EFAXIL XL

Main information

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

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0281/136/001
  • Authorization date:
  • 02-12-2008
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

EfaxilXL75mgProlonged-releaseCapsules

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachprolonged-releasecapsulecontains75mgofvenlafaxineasvenlafaxinehydrochloride.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Prolonged-releaseCapsule.

Fleshopaque/fleshopaque,size0hardgelatincapsulescontainingtwowhiteround,biconvexfilm-coatedtablets.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofmajordepressiveepisodes.

Forpreventionofrecurrenceofmajordepressiveepisodes.

Treatmentofsocialanxietydisorder.

4.2Posologyandmethodofadministration

Majordepressiveepisodes

Therecommendedstartingdoseforprolonged-releasevenlafaxineis75mggivenoncedaily.Patientsnotresponding

totheinitial75mg/daydosemaybenefitfromdoseincreasesuptoamaximumdoseof375mg/day.Dosageincreases

canbemadeatintervalsof2weeksormore.Ifclinicallywarrantedduetosymptomseverity,doseincreasescanbe

madeatmorefrequentintervals,butnotlessthan4days.Becauseoftheriskofdose-relatedadverseeffects,dose

incrementsshouldbemadeonlyafteraclinicalevaluation(seesection4.4).Thelowesteffectivedoseshouldbe

maintained.

Patientsshouldbetreatedforsufficientperiodoftime,usuallyseveralmonthsorlonger.Treatmentshouldbe

reassessedregularlyonacase-by-casebasis.Longer-termtreatmentmayalsobeappropriateforpreventionof

recurrenceofmajordepressiveepisodes(MDE).Inmostofthecases,therecommendeddoseinpreventionof

recurrenceofMDEisthesameastheoneusedduringthecurrentepisode.

Antidepressivemedicinalproductsshouldcontinueforatleastsixmonthsfollowingremission.

Socialanxietydisorder

Therecommendeddoseforprolonged-releasevenlafaxineis75mggivenoncedaily.Thereisnoevidencethathigher

dosesconferanyadditionalbenefit.

However,inindividualpatientsnotrespondingtotheinitial75mg/day,increasesuptoamaximumdoseof225mg/day

maybeconsidered.Dosageincreasescanbemadeatintervalsof2weeksormore.

Becauseoftheriskofdose-relatedadverseeffects,doseincrementsshouldbemadeonlyafteraclinicalevaluation(see

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Patientsshouldbetreatedforasufficientperiodoftime,usuallyseveralmonthsorlonger.Treatmentshouldbe

reassessedregularly,onacase-by-casebasis.

UseinElderlyPatients:

Nospecificdoseadjustmentsofvenlafaxineareconsiderednecessarybasedonpatientagealone.However,caution

shouldbeexercisedintreatingtheelderly(e.g.duetothepossibilityofrenalimpairment,thepotentialforchangesin

neurotransmittersensitivityandaffinityoccurringwithaging).Thelowesteffectivedoseshouldalwaysbeused,and

patientsshouldbecarefullymonitoredwhenanincreaseinthedoseisrequired.

UseinChildrenandAdolescentsundertheageof18years:

Venlafaxineisnotrecommendedforuseinchildrenandadolescents.

Controlledclinicalstudiesinchildrenandadolescentswithmajordepressivedisorderfailedtodemonstrateefficacy

anddonotsupporttheuseofvenlafaxineinthesepatients(seesection4.4and4.8).

Theefficacyandsafetyofvenlafaxineforotherindicationsinchildrenandadolescentsundertheageof18havenot

beenestablished.

Useinpatientswithhepaticimpairment

Inpatientswithmildandmoderatehepaticimpairment,ingenerala50%dosereductionshouldbeconsidered.

However,duetointer-individualvariabilityinclearance,individualisationofdosagemaybedesirable.

