FLUMAZENIL

Main information

  • Trade name:
  • FLUMAZENIL Solution for Injection 0.1 Mg/ Ml
  • Dosage:
  • 0.1 Mg/ Ml
  • Pharmaceutical form:
  • Solution for Injection
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • FLUMAZENIL Solution for Injection 0.1 Mg/Ml
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0736/025/001
  • Authorization date:
  • 09-11-2007
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Flumazenil0.1mg/mlsolutionforinjection

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachmlcontains0.1mgflumazenil.

1ampoulewith5mlcontains0.5mgflumazenil.

1ampoulewith10mlcontains1mgflumazenil.

Excipient:Sodium3.7mg/ml.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Solutionforinjection

concentrateforsolutionforinfusion

clearcolourlesssolution

pH3.9–5.0

4CLINICALPARTICULARS

4.1TherapeuticIndications

Flumazenilisindicatedforthecompleteorpartialreversalofthecentralsedativeeffectsofbenzodiazepines.Itmay

thereforebeusedinanaesthesiaandintheintensivecareinthefollowingsituations:

Inanaesthesia

Terminationofhypnosedativeeffectsingeneralanaesthesiainducedand/or

maintainedwithbenzodiazepinesinhospitalizedpatients.

Reversalofbenzodiazepinesedationinshort-termdiagnosticandtherapeutic

proceduresinambulatorypatientsandhospitalizedpatients.

Inintensivecaresituations

Forthespecificreversalofthecentraleffectsofbenzodiazepines,inordertorestorespontaneousrespiration.

Fordiagnosisandtreatmentofintoxicationsoroverdosewithonlyormainlybenzodiazepines.

4.2Posologyandmethodofadministration

Flumazenilshouldbeadministeredintravenouslybyananaesthetistorexperiencedphysician.

Flumazenilmaybeadministeredasinjectionorasinfusion(Forinstructionsondilutionoftheproductbefore

administration,seesection6.6).

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Thismedicinalproductisforsingleuseonly.Itshouldbeinspectedvisuallypriortouseandshouldonlybeusedifthe

solutionisclearandpracticallyfreefromparticles

Adults:

Anaesthesia

Therecommendedstartingdoseis0.2mgadministeredintravenouslyover15seconds.Iftherequiredlevelof

consciousnessisnotobtainedwithin60seconds,afurtherdoseof0.1mgcanbeinjectedandrepeatedat60-second

intervals,uptoamaximumdoseof1.0mg.Theusualdoserequiredliesbetween0.3and0.6mg,butmaydeviate

dependingonthepatient’scharacteristicsandthebenzodiazepineused.

IntensiveCare

Therecommendedstartingdoseis0.2mgadministeredintravenouslyover15seconds.Iftherequiredlevelof

consciousnessisnotobtainedwithin60seconds,afurtherdoseof0.1mgcanbeinjectedandrepeatedat60-second

intervals,uptoatotaldoseof2mgoruntilthepatientawakes.

Ifdrowsinessrecurs,anintravenousinfusionof0.1–0.4mg/hmaybeuseful.

Therateofinfusionshouldbeadjustedindividuallytoachievethedesiredlevelofