ANEXATE 500 Migrograms/5ml Solution for Inj/Inf

Ireland - English - HPRA (Health Products Regulatory Authority)

Buy It Now

Active ingredient:
FLUMAZENIL
Available from:
Roche Products Limited
ATC code:
V03AB25
INN (International Name):
FLUMAZENIL
Dosage:
500 Migrograms/5ml
Pharmaceutical form:
Solution for Inj/Inf
Prescription type:
Product subject to prescription which may not be renewed (A)
Therapeutic area:
Antidotes
Authorization status:
Authorised
Authorization number:
PA0050/072/001
Authorization date:
1988-02-18

1

Packageleaflet:Informationforthepatient Ireland

Anexate ®

500micrograms/5mlsolution forinjection orinfusion Roche

Flumazenil

Readallofthis leafletcarefullybefore youstarttakingthis medicinebecause itcontains important

informationforyou.

Keepthis leaflet.You mayneed to read itagain.

Ifyou haveanyfurtherquestions,askyourdoctor, orpharmacistornurse.

Ifanyofthe side effects, talkto yourdoctor, orpharmacistornurse.This includes anypossible side

effects notlistedinthis leaflet.See section4.

Whatisinthisleaflet:

1. WhatAnexateisand whatitisused for

2. Whatyou need to knowbeforeyouare givenAnexate

3. HowAnexate willbe given

4. Possible side effects

5. HowAnexate is stored

6. Contentsofthepackand otherinformation

1. WhatAnexateis andwhatitis usedfor

Anexatecontainsa medicine calledflumazenil.Itis usedtowake youupafteryouhave beenmade sleepy

bya medicinecalleda‘benzodiazepine’.

Anexatereverses the effects ofthe‘benzodiazepine’medicine.Itis usedto:

Wakeyouup afteran operation ormedicaltest.

Help you to breatheforyourselfand wakeup ifyou havebeen on aventilatorinintensive care.

Reverseanyunexpectedeffects ofbenzodiazepine treatment

Treatbenzodiazepineoverdose

Helpfind thereason forlossofconsciousnessinunconsciouspatients.

Anexate is alsousedin children (morethan 1 yearold)towakethemupaftertheyhave beengivena

‘benzodiazepine’medicinetomake themsleepyduringa medicalprocedure.

2. Whatyouneedtoknow beforeyouaregivenAnexate

You mustnotbegivenAnexateifyouare allergic (hypersensitive)to:

FlumazeniloranyoftheotheringredientsofAnexate(listedinsection6).

‘Benzodiazepine’medicines.Theseincludediazepam,midazolamandtemazepam.

You mustnotbegivenAnexateifanyoftheaboveapplyto you.Ifyou arenotsure, talkto yourdoctoror

nursebeforehavingAnexate.

You mustnotbegivenAnexateif:

Youare alreadytakinga‘benzodiazepine’medicinetotreata veryserious illness (suchas raisedintra-

cranialpressure orstatus epilepticus).

You havetakena ‘benzodiazepine’medicineandcertainanti-depressantmedicinesatthe same time and

thishasmadeyou ill.These anti-depressantmedicines(knownas tricyclic ortetracyclic anti-

depressants)includemedicines suchasamitriptyline, imipramineand dothiepin hydrochloride.

You mustnotbegivenAnexateifanyoftheaboveapplyto you.Ifyou arenotsure, talkto yourdoctoror

nursebeforehavingAnexate.

2

Warningsand precautions

TalktoyourdoctorornursebeforehavingAnexateif:

Youhaveahead injury.

Youhave epilepsyandare beingtreatedwitha‘benzodiazepine’medicine.

Youareverynervousabouthavingyouroperation ormedicaltest.

You haveahistoryofanxiety.

Youhave heartdiseaseorliverproblems.

Ifanyoftheaboveapplyto you, orifyou arenotsure,talktoyourdoctorornursebeforeyouhaveAnexate.

Othermedicinesand Anexate

Tellyourdoctorornurseifyou aretakingorhave recentlytakenanyothermedicines.Thisincludes

medicinesthatyou buywithoutaprescription and herbalmedicines.This is becauseAnexatecanaffectthe

waysome othermedicines work.Also someothermedicines canaffectthe wayAnexateworks.

In particular, tellyourdoctorornurseifyou aretakinganyofthefollowingmedicines:

‘Benzodiazepine’medicines,evenifyouhave nottakentheminthe lastfewweeks.These include

diazepam,midazolamandtemazepam.