Therearelimiteddatainpatientswithseverehepaticimpairment.Cautionisadvised,andadosereductionbymore

than50%shouldbeconsidered.Thepotentialbenefitshouldbeweighedagainsttheriskinthetreatmentofpatients

withseverehepaticimpairment.

Useinpatientswithrenalimpairment

Althoughnochangeindosageisnecessaryforpatientswithglomerularfiltrationrate(GFR)between30-70ml/minute,

cautionisadvised.Forpatientsthatrequirehaemodialysisandinpatientswithsevererenalimpairment(GFR<30

ml/min),thedoseshouldbereducedby50%.Becauseofinter-individualvariabilityinclearanceinthesepatients,

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.

4.3Contraindications

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Concomitanttreatmentwithirreversiblemonamineoxidaseinhibitors(MAOIs)iscontraindicatedduetothe

riskofserotoninsyndromewithsymptomssuchasagitation,tremorandhyperthermia.Venlafaxinemustnotbe

initiatedforatleast14daysafterdiscontinuationoftreatmentwithanirreversibleMAOI.

Venlafaxinemustbediscontinuedforaleast7daysbeforestartingtreatmentwithirreversibleMAOI(seesections4.4

and4.5).

4.4Specialwarningsandprecautionsforuse

Suicide/suicidalthoughtsorclinicalworsening:

Depressionisassociatedwithanincreasedriskofsuicidalthoughts,selfharm,andsuicide(suicide-relatedevents).

Thisriskpersistsuntilsignificantremissionoccurs.Asimprovementmaynotoccurduringthefirstfewweeksormore

oftreatment,patientsshouldbecloselymonitoreduntilsuchimprovementoccurs.Itisgeneralclinicalexperiencethat

theriskofsuicidemayincreaseintheearlystagesofrecovery.

Otherpsychiatricconditionsforwhichvenlafaxineisprescribedcanalsobeassociatedwithanincreasedriskof

suicide-relatedevents.Inaddition,theseconditionsmaybeco-morbidwithmajordepressivedisorder.Thesame

precautionsobservedwhentreatingpatientswithmajordepressivedisordershouldthereforebeobservedwhentreating

patientswithotherpsychiatricdisorders.

Patientswithahistoryofsuicide-relatedevents,thoseexhibitingasignificantdegreeofsuicidalideationpriorto

commencementoftreatmentareknowntobeatgreaterriskofsuicidalthoughtsorsuicideattempts,andshouldreceive

carefulmonitoringduringtreatment.Ameta-analysisofplacebo-controlledclinicaltrialsofantidepressantdrugsin

adultpatientswithpsychiatricdisordersshowedanincreasedriskofsuicidalbehaviourwithantidepressantscompared

toplaceboinpatientslessthan25yearsold.

Closesupervisionofpatientsandinparticularthoseathighriskshouldaccompanydrugtherapyespeciallyinearly

treatmentandfollowingdosechanges.Patients(andcaregiversofpatients)shouldbealertedabouttheneedtomonitor

foranyclinicalworsening,suicidalbehaviourorthoughtsandunusualchangesinbehaviourandtoseekmedicaladvice

immediatelyifthesesymptomspresent.

Useinchildrenandadoloscentsunder18yearsofage:

EfaxilXLshouldnotbeusedinthetreatmentofchildrenandadolescentsundertheageof18years.Suicide-related

behaviours(suicideattemptandsuicidalthoughts),andhostility(predominantlyaggression,oppositionalbehaviourand

anger)weremorefrequentlyobservedinclinicaltrialsamongchildrenandadolescentstreatedwithantidepressants

comparedtothosetreatedwithplacebo.If,basedonclinicalneed,adecisiontotreatisneverthelesstaken,thepatient

shouldbecarefullymonitoredfortheappearanceofsuicidalsymptoms.Inaddition,long-termsafetydatainchildren

andadolescentsconcerninggrowth,maturationandcognitiveandbehaviouraldevelopmentarelacking.

