EDRONAX

Main information

  • Trade name:
  • EDRONAX Tablets 4 Milligram
  • Dosage:
  • 4 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • EDRONAX Tablets 4 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0936/089/002
  • Authorization date:
  • 10-04-2002
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Edronax4mgTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Onetabletcontains4mgofreboxetine

Forfulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablet

White,round,convextabletwithabreaklineononeside.A‘P’ismarkedontheleftsideofthebreakline.A‘U’is

markedontherightsideofthebreakline.Thesideoppositethebreaklineismarked‘7671’.Thetabletcanbedivided

intoequalhalves.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Reboxetineisindicatedfortheacutetreatmentofdepressiveillness/majordepressionandformaintainingtheclinical

improvementinpatientsinitiallyrespondingtotreatment.

4.2Posologyandmethodofadministration

Reboxetineisfororaluse.

Useinadults

Therecommendedtherapeuticdoseis4mgtwiceaday(b.i.d.)i.e.8mg/dayadministeredorally.Thefulltherapeutic

dosecanbegivenuponstartingtreatment.After3-4weeks,thisdosecanbeincreasedto10mg/dayincaseof

incompleteclinicalresponse.Themaximumdailydoseshouldnotexceed12mg.Theminimumeffectivedosehasnot

yetbeenestablished.

Useintheelderly

Elderlypatientshavebeenstudiedinclinicaltrialsatdosesof2mgb.i.d.However,safetyandefficacyhavenotbeen

evaluatedinplacebo-controlledconditions.Therefore,asforotherantidepressantsthathavenotbeenstudiedin

placebo-controlledconditions,reboxetinecannotberecommended.

Useinchildrenandadolescentsundertheageof18years

Reboxetineshouldnotbeusedinthetreatmentofchildrenandadolescentsundertheageof18years(seesection4.4).

Useinpatientswithrenalorhepaticinsufficiency

Thestartingdoseinpatientswithrenalorhepaticinsufficiencyshouldbe2mgb.i.dwhichcanbeincreasedbasedon

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4.3Contraindications

Knownhypersensitivitytoreboxetineoranyofthecomponentsoftheproduct.

4.4Specialwarningsandprecautionsforuse

Useinchildrenandadolescentsunder18yearsofage

Reboxetineshouldnotbeusedinthetreatmentofchildrenandadolescentsundertheageof18years.Suicide-related

behaviours(suicideattemptandsuicidalthoughts),andhostility(predominantlyaggression,oppositionalbehaviourand

anger)weremorefrequentlyobservedinclinicaltrialsamongchildrenandadolescentstreatedwithantidepressants

comparedtothosetreatedwithplacebo.If,basedonclinicalneed,adecisiontotreatisneverthelesstaken,thepatient

shouldbecarefullymonitoredfortheappearanceofsuicidalsymptoms.Inaddition,long-termsafetydatainchildren

andadolescentsconcerninggrowth,maturationandcognitiveandbehaviouraldevelopmentarelacking.

Asreboxetinehasnotbeentestedinpatientswithconvulsivedisordersinclinicalstudiesandsincerarecasesof

seizureshavebeenreportedinclinicalstudies,itshouldbegivenunderclosesupervisiontosubjectswithahistoryof

convulsivedisordersanditmustbediscontinuedifthepatientdevelopsseizures.

ConcomitantuseofMAO-inhibitorsandreboxetineshouldbeavoidedinviewofthepotentialrisk(tyramine-like

effect)basedontheirmechanismsofaction.

Concomitantuseofreboxetinewithotherantidepressants(tricyclics,MAOinhibitors,SSRIsandlithium)hasnotbeen

evaluatedduringclinicaltrials.

Aswithallantidepressants,switchestomania/hypomaniahaveoccurredduringtheclinicalstudies.Closesupervision

ofbipolarpatientsis,therefore,recommended.

Suicide/suicidalthoughtsorclinicalworsening

Depressionisassociatedwithanincreasedriskofsuicidalthoughts,selfharmandsuicide(suicide -relatedevents).

Thisriskpersistsuntilsignificantremissionoccurs.Asimprovementmaynotoccurduringthefirstfewweeksormore

oftreatment,patientsshouldbecloselymonitoreduntilsuchimprovementoccurs.Itisgeneralclinicalexperiencethat

theriskofsuicidemayincreaseintheearlystagesofrecovery.