Zopiclone(used tohelpyousleep).

Medicinesthatchangeyourmood orbehaviour.Theseincludemedicines calledtranquillisers,anti-

depressantsandsedatives.

Pregnancyandbreast-feeding

Ifyou arepregnantorbreast-feeding, thinkyou maybepregnantorareplanningtohave a baby,orare

breast-feeding, askyourdoctororpharmacistforadvicebeforetakingthismedicine.

Drivingand usingmachines

Donotdriveoruseanytoolsormachines foratleast24hours afterhavingAnexate.

Do notdo anythingthatisphysicallyormentallydemandingforatleast24 hoursafterhavingAnexate.

This is becausethe effects ofthe ‘benzodiazepine’medicinemayreturn andyoumaystarttofeelsleepy

again.

Anexatecontainssodium

Thismedicinecontainslessthan1mmolsodium(23mg)pertheusualmaximumdose

(600micrograms).

3. HowAnexatewill begiven

Anexatewillbegiven to you byadoctor.It will begivento youas aslowinjection into oneofyourveins.

ThedoseofAnexatevariesfromonepatientto another. Itdependson yourage, weight, howwellyourliver

and kidneysareworkingandwhatyou need themedicinefor.Thedoctorwillworkouthowmuch to give

you.

Ifyou haveanyfurtherquestionson theuseofthismedicine, askyourdoctorornurse.

4. Possiblesideeffects

3

Like allmedicinesAnexatecancause side effects,althoughnoteverybody getsthem.

Seeyourdoctorstraightaway ifyougetthefollowing sideeffects:

Allergic reactions(unknown:frequencycannotbe estimatedfromthe available data):

Suddenswellingofthethroat, face, lipsormouth.This canmake itdifficulttobreathe orswallow.

Sudden swellingofthehands, feetorankles.

Skin rash oritching.

Breathingproblems(veryrare,affectlessthan 1 in 10,000 people):

Respiratoryarrest.Earlysignsincludesuddenlynoisy, difficultand uneven breathing. Yourskin may

becomeblue.

Heartandcirculation(veryrare,affectlessthan 1 in 10,000 people):

Asudden changein blood pressureand heartrate(Haemodynamicshock). Earlysignsincludefeeling

confused, faintand unwell.

Other possible side effects:

Common(affectlessthan 1 in 10 people):

Feelingsickorbeingsickespeciallyifyouhave alsohadanyopiate drugs (e.g.morphine).

Uncommon(affectlessthan 1 in 100 people):

Beingaware ofyourheartrate (palpitations).

Feelinganxiousorfrightened.

These effectsaremost likelytohappenifyouhavewoken up too quickly.

Unknown(frequencyofpeopleaffected unknown):

Panic attacks (inpeople whohave hadpanic attacks inthe past).

Abnormalcrying.

Feelingagitated.

Beingaggressive.

Convulsions(seizures).These are more likelyinpeople whoalreadyhave epilepsyorsevere liver

problemsorinpeoplewho havetaken ‘benzodiazepine’medicinesforalongtime.Convulsionsare also

more likelyinpeople givenAnexate afteranoverdoseofmorethan onemedicine, includingatleastone

‘benzodiazepine’,especiallyiftakenwithcertainanti-depressants.

Increased blood pressureon wakingup (shortlived).

Increasedheartrateon wakingup (shortlived).

Feelingcold (mostlikelyto happen ifyou havewoken up too quickly).

Redness ofthe face andneck(flushing).

Withdrawalsymptoms, forexample:

-Feelingagitated, anxious, confused, dizzy, sweaty,

-Havingmood swings, distortedsenses,anincreasedheartrate.

Withdrawalsymptomsusuallyhappen ifyou aregiven high dosesofAnexatequicklyand/orwhen you

haverecentlytaken‘benzodiazepine’medicines(forexampleto help you sleep orto treatanxiety).This

mayhappenevenifyoustoppedtakingthese medicines a fewdays orweeks before havingAnexate.

The side effects seeninchildrenare similartothose seeninadults.IfAnexatehasbeen used to wakeup

childrenaftera medicaltestitmaycause themtocryabnormally,feelagitatedorbe aggressive.

Ifanyoftheside effectsbecomeseriousortroublesome, orifyou noticeanysideeffectsnotlisted in this

leaflet,please tellyourdoctorornurse.

Reportingofside effects

4

Ifyougetanyside effects,talkto yourdoctoror, pharmacistornurse.This includes anypossible side

effects notlistedinthis leaflet.Youcanalsoreportside effects directly(see details below).Byreporting

sideeffectsyou can help providemoreinformation on thesafetyofthis medicine.

