenlafaxine

Abruptdiscontinuationshouldbeavoided.Whenstoppingtreatmentwithvenlafaxine,thedoseshouldbegradually

reducedoveraperiodofatleastonetotwoweeksinordertoreducetheriskofwithdrawalreactions(seesections4.4

and4.8).Ifintolerablesymptomsoccurfollowingadecreaseinthedoseorupondiscontinuationoftreatment,then

resumingthepreviouslyprescribeddosemaybeconsidered.Subsequently,thephysicianmaycontinuedecreasingthe

dose,butatamoregradualrate.

Fororaluse.

Itisrecommendedthatvenlafaxineprolonged -releasecapsulesbetakenwithfood,atapproximatelythesametime

eachday.Capsulesmustbeswallowedwholewithfluidandnotdivided,crushed,chewed,ordissolved.

Patientstreatedwithvenlafaxineimmediate -releasetabletsmaybeswitchedtovenlafaxineprolonged-releasecapsules

atthenearestequivalentdailydosage.Forexample,venlafaxineimmediate -releasetablets37.5mgtwicedailymaybe

switchedtovenlafaxineprolonged -releasecapsules75mgoncedaily.Individualdosageadjustmentsmaybe

necessary.

Venlafaxineprolonged -releasecapsulescontainspheroids,whichreleasetheactivesubstanceslowlyintothedigestive

tract.Theinsolubleportionofthesespheroidsiseliminatedandmaybeseeninfaeces.

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients.

Concomitanttreatmentwithirreversiblemonoamineoxidaseinhibitors(MAOIs)iscontraindicatedduetotheriskof

serotoninsyndromewithsymptomssuchasagitation,tremorandhyperthermia.Venlafaxinemustnotbeinitiatedforat

least14daysafterdiscontinuationoftreatmentwithanirreversibleMAOI.

Venlafaxinemustbediscontinuedforatleast7daysbeforestartingtreatmentwithanirreversibleMAOI(seesections

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4.4Specialwarningsandprecautionsforuse

Suicide/suicidalthoughtsorclinicalworsening

Depressionisassociatedwithanincreasedriskofsuicidalthoughts,selfharmandsuicide(suicide-relatedevents).

Thisriskpersistsuntilsignificantremissionoccurs.Asimprovementsmaynotoccurduringthefirstfewweeksor

moreoftreatment,patientsshouldbecloselymonitoreduntilsuchimprovementoccurs.Itisgeneralclinicalexperience

thattheriskofsuicidemayincreaseintheearlystagesofrecovery.

Otherpsychiatricconditionsforwhichvenlafaxineisprescribedcanalsobeassociatedwithanincreasedriskof

suicide-relatedevents.Inaddition,theseconditionsmaybeco-morbidwithmajordepressivedisorder.Thesame

precautionsobservedwhentreatingpatientswithmajordepressivedisordershouldthereforebeobservedwhentreating

patientswithotherpsychiatricdisorders.

Patientswithahistoryofsuicide-relatedevents,orthoseexhibitingasignificantdegreeofsuicidalideationpriorto

commencementoftreatmentareknowntobeatgreaterriskofsuicidalthoughtsorsuicideattempts,andshouldreceive

carefulmonitoringduringtreatment.Ameta-analysisofplacebo-controlledclinicaltrialsofantidepressantdrugsin

adultpatientswithpsychiatricdisordersshowedanincreasedriskofsuicidalbehaviourwithantidepressantscompared

toplaceboinpatientslessthan25yearsold.

Closesupervisionofpatientsandinparticularthoseathighriskshouldaccompanydrugtherapyespeciallyinearly

treatmentandfollowingdosechanges.Patients(andcaregiversofpatients)shouldbealertedabouttheneedtomonitor

foranyclinicalworsening,suicidalbehavioursofthoughtsandunusualchangesinbehaviourandtoseekmedical

adviceimmediatelyifthesesymptomspresent.

Useinchildrenandadolescentsunder18yearsofage

Venlafaxineshouldnotbeusedinthetreatmentofchildrenandadolescentsundertheageof18years.

Suicide-relatedbehaviours(suicideattemptandsuicidalthoughts)andhostility(predominantlyaggression,

oppositionalbehaviourandanger)weremorefrequentlyobservedinclinicaltrialsamongchildrenandadolescents

treatedwithantidepressantscomparedtothosetreatedwithplacebo.If,basedonclinicalneed,adecisiontotreatis

neverthelesstaken,thepatientshouldbecarefullymonitoredfortheappearanceofsuicidalsymptoms.Inaddition,

long-termsafetydatainchildrenandadolescentsconcerninggrowth,maturationandcognitiveandbehavioural

developmentarelacking.