Serotoninsyndrome:

Aswithotherserotonergicagents,serotoninsyndrome,apotentiallylife-threateningcondition,mayoccurwith

venlafaxinetreatment,particularlywithconcomitantuseofotheragents,suchasMAO-inhibitors,thatmayaffectthe

serotonergicneurotransmittersystem(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).

Narrow-angleglaucoma

Mydriasismayoccurinassociationwithvenlafaxine.Itisrecommendedthatpatientswithraisedintraocularpressure

orpatientsatriskforacutenarrow-angleglaucoma(angle-closureglaucoma)becloselymonitored.

Bloodpressure:

Dose-relatedincreasesinbloodpressurehavebeencommonlyreportedwithvenlafaxine.Insomecases,severely

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Allpatientsshouldbecarefullyscreenedforhighbloodpressureandpreexistinghypertensionshouldbecontrolled

beforeinitationoftreatment.Bloodpressureshouldbereviewedperiodically,afterinitiationoftreatmentandafter

doseincreases.Cautionshouldbeexercisedinpatientswhoseunderlyingconditionsmightbecompromisedby

increasesinbloodpressure,e.g.,thosewithimpairmentcardiacfunction.

Heartrate:

Increasesinheartratecanoccur,particularlywithhigherdoses.Cautionshouldbeexercisedinpatientswhose

underlyingconditionsmightbecompromisedbyincreasesinheartrate.

Cardiacdiseaseandriskofarrhythmia:

Venlafaxinehasnotbeenevaluatedinpatientswitharecenthistoryofmyocardialinfarctionorunstableheartdisease.

Therefore,itshouldbeusedwithcautioninthesepatients.

Inpostmarketingexperience,fatalcardiacarrhythmiashavebeenreportedwiththeuseofvenlafaxine,especiallyin

overdose.Thebalanceofrisksandbenefitsshouldbeconsideredbeforeprescribingvenlafaxinetopatientsathighrisk

ofseriouscardiacarrhythmia.

Convulsions:

Convulsionsmayoccurwithvenlafaxinetherapy.Aswithallantidepressants,venlafaxineshouldbeintroducedwith

cautioninpatientswithahistoryofconvulsions,andconcernedpatientsshouldbecloselymonitored.Treatmentshould

bediscontinuedinanypatientwhodevelopsseizures.

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

cholesterollevelsshouldbeconsideredduringlong-termtreatment.

Co-administrationwithweightlossagents:

Thesafetyandefficacyofvenlafaxinetherapyincombinationwithweightlossagents,includingphentermine,havenot

beenestablished.Co-administrationofvenlafaxineandweightlossagentsisnotrecommended.Venlafaxineisnot

indicatedforweightlossaloneorincombinationwithotherproducts.

Mania/hypomania:

Mania/hypomaniamayoccurinasmallproportionofpatientswithmooddisorderswhohavereceivedantidepressants,

includingvenlafaxine.Aswithotherantidepressants,venlafaxineshouldbeusedcautiouslyinpatientswithahistoryor

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Aggression:

Aggressionmayoccurinasmallnumberofpatientswhohavereceivedantidepressants,includingvenlafaxine.This

hasbeenreportedunderinitiation,dosechangesanddiscontinuationoftreatment.Aswithotherantidepressants,

venlafaxineshouldbeusedcautiouslyinpatientswithahistoryofaggression.

Discontinuationoftreatment:

Withdrawalsymptoms,whentreatmentisdiscontinued,arecommon,particularlyifdiscontinuationisabrupt(see

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

approximately31%ofpatientstreatedwithvenlafaxineand17%ofpatientstakingplacebo.Theriskofwithdrawal

symptomsmaybedependentonseveralfactors,includingthedurationanddoseoftherapyandtherateofdose

reduction.Dizziness,sensorydisturbances(includingparaesthesia),sleepdisturbances(includinginsomniaandintense

dreams),agitationoranxiety,nauseaand/orvomiting,tremorandheadachearethemostcommonlyreportedreactions.