HPRAPharmacovigilance

EarlsfortTerrace

IRL-Dublin 2

Tel:+353 1 6764971

Fax:+353 1 6762517

Website: www.hpra.ie

e-mail: medsafety@hpra.ie

5. HowAnexateis stored

YourdoctororpharmacistisresponsibleforstoringAnexate.Theyarealso responsiblefordisposingof

anyunusedAnexate correctly.

Keep outofthesightandreachofchildren.

Donotuse afterthe expirydate whichis statedonthe pack.

Anexatedoesnotneedanyspecialstorage conditions.

6. Contentsofthepackand otherinformation

WhatAnexatecontains

The active substance inAnexate500 micrograms/5mlsolution forinjection orinfusionisflumazenil.Each

millilitre(ml)ofliquid medicinecontains100 microgramsofflumazenil.Eachampoule (smallglass bottle)

contains500 microgramsofflumazenil(in5 mlofliquid).

Theotheringredients aredisodiumedetate,glacialacetic acid(E260), sodiumchloride, sodiumhydroxide

(E524)(for pHadjustment)and waterforinjections.

WhatAnexatelookslikeand contentsofthepack

Anexateisaclearalmostcolourlessliquid (‘solution forinjection orinfusion’).Thisliquid maybefurther

dilutedtomakeit weakerbeforeit isgiventoyou.

Anexateissupplied inclearglass ampoules inpacksof5.

MarketingAuthorisationHolder

RocheProductsLimited

6FalconWay

ShirePark

Welwyn Garden City, AL7 1TW

United Kingdom

Manufacturer

Roche Pharma AG

Emil-Barell-Str.1

D-79639 Grenzach-Wyhlen

Germany

This leafletwas lastrevisedinOctober2014

5

-------------------------------------------------------------------------------------------------------------------------

Thisinformation isintended formedicalorhealthcareprofessionalsonly:

Thetear-offportion aboveisintended forthepatient

INFORMATION FORHEALTHCAREPROFESSIONALS

Anexate ®

500 micrograms/5ml solution for injectionor infusion

Flumazenil

Pleasereferto theSummaryofProductCharacteristicsforfullprescribinginformation.

Presentation

Clearglass 5mlampoules.Excipients are disodiumedetate,glacialacetic acid(E260), sodiumchloride,

sodiumhydroxide(E524)(forpHadjustment)and waterforinjections.The solutionis clearandalmost

colourless.Cartonsof5ampoules.

Posology andmethodofadministration

Flumazenilmustbe administeredintravenouslybyananaesthetistora doctorwithexperience in

anaesthesiologyandinaunit havingtheappropriatefacilitiesavailable. Flumazenilmaybe administered

eitherundiluted ordiluted.

Itcanbe administeredtogetherwithotherreanimationmeasures.

Anaesthesiology

Theinitialdoseis200 microgramsadministered intravenouslyin 15 seconds. Ifthedesired degreeof

consciousnessisnotobtained within 60 seconds, asecond doseof100 microgramscan beadministered.

This maybe repeatedat60secondintervals where necessary,uptoa maximumtotaldose of1mg. The

usualdoseis300–600 micrograms.

Intensive care

Therecommended initialdoseofflumazenilis300 micrograms intravenously.Ifthe desiredlevelof

consciousnessisnotobtained within 60 seconds, arepeatdoseof100 microgramsmaybeadministered.If

necessary,this maybe repeatedat60secondintervals uptoa totaldose of2mg.Ifdrowsiness recurs, a

second bolusinjection offlumazenilmaybeadministered.An intravenousinfusion of100–400 micrograms

perhourhasalso been shown to beuseful. Thedosageand rateofinfusion should beindividuallyadjusted

toachieve the desiredlevelofsedation.

Hepaticimpairment

Since flumazenilis primarilymetabolizedinthe liver,carefultitrationofdosage is recommendedinpatients

with impaired hepaticfunction.

Use inrenalinsufficiency

Nodosage adjustments are necessaryinpatients withrenal impairment.

Childrenabove1 yearofage

Forthereversalofconscioussedation induced with benzodiazepinesin children >1 yearofage, the

recommended initialdoseis10 micrograms/kg(up to 200 micrograms)administered intravenouslyover15

seconds.Ifthedesired levelofconsciousnessisnotobtained afterwaitingan additional45 seconds, further

injection of10 micrograms/kgmaybeadministered (up to 200 micrograms)and repeated at60 second

intervals where necessary(a maximumof4times)toamaximumtotaldoseof50 micrograms/kgor1 mg,

whicheveris lower.Thedoseshould beindividualised based on thepatient’sresponse.Nodata are

available onthe safetyandefficacyofrepeatedadministrationofflumazeniltochildrenforre-sedation.