Serotoninsyndrome

Aswithotherserotonergicagents,thedevelopmentofapotentiallylife-threateningserotonin-syndromeorNeuroleptic

MalignantSyndrome(NMS)-likereactions,mayoccurwithvenlafaxinetreatment,particularlywithconcomitantuseof

otherserotonergicagents(includingSSRIs,SNRIsandtriptans),withagentsthatimpairmetabolismofserotoninsuch

asMAO-inhibitors,orwithantipsychoticsorotherdopamineantagonists(seesections4.3and4.5).

Serotoninsyndromesymptomsmayincludementalstatuschanges(e.g.,agitation,hallucinations,coma),autonomic

instability(e.g.,tachycardia,labilebloodpressure,hyperthermia),neuromuscularaberrations(e.g.,hyperreflexia,

incoordination)and/orgastrointestinalsymptoms(e.g.,nausea,vomiting,diarrhoea).Serotoninsyndromeinitsmost

severeform,canresembleNMS,whichincludeshyperthermia,musclerigidity,autonomicinstabilitywithpossible

rapidfluctuationofvitalsignsandmentalstatuschanges.

Ifconcomitanttreatmentwithvenlafaxineandotheragentsthatmayaffecttheserotonergicand/ordopaminergic

neurotransmittersystemsisclinicallywarranted,carefulobservationofthepatientisadvised,particularlyduring

treatmentinitiationanddoseincreases.

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Narrow-angleglaucoma

Mydriasismayoccurinassociationwithvenlafaxine.Itisrecommendedthatpatientswithraisedintraocularpressure

orpatientsatriskforacutenarrow-angleglaucoma(angle-closureglaucoma)becloselymonitored.

Bloodpressure

Dose-relatedincreasesinbloodpressurehavebeencommonlyreportedwithvenlafaxine.Insomecases,severely

elevatedbloodpressurerequiringimmediatetreatmenthasbeenreportedinpost-marketingexperience.Allpatients

shouldbecarefullyscreenedforhighbloodpressureandpre-existinghypertensionshouldbecontrolledbefore

initiationoftreatment.Bloodpressureshouldbereviewedperiodically,afterinitiationoftreatmentandafterdose

increases.Cautionshouldbeexercisedinpatientswhoseunderlyingconditionsmightbecompromisedbyincreasesin

bloodpressure,e.g.,thosewithimpairedcardiacfunction.

Heartrate

Increasesinheartratecanoccur,particularlywithhigherdoses.Cautionshouldbeexercisedinpatientswhose

underlyingconditionsmightbecompromisedbyincreasesinheartrate.

Cardiacdiseaseandriskofarrhythmia

Venlafaxinehasnotbeenevaluatedinpatientswitharecenthistoryofmyocardialinfarctionorunstableheartdisease.

Therefore,itshouldbeusedwithcautioninthesepatients.

Inpost-marketingexperience,fatalcardiacarrhythmiashavebeenreportedwiththeuseofvenlafaxine,especiallyin

overdose.Thebalanceofrisksandbenefitsshouldbeconsideredbeforeprescribingvenlafaxinetopatientsathighrisk

ofseriouscardiacarrhythmia.

Convulsions

Convulsionsmayoccurwithvenlafaxinetherapy.Aswithallantidepressants,venlafaxineshouldbeintroducedwith

cautioninpatientswithahistoryofconvulsions,andconcernedpatientsshouldbecloselymonitored.Treatment

shouldbediscontinuedinanypatientwhodevelopsseizures.

Hyponatraemia

Casesofhyponatraemiaand/ortheSyndromeofInappropriateAntidiureticHormone(SIADH)secretionmayoccur

withvenlafaxine.Thishasmostfrequentlybeenreportedinvolume-depletedordehydratedpatients.Elderlypatients,

patientstakingdiuretics,andpatientswhoareotherwisevolume-depletedmaybeatgreaterriskforthisevent.

Abnormalbleeding

Medicinalproductsthatinhibitserotoninuptakemayleadtoreducedplateletfunction.Theriskofskinandmucous

membranebleeding,includinggastrointestinalhaemorrhage,maybeincreasedinpatientstakingvenlafaxine.Aswith

otherserotonin-reuptakeinhibitors,venlafaxineshouldbeusedcautiouslyinpatientspredisposedtobleeding,

includingpatientsonanticoagulantsandplateletinhibitors.

Serumcholesterol

Clinicallyrelevantincreasesinserumcholesterolwererecordedin5.3%ofvenlafaxine-treatedpatientsand0.0%of

placebo-treatedpatientstreatedforatleast3monthsinplacebo-controlledclinicaltrials.Measurementofserum

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Co-administrationwithweightlossagents

Thesafetyandefficacyofvenlafaxinetherapyincombinationwithweightlossagents,includingphentermine,havenot

beenestablished.Co-administrationofvenlafaxineandweightlossagentsisnotrecommended.Venlafaxineisnot

indicatedforweightlossaloneorincombinationwithotherproducts.

Mania/hypomania

Mania/hypomaniamayoccurinasmallproportionofpatientswithmooddisorderswhohavereceivedantidepressants,

includingvenlafaxine.Aswithotherantidepressants,venlafaxineshouldbeusedcautiouslyinpatientswithahistory

orfamilyhistoryofbipolardisorder.