Patientswithahistoryofsuicide -relatedevents,orthoseexhibitingasignificantdegreeofsuicidalideationpriorto

commencementoftreatmentareknowntobeatgreaterriskofsuicidalthoughtsorsuicideattempts,andshouldreceive

carefulmonitoringduringtreatment.Ameta -analysisofplacebo-controlledclinicaltrialsofantidepressantdrugsin

adultpatientswithpsychiatricdisordersshowedanincreasedriskofsuicidalbehaviourwithantidepressantscompared

toplaceboinpatientslessthan25yearsold.

Closesupervisionofpatientsandinparticularthoseathighriskshouldaccompanydrugtherapyespeciallyinearly

treatmentandfollowingdosechanges.Patients(andcaregiversofpatients)shouldbealertedabouttheneedtomonitor

foranyclinicalworsening,suicidalbehaviourorthoughtsandunusualchangesinbehaviourandtoseekmedicaladvice

immediatelyifthesesymptomspresent.

Clinicalexperiencewithreboxetineinpatientsaffectedbyseriousconcomitantsystemicillnessesislimited.Close

supervisionshouldbeappliedinpatientswithcurrentevidenceofurinaryretention,prostatichypertrophy,glaucoma

andhistoryofcardiacdisease.

Atdoseshigherthanthemaximumrecommended,orthostatichypotensionhasbeenobservedwithgreaterfrequency

thanthatobservedatrecommendeddoses.Particularattentionshouldbepaidwhenadministeringreboxetinewithother

drugsknowntolowerbloodpressure.

Clinicalexperiencewithreboxetineinthelong-termtreatmentofelderlypatientsis,atpresent,limited.Inthis

population,loweringofmeanpotassiumlevelswasfoundstartingfromweek14;themagnitudeofthisreductiondid

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

InvitrometabolismstudiesindicatethatreboxetineisprimarilymetabolisedbytheCYP3A4isozymeofcytochrome

P450;reboxetineisnotmetabolisedbyCYP2D6.ThereforepotentinhibitorsofCYP3A4(ketoconazole,nefazadone,

erythromycinandfluvoxamine),wouldbeexpectedtoincreaseplasmaconcentrationsofreboxetine.Inastudyin

healthyvolunteers,ketoconazole,apotentinhibitorofCYP3A4,wasfoundtoincreaseplasmaconcentrationsofthe

reboxetineenantiomersbyapproximately50%.Becauseofreboxetine’snarrowtherapeuticmargin,inhibitionof

eliminationisamajorconcern.Reboxetine,thereforeshouldnotbegiventogetherwithdrugsknowntoinhibit

CYP3A4suchasazoleantifungalagents,macrolideantibioticssuchaserythromycin,orfluvoxamine.

InvitrostudieshaveshownthatreboxetinedoesnotinhibittheactivityofthefollowingP450isoenzymes:CYP1A2,

CYP2C9,CYP2C19andCYP2E1.Pharmacokineticinteractionswouldnotbeexpectedwithcompoundsmetabolised

bytheenzymes.Atconcentrationswhichexceedthoseinclinicaluse,reboxetineinhibitsCYP2D6andCYP3A4,

however,theresultsofinvivostudiessuggestthatinteractionswithotherdrugsmetabolisedbytheseenzymesare

unlikely.

Nosignificantreciprocalpharmacokineticinteractionhasbeenfoundbetweenreboxetineandlorazepam.Duringtheir

co-administrationinhealthyvolunteers,mildtomoderatedrowsinessandshortlastingorthostaticaccelerationofheart

ratehavebeenobserved.

Reboxetinedoesnotappeartopotentiatetheeffectofalcoholoncognitivefunctionsinhealthyvolunteers.

ConcomitantuseofMAO-inhibitorsandreboxetineshouldbeavoidedinviewofthepotentialrisk(tyramine-like

effect)basedontheirmechanismsofaction.

Concomitantuseofreboxetinewithotherantidepressants(tricyclics,MAOinhibitors,SSRIsandlithium)hasnotbeen

evaluatedduringclinicaltrials.

Concomitantuseofergotderivativesandreboxetinemightresultinincreasedbloodpressure.

Foodintakedelayedtheabsorptionofreboxetine,butdidnotsignificantlyinfluencetheextentofabsorption.

Althoughdataarenotavailablefromclinicalstudies,thepossibilityofhypokalaemiawithconcomitantuseof

potassiumlosingdiureticsshouldbeconsidered.