Elderly

Nospecific data are available onthe use ofAnexate inthe elderly,butitshouldbe rememberedthatthis

population ismoresensitiveto theeffectsofbenzodiazepinesand should betreated with duecaution.

6

Theindividuallytitrated,slowinjectionsorinfusionsofAnexateshould notproducewithdrawalsymptoms,

even in patientsexposed to high dosesofbenzodiazepinesand/orforlongperiodsoftime. If, however,

unexpected signsofstimulation occur, an individuallytitrated doseofdiazepam(Valium)ormidazolam

(Hypnovel)should begiven byslowintravenousinjection.

Ifasignificantimprovementin consciousnessorrespiratoryfunction isnotobtained afterrepeated dosesof

Anexate, anon-benzodiazepineaetiologymustbeassumed.

Instructions for use

Anexateampoulesolutionmaybedilutedwith SodiumChlorideIntravenousInfusion BPorDextrose5%

IntravenousInfusion BP.

Anexateinfusion should beadministered within24hoursofpreparation.

No preparationsotherthan thoserecommended should beadded to theAnexateampouleormixedwiththe

Anexateinfusion solution.

Forsingleuseonly.Discard anyunused contents.

Shelflife

Unopened:5 years.

Onceopened:Theproductshould beused immediatelyafteropening.

Oncediluted:Chemicalandphysicalin-usestabilityhasbeen demonstrated for24 hoursatroom

temperature.

Fromamicrobiologicalpointofviewtheproductshould beused immediately. Ifnotused immediately, in-

use storage times andconditions priortouse are the responsibilityoftheuserand would normallynotbe

longerthan 24 hoursat2 to 8 °Cunlessdilution hastaken placein controlled and validated aseptic

conditions.

Specialprecautions for storage

Unopened:Thismedicinalproductdoesnotrequireanyspecialstorage conditions.

Oncediluted:Seesection (Shelflife)aboveforstorageconditionsofthediluted product.

Thishealthcare professionalleafletwas lastrevisedinOctober2014

Document Outline

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Anexate500micrograms/5ml,solutionforinjectionorinfusion.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Each5mlampoulecontains500microgramsofflumazenil(100microgramsperml).

Excipient(s)withknowneffect:Sodium3.7mg/ml

Forthefulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Solutionforinjectionandinfusion.

Aclear,almostcolourless,sterileaqueoussolution.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Anexateisindicatedforthecompleteorpartialreversalofthecentralsedativeeffectsofbenzodiazepines.Itmay

thereforebeusedinthefollowingsituations:

Terminationofgeneralanaesthesiainducedand/ormaintainedwithbenzodiazepines.

Reversalofbenzodiazepinesedationinshortdiagnosticandtherapeuticprocedures.

Reversalofparadoxicalreactionsduetobenzodiazepines.

Forthediagnosisand/ormanagementofdeliberateoraccidentalbenzodiazepineoverdosage.

Asadiagnosticmeasureinunconsciousnessofunknownorigin,todifferentiatebetweeninvolvementof

benzodiazepinesandotheraetiologies.

Forthespecificreversalofthecentraleffectsofbenzodiazepines,toallowreturntospontaneousrespirationand

consciousness,inpatientsinintensivecare.

Forthereversalofconscioussedationinducedwithbenzodiazepinesinchildren>1yearofage.

4.2Posologyandmethodofadministration

Flumazenilmustbeadministeredintravenouslybyananaesthetistoradoctorwithexperienceinanaesthesiologyandin

aunithavingtheappropriatefacilitiesavailable.Flumazenilmaybeadministeredeitherundilutedordiluted.

Fordilution,seesection6.6.

Itcanbeadministeredtogetherwithotherreanimationmeasures.

