EFEXOR XL

Main information

  • Trade name:
  • EFEXOR XL
  • Dosage:
  • 75 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:
  • PPA1659/004/001
  • Authorization date:
  • 19-11-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

EfexorXL75mgProlonged-releasecapsules,hard

2QUALITATIVEANDQUANTITATIVECOMPOSITION

EachEfexorXL75mgprolonged-releasehardcapsulecontains75mgofvenlafaxineasvenlafaxinehydrochloride.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Prolonged-releasecapsule,hard

ProductimportedfromtheUnitedKingdom:

Opaquepeachcapsuleprintedinredwith‘W’and‘75’.

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.

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Generalisedanxietydisorder

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,increasesuptoamaximumdoseof225

mg/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)between30 -70

ml/minute,cautionisadvised.Forpatientsthatrequirehaemodialysisandinpatientswithsevererenalimpairment

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

patients,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.Individualdosageadjustmentsmaybenecessary.

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-feedingtothechildandthebenefitofEfexor

XLtherapytothewoman.

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 Mucousmembrane

bleeding,Prolonged

bleedingtime,

Thrombocytopaenia,

Blooddyscrasias,

(including

agranulocytosis,

aplasticanaemia,

neutropaeniaand

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Metabolic/

Nutritional Serumcholesterol

increased,Weight

loss Weightgain Abnormalliver

functiontests,

Hyponatraemia,

Hepatitis,Syndrome

ofInappropriate

Antidiuretic

HormoneSecretion

(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

coordination

andbalance Akathisia/

Psychomotor

restlessness,

Convulsion,

Manic

reaction Neuroleptic

Malignant

Syndrome(NMS),

Serotonergic

syndrome,Delirium,

Extrapyramidal

reactions(including

dystoniaand

dyskinaesia),tardive

dyskinaesia,

Suicidalideation

andbehaviours**,

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,

diarrhoea Pancreatitis

Skin Sweating

(including

night

sweats)

[12.2%] Rash,Alopecia Erythema

multiforme,

Toxicepidermal

necrolysis,Stevens-

Johnsonsyndrome,

Pruritus,Urticaria

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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

hostilityand,especiallyinmajordepressivedisorder,self-harm.

Particularly,thefollowingadversereactionswereobservedinpaediatricpatients:abdominalpain,agitation,dyspepsia,

ecchymosis,epistaxis,andmyalgia.

4.9Overdose

Inpostmarketingexperience,overdosewithvenlafaxinewasreportedpredominantlyincombinationwithalcohol

and/orothermedicinalproducts.

Themostcommonlyreportedeventsinoverdoseincludetachycardia,changesinlevelofconsciousness(ranging

fromsomnolencetocoma),mydriasis,convulsion,andvomiting.Otherreportedeventsinclude

Urogenital Abnormal

ejaculation/orgasm

(males),

Anorgasmia,

Erectile

dysfunction

(impotence),

Urination

impaired(mostly

hesitancy),

Menstrual

disorders

associatedwith

increasedbleeding

orincreased

irregularbleeding

(e.g.,menorrhagia,

metrorrhagia),

Abnormal

orgasm

(females),

Urinary

retention Urinary

incontinence

Bodyasawhole Asthenia(fatigue),

Chills Angioedema,

Photo-

sensitivity

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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.

Invitrostudiesrevealedthatvenlafaxinehasvirtuallynoaffinityforopiateorbenzodiazepinesensitivereceptors.

Majordepressiveepisodes

Theefficacyofvenlafaxineimmediate-releaseasatreatmentformajordepressiveepisodeswasdemonstratedinfive

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

375mg/day.Theefficacyofvenlafaxineprolonged -releaseasatreatmentformajordepressiveepisodeswas

establishedintwoplacebo -controlled,short-termstudiesfor8and12weeksduration,whichincludedadoserangeof

75to225mg/day.

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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

establishedintwo8 -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

open-labelphase(75,150,or225mg).

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

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ofvenlafaxineprolonged-releasecapsules,peakplasmaconcentrationsofvenlafaxineandODVareattainedwithin

5.5hoursand9hours,respectively.Whenequaldailydosesofvenlafaxineareadministeredaseitheranimmediate-

releasetabletorprolonged -releasecapsule,theprolonged-releasecapsuleprovidesaslowerrateofabsorption,butthe

sameextentofabsorptioncomparedwiththeimmediate-releasetablet.Fooddoesnotaffectthebioavailabilityof

venlafaxineandODV.

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

severehepaticimpairment(seesection4.2).

Patientswithrenalimpairment

Indialysispatients,venlafaxineeliminationhalf-lifewasprolongedbyabout180%andclearancereducedbyabout

57%comparedtonormalsubjects,whileODVeliminationhalf-lifewasprolongedbyabout142%andclearance

reducedbyabout56%.Dosageadjustmentisnecessaryinpatientswithsevererenalimpairmentandinpatientsthat

requirehaemodialysis(seesection4.2).

5.3Preclinicalsafetydata

Studieswithvenlafaxineinratsandmicerevealednoevidenceofcarcinogenesis.Venlafaxinewasnotmutagenicina

widerangeofinvitroandinvivotests.

Animalstudiesregardingreproductivetoxicityhavefoundinratsadecreaseinpupweight,anincreaseinstillborn

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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

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

IPSHealthcareLimited

SterlingHouse

Oldham

Lancashire

OL99LY

UnitedKingdom

8PARALLELPRODUCTAUTHORISATIONNUMBER

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9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:19 th

November2010

10DATEOFREVISIONOFTHETEXT

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