Aggression

Aggressionmayoccurinasmallnumberofpatientswhohavereceivedantidepressants,includingvenlafaxine.This

hasbeenreportedunderinitiation,dosechangesanddiscontinuationoftreatment.

Aswithotherantidepressants,venlafaxineshouldbeusedcautiouslyinpatientswithahistoryofaggression.

Discontinuationoftreatment

Withdrawalsymptoms,whentreatmentisdiscontinued,arecommon,particularlyifdiscontinuationisabrupt(see

section4.8).Inclinicaltrials,adverseeventsseenontreatmentdiscontinuation(taperingandpost-tapering)occurredin

approximately31%ofpatientstreatedwithvenlafaxineand17%ofpatientstakingplacebo.

Theriskofwithdrawalsymptomsmaybedependentonseveralfactors,includingthedurationanddoseoftherapyand

therateofdosereduction.Dizziness,sensorydisturbances(includingparaesthesia),sleepdisturbances(including

insomniaandintensedreams),agitationoranxiety,nauseaand/orvomiting,tremorandheadachearethemost

commonlyreportedreactions.Generally,thesesymptomsaremildtomoderate;however,insomepatientstheymaybe

severeinintensity.Theyusuallyoccurwithinthefirstfewdaysofdiscontinuingtreatment,buttherehavebeenvery

rarereportsofsuchsymptomsinpatientswhohaveinadvertentlymissedadose.Generally,thesesymptomsareself-

limitingandusuallyresolvewithin2weeks,thoughinsomeindividualstheymaybeprolonged(2-3monthsormore).

Itisthereforeadvisedthatvenlafaxineshouldbegraduallytaperedwhendiscontinuingtreatmentoveraperiodof

severalweeksormonths,accordingtothepatient’sneeds(seesection4.2).

Akathisia/psychomotorrestlessness

Theuseofvenlafaxinehasbeenassociatedwiththedevelopmentofakathisia,characterisedbyasubjectively

unpleasantordistressingrestlessnessandneedtomoveoftenaccompaniedbyaninabilitytositorstandstill.Thisis

mostlikelytooccurwithinthefirstfewweeksoftreatment.Inpatientswhodevelopthesesymptoms,increasingthe

dosemaybedetrimental.

Drymouth

Drymouthisreportedin10%ofpatientstreatedwithvenlafaxine.Thismayincreasetheriskofcaries,andpatients

shouldbeadvisedupontheimportanceofdentalhygiene

Diabetes

Inpatientswithdiabetes,treatmentwithanSSRIorvenlafaxinemayalterglycaemiccontrol.Insulinand/ororal

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

MonoamineOxidaseInhibitors(MAOI)

Irreversiblenon-selectiveMAOIs

Venlafaxinemustnotbeusedincombinationwithirreversiblenon-selectiveMAOIs.Venlafaxinemustnotbeinitiated

foratleast14daysafterdiscontinuationoftreatmentwithanirreversiblenon-selectiveMAOI.Venlafaxinemustbe

discontinuedforatleast7daysbeforestartingtreatmentwithanirreversiblenon-selectiveMAOI(seesections4.3and

4.4).

Reversible,selectiveMAO-Ainhibitor(moclobemide)

Duetotheriskofserotoninsyndrome,thecombinationofvenlafaxinewithareversibleandselectiveMAOI,suchas

moclobemide,isnotrecommended.FollowingtreatmentwithareversibleMAO-inhibitor,ashorterwithdrawalperiod

than14daysmaybeusedbeforeinitiationofvenlafaxinetreatment.Itisrecommendedthatvenlafaxineshouldbe

discontinuedforatleast7daysbeforestartingtreatmentwithareversibleMAOI(seesection4.4).

Reversible,non-selectiveMAOI(linezolid)

Theantibioticlinezolidisaweakreversibleandnon-selectiveMAOIandshouldnotbegiventopatientstreatedwith

venlafaxine(seesection4.4).

SevereadversereactionshavebeenreportedinpatientswhohaverecentlybeendiscontinuedfromanMAOIand

startedonvenlafaxineorhaverecentlyhadvenlafaxinetherapydiscontinuedpriortoinitiationofanMAOI.These

reactionshaveincludedtremor,myoclonus,diaphoresis,nausea,vomiting,flushing,dizziness,andhyperthermiawith

featuresresemblingneurolepticmalignantsyndrome,seizures,anddeath.

Serotoninsyndrome

Aswithotherserotonergicagents,serotoninsyndromeapotentiallylife-threateningcondition,mayoccurwith

venlafaxinetreatment,particularlywithconcomitantuseofotheragentsthatmayaffecttheserotonergic

neurotransmittersystem(includingtriptans,SSRIs,SNRIs,lithium,sibutramine,tramadol,orSt.John'swort

[Hypericumperforatum]),withmedicinalagentswhichimpairmetabolismofserotonin(includingMAOIs),orwith

serotoninprecursors(suchastryptophansupplements).