Anaesthesiology

Theinitialdoseis200microgramsadministeredintravenouslyin15seconds.Ifthedesireddegreeofconsciousnessis

notobtainedwithin60seconds,aseconddoseof100microgramscanbeadministered.Thismayberepeatedat60-

Health Products Regulatory Authority

______________________________________________________________________________________________________________________

Date Printed 21/10/2014 CRN 2147173 page number: 1

Intensivecare

Therecommendedinitialdoseofflumazenilis300microgramsintravenously.Ifthedesiredlevelofconsciousnessis

notobtainedwithin60seconds,arepeatdoseof100microgramsmaybeadministered.Ifnecessary,thismaybe

repeatedat60secondintervalsuptoatotaldoseof2mg.Ifdrowsinessrecurs,asecondbolusinjectionofflumazenil

maybeadministered.Anintravenousinfusionof100–400microgramsperhourhasalsobeenshowntobeuseful.The

dosageandrateofinfusionshouldbeindividuallyadjustedtoachievethedesiredlevelofsedation.

Hepaticimpairment:

Sinceflumazenilisprimarilymetabolizedintheliver,carefultitrationofdosageisrecommendedinpatientswith

impairedhepaticfunction.

Useinrenalinsufficiency

Nodosageadjustmentsarenecessaryinpatientswithrenalimpairment.

Childrenabove1yearofage

Forthereversalofconscioussedationinducedwithbenzodiazepinesinchildren>1yearofage,therecommended

initialdoseis10micrograms/kg(upto200micrograms)administeredintravenouslyover15seconds.Ifthedesired

levelofconsciousnessisnotobtainedafterwaitinganadditional45seconds,furtherinjectionof10micrograms/kg

maybeadministered(upto200micrograms)andrepeatedat60secondintervalswherenecessary(amaximumof4

times)toamaximumtotaldoseof50micrograms/kgor1mg,whicheverislower.Thedoseshouldbeindividualised

basedonthepatient’sresponse.Nodataareavailableonthesafetyandefficacyofrepeatedadministrationof

flumazeniltochildrenforre-sedation.

Elderly

NospecificdataareavailableontheuseofAnexateintheelderly,butitshouldberememberedthatthispopulationis

moresensitivetotheeffectsofbenzodiazepinesandshouldbetreatedwithduecaution.

Theindividuallytitrated,slowinjectionsorinfusionsofAnexateshouldnotproducewithdrawalsymptoms,evenin

patientsexposedtohighdosesofbenzodiazepinesand/orforlongperiodsoftime.If,however,unexpectedsignsof

stimulationoccur,anindividuallytitrateddoseofdiazepam(Valium)ormidazolam(Hypnovel)shouldbegivenby

slowintravenousinjection.

IfasignificantimprovementinconsciousnessorrespiratoryfunctionisnotobtainedafterrepeateddosesofAnexate,a

non-benzodiazepineaetiologymustbeassumed.

4.3Contraindications

Flumazeniliscontra-indicatedinpatients:

withhypersensitivitytotheactivesubstance,benzodiazepinesoranyoftheexcipients.

whohavebeenadministeredbenzodiazepinesforthetreatmentofapotentiallylife-threateningcondition(e.g.

increasedintracranialpressureorstatusepilepticus).

4.4Specialwarningsandprecautionsforuse

Untilsufficientdataareavailable,flumazenilshouldonlybeadministeredtochildrenbelowtheageof1yearifthe

riskstothepatient(especiallyinthecaseofaccidentaloverdose)havebeenweighedupagainstthebenefitsofthe

treatment.

Eliminationmaybedelayedinpatientswithhepaticimpairment.

Theantagonisticeffectofflumazenilisspecifictobenzodiazepines;aneffectisthereforenottobeexpectedifthe'non-

awakening'iscausedbyothersubstances.Ifflumazenilisadministeredforanesthesiologyattheendoftheoperation,

theeffectofanyperipheralmusclerelaxantsmustfirsthavedisappeared.Becauseflumazenilgenerallyhasashorter

durationofactionthanthebenzodiazepinesandthereforesedationcanre-occur,theclinicalstateofthepatientmustbe

Health Products Regulatory Authority

______________________________________________________________________________________________________________________

Date Printed 21/10/2014 CRN 2147173 page number: 2

Inhigh-riskpatients,thebenefitsofabenzodiazepine-inducedsedationshouldbeweighedagainsttherisksofarapid

returntoconsciousness.Inpatients(e.g.withcardiacproblems),maintenanceofacertaindegreeofsedationduringthe

earlypost-operativeperiodmaybepreferabletocompleteconsciousness.

Rapidinjectionofflumazenilshouldbeavoided.Inpatientswithhighdoseand/orlong-termexposureto

benzodiazepinesendingatanytimewithintheweeksprecedingflumazeniladministration,rapidinjectionofdoses

equaltoorhigherthan1mghasledtowithdrawalsymptoms,includingpalpitations,agitation,anxiety,emotional

labilityaswellasmildconfusionandsensorydistortions.