4.6Fertility,pregnancyandlactation

PREGNANCY

Noclinicaltrialdataonexposuretoreboxetineduringpregnancyareavailable.However,postmarketingsafetydataon

averylimitednumberofexposedpregnanciesindicatenoadverseeffectsofreboxetineonpregnancyoronthehealth

ofthefoetus/newbornchild.

Animalstudiesingeneraldonotindicatedirectorindirectharmfuleffectswithrespecttopregnancy,embryonal/foetal

developmentorparturition.Someimpairmentofgrowthanddevelopmenthasbeennotedinratneonates(seesection

5.3).

Reboxetineshouldonlybeusedinpregnancyifthepotentialbenefitsoftreatmenttothemotheroutweighthepossible

riskstothedevelopingfoetus.

LACTATION

Reboxetineisknowntobeexcretedinbreastmilk.Thelevelofactivesubstancetransferredinbreastmilkis

anticipatedtobeverylow,howeverthereisinsufficientinformationtoexcludearisktothenursinginfant.Theuseof

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4.7Effectsonabilitytodriveandusemachines

Althoughreboxetinehasbeenshowntohavenegligibleeffectonpsychomotorperformanceinhealthyvolunteers,any

psychoactivedrugcanimpairjudgementorskills.Patientsshouldbecautionedaboutdrivingoroperatinghazardous

machineryuntilreasonablycertainthattheirperformancehasnotbeenaffected.

4.8Undesirableeffects

Over2100patientsreceivedreboxetineinclinicalstudies,approximately250ofwhichreceivedreboxetineforatleast

1year.

Commonadverseeventscausingwithdrawalatleasttwiceasoftenonreboxetinethanplaceboincludeinsomnia,

dizziness,drymouth,nausea,sweating,sensationofincompletebladderemptying(malesonly),urinaryhesitancy

(malesonly)andheadache.

Theinformationbelowreferstoshort-termcontrolledstudies.Verycommonorcommonadverseeventsthatareat

leasttwotimeshigheronreboxetinethanplaceboarelistedbelow.

[Verycommon(1/10,Common(1/100, <

1/10)]

Nervoussystemdisorders:

Verycommon:insomnia,Common:vertigo

Cardiacdisorders:

Common:tachycardia,palpitation,vasodilation,posturalhypotension

Eyedisorders:

Common:abnormalityofaccommodation

Gastrointestinaldisorders:

Verycommon:drymouth,constipation

Common:lackorlossofappetite

Skinandsubcutaneousdisorders:

Verycommon:sweating

Renalandurinarydisorders:

Common:urinaryhesitancy,sensationofincompletebladderemptying,urinarytractinfection

Reproductivesystemandbreastdisorders:

Common:erectiledysfunction(malesonly),ejaculatorypain(malesonly),ejaculatorydelay(malesonly),testicular

disorder-primarilypain(malesonly)

Generaldisordersandadministrativesiteconditions:

Common:chills

Inadditiontherehavebeenspontaneousreportsofagitation,anxiety,irritability,aggressivebehaviour,hallucination,

peripheralcoldness,nausea,vomiting,allergicdermatitis/rash,paraesthesia,hypertension,Raynaud’sphenomenon,

hyponatremiaandtesticularpain.

Casesofsuicidalideationandsuicidalbehaviourshavebeenreportedduringreboxetinetherapyorearlyaftertreatment

discontinuation(seesection4.4).

Asforlong-termtolerability,143reboxetine-treatedand140placebo-treatedadultpatientsparticipatedinalongterm

placebocontrolledstudy.Adverseeventsnewlyemergedonlongtermtreatmentin28%ofthereboxetinetreated

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Therewasasimilarriskofthedevelopmentofindividualeventswithreboxetineandplacebo.Inthelongtermstudies,

noindividualeventswereseenwhichhavenotbeenseenonshorttermtreatment.

Inshort-termcontrolledstudiesofpatientswithdepression,noclinicallysignificantbetween-genderdifferenceswere

notedinthefrequencyoftreatmentemergentsymptoms,withtheexceptionofurologicevents(suchasthesensationof

incompletebladderemptying,urinaryhesitancyandurinaryfrequency),whichwerereportedinahigherpercentageof

reboxetine-treatedmalepatients(31.4%[143/456])thanreboxetine-treatedfemalepatients(7.0%[59/847]).In

contrast,thefrequencyofurologic-relatedeventswassimilaramongmale(5.0%[15/302])andfemale(8.4%[37/440])

placebo-treatedpatients.