IfconcomitanttreatmentofvenlafaxinewithanSSRI,anSNRIoraserotoninreceptoragonist(triptan)isclinically

warranted,carefulobservationofthepatientisadvised,particularlyduringtreatmentinitiationanddoseincreases.The

concomitantuseofvenlafaxinewithserotoninprecursors(suchastryptophansupplements)isnotrecommended(see

section4.4).

CNS-activesubstances

TheriskofusingvenlafaxineincombinationwithotherCNS-activesubstanceshasnotbeensystematicallyevaluated.

Consequently,cautionisadvisedwhenvenlafaxineistakenincombinationwithotherCNS-activesubstances.

Ethanol

Venlafaxinehasbeenshownnottoincreasetheimpairmentofmentalandmotorskillscausedbyethanol.However,as

withallCNS-activesubstances,patientsshouldbeadvisedtoavoidalcoholconsumption.

Effectofothermedicinalproductsonvenlafaxine

Ketoconazole(CYP3A4inhibitor)

ApharmacokineticstudywithketoconazoleinCYP2D6extensive(EM)andpoormetabolisers(PM)resultedinhigher

AUCofvenlafaxine(70%and21%inCYP2D6PMandEMsubjects,respectively)andO-desmethylvenlafaxine(33%

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ConcomitantuseofCYP3A4inhibitors(e.g.,atazanavir,clarithromycin,indinavir,itraconazole,voriconazole,

posaconazole,ketoconazole,nelfinavir,ritonavir,saquinavir,telithromycin)andvenlafaxinemayincreaselevelsof

venlafaxineandO-desmethylvenlafaxine.Therefore,cautionisadvisedifapatient’stherapyincludesaCYP3A4

inhibitorandvenlafaxineconcomitantly.

Effectofvenlafaxineonothermedicinalproducts

Lithium

Serotoninsyndromemayoccurwiththeconcomitantuseofvenlafaxineandlithium(seeSerotoninsyndrome).

Diazepam

Venlafaxinehasnoeffectsonthepharmacokineticsandpharmacodynamicsofdiazepamanditsactivemetabolite,

desmethyldiazepam.DiazepamdoesnotappeartoaffectthepharmacokineticsofeithervenlafaxineorO-

desmethylvenlafaxine.Itisunknownwhetherapharmacokineticand/orpharmacodynamicinteractionwithother

benzodiazepinesexists.

Imipramine

Venlafaxinedidnotaffectthepharmacokineticsofimipramineand2-OH-imipramine.Therewasadose-dependent

increaseof2-OH-desipramineAUCby2.5to4.5-foldwhenvenlafaxine75mgto150mgdailywasadministered.

ImipraminedidnotaffectthepharmacokineticsofvenlafaxineandO-desmethylvenlafaxine.Theclinicalsignificance

ofthisinteractionisunknown.Cautionshouldbeexercisedwithco-administrationofvenlafaxineandimipramine.

Haloperidol

Apharmacokineticstudywithhaloperidolhasshowna42%decreaseintotaloralclearance,a70%increaseinAUC,

an88%increaseinC

,butnochangeinhalf-lifeforhaloperidol.Thisshouldbetakenintoaccountinpatients

treatedwithhaloperidolandvenlafaxineconcomitantly.Theclinicalsignificanceofthisinteractionisunknown.

Risperidone

VenlafaxineincreasedtherisperidoneAUCby50%,butdidnotsignificantlyalterthepharmacokineticprofileofthe

totalactivemoiety(risperidoneplus9-hydroxyrisperidone).Theclinicalsignificanceofthisinteractionisunknown.

Metoprolol

Concomitantadministrationofvenlafaxineandmetoprololtohealthyvolunteersinapharmacokineticinteraction

studyforbothmedicinalproductsresultedinanincreaseofplasmaconcentrationsofmetoprololbyapproximately30-

40%withoutalteringtheplasmaconcentrationsofitsactivemetabolite,

-hydroxymetoprolol.Theclinicalrelevanceofthisfindinginhypertensivepatientsisunknown.

Metoprololdidnotalterthepharmacokineticprofileofvenlafaxineoritsactivemetabolite,

O-desmethylvenlafaxine.Cautionshouldbeexercisedwithco-administrationofvenlafaxineandmetoprolol.

Indinavir

Apharmacokineticstudywithindinavirhasshowna28%decreaseinAUCanda36%decreaseinCmaxforindinavir.

IndinavirdidnotaffectthepharmacokineticsofvenlafaxineandO-desmethylvenlafaxine.Theclinicalsignificanceof

thisinteractionisunknown.

4.6Fertility,pregnancyandlactation

Pregnancy

Therearenoadequatedatafromtheuseofvenlafaxineinpregnantwomen.

Studiesinanimalshaveshownreproductivetoxicity(seesection5.3).Thepotentialriskforhumansisunknown.