Inpatientswhoareanxiousduringthepreoperativephaseorinpatientswhoareknowntosufferfromchronicor

transientanxiety,thedosageofflumazenilshouldbeadjustedcarefully.

However,aftermajorsurgery,thepostoperativepainshouldbeconsideredanditmaybepreferabletokeepthepatient

lightlysedated.

Forpatientswhohavebeentreatedchronicallywithhighdosesofbenzodiazepines,theadvantagesoftheuseof

flumazenilshouldbecarefullyweighedupagainsttheriskofwithdrawalsymptoms;if,despitecarefuldosing,

withdrawalsymptomsoccur,treatmentwithlowdosesofbenzodiazepines,titratedintravenouslyaccordingtothe

patient’sresponse,maybeconsideredifnecessary.

Useoftheantagonistisnotrecommendedinpatientswithepilepsywhohavebeentreatedwithbenzodiazepinesfora

prolongedperiod.Althoughflumazenilexertsaslightintrinsicanticonvulsanteffect,theabruptsuppressionofthe

protectiveeffectofabenzodiazepineagonistcaninduceconvulsionsinepilepticpatients.

Inpatientswithseverebraininjury(and/orinstableintracranialpressure)whoarebeingtreatedwithflumazenil–to

antagonisetheeffectsofbenzodiazepines–increasedintracranialpressuremaydevelop.

Particularcautionisnecessarywhenusingflumazenilincasesofmixed-drugoverdose.Inparticularinthecaseofan

intoxicationwithbenzodiazepinesandcyclicantidepressants,certaintoxiceffectssuchasconvulsionsandcardiac

arrhythmias,whicharecausedbytheseantidepressantsbutwhichemergelessreadilyonconcomitantadministration

withbenzodiazepines,areexacerbatedonadministrationofflumazenil.

Patientswhohavereceivedflumazenilforthereversalofbenzodiazepineeffectsshouldbemonitoredforresedation,

respiratorydepressionorotherresidualbenzodiazepineeffectsforanappropriateperiodbasedonthedoseandduration

ofeffectofthebenzodiazepineemployed.Becausepatientswithunderlyinghepaticimpairmentmayexperience

delayedeffectsasdescribedabove,anextendedobservationperiodmayberequired.

Flumazenilisnotrecommendedforthetreatmentforbenzodiazepinedependenceorforthetreatmentofprotracted

benzodiazepineabstinencesyndromes.

Anexatecontainssodium,butlessthan1mmol(23mg)sodiumpermillilitre.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Flumazenilantagonisesthecentraleffectsofbenzodiazepinesbycompetitiveinteractionatthereceptor.Theeffectsof

non-benzodiazepineagoniststhatactingviathebenzodiazepinereceptor,suchaszopiclone,triazolopyridazineandothers

arealsoblockedbyflumazenil.Interactionswithothercentrallyactingsubstanceshavenotbeenobserved.The

pharmacokineticsofbenzidiazeinesarenotinfluencedbytheantagonistflumazenil.

Onadministeringflumazenilconcomitantlywiththebenzodiazepinesmidazolam,flunitrazepamandlormetazepam,the

pharmacokineticparametersofflumazenilwereunaffected.

However,particularcautionisnecessarywhenusingAnexateincasesofintentionaloverdosagesincethetoxiceffectsof

otherpsychotropicdrugs(especiallytricyclicantidepressants)takenconcurrentlymayincreasewiththesubsidenceofthe

Health Products Regulatory Authority

______________________________________________________________________________________________________________________

Date Printed 21/10/2014 CRN 2147173 page number: 3

Thereisnopharmacokineticinteractionbetweenethanolandflumazenil.

4.6Fertility,pregnancyandlactation

Pregnancy

Thereareinsufficientdataonuseinhumanpregnancyforanassessmentofpossibleharmfuleffectsandefficacyinthe

foetus.Cautionisthereforerequired.Todate,thereisnoevidenceofharmfuleffectsinanimalstudies.Theefficacyin

thefoetushasnotbeeninvestigatedinanimalstudies.

Breast-feeding

Itisunknownwhetherflumazenilisexcretedinhumanmilk.Inemergencysituations,however,theparenteral

administrationofflumazeniltoapatientwhoisbreastfeedingisnotcontraindicated.