Generally,thesesymptomsaremildtomoderate;however,insomepatientstheymaybesevereinintensity.They

usuallyoccurwithinthefirstfewdaysofdiscontinuingtreatment,buttherehavebeenveryrarereportsofsuch

symptomsinpatientswhohaveinadvertentlymissedadose.Generally,thesesymptomsareself-limitingandusually

resolvewithin2weeks,thoughinsomeindividualstheymaybeprolonged(2-3monthsormore).Itistherefore

advisedthatvenlafaxineshouldbegraduallytaperedwhendiscontinuingtreatmentoveraperiodofseveralweeksor

months,accordingtothepatient’sneeds(seesection4.2).

Akathisia/psychomotorrestlessness:

Theuseofvenlafaxinehasbeenassociatedwiththedevelopmentofakathisia,characterisedbyasubjectively

unpleasantordistressingrestlessnessandneedtomoveoftenaccompaniedbyaninabilitytositorstandstill.Thisis

mostlikelytooccurwithinthefirstfewweeksoftreatment.Inpatientswhodevelopthesesymptoms,increasingthe

dosemaybedetrimental.

Drymouth

Drymouthisreportedin10%ofpatientstreatedwithvenlafaxine.Thismayincreasetheriskofcaries,andpatients

shouldbeadvisedupontheimportanceofdentalhygiene.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

MonoamineOxidaseInhibitors(MAOI)

Irreversiblenon-selectiveMAOIs

Venlafaxinemustnotbeusedincombinationwithirreversiblenon-selectiveMAOIs. Venlafaxinemustnotbe

initiatedforatleast14daysafterdiscontinuationoftreatmentwithanirreversiblenonselectiveMAOI.Venlafaxine

mustbediscontinuedforatleast7daysbeforestartingtreatmentwithanirreversiblenon-selectiveMAOI(seesections

4.3and4.4).

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).Severeadversereactionshavebeenreportedinpatientswhohaverecentlybeen

discontinuedfromanMAOIandstartedonvenlafaxine,orhaverecentlyhadvenlafaxinetherapydiscontinuedpriorto

initiationofanMAOI.Thesereactionshaveincludedtremor,myoclonus,diaphoresis,nausea,vomiting,flushing,

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Serotoninsyndrome

Aswithotherserotonergicagents,serotoninsyndromemayoccurwithvenlafaxinetreatment,particularlywith

concomitantuseofotheragentsthatmayaffecttheserotonergicneurotransmittersystem(includingtriptans,SSRIs,

SNRIs,lithium,sibutramine,tramadol,orSt.John'sWort[Hypericumperforatum]),withmedicinalagentswhich

impairmetabolismofserotonin(includingMAOIs),orwithserotoninprecursors(suchastryptophansupplements).If

concomitanttreatmentofvenlafaxinewithanSSRI,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%

and23%inCYP2D6PMandEMsubjects,respectively)followingadministrationofketoconazole.Concomitantuseof

CYP3A4inhibitors(e.g.,atazanavir,clarithromycin,indinavir,itraconazole,voriconazole,posaconazole,ketoconazole,

nelfinavir,ritonavir,saquinavir,telithromycin)andvenlafaxinemayincreaselevelsofvenlafaxineandO-

desmethylvenlafaxine.Therefore,cautionisadvisedifapatient’stherapyincludesaCYP3A4inhibitorandvenlafaxine

concomitantly.

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%increaseinCmax,butnochangeinhalf-lifeforhaloperidol.Thisshouldbetakenintoaccountinpatients

treatedwithhaloperidolandvenlafaxineconcomitantly.Theclinicalsignificanceofthisinteractionisunknown.