Venlafaxinemustonlybeadministeredtopregnantwomeniftheexpectedbenefitsoutweighanypossiblerisk.

Aswithotherserotoninreuptakeinhibitors(SSRIs/SNRIs),discontinuationsymptomsmayoccurinthenewbornsif

venlafaxineisuseduntilorshortlybeforebirth.Somenewbornsexposedtovenlafaxinelateinthethirdtrimesterhave

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Suchcomplicationscanariseimmediatelyupondelivery.

EpidemiologicaldatahavesuggestedthattheuseofSSRIsinpregnancy,particularlyinlatepregnancy,mayincrease

theriskofpersistentpulmonaryhypertensioninthenewborn(PPHN).Althoughnostudieshaveinvestigatedan

associationofPPHNtoSNRItreatment,thispotentialriskcannotberuledoutwithvenlafaxinetakingintoaccountthe

relatedmechanismofaction(inhibitionofthere-uptakeofserotonin).

ThefollowingsymptomsmaybeobservedinneonatesifthemotherhasusedanSSRI/SNRIlateinpregnancy:

irritability,tremor,hypotonia,persistentcrying,anddifficultyinsuckingorinsleeping.Thesesymptomsmaybedueto

eitherserotonergiceffectsorexposuresymptoms.Inthemajorityofcases,thesecomplicationsareobserved

immediatelyorwithin24hoursafterpartus.

Lactation

Venlafaxineanditsactivemetabolite,O-desmethylvenlafaxine,areexcretedinbreastmilk.Arisktothesucklingchild

cannotbeexcluded.Therefore,adecisiontocontinue/discontinuebreast-feedingortocontinue/discontinuetherapy

withEfexorXLshouldbemade,takingintoaccountthebenefitofbreast-feedingtothechildandthebenefitof

EfexorXLtherapytothewoman.

4.7Effectsonabilitytodriveandusemachines

Anypsychoactivemedicinalproductmayimpairjudgment,thinking,andmotorskills.Therefore,anypatientreceiving

venlafaxineshouldbecautionedabouttheirabilitytodriveoroperatehazardousmachinery.

4.8Undesirableeffects

Themostcommonly(>1/10)reportedadversereactionsinclinicalstudieswerenausea,drymouth,headacheand

sweating(includingnightsweats).

Adversereactionsarelistedbelowbysystemorganclassandfrequency.

Frequenciesaredefinedas:verycommon(>1/10),common(>1/100to<1/10),uncommon(>1/1,000to<1/100),rare

(>1/10,000to<1/1,000),notknown(cannotbeestimatedfromtheavailabledata).

BodySystem Very

Common Common Uncommon Rare NotKnown

Haematological/

Lymphatic Ecchymosis,

Gastrointestinal

haemorrhage Mucous

membrane

bleeding,

Prolonged

bleedingtime,

Thrombocytopaenia,

Blooddyscrasias,

(including

agranulocytosis,

aplasticanaemia,

neutropaeniaand

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Metabolic/

Nutritional Serumcholesterol

increased,Weight

loss Weightgain Abnormalliver

functiontests,

Hyponatraemia,

Hepatitis,

Syndromeof

Inappropriate

Antidiuretic

Hormone

Secretion

(SIADH),

Prolactin

increased

Nervous Drymouth

(10.0%),

Headache

(30.3%)* Abnormaldreams,

Decreasedlibido,

Dizziness,

Increasedmuscle

tonus

(hypertonia),

Insomnia,

Nervousness,

Paresthesia,

Sedation,Tremor,

Confusion,

Apathy,

Hallucinations,

Myoclonus,

Agitation,

Impaired

coordinationand

balance Akathisia/

Psychomotor

restlessness,

Convulsion,

Manicreaction Neuroleptic

Malignant

Syndrome(NMS),

Serotonergic

syndrome,

Delirium,

Extrapyramidal

reactions

(including

dystoniaand

dyskinaesia),

tardive

dyskinaesia,

Suicidalideation

behaviours**,

Vertigo,

Aggression***

Special

Senses Abnormalityof

accommodation,

Mydriasis,Visual

disturbance Alteredtaste

sensation,

Tinnitus Angle-closure

glaucoma

Cardiovascular Hypertension,

Vasodilatation

(mostlyhot

flashes/flushes),

Palpitations Postural

hypotension,

Syncope,

Tachycardia Hypotension,QT

prolongation,

Ventricular

fibrillation,

Ventricular

tachycardia

(includingtorsade

depointes)

Respiratory Yawning Pulmonary

eosinophilia

Digestive Nausea

(20.0%) Appetite

decreased

(anorexia),

Constipation,

Vomiting Bruxism,

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*Inpooledclinicaltrials,theincidenceofheadachewas30.3%withvenlafaxineversus31.3%withplacebo.

**Casesofsuicidalideationandsuicidalbehaviourshavebeenreportedduringvenlafaxinetherapyorearlyafter

treatmentdiscontinuation(seesection4.4).