4.7Effectsonabilitytodriveandusemachines

Althoughpatientsareawakeandconsciousafteradministrationofflumazenil,theyshouldbeadvisednottooperate

dangerousmachineryordriveavehicleduringthefirst24hoursbecausetheeffectoftheearlieradministered

benzodiazepinemayrecur.

4.8Undesirableeffects

Theadverseeventslistedbelowhavebeenreported.Adverseeventsusuallysubsiderapidlywithouttheneedfor

specialtreatment.

Frequencycategoriesaredefinedusingthefollowingconvention:verycommon(1/10);common(1/100to<1/10);

uncommon(1/1,000to<1/100);rare(1/10,000to<1/1,000);veryrare(<1/10,000);unknown(cannotbeestimated

fromtheavailabledata).

ImmuneSystemDisorders

Unknown:Hypersensitivityreactions,includinganaphylaxis,mayoccur.

Psychiatricdisorders

Uncommon:anxiety,fear : followingrapidinjection,generallydidnotrequiretreatment.

Unknown:Withdrawalsymptoms(e.g.,agitation,anxiety,emotionallability,confusion,sensorydistortions,

tachycardia,dizziness,sweating),followingrapidinjectionofdosesof1mgormoreinpatientswithhigh-doseand/or

long-termexposuretobenzodiazepinesendingatanytimewithintheweeksprecedingflumazeniladministration(see

section4.4);panicattacks(inpatientswithahistoryofpanicreactions);abnormalcrying,agitation,aggressive

reactions(thesideeffectprofileinchildrenisgenerallysimilartothatinadults.Whenflumazenilhasbeenusedforthe

reversalofconscioussedation,abnormalcrying,agitationandaggressivereactionshavebeenreported).

Nervoussystemdisorders

Unknown:Seizures:particularlyinpatientsknowntosufferfromepilepsyorseverehepatic

impairment,mainlyafterlong-termtreatmentwithbenzodiazepinesorincasesofmixed-drugoverdose(seesection

4.4).

Cardiacdisorders

Uncommon:Palpitations:followingrapidinjection,generallydidnotrequiretreatment.

Veryrare:haemodynamicshock

Unknown:Transientincreasesinheartrate(onawakening).

Respiratorydisorders

Veryrare:respiratoryarrest

Vasculardisorders

Health Products Regulatory Authority

______________________________________________________________________________________________________________________

Date Printed 21/10/2014 CRN 2147173 page number: 4

Gastrointestinaldisorders

Common:Nausea:vomiting:duringpost-operativeuse,particularlyifopiateshavealsobeenused.

Skinandsubcutaneoustissuedisorders

Unknown:Flushing.

Generaldisordersandadministrationsiteconditions

Unknown:Chills:followingrapidinjection,generallydidnotrequiretreatment.

Reportingofsuspectedadversereactions

Reportingsuspectedadversereactionsafterauthorisationofthemedicinalproductisimportant.Itallowscontinued

monitoringofthebenefit/riskbalanceofthemedicinalproduct.Healthcareprofessionalsareaskedtoreportany

suspectedadversereactionsvia:HPRAPharmacovigilance,EarlsfortTerrace,IRL-Dublin2,Tel:+35316764971;

Fax:+35316762517;Website:www.hpra.ie;e-mail:medsafety@hpra.ie

4.9Overdose

Incasesofmixed-drugoverdose,particularlywithcyclicantidepressants,toxiceffects(suchasconvulsionsandcardiac

dysrhythmias)mayemergewiththereversalofbenzodiazepineeffectsbyflumazenil.

Thereisverylimitedexperienceofacuteoverdoseinhumanswithflumazenil.

Thereisnospecificantidoteforoverdosewithflumazenil.Treatmentshouldconsistofgeneralsupportivemeasures

includingmonitoringofvitalsignsandobservationoftheclinicalstatusofthepatient.

Evenatdosagesof100mgi.v.,nosymptomsofoverdosagewereobserved.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:benzodiazepineantagonist;ATCcode:V03AB25

Mechanismofaction

Anexate,animidazobenzodiazepine,isaspecificcompetitiveinhibitorofsubstanceswhichactviathebenzodiazepine

receptors,specificallyblockingtheircentraleffects.

Thehypnotic-sedativeeffectsoftheagonistarerapidlyreversedbyAnexateandmaythenreappeargraduallywithina

fewhours,dependingonthehalf-lifeanddoseratiooftheagonistandantagonist.

5.2Pharmacokineticproperties

Thepharmacokineticsofflumazenilaredose-proportionalwithinandabovethetherapeuticrange(upto100mg).