Risperidone

VenlafaxineincreasedtherisperidoneAUCby50%,butdidnotsignificantlyalterthe

pharmacokineticprofileofthetotalactivemoiety(risperidoneplus9-hydroxyrisperidone).Theclinicalsignificanceof

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Metoprolol

Concomitantadministrationofvenlafaxineandmetoprololtohealthyvolunteersinapharmacokineticinteractionstudy

forbothmedicinalproductsresultedinanincreaseofplasmaconcentrationsofmetoprololbyapproximately30-40%

withoutalteringtheplasmaconcentrationsofitsactivemetabolite,-hydroxymetoprolol.Theclinicalrelevanceofthis

findinginhypertensivepatientsisunknown.Metoprololdidnotalterthepharmacokineticprofileofvenlafaxineorits

activemetabolite,O-desmethylvenlafaxine.Cautionshouldbeexercisedwithco-administrationofvenlafaxineand

metoprolol.

Indinavir

Apharmacokineticstudywithindinavirhasshowna28%decreaseinAUCanda36%decreaseinCmaxforindinavir.

IndinavirdidnotaffectthepharmacokineticsofvenlafaxineandO-desmethylvenlafaxine.Theclinicalsignificanceof

thisinteractionisunknown.

4.6Fertility,pregnancyandlactation

Pregnancy

Therearenoadequatedatafromtheuseofvenlafaxineinpregnantwomen.

Studiesinanimalshaveshownreproductivetoxicity(seesection5.3).Thepotentialriskforhumansisunknown.

Venlafaxinemustonlybeadministeredtopregnantwomeniftheexpectedbenefitsoutweighanypossiblerisk.

Aswithotherserotoninreuptakeinhibitors(SSRIs/SNRIs),discontinuationsymptomsmayoccurinthenewbornsif

venlafaxineisuseduntilorshortlybeforebirth.Somenewbornsexposedtovenlafaxinelateinthethirdtrimesterhave

developedcomplicationsrequiringtube-feeding,respiratorysupportorprolongedhospitalisation.Suchcomplications

canariseimmediatelyupondelivery.

ThefollowingsymptomsmaybeobservedinneonatesifthemotherhasusedanSSRI/SNRIlateinpregnancy:

irritability,tremor,hypotonia,persistentcrying,anddifficultyinsuckingorinsleeping.Thesesymptomsmaybedue

toeitherserotonergiceffectsorexposuresymptoms.Inthemajorityofcases,thesecomplicationsareobserved

immediatelyorwithin24hoursafterpartus.

EpidemiologicaldatahavesuggestedthattheuseofSSRIsinpregnancy,particularlyinlatepregnancy,mayincrease

theriskofpersistentpulmonaryhypertensioninthenewborn(PPHN).Althoughthereisnoevidencefortheassociation

ofPPHNtoSNRItreatment,thispotentialriskcannotberuledoutwithEfaxiltakingintoaccounttherelated

mechanismsofaction(increaseinserotoninconcentrations).

Lactation

Venlafaxineanditsactivemetabolite,O-desmethylvenlafaxine,areexcretedinbreastmilk.Arisktothesucklingchild

cannotbeexcluded.Therefore,adecisiontocontinue/discontinuebreast-feedingortocontinue/discontinuetherapy

withEfaxilXLshouldbemade,takingintoaccountthebenefitofbreast-feedingtothechildandthebenefitofEfaxil

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

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BodySystem Very

Common Common Uncommon Rare NotKnown

Haematological

/Lymphatic Ecchymosis,

Gastrointestinal

haemorrhage Mucousmembrane

bleeding,Prolonged

bleedingtime,

Thrombocytopaenia,

Blooddyscrasias,

(including

agranulocytosis,

aplasticanaemia,

neutropaeniaand

pancytopaenia)

Metabolic/

Nutritional Serum

cholesterol

increased,

Weight

loss Weightgain Abnormalliver

functiontests,

Hyponatraemia,

Hepatitis,Syndrome

ofInappropriate

Antidiuretic

HormoneSecretion

(SIADH),Prolactin

increased

Nervous Dry

mouth

(10.0%),

Headache

(30.3%)* Abnormal

dreams,

Decreased

libido,

Dizziness,

Increased

muscle

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**

SpecialSenses 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

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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,headacheandflusyndromearethemostcommonlyreportedreactions.