Discontinuationofvenlafaxine(particularlywhenabrupt)commonlyleadstowithdrawalsymptoms.Dizziness,

sensorydisturbances(includingparaethesia),sleepdisturbances(includinginsomniaandintensedreams),agitationor

anxiety,nauseaand/orvomiting,tremor,vertigo,headacheandflusyndromearethemostcommonlyreported

reactions.Generally,theseeventsaremildtomoderateandareself-limiting;however,insomepatients,theymaybe

severeand/orprolonged.Itisthereforeadvisedthatwhenvenlafaxinetreatmentisnolongerrequired,gradual

discontinuationbydosetaperingshouldbecarriedout(seesections4.2and4.4).

Paediatricpatients

Ingeneral,theadversereactionprofileofvenlafaxine(inplacebo-controlledclinicaltrials)inchildrenandadolescents

(ages6to17)wassimilartothatseenforadults.Aswithadults,decreasedappetite,weightloss,increasedblood

pressure,andincreasedserumcholesterolwereobserved(seesection4.4).

Inpaediatricclinicaltrialstheadversereactionsuicidalideationwasobserved.Therewerealsoincreasedreportsof

Skin Sweating

(including

night

sweats)

[12.2%] Rash,Alopecia Erythema

multiforme,

Toxicepidermal

necrolysis,

Stevens-

Johnson

syndrome,

Pruritus,Urticaria

Musculoskeletal Rhabdomyolysis

Urogenital Abnormal

ejaculation/orgasm

(males),

Anorgasmia,

Erectile

dysfunction

(impotence),

Urination

impaired(mostly

hesitancy),

Menstrual

disorders

associatedwith

increased

bleeding

orincreased

irregularbleeding

(e.g.,

menorrhagia,

metrorrhagia),

Abnormal

orgasm

(females),

Urinary

retention Urinary

incontinence

Bodyasawhole Asthenia

(fatigue),

Chills Angioedema,

Photo-sensitivity

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Particularly,thefollowingadversereactionswereobservedinpaediatricpatients:abdominalpain,agitation,dyspepsia,

ecchymosis,epistaxis,andmyalgia.

4.9Overdose

Inpostmarketingexperience,overdosewithvenlafaxinewasreportedpredominantlyincombinationwithalcohol

and/orothermedicinalproducts.

Themostcommonlyreportedeventsinoverdoseincludetachycardia,changesinlevelofconsciousness(ranging

from somnolence to coma), mydriasis, convulsion, and vomiting.Other reported events include

electrocardiographicchanges(e.g.,prolongationofQTinterval,bundlebranchblock,QRSprolongation),

ventriculartachycardia,bradycardia,hypotension,vertigo,anddeath.

Publishedretrospectivestudiesreportthatvenlafaxine,overdosagemaybeassociatedwithanincreasedriskoffatal

outcomescomparedtothatobservedwithSSRIantidepressantproducts,butlowerthanthatfortricyclic

antidepressants.

Epidemiologicalstudieshaveshownthatvenlafaxine-treatedpatientshaveahigherburdenofsuicideriskfactors

thanSSRIpatients.Theextenttowhichthefindingofanincreasedriskoffataloutcomescanbeattributedtothe

toxicityofvenlafaxineinoverdosageasopposedtosomecharacteristicsofvenlafaxine-treatedpatientsisnotclear.

Prescriptionsofvenlafaxineshouldbewrittenforthesmallestquantityofdrugconsistentwithgoodpatient

management,inordertoreducetheriskofoverdose.

RecommendedTreatment

Generalsupportiveandsymptomaticmeasuresarerecommended;cardiacrhythmandvitalsignsmustbe

monitored.Whenthereisariskofaspiration,inductionofemesisisnotrecommended.

GastricLavagemaybeindicatedifperformedsoonafteringestionorinsymptomaticpatients.

Administrationofactivatedcharcoalmayalsolimitabsorptionoftheactivesubstance.

Forceddiuresis,dialysis,hemoperfusionandexchangetransfusionareunlikelytobeofbenefit.

Nospecificantidotesforvenlafaxineareknown

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Otherantidepressants-ATCcode:NO6AX16.

Themechanismofvenlafaxine'santidepressantactioninhumansisbelievedtobeassociatedwithitspotentiationof

neurotransmitteractivityinthecentralnervoussystem.Preclinicalstudieshaveshownthatvenlafaxineanditsmajor

metabolite,O -desmethylvenlafaxine(ODV),areinhibitorsofserotoninandnoradrenalinereuptake.Venlafaxinealso

weaklyinhibitsdopamineuptake.Venlafaxineanditsactivemetabolitereduce -adrenergicresponsivenessafterboth

acute(singledose)andchronicadministration.VenlafaxineandODVareverysimilarwithrespecttotheiroverall

actiononneurotransmitterreuptakeandreceptorbinding.

