EFEXOR

Main information

  • Trade name:
  • EFEXOR Tablets 37.5mg Milligram
  • Dosage:
  • 37.5mg Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • EFEXOR Tablets 37.5mg Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA0465/085/001B
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Efexor37.5mgTablets.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains37.5mgofvenlafaxine(ashydrochloride).

Excipients: Lactose

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablet.

ProductimportedfromGreece:

Peachcoloured,shieldshapedtabletimpressedwiththetabletstrength‘37.5’andembossedwitha‘W’ononeface,

andplainontheother.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Efexorisindicatedforthetreatmentofdepressiveillnessinbothhospitalisedpatientsandoutpatients,including

depressionaccompaniedbyanxiety.

FollowinganinitialresponseEfexorisindicatedforthepreventionofrelapsesoftheinitialepisodeofdepressionorfor

thepreventionoftherecurrenceofnewepisodes.

4.2Posologyandmethodofadministration

Adults:

Theusualrecommendeddoseis75mgperdaygivenintwodivideddoses(37.5mgtwicedaily).If,afterseveralweeks,

furtherclinicalimprovementisrequired,thedosemaybeincreasedto150mgperdaygivenintwodivideddoses

(75mgtwicedaily).

If,inthejudgementofthephysician,ahigherdoseisrequired,forexampleinmoreseverelydepressedorhospitalised

patients,astartingdoseof150mgperdaymaybegivenintwodivideddoses(75mgtwicedaily).Thedailydosemay

thenbeincreasedbyupto75mgeverytwoorthreedaysuntilthedesiredresponseisachieved.Themaximum

recommendeddoseis375mgperday.Thedoseshouldthenbegraduallyreducedtotheusualdosage,consistentwith

patientresponseandtolerance.

Usually,thedosageforpreventionofrelapseorforpreventionofrecurrenceofanewepisodeissimilartothatused

duringtheindexepisode.Patientsshouldbere-assessedregularlyinordertoevaluatethebenefitoflong-termtherapy.

ItisrecommendedthatEfexorbetakenwithfood.

PatientswithRenalorHepaticImpairment:

Forpatientswithmildrenalimpairment(GFR>30ml/minute)ormildhepaticimpairment(PT<14seconds),nochange

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 11/05/2009 CRN 2065616 page number: 1

Forpatientswithmoderaterenalimpairment(GFR10-30ml/minute)ormoderatehepaticimpairment(PT14-18

seconds),thedoseshouldbereducedby50%.

Thisdosemaybegivenoncedailyduetothelongerhalf-livesofvenlafaxineandO-desmethylvenlafaxine(ODV)in

thesepatients.

InsufficientdataareavailabletosupporttheuseofEfexorinpatientswithsevererenalimpairment(GFR

<10ml/minute)orseverehepaticimpairment(PT>18seconds).

ElderlyPatients:

Noadjustmentintheusualdosageisrecommendedforelderlypatients.Inatrialinvestigatingthekineticsof

venlafaxineintheelderly,thehalf-life(atsteady-stateconditions)wasprolongedby1-2hours,mainlyinthemale

subjects.Thiswasapparentlyduetoan18%reductionintheclearanceofvenlafaxineandO-desmethylvenlafaxine.

Thesmallincreaseinsteady-stateplasmalevelsofvenlafaxineandO-desmethylvenlafaxinewhichresulted,wasnot

judgedtobeclinicallysignificant;noadjustmentindosageisnecessary.However,aswithanytherapy,cautionshould

beexercisedintreatingtheelderly(eg.duetothepossibilityofrenalimpairment.Seealsodosagerecommendationsfor

renalimpairment).Thelowesteffectivedoseshouldalwaysbeusedandpatientsshouldbecarefullymonitoredwhen

anincreaseinthedoseisrequired.

Children/Adolescents:

ControlledclinicalstudiesinchildrenandadolescentswithMajorDepressiveDisorderfailedtodemonstrateefficacy

anddonotsupporttheuseofEfexorinthesepatients(seesections4.3Contra-indicationsand4.8UndesirableEffects).