Intheelderlypopulation,frequencyoftotaladverseevents,aswellasofindividualevents,wasnohigherthanthat

reportedabove.

Inpre-marketingclinicalstudies,signsandsymptomsnewlyreportedonabruptdiscontinuationwereinfrequentand

lessfrequentinpatientstreatedwithreboxetine(4%)thaninthosetreatedwithplacebo(6%).Inpost-marketing

experience,therehavebeenafewspontaneousreportsofwithdrawalsymptomsincludingheadache,dizziness,

nervousnessandnausea;however,noconsistentpatternofeventsoncessationoftreatmentwithreboxetinewasevident

inthesereports.

Inthoseshort-termstudiesindepressionwhereheartratewasassessedwithECG,reboxetinewasassociatedwithmean

increasesinheartrate,comparedtoplacebo,of6to12beatsperminute.

Inallshort-termcontrolledstudiesindepression,themeanchangeinpulse(inbeatsperminute)forreboxetine-treated

patientswas3.0,6.4and2.9inthestanding,sittingandsupinepositionsrespectively,comparedwith0,0,and–0.5for

placebo-treatedpatientsinthecorrespondingpositions.Inthesesamestudies,0.8%ofreboxetine-treatedpatients

discontinuedthedrugbecauseoftachycardiacomparedwith0.1%ofplacebo-treatedpatients.

4.9Overdose

Theacutetoxicitystudiescarriedoutinanimalsindicateaverylowtoxicity,withawidesafetymarginwithrespectto

thepharmacologicallyactivedoses.ClinicalsignsandcauseofdeathwererelatedtoCNSstimulation(mainly

convulsivesymptoms).

Inafewcasesdoseshigherthanthoserecommendedwereadministeredtopatients(12mgto20mg/day)foraperiod

rangingfromafewdaystosomeweeksduringclinicalstudies:newlyreportedcomplaintsincludepostural

hypotension,anxietyandhypertension.Elderlymightbeparticularlyvulnerabletooverdose.

Inpremarketingclinicalstudies,therewere5reportsofreboxetineoverdosealoneorincombinationwithother

pharmacologicagents.Theamountofreboxetineingestedwas52mgasthesoleagentby1patientand20mgin

combinationwithotheragentsbyanotherpatient.Theremaining3patientsingestedunknownquantitiesof

reboxetine.All5patientsrecoveredfully.TherewerenoreportsofECGabnormalities,coma,orconvulsions

followingoverdosewithreboxetinealone.

Inpostmarketingexperience,therehavebeenfewreportsofoverdoseinpatientstakingreboxetinealone;noneofthese

haveprovedfatal.Non-fataloverdosesinpatientshavebeenreportedforpatientstakingupto240mgofreboxetine.

Onefataloverdosewasreportedinapatientwhoingestedreboxetineincombinationwithamitriptyline(doses

unknown).

Incaseofoverdose,monitoringofcardiacfunctionandvitalsignsisrecommended.Generalsymptomaticsupportive

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:OtherAntidepressants

ATCcode:N06AX18

Reboxetineisahighlyselectiveandpotentinhibitorofnoradrenalinereuptake.Ithasonlyaweakeffectonthe5-HT

reuptakeanddoesnotaffecttheuptakeofdopamine.

Noradrenalinereuptakeinhibitionandtheconsequentincreaseofnoradrenalineavailabilityinthesynapticcleftand

modificationofnoradrenergictransmission,reportedlyisamongthemostrelevantmechanismsofactionofknown

antidepressantdrugs.

Invitro,studieshaveshownthatreboxetinehasnosignificantaffinityforadrenergic(

,)andmuscarinic

receptors;antagonismofsuchreceptorshasbeendescribedtobeassociatedwithcardiovascular,anticholinergicand

sedativesideeffectsofotherantidepressantdrugs.

Reboxetineisdevoidofinvitrobindingaffinityforeither

adrenoceptors,however,afunctionalinterference

with-adrenoceptorsathighdosesinvivocannotbeexcluded.

5.2Pharmacokineticproperties

Afteroraladministrationofasingle4mgreboxetinedosetohealthyvolunteers,peaklevelsofabout130ng/mlare

achievedwithin2hpost-dosing.Dataindicatethatabsolutebioavailabilityisatleast60%.

Reboxetineplasmalevelsdecreasedmonoexponentiallywithahalf-lifeofabout13h.Steady-stateconditionsare

observedwithin5days.Linearityofthepharmacokineticswasshownintherangeofsingleoraldosesintheclinically

recommendeddose-ranges.