Distribution

Flumazenil,aweaklipophilicbase,isabout50%boundtoplasmaproteins.Albuminaccountsfortwothirdsofplasma

proteinbinding.Flumazenilisextensivelydistributedintheextravascularspace.Plasmaconcentrationsofflumazenil

decreasewithahalf-lifeof4–11minutesduringthedistributionphase.Thevolumeofdistributionatsteadystateis

0.9–1.1l/kg.

BiotransformationFlumazenilisextensivelymetabolisedintheliver.Thecarboxylicacidmetaboliteisthemain

metaboliteinplasma(freeform)andurine(freeformanditsglucuronide).Thismainmetaboliteshowedno

Health Products Regulatory Authority

______________________________________________________________________________________________________________________

Date Printed 21/10/2014 CRN 2147173 page number: 5

Elimination

Flumazenilisalmostcompletely(99%)eliminatedbynonrenalroutes.Practicallynounchangedflumazenilisexcreted

intheurine,suggestingcompletemetabolicdegradationofthedrug.Eliminationofradiolabelleddrugisessentially

completewithin72hours,with90-95%oftheradioactivityappearinginurineand5-10%inthefaeces.Elimination

israpid,asshownbyashorteliminationhalf-lifeof40-80minutes.Thetotalplasmaclearanceofflumazenilis0.8–

1.0l/hr/kgandcanbeattributedalmostentirelytohepaticclearance.

Ingestionoffoodduringanintravenousinfusionofflumazenilresultsina50%increaseinclearance,mostlikelydueto

theincreasedhepaticbloodflowthataccompaniesameal.

Pharmacokineticsinspecialpopulations

Inpatientswithimpairedliverfunction,theeliminationhalf-lifeofflumazenilislonger(1.3hoursinmoderate

impairmentand2.4hoursinseverelyimpairedpatients)andthetotalbodyclearancelowerthaninhealthysubjects.

Thepharmacokineticsofflumazenilarenotsignificantlyaffectedintheelderly,bygender,haemodialysisorrenal

failure.

Paediatricpopulation

Inchildrenaboveoneyearofage,thehalf-lifeeliminationisshorterandthevariabilityishigherthaninadults

(approximately40minwitharangeof20to75minrespectively).Clearanceandvolumeofdistribution,bykgofbody

weightarethesameasinadults.

5.3Preclinicalsafetydata

Otherthanpreclinicalinformationprovidedundersection4.6,nofurtherinformationisrelevant.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Disodiumedetate

Glacialaceticacid(E260)

Sodiumchloride

Sodiumhydroxide(E524)(forpHadjustment)

Waterforinjections

6.2Incompatibilities

Nopreparationsotherthanthoserecommendedinsection6.6shouldbeaddedtotheAnexateampouleormixedwith

theAnexateinfusionsolution.

6.3Shelflife

Unopened:5years.

Onceopened:Theproductshouldbeusedimmediatelyafteropening.

Oncediluted:Chemicalandphysicalin-usestabilityhasbeendemonstratedfor24hoursatroomtemperature.

Fromamicrobiologicalpointofviewtheproductshouldbeusedimmediately.Ifnotusedimmediately,in-usestorage

timesandconditionspriortousearetheresponsibilityoftheuserandwouldnormallynotbelongerthan24hoursat2

Health Products Regulatory Authority

______________________________________________________________________________________________________________________

Date Printed 21/10/2014 CRN 2147173 page number: 6

6.4Specialprecautionsforstorage

Unopened:Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

Oncediluted:Seesection6.3forstorageconditionsofthedilutedproduct.

6.5Natureandcontentsofcontainer

5ml,clear,typeIglassampoule.Packof5

6.6Specialprecautionsfordisposalandotherhandling

Diluents

AnexateampoulesolutionmaybedilutedwithSodiumChlorideIntravenousInfusionBP,orDextrose5%Intravenous

InfusionBP.

NopreparationsotherthanthoserecommendedshouldbeaddedtoAnexateampouleormixedwithAnexatesolution.

Forsingleuseonly.

Discardanyunusedcontents.

7MARKETINGAUTHORISATIONHOLDER

RocheProductsLimited

6FalconWay

ShirePark

WelwynGardenCity

AL71TW

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA0050/072/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:18February1988

Dateoflastrenewal:18February2008

10DATEOFREVISIONOFTHETEXT

Health Products Regulatory Authority

______________________________________________________________________________________________________________________

Date Printed 21/10/2014 CRN 2147173 page number: 7

Similar products

Search alerts related to this product

View documents history

Share this information