TheefficacyandsafetyofEfexorforotherindicationsinchildrenandadolescentsundertheageof18havenotyet

beenestablished.

Maintenance/Continuation/ExtendedTreatment:

Thephysicianshouldperiodicallyre-evaluatetheusefulnessoflong-termtreatmentwithEfexorfortheindividual

patient.Itisgenerallyagreedthatacuteepisodesofmajordepressionrequireseveralmonthsorlongerofsustained

therapy.Efexorhasbeenshowntobeefficaciousduringlong-term(upto12months)treatment.

Inclinicaltrialsvenlafaxinewasdemonstratedtobeeffectiveforpreventingrelapse,orrecurrenceofnewepisodes,in

patientsrespondingtovenlafaxinetreatmentduringtheindexepisode.

DiscontinuingEfexor:

Discontinuationeffectsarewellknowntooccurwiththeabruptwithdrawalofotherantidepressants.Whilewithdrawal

reactionswithEfexorhavenotbeensystematicallyevaluatedincontrolledclinicaltrials,aretrospectivesurveyof

eventsoccurringduringtaperorfollowingdiscontinuationofEfexorrevealedthefollowingeventsthatoccurredatan

incidenceofatleast5%andatleasttwicetheplaceboincidence:fatigue,headache,nausea,dizziness,sleepdisturbance

andnervousness.Diarrhoeaandonehypomanicepisodewasalsoreported.

Inpost-marketingexperience,symptomsreportedfollowingdiscontinuation,dosereductionortaperingofvenlafaxine

atvariousdoseshavealsoincludedconfusion,paraesthesia,sweating,vertigoandvomiting.Itistherefore

recommendedthatwhendiscontinuingEfexoraftermorethanoneweek'stherapy,thedoseshouldbegradually

reducedoveratleastoneweekandthepatientmonitoredinordertominimisetheriskofwithdrawalreactions.

Theperiodrequiredfordiscontinuationmaydependonthedose,durationoftherapyandtheindividualpatient.

4.3Contraindications

Knownorsuspectedpregnancy.

InsufficientdataareavailabletosupporttheuseofEfexorinlactatingwomen.Therefore,suchuseiscontra-

indicated.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 11/05/2009 CRN 2065616 page number: 2

Concomitantuseofvenlafaxinewithmonoamineoxidaseinhibitors.(SeeInteractionswithothermedicinal

productsandotherformsofinteraction).

Efexorshouldnotbeusedinchildrenandadolescentsundertheageof18yearswithMajorDepressiveDisorder

(seesection4.8Undesirableeffects).

4.4Specialwarningsandprecautionsforuse

Suicide/suicidalthoughtsorclinicalworsening:

Depressionisassociatedwithanincreasedriskofsuicidalthoughts,selfharmandsuicide(suicide-relatedevents).This

riskpersistsuntilsignificantremissionoccurs.Asimprovementmaynotoccurduringthefirstfewweeksormoreof

treatment,patientsshouldbecloselymonitoreduntilsuchimprovementoccurs.Itisgeneralclinicalexperiencethatthe

riskofsuicidemayincreaseintheearlystagesofrecovery.

OtherpsychiatricconditionsforwhichEfexorisprescribedcanalsobeassociatedwithanincreasedriskofsuicide-

relatedevents.Inaddition,theseconditionsmaybeco-morbidwithmajordepressivedisorder.Thesameprecautions

observedwhentreatingpatientswithmajordepressivedisordershouldthereforebeobservedwhentreatingpatients

withotherpsychiatricdisorders.