Venlafaxinehasvirtuallynoaffinityforratbrainmuscarinic,cholinergic,H

-histaminergicor

-adrenergicreceptors

invitro.Pharmacologicalactivityatthesereceptorsmayberelatedtovarioussideeffectsseenwithother

antidepressantmedicinalproducts,suchasanticholinergic,sedativeandcardiovascularsideeffects.

Venlafaxinedoesnotpossessmonoamineoxidase(MAO)inhibitoryactivity.

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Majordepressiveepisodes

Theefficacyofvenlafaxineimmediate-releaseasatreatmentformajordepressiveepisodeswasdemonstratedinfive

randomised,double -blind,placebo-controlled,short-termtrialsrangingfrom4to6weeksduration,fordosesupto

375mg/day.Theefficacyofvenlafaxineprolonged -releaseasatreatmentformajordepressiveepisodeswas

establishedintwoplacebo -controlled,short-termstudiesfor8and12weeksduration,whichincludedadoserangeof

75to225mg/day.

Inonelonger-termstudy,adultoutpatientswhohadrespondedduringan8 -weekopentrialonvenlafaxine

prolonged -release(75,150,or225mg)wererandomisedtocontinuationoftheirsamevenlafaxineprolonged-release

doseortoplacebo,forupto26weeksofobservationforrelapse.

Inasecondlonger-termstudy,theefficacyofvenlafaxineinpreventionofrecurrentdepressiveepisodesfora

-monthperiodwasestablishedinaplacebo-controlleddouble-blindclinicaltrialinadultoutpatientswithrecurrent

majordepressiveepisodeswhohadrespondedtovenlafaxinetreatment(100to200mg/day,onab.i.d.schedule)onthe

lastepisodeofdepression.

Generalisedanxietydisorder

Theefficacyofvenlafaxineprolonged -releasecapsulesasatreatmentforgeneralisedanxietydisorder(GAD)was

established in two 8 -week,placebo-controlled,fixed-dosestudies(75to225mg/day),one6-month,

placebo -controlled,fixed-dosestudy(75to225mg/day),andone6-month,placebo-controlled,flexible-dosestudy

(37.5,75,and150mg/day)inadultoutpatients.

Whiletherewasalsoevidenceforsuperiorityoverplaceboforthe37.5mg/daydose,thisdosewasnotasconsistently

effectiveasthehigherdoses.

Socialanxietydisorder

Theefficacyofvenlafaxineprolonged -releasecapsulesasatreatmentforsocialanxietydisorderwasestablishedin

fourdouble -blind,parallel-group,12-week,multi-center,placebo-controlled,flexible-dosestudiesandonedouble-

blind,parallel -group,6-month,placebo-controlled,fixed/flexible-dosestudyinadultoutpatients.Patientsreceived

dosesinarangeof75to225mg/day.Therewasnoevidenceforanygreatereffectivenessofthe150to225mg/day

groupcomparedtothe75mg/daygroupinthe6 -monthstudy.

Panicdisorder

Theefficacyofvenlafaxineprolonged -releasecapsulesasatreatmentforpanicdisorderwasestablishedintwo

double-blind,12-week,multi -center,placebo-controlledstudiesinadultoutpatientswithpanicdisorder,withor

withoutagoraphobia.Theinitialdoseinpanicdisorderstudieswas37.5mg/dayfor7days.Patientsthenreceivedfixed

dosesof75or150mg/dayinonestudyand75or225mg/dayintheotherstudy.

Efficacywasalsoestablishedinonelong -termdouble-blind,placebo-controlled,parallel-groupstudyofthe

long -termsafety,efficacy,andpreventionofrelapseinadultoutpatientswhorespondedtoopen-labeltreatment.

Patientscontinuedtoreceivethesamedoseofvenlafaxineprolonged -releasethattheyhadtakenattheendofthe

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5.2Pharmacokineticproperties

Venlafaxineisextensivelymetabolised,primarilytotheactivemetabolite,O-desmethylvenlafaxine(ODV).Mean±

SDplasmahalf-livesofvenlafaxineandODVare5±2hoursand11±2hours,respectively.Steady-stateconcentrations

ofvenlafaxineandODVareattainedwithin3daysoforalmultiple -dosetherapy.VenlafaxineandODVexhibitlinear

kineticsoverthedoserangeof75mgto450mg/day.

Absorption

Atleast92%ofvenlafaxineisabsorbedfollowingsingleoraldosesofimmediate-releasevenlafaxine.Absolute

bioavailabilityis40%to45%duetopresystemicmetabolism.Afterimmediate-releasevenlafaxineadministration,the

peakplasmaconcentrationsofvenlafaxineandODVoccurin2and3hours,respectively.Followingtheadministration

ofvenlafaxineprolonged-releasecapsules,peakplasmaconcentrationsofvenlafaxineandODVareattainedwithin5.5

hoursand9hours,respectively.Whenequaldailydosesofvenlafaxineareadministeredaseitheranimmediate-release

tabletorprolonged -releasecapsule,theprolonged-releasecapsuleprovidesaslowerrateofabsorption,butthesame

extentofabsorptioncomparedwiththeimmediate-releasetablet.Fooddoesnotaffectthebioavailabilityofvenlafaxine

andODV.