Generally,theseeventsaremildtomoderateandareself-limiting;however,insomepatients,theymaybesevere

and/orprolonged.Itisthereforeadvisedthatwhenvenlafaxinetreatmentisnolongerrequired,gradualdiscontinuation

bydosetaperingshouldbecarriedout(seesections4.2and4.4).

Paediatricpatients

Ingeneral,theadversereactionprofileofvenlafaxine(inplacebo-controlledclinicaltrials)inchildrenandadolescents

Digestive Nausea

(20.0%) Appetite

decreased

(anorexia),

Constipation,

Vomiting Bruxism,

Diarrhoea Pancreatitis

Skin Sweating

(including

night

sweats)

[12.2%] Rash,Alopecia Erythema

multiforme,Toxic

epidermal

necrolysis,Stevens-

Johnsonsyndrome,

Pruritus,Urticaria

Musculoskeletal Rhabdomyolysis

Urogenital Abnormal

ejaculation/orgasm

(males),

Anorgasmia,

Erectile

dysfunction

(impotence),

Urination

impaired

(mostly

hesitancy),

Menstrual

disorders

associatedwith

increased

bleeding

orincreased

irregular

bleeding

(e.g.,

menorrhagia,

metrorrhagia),

Abnormal

orgasm

(females),

Urinary

retention

Bodyasa

Whole Asthenia

(fatigue),

Chills Photosensitivity

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Aswithadults,decreasedappetite,weightloss,increasedbloodpressure,andincreasedserumcholesterolwere

observed(seesection4.4).

Inpaediatricclinicaltrialstheadversereactionsuicidalideationwasobserved.Therewerealsoincreasedreportsof

hostilityand,especiallyinmajordepressivedisorder,self-harm.

Particularly,thefollowingadversereactionswereobservedinpaediatricpatients:abdominalpain,agitation,dyspepsia,

ecchymosis,epistaxis,andmyalgia.

4.9Overdose

Inpostmarketingexperience,overdosewithvenlafaxinewasreportedpredominantlyincombinationwithalcohol

and/orothermedicinalproducts.Themostcommonlyreportedeventsinoverdoseincludetachycardia,changesinlevel

ofconsciousness(rangingfromsomnolencetocoma),mydriasis,convulsion,andvomiting.Otherreportedevents

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

ventriculartachycardia,bradycardia,hypotension,vertigo,anddeath.

Publishedretrospectivestudiesreportthatvenlafaxineoverdosagemaybeassociatedwithanincreasedriskoffatal

outcomescomparedtothatobservedwithSSRIantidepressantproducts,butlowerthanthatfortricyclic

antidepressants.Epidemiologicalstudieshaveshownthatvenlafaxine-treatedpatientshaveahigherburdenofsuicide

riskfactorsthanSSRIpatients.Theextenttowhichthefindingofanincreasedriskoffataloutcomescanbeattributed

tothetoxicityofvenlafaxineinoverdosage,asopposedtosomecharacteristicsofvenlafaxine-treatedpatients,isnot

clear.Prescriptionsforvenlafaxineshouldbewrittenforthesmallestquantityofthemedicinalproductconsistentwith

goodpatientmanagementinordertoreducetheriskofoverdose.

Recommendedtreatment

Generalsupportiveandsymptomaticmeasuresarerecommended;cardiacrhythmandvitalsignsmustbemonitored.