Patientswithahistoryofsuicide-relatedevents,orthoseexhibitingasignificantdegreeofsuicidalideationpriorto

commencementoftreatmentareknowntobeatgreaterriskofsuicidalthoughtsorsuicideattempts,andshouldreceive

carefulmonitoringduringtreatment.Ameta-analysisofplacebo-controlledclinicaltrialsofantidepressantdrugsin

adultpatientswithpsychiatricdisordersshowedanincreasedriskofsuicidalbehaviourwithantidepressantscompared

toplaceboinpatientslessthan25yearsold.

Closesupervisionofpatientsandinparticularthoseathighriskshouldaccompanydrugtherapyespeciallyinearly

treatmentandfollowingdosechanges.Patients(andcaregiversofpatients)shouldbealertedabouttheneedtomonitor

foranyclinicalworsening,suicidalbehaviourorthoughtsandunusualchangesinbehaviourandtoseekmedicaladvice

immediatelyifthesesymptomspresent.

Theriskofsuicideattemptmustbeconsideredinalldepressedpatients.Thesmallestquantityoftabletsshould

beprescribedconsistentwithgoodpatientmanagementinordertoreducethepossibilityofoverdose.

Inclinicaltrialswithvenlafaxinetablets,seizureswerereportedin0.2%ofallvenlafaxine-treatedpatients.All

patientsrecovered.NoseizuresoccurredinEfexor–treatedpatientsduringclinicaltrials.

However,aswithallantidepressants,Efexorshouldbeintroducedwithcautioninpatientswithahistoryof

seizureandshouldbediscontinuedinanypatientdevelopingaseizure.

Duringclinicaltrials,rashdevelopedin3%ofpatientstreatedwithvenlafaxine.Patientsshouldbeadvisedto

notifytheirphysicianiftheydeveloparash,urticariaorarelatedallergicphenomenon.

Doserelatedincreasesinbloodpressurehavebeenreportedinpatientsreceivingvenlafaxine.Inall

premarketingtrials,2.2%ofvenlafaxinetreatedpatientswerejudgedtohaveclinicallysignificantblood

pressureincreasescompatedwith0.4%ofplacebo-treatedpatients.Ingeneral,patientstreatedwith200mgper

dayshowedminorincreases,whileinashort-termdose-rangingstudywithEfexorTablets,thehighestdose

(300to375mg/day)wasassociatedwithmeanincreasesinsupineanddiastolicbloodpressureofapproximately

4mmHgbyweek4,and7mmHgbyweek6.Measurementofbloodpressureisthereforerecommendedfor

patientsreceivingvenlafaxine.

Thepresenceoftreatedhypertensionorelevatedbloodpressureatbaselinedidnotseemtopredisposepatients

tofurtherincreasesduringEfexortherapy.

DuetothepossibilityofdrugabusewithCNS-activedrugs,physiciansshouldevaluatepatientsforahistoryof

drugabuse,andfollowsuchpatientsclosely.Clinicalstudieshaveshownnoevidenceofdrug-seeking

behaviour,developmentoftolerance,ordoseescalationovertimeamongpatientstakingEfexor.

Venlafaxinehasnotbeenevaluatedorusedtoanyappreciableextentinpatientswitharecenthistoryof

myocardialinfarctionorunstableheartdisease.Therefore,itshouldbeusedwithcautioninthesepatients.

Clinicallysignificantelectrocardiogramfindingswereobservedin1%ofvenlafaxinetreatedpatientscompared

with0.2%ofplacebo-treatedpatients.ClinicallysignificantchangesinPR,QRSorQTcintervalswererarely

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 11/05/2009 CRN 2065616 page number: 3

Increasesinheartratecanoccur,particularlyathighdoses.Inclinicaltrialsthemeanheartratewasincreased

byapproximately4beats/minuteinpatientstreatedwithvenlafaxine.Cautionshouldbeexercisedinpatients

whoseunderlyingconditionsmightbecompromisedbyincreasesinheartrate.

Theclearancesofvenlafaxineanditsactivemetabolitearedecreasedandhalf-livesincreasedinpatientswith

moderatetosevererenalimpairmentorcirrhosisoftheliver.Therefore,Efexorshouldbeusedwithcautionin

thesepatients.Alowerorlessfrequentdosemightbenecessaryinsuchpatientsasindicatedaboveunder

"PosologyandMethodofAdministration".