Thedrugappearstobedistributedintototalbodywater.Reboxetineis97%boundtohumanplasmaproteinsinyoung

and92%inelderly(withaffinitymarkedlyhigherfor

acidglycoproteinthanalbumin),withnosignificant

dependenceoftheconcentrationofdrug.

ReboxetineispredominantlymetabolisedinvitroviacytochromeP4503A(CYP3A4).Invitrostudieshaveshownthat

reboxetinedoesnotinhibittheactivityofthefollowingisoenzymesofcytochromeP450:CYP1A2,CYP2C9,

CYP2C19,andCYP2E1.ReboxetineinhibitsbothCYP2D6andCYP3A4withlowbindingaffinities,buthasshown

noeffectintheinvivoclearanceofdrugsmetabolisedbytheseenzymes.Reboxetineshouldbeco-prescribedwith

cautionwithpotentinhibitorsofCYP3A4.

Theamountofradioactivityexcretedinurineaccountsfor78%ofthedose.Eventhoughunchangeddrugis

predominantinthesystemiccirculation(70%oftotalradioactivity,intermsofAUC),only10%ofthedoseisexcreted

asunchangeddruginurine.Thesefindingssuggestthatbiotransformationrulestheoveralleliminationofreboxetine

andthatmetabolitesexcretionislimitedbytheirformation.Themainmetabolicpathwaysidentifiedare2-O-

dealkylation,hydroxylationoftheethoxyphenoxyringandoxidationofthemorpholinering,followedbypartialor

completeglucuro-orsulpho-conjugation.

Thedrugisavailableasaracemicmixture(withbothenantiomersbeingactiveintheexperimentalmodels):nochiral

inversion,norreciprocalpharmacokineticinterferencesbetweenenantiomershavebeenobserved.Plasmalevelsofthe

morepotentSSenantiomerareabouttwotimeslowerandurinaryexcretiontwotimeshigherthanthoseofthe

enantiomericcounterpart.Nosignificantdifferenceswereobservedintheterminalhalf-livesofthetwoenantiomers.

Increasesinsystemicexposureandhalf-lifeofapproximatelytwo-foldareobservedinpatientswithrenalinsufficiency

andhepaticinsufficiency.Similarorsomewhatgreater(3-fold)increasesinsystemicexposurealsooccurinelderly

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5.3Preclinicalsafetydata

Reboxetinedidnotinducegenemutationsinbacterialormammaliancellsinvitrobutinducedchromosomal

aberrationsinhumanlymphocytesinvitro.ReboxetinedidnotcauseDNAdamageinyeastcellsorrathepatocytesin

vitro.Reboxetinedidnotcausechromosomaldamageinaninvivomousemicronucleustest,anddidnotincrease

tumorincidenceincarcinogenecitystudiesinmiceandrats.

Haemosiderosiswasreportedintoxicitystudiesinratsonly.

Studiesinanimalshavenotdemonstratedanyteratogeniceffectoranyeffectofthecompoundonglobalreproductive

performance.

Dosagesthatproducedplasmaconcentrationswithinthetherapeuticrangeforhumansinducedanimpairmentof

growthanddevelopmentandlongtermbehaviouralchangesinoffspringofrats.

Inratsreboxetineisexcretedinmilk.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Cellulosemicrocrystalline

Calciumhydrogenphosphatedihydrate

Crospovidone

Silica,colloidalhydrated

Magnesiumstearate

6.2Incompatibilities

Notapplicable

6.3Shelflife

3years

6.4Specialprecautionsforstorage

Donotstoreabove25°C.

6.5Natureandcontentsofcontainer

Thetabletsarecontainedeitherinamberglass,typeIII,bottle,closedwithanaluminiumpilfer-proofscrewcap

equippedwithapolyethyleneunderdcaporinaluminium-PVDC/PVC-PVDCopaqueblisters.

Eachpackcontains: 10,20,50,60,100,120,and180tabletsinblisters;and60tabletsinglassbottles.

Multipacksof3x60,5x60and10x60tabletsinblisters;and3x60,5x60and10x60tabletsinglassbottles.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

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7MARKETINGAUTHORISATIONHOLDER

PharmaciaIreland

9Riverwalk

NationalDigitalPark

CitywestBusinessCampus

Dublin24

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA0936/089/002

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:28November1997

Dateoflastrenewal:10April2007

10DATEOFREVISIONOFTHETEXT

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