Whenthereisariskofaspiration,inductionofemesisisnotrecommended.Gastriclavagemaybeindicatedif

performedsoonafteringestionorinsymptomaticpatients.Administrationofactivatedcharcoalmayalsolimit

absorptionoftheactivesubstance.Forceddiuresis,dialysis,hemoperfusionandexchangetransfusionareunlikelytobe

ofbenefit.Nospecificantidotesforvenlafaxineareknown.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Otherantidepressants

ATCcode:N06AX16

Themechanismofvenlafaxine'santidepressantactioninhumansisbelievedtobeassociatedwithitspotentiationof

neurotransmitteractivityinthecentralnervoussystem.Preclinicalstudieshaveshownthatvenlafaxineanditsmajor

metabolite,O-desmethylvenlafaxineODV,areinhibitorsofserotoninandnoradrenalinereuptake.Venlafaxinealso

weaklyinhibitsdopamineuptake.Venlafaxineanditsactivemetabolitereduce-adrenergicresponsivenessafterboth

acute(singledose)andchronicadministration.VenlafaxineandODVareverysimilarwithrespecttotheiroverall

actiononneurotransmitterreuptakeandreceptorbinding.

Venlafaxinehasvirtuallynoaffinityforratbrainmuscarinic,cholinergic,H1-histaminergicor1-adrenergicreceptors

invitro.Pharmacologicalactivityatthesereceptorsmayberelatedtovarioussideeffectsseenwithother

antidepressantmedicinalproducts,suchasanticholinergic,sedativeandcardiovascularsideeffects.

Venlafaxinedoesnotpossessmonoamineoxidase(MAO)inhibitoryactivity.

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Majordepressiveepisodes

Theefficacyofvenlafaxineimmediate-releaseasatreatmentformajordepressiveepisodeswasdemonstratedinfive

randomised,double-blind,placebo-controlled,short-termtrialsrangingfrom4to6weeksduration,fordosesupto375

mg/day.Theefficacyofvenlafaxineprolonged-releaseasatreatmentformajordepressiveepisodeswasestablishedin

twoplacebo-controlled,short-termstudiesfor8and12weeksduration,whichincludedadoserangeof75to225

mg/day.

Inonelonger-termstudy,adultoutpatientswhohadrespondedduringan8-weekopentrialonvenlafaxineprolonged-

release(75,150,or225mg)wererandomisedtocontinuationoftheirsamevenlafaxineprolonged-releasedoseorto

placebo,forupto26weeksofobservationforrelapse.

Inasecondlonger-termstudy,theefficacyofvenlafaxineinpreventionofrecurrentdepressiveepisodesfora12-

monthperiodwasestablishedinaplacebo-controlleddouble-blindclinicaltrialinadultoutpatientswithrecurrent

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

lastepisodeofdepression.

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.

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

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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

pups,andanincreaseinpupdeathsduringthefirst5daysoflactation.Thecauseofthesedeathsisunknown.These

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

effectdoseforthesefindingswas1.3timesthehumandose.Thepotentialriskforhumansisunknown.

ReducedfertilitywasobservedinastudyinwhichbothmaleandfemaleratswereexposedtoODV.Thisexposurewas

approximately1to2timesthatofahumanvenlafaxinedoseof375mg/day.Thehumanrelevanceofthisfindingis

unknown.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Capsulecontent:

Hypromellose

AmmonioMethacrylateCopolymer(typeB)

Sodiumlaurylsulphate

Magnesiumstearate

Coatingcontains:

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Capsuleshell:

Gelatin

Redironoxide(E172)

Titaniumdioxide(E171)

6.2Incompatibilities

Notapplicable.

6.3Shelflife

3years.

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequiredanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

ThecapsulesaresuppliedinopaquePVC/PE/PVDC/Alblisters.Eachpackcontains7,14,28or30prolonged-releasecapsules.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

PinewoodLaboratoriesLimited,

Ballymacarbry,

Clonmel,

Co.Tipperary.

8MARKETINGAUTHORISATIONNUMBER

PA0281/136/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:2ndDecember2008

10DATEOFREVISIONOFTHETEXT

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