Posturalhypotensionhasbeenobservedoccasionallyduringvenlafaxinetreatment.Patients,especiallythe

elderly,shouldbealertedtothepossibilityofdizzinessorunsteadiness.

Casesofhypomatraemiaand/orSyndromeofInappropriateAntidiureticHormonesecretion(SIADH)may

occurwithvenlafaxine,usuallyinvolume-depletedordehydratedpatients,includingpatientstakingdiuretics

andtheelderly.

WomenofchildbearingpotentialshouldemployadequatecontraceptionwhilsttakingEfexor.

Activationofmaniaorhypomaniahasbeenreportedrarelyinpatientswhohavereceivedantidepressants,

includingvenlafaxine.Aswithallantidepressants,EfexorXLshouldbeusedwithcautioninpatientswitha

historyofmania.

Mydriasishasbeenreportedinassociationwithvenlafaxine;thereforepatientswithraisedintraocularpressure

oratariskofnarrowangleglaucomashouldbemonitoredclosely.

Aswithserotonin-reuptakeinhibitors,theriskofskinandmucousmembranebleedingmaybeincreasedin

patientstakingvenlafaxine.Efexorshouldbeusedwithcautioninpatientspredisposedtobleedingatthese

sites.

Useinchildrenandadolescentsundertheageof18:

Efexorshouldnotbeusedinthetreatmentofchildrenandadolescentsundertheageof18years.Suicide-

relatedbehaviours(suicidalattemptandsuicidalthoughts),andhostility(predominantlyaggression,

oppositionalbehavioursandanger)weremorefrequentlyobservedinclinicaltrialsamongchildrenand

adolescentstreatedwithantidepressantscomparedtothosetreatedwithplacebo.If,basedonclinicalneed,a

decisiontotreatisneverthelesstaken,thepatientshouldbecarefullymonitoredfortheappearanceofsuicidal

symptoms.Inaddition,long-termsafetydatainchildrenandadolescentsconcerninggrowth,maturationand

cognitiveandbehaviouraldevelopmentarelacking.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

MAOIs:

Adversereactions,someserious,havebeenreportedwhenvenlafaxinetherapyisinitiatedsoonafterdiscontinuationof

anMAOI,andwhenanMAOIisinitiatedsoonafterdiscontinuationofvenlafaxine.Thesereactionshaveincluded

tremor,myoclonus,diaphoresis,nausea,vomiting,flushing,dizziness,hyperthermiawithfeaturesresembling

neurolepticmalignantsyndrome,seizuresanddeath.Giventhesereactionsreportedwithconcomitantorimmediately

consecutiveadministrationofMAOIswithotherantidepressantswithpharmacologicalpropertiessimilartoEfexor,do

notuse

EfexorincombinationwithanMAOI,orwithinatleast14daysofdiscontinuingMAOItreatment.Allowatleast7

daysafterstoppingEfexorbeforestartinganMAOI.(SeealsoContraindications).

OtherCNS-activedrugs:

TheriskofusingEfexorincombinationwithotherCNS-activedrugshasnotbeensystematicallyevaluated,exceptin

thecasesdescribedbelow.ConsequentlycautionisadvisediftheconcomitantadministrationofEfexorandotherCNS-

activedrugsisrequired.

Lithium:Thesteady-statepharmacokineticsofvenlafaxineadministeredat150mg/daywerenotaffectedwhenasingle

600mgoraldoseoflithiumwasco-administered.O-desmethylvenlafaxine(ODV)wasalsounaffected.Venlafaxine

hadnoeffectonthepharmacokineticsoflithium.