Distribution

VenlafaxineandODVareminimallyboundattherapeuticconcentrationstohumanplasmaproteins(27%and30%,

respectively).Thevolumeofdistributionforvenlafaxineatsteady-stateis4.4±1.6L/kgfollowingintravenous

administration.

Metabolism

Venlafaxineundergoesextensivehepaticmetabolism.Invitroandinvivostudiesindicatethatvenlafaxineis

biotransformedtoitsmajoractivemetabolite,ODV,byCYP2D6.Invitroandinvivostudiesindicatethatvenlafaxine

ismetabolisedtoaminor,lessactivemetabolite,N -desmethylvenlafaxine,byCYP3A4.Invitroandinvivostudies

indicatethatvenlafaxineisaweakinhibitorofCYP2D6.VenlafaxinedidnotinhibitCYP1A2,CYP2C9,orCYP3A4.

Elimination

Venlafaxineanditsmetabolitesareexcretedprimarilythroughthekidneys.Approximately87%ofavenlafaxinedose

isrecoveredintheurinewithin48hoursaseitherunchangedvenlafaxine(5%),unconjugatedODV(29%),conjugated

ODV(26%),orotherminorinactivemetabolites(27%).Mean±SDplasmasteady -stateclearancesofvenlafaxineand

ODVare1.3±0.6L/h/kgand0.4±0.2L/h/kg,respectively.

Specialpopulations

Ageandgender

SubjectageandgenderdonotsignificantlyaffectthepharmacokineticsofvenlafaxineandODV.

CYP2D6extensive/poormetabolisers

PlasmaconcentrationsofvenlafaxinearehigherinCYP2D6poormetabolisersthanextensivemetabolisers.Because

thetotalexposure(AUC)ofvenlafaxineandODVissimilarinpoorandextensivemetabolisers,thereisnoneedfor

differentvenlafaxinedosingregimensforthesetwogroups.

Patientswithhepaticimpairment

InChild-PughA(mildlyhepaticallyimpaired)andChild-PughB(moderatelyhepaticallyimpaired)subjects,

venlafaxineandODVhalf-liveswereprolongedcomparedtonormalsubjects.Theoralclearanceofbothvenlafaxine

andODVwasreduced.Alargedegreeofintersubjectvariabilitywasnoted.Therearelimiteddatainpatientswith

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Patientswithrenalimpairment

Indialysispatients,venlafaxineeliminationhalf-lifewasprolongedbyabout180%andclearancereducedbyabout

57%comparedtonormalsubjects,whileODVeliminationhalf-lifewasprolongedbyabout142%andclearance

reducedbyabout56%.Dosageadjustmentisnecessaryinpatientswithsevererenalimpairmentandinpatientsthat

requirehaemodialysis(seesection4.2).

5.3Preclinicalsafetydata

Studieswithvenlafaxineinratsandmicerevealednoevidenceofcarcinogenesis.Venlafaxinewasnotmutagenicina

widerangeofinvitroandinvivotests.

Animalstudiesregardingreproductivetoxicityhavefoundinratsadecreaseinpupweight,anincreaseinstillborn

pups,andanincreaseinpupdeathsduringthefirst5daysoflactation.Thecauseofthesedeathsisunknown.These

effectsoccurredat30mg/kg/day,4timesthehumandailydoseof375mgofvenlafaxine(onanmg/kgbasis).The

-effectdoseforthesefindingswas1.3timesthehumandose.Thepotentialriskforhumansisunknown.

ReducedfertilitywasobservedinastudyinwhichbothmaleandfemaleratswereexposedtoODV.Thisexposurewas

approximately1to2timesthatofahumanvenlafaxinedoseof375mg/day.Thehumanrelevanceofthisfindingis

unknown.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Microcrystallinecellulose

Ethylcellulose

Hypromellose

Gelatin

Redandyellowironoxides(E172)

Titaniumdioxide(E171)

PrintingInk

6.2Incompatibilities

Notapplicable

6.3Shelflife

Theshelf-lifeexpirydateofthisproductshallbethedateshownontheblisterandouterpackageoftheproductonthe

marketinthecountryoforigin.

6.4Specialprecautionsforstorage

Storeintheoriginalpackaging.Donotstoreabove25°C.

6.5Natureandcontentsofcontainer

Blisterpackcontaining28capsules.Inanover-labelledoutercarton.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

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7PARALLELPRODUCTAUTHORISATIONHOLDER

IPSHealthcareLimited

SterlingHouse

Oldham

Lancashire

OL99LY

UnitedKingdom

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1659/4/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:19 th

November2010

10DATEOFREVISIONOFTHETEXT

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