Imipramine/desipramine:Themetabolismofimipramineanditsmetabolite2-OH-imipraminewereunaffectedby

venlafaxinealthoughthetotalrenalclearanceof2-hydroxydesiprainewasreducedanddesiramineAUCandC

were

increasedbyapproximately35%.ImipraminepartiallyinhibitedtheformationofODVbutthetotalconcentrationof

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 11/05/2009 CRN 2065616 page number: 4

Haloperidol:Inapharmacokineticstudyco-administrationofvenlafaxinewithasingle2mgoraldoseofhaloperidol

resultedina42%decreaseinrenalclearance,a70%increaseinAUCandan88%increaseinC

forhaloperidol.

Theeliminationhalf-liferemainedunchanged.

Diazepam:ThepharmacokineticprofilesofvenlafaxineandODVwerenotsignificantlyalteredbytheadministration

ofdiazepam.Venlafaxinehasnoeffectonthepharmacokineticprofileofdiazepamoronthepsychomotoror

psychometriceffectsinducedbydiazepam.

Clozapine:Increasedlevelsofclozapine,thatweretemporallyassociatedwithadverseevents,includingseizures,have

beenreportedfollowingtheadditionofvenlafaxine.

Risperidone:VenlafaxineincreasedtherisperidoneAUCby32%butdidnotsignificantlyalterthepharmacokinetic

profileofthetotalactivemoiety(risperidoneplus9-hydroxyrisperidone).

Alcohol:Venlafaxinehasbeenshownnottoincreasetheimpairmentofmentalormotorskillscausedbyethanol.

However,aswithallCNS-activedrugs,patientsshouldbeadvisedtoavoidalcoholconsumptionwhiletakingEfexor.

ECT:ThereislittleclinicalexperienceoftheconcurrentuseofvenlafaxinewithECT.Asprolongedseizureactivity

hasbeenreportedwithconcomitantSSRIantidepressants,cautionisadvised.

DrugsmetabolisedbyCytochromeP450isoenzymes:Venlafaxineisprimarilymetabolisedtoitsequallyactive

metabolite,ODV,bythecytochromeP450enzymeCYP2D6.However,unlikemanyotherantidepressants,nodosage

adjustmentisnecessarywhenEfexorisadministeredconcomitantlywithdrugswhichinhibitCYP2D6,orwhenusedin

patientswhoarepoorCYP2D6metabolisers,sincethetotalconcentrationofactivecompound(venlafaxineandODV)

isnotaffected.

ThemajoreliminationpathwaysforvenlafaxinearethroughCYP2D6andCYP3A4.Therefore,cautionshouldbeused

withconcomitantintakeofdrugswhichinhibitbothoftheseenzymes.Suchinteractionshavenotbeenstudiedtodate.

VenlafaxineisarelativelyweakinhibitorofCYP2D6anddoesnotinhibitCYP1A2,CYP2C9orCYP3A4.Therefore,

Efexorisnotexpectedtointeractwithotherdrugsmetabolisedbythesehepaticenzymes.

Cimetidine:Cimetidineinhibitedthefirst-passmetabolismofvenlafaxinebuthadnosignificanteffectontheformation

oreliminationofODV,whichispresentinmuchgreaterquantitiesinthesystemiccirculation.Nodosageadjustment

thereforeseemsnecessarywhenEfexorXLiscoadministeredwithcimetidine.Forelderlypatients,orpatientswith

hepaticdysfunctiontheinteractioncouldpotentiallybemorepronounced,andforsuchpatientsclinicalmonitoringis

indicatedwhenEfexorXLisadministeredwithcimetidine.

Antihypertensives:ThereisnoevidencesuggestingincompatibilitybetweentreatmentwithEfexorandtreatmentwith

eitherantihypertensives(including-blockers,ACEinhibitorsanddiuretics)orhypoglycaemicagents.

Plasmaproteinbinding:VenlafaxineandODVare27%and30%boundtoplasmaproteinsrespectively.Drug

interactionsduetoproteinbindingofvenlafaxineandODVarethereforenotexpected.

Warfarin:PotentiationofanticoagulanteffectsincludingincreasesinPTorINRhavebeenreportedinpatientstaking

warfarinfollowingtheadditionofvenlafaxine.

Indinavir:Apharmacokineticstudywithindinavirhasshowna28%decreaseinAUCanda36%decreaseinC

indinavir.IndinavirdidnotaffectthepharmacokineticsofvenlafaxineandODV.Theclinicalsignificanceofthis

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 11/05/2009 CRN 2065616 page number: 5

4.6Pregnancyandlactation

ThesafetyofEfexorforuseduringhumanpregnancyhasnotbeenestablished.Therefore,theuseofEfexorduring

knownorsuspectedpregnancyiscontra-indicated.Patientsshouldbeadvisedtonotifytheirphysicianiftheybecome

pregnantorintendtobecomepregnantduringtherapy.

Thereisevidencetosuggestthatvenlafaxineanditsmetabolite,ODV,transfersintobreastmilk.Thereforetheuseof

venlafaxineinlactatingwomeniscontra-indicated.

4.7Effectsonabilitytodriveandusemachines

AlthoughVenlafaxinehasbeenshownnottoaffectpsychomotor,cognitive,orcomplexbehaviourperformancein

healthyvolunteers,anypsychoactivedrugmayimpairjudgement,thinkingormotorskills.Thereforepatientsshould

becautionedabouttheirabilitytodriveacaroroperatehazardousmachinery.

4.8Undesirableeffects

Casesofsuicidalideationandsuicidalbehaviourshavebeenreportedduringvenlafaxinetherapyorearlyafter

treatmentdiscontinuation(seesection4.4)

Themostcommonlyobservedadverseeventsassociatedwiththeuseofvenlafaxineinclinicaltrials,andwhich

occurredmorefrequentlythanthosewhichwereassociatedwithplacebowere:nausea,insomnia,drymouth,

somnolence,dizziness,constipation,sweating,nervousness,astheniaandabnormalejaculation/orgasm.

Theoccurrenceofmostoftheseadverseeventswasdose-related,andthemajorityofthemdecreasedinintensityand

frequencyovertime.Theygenerallydidnotleadtocessationoftreatment.

Adverseeventsobservedwithvenlafaxine,botspontaneousandclinicaltrialsreportings,areclassifiedinbodysystems

andlistedbelowasverycommon(>1/10);common(<1/10and>1/100);uncommon(<1/100and>1/1000);rare

(<1/1000):

Bloodandlymphaticsystemdisorders–Uncommon:ecchymosis,mucousmembranebleeding;Rare:prolonged

bleedingtime,haemorrhage,thrombocytopenia.

Cardiovascularandvasculardisorders(seeSpecialwarningsandspecialprecautionsforuse)Common:

hypertension,palpitation,vasodilatation;Uncommon:posturalhypotension,syncope,arrhythmias(including

tachycardia).

Gastrointestinaldisorders–Verycommon:constipation,nausea(seebelow);Common:anorexia,diarrhoea,

dyspepsia,vomiting;Uncommon:bruxism.

Generaldisorders–Verycommon:asthenia,headache;Common:abdominalpain,abnormaldreams,chills,pyrexia;

Rare:anaphylaxis

Metabolicandnutritionaldisorders–Common:changesinserumcholestrol(seebelow);weightgainorloss;

Uncommon:hyponatraemiaincludingSIADH(seeSpecialwarningsandspecialprecautionsforuse),increasedliver

enzymes(seebelow);Rare:hepatitis.

Musculo-skeletaldisorders–Common:arthralgia,myalgia;Uncommon:musclespasm.

Neurologicaldisorders–Verycommon:dizziness,drymouth,insomnia,nervousness,somnolence;Common:

agitation,anxiety,confusion,hypertonia,paraesthesia,tremor;Uncommon:hallucinations,myoclonus;Rare:

disordersofbalanceandcoordination,dyskinesia,dystonia,maniaorhypomania(seeSpecialwarningsandspecial

precautionsforuse),neurolepticmalignantsyndrome-likeeffects,seizures(seeSpecialWarningsandspecial

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 11/05/2009 CRN 2065616 page number: 6

Renalandurinarydisorders–Common:urinaryfrequency;Uncommon:urinaryretention.

Reproductiveandbreastdisorders–Verycommon:abnormalejaculation/orgasm;Common:decreasedlibido,

impotence,menstrualcycledisorders;Rare:galactorrhoea.

Respiratorysystemdisorders–Common:dyspnoea,yawning.

Skinandsubcutaneoustissuedisorders–Verycommon:sweating;Common:pruritis,rash;Uncommon:angioedema,

maculopapulareruptions,urticaria,photosensitivityreactions;Rare:erythemamultiforme,StevensJohnsonsyndrome.

Specialsenses–Common:abnormalvision/accommodation,mydriasis,tinnitus;Uncommon:alteredtastesensation.

Adverseeventsfrompaediatricclinicaltrials:

InpaediatricMDDclinicaltrialsthefollowingadverseeventswerereportedatafrequencyofatleast2%ofpatients

andoccurredatarateofatleasttwicethatofplacebo:abdominalpain,chestpain,tachycardia,anorexia,weightloss,

constipation,dyspepsia,nausea,ecchymosis,epistaxis,mydriasis,myalgia,dizziness,emotionallability,tremor,

hostilityandsuicidalideation.

Specialnotes:

Allergicreactionsincludingurticariaormaculopapulareruptionsaccompaniedbypruritusorangioedemagenerally

resolverapidlyafterdrugdiscontinuation.

Nauseaismostcommonatthestartoftreatmentwiththeincidencedecreasingoverthefirstfewweeks.Thenausea

experiencedwithEfexorisusuallymildtomoderate,andinfrequentlyresultsinvomitingorwithdrawal.Theincidence

increaseswithhigherdosesparticularlywhenthedoseisincreasedrapidly.

Reversibleincreasesinliverenzymesareseeninasmallnumberofpatientstreatedwithvenlafaxine.Thesegenerally

resolveondiscontinuationoftherapy.

Serumcholesterolmaybeincreasedparticularlywithprolongedadministrationandpossiblywithhigherdoses.In

placebo-controlledclinicaltrials,anincreaseinserumcholesterolfrombaseline,of/1.3mmol/L(50mg/dL)andtoa

valueof/6.7mmol/L(260mg/dL),wasobservedin3%ofvenlafaxine-treatedpatientscomparedwith2%ofplacebo-

treatedpatients.

Withdrawalreactionsreportedonabruptcessation,dosereductionortaperingofvenlafaxineincludefatigue,

somnolence,headache,nauseaorvomiting,lossofappetite,dizziness,light-headedness,anorexia,drymouth,

diarrhoea,insomnia,nightmares,nervousness,agitation,anxiety,confusion,hypomania,weakness,decreasedco-

ordination,tinnitus,tremor,paraesthesia,sweatingandvertigo.Themajorityofsymptomsexperiencedonwithdrawal

ofEfexorarenon-seriousandself-limiting(seealsoPosologyandAdministration).

4.9Overdose

Electrocardiogramchanges(e.g.prolongationofQTinterval,bundlebranchblock,QRSprolongation),sinusand

ventriculartachycardia,bradycardiaandseizures,hypotensionandchangesinlevelofconsciousnesshavebeen

reportedinassociatedwithoverdosageovvenlafaxine,usuallywhenincombinationwithalcoholand/orotherCNS

drugs.

ManagementofOverdosage–Ensureanadequateairway,oxygenationandventilation.Monitoringofcardiacrhythm

andvitalsignsisrecommendedasaregeneralsupportiveandsymptomaticmeasures.Useofactivatedcharcoal,

inductionofemesisorgastriclavageshouldbeconsidered.NospecificantidotesforEfexorareknown.

Thehaemodialysisclearanceofvenlafaxineanditsmainactivemetabolitearelow,therefore,theyarenotconsidered

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 11/05/2009 CRN 2065616 page number: 7

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Efexorisastructurallynovelantidepressantwhichischemicallyunrelatedtotricyclic,tetracyclic,orotheravailable

antidepressantagents.Itisaracematewithtwoactiveenantiomers.

ThemechanismofEfexor'santidepressantactioninhumansisbelievedtobeassociatedwithitspotentiationof

neurotransmitteractivityinthecentralnervoussystem.Preclinicalstudieshaveshownthatvenlafaxineanditsmajor

metabolite,O-desmethylvenlafaxine,arepotentneuronalserotoninandnoradrenalinere-uptakeinhibitors(SNRI)and

weakinhibitorsofdopaminereuptake.

Inaddition,venlafaxineandO-desmethylvenlafaxinereduce -adrenergicresponsivenessinanimalsafterbothacute

(singledose)andchronicadministration.Venlafaxineanditsmajormetaboliteappeartobeequipotentwithrespectto

theiroverallactiononneurotransmitterre-uptake.

Venlafaxinehasvirtuallynoaffinityforratbrainmuscarinic,histaminergicoradrenergicreceptorsinvitro.

Pharmacologicactivityatthesereceptorsmayberelatedtovariousside-effectsseenwithotherantidepressantdrugs,

suchasanticholinergic,sedativeandcardiovasculareffects.

5.2Pharmacokineticproperties

Venlafaxineiswellabsorbedandundergoesextensivefirst-passmetabolism.Meanpeakplasmaconcentrationsof

venlafaxinerangefromapproximately33to172ng/mlafter25to150mgsingledoses,andarereachedin

approximately2.4hours.Venlafaxineisextensivelymetabolisedintheliver.

O-desmethylvenlafaxineisthemajoractivemetaboliteofvenlafaxine.Themeandispositionhalf-lifeofvenlafaxine

andO-desmethylvenlafaxineisapproximately5and11hours,respectively.MeanpeakO-desmethylvenlafaxine

plasmaconcentrationsrangefromapproximately61to325ng/mlandarereachedinapproximately4.3hours.Plasma

concentrationsofvenlafaxineandO-desmethylvenlafaxinegenerallycorrelatedwellwithdoselevels.Venlafaxineand

O-desmethylvenlafaxineare27%and30%boundtoplasmaproteinsrespectively.O-desmethylvenlafaxine,other

minorvenlafaxinemetabolites,andnon-metabolisedvenlafaxineareexcretedprimarilythroughthekidneys.

5.3Preclinicalsafetydata

TheoralLD

ofvenlafaxineinmicewas405mg/kginfemaleratsand673mg/kginmalerats.Thesevaluesare

equivalentto45-90timesthemaximumrecommendedhumandose.

Studieswithvenlafaxineinratsandmicerevealednoevidenceofcarcinogenesis.Venlafaxinewasnotmutagenicina

widerangeofinvitroandinvivotests.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Microcrystallinecellulose

LactoseMonohydrate

Sodiumstarchglycolate

Magnesiumstearate

Yellowironoxide(E172)

Brownironoxide(E172)

6.2Incompatibilities

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 11/05/2009 CRN 2065616 page number: 8

6.3ShelfLife

Theshelf-lifeexpirydateofthisproductisthedateshownonthecontainerandouterpackageoftheproductonthe

marketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.

Storeintheoriginalpackage.

6.5Natureandcontentsofcontainer

Blisterspackscontaining28tabletsinanoutercardboardcarton.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7ParallelProductAuthorisationHolder

PCOManufacturingLimited

Unit10,AshbourneBusinessPark

Rath

Ashbourne

Co.Meath

8ParallelProductAuthorisationNumber

PPA0465/085/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Firstdayofauthorisation: 22February2002

Lastdayofauthorisation: 22February2007

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 11/05/2009 CRN 2065616 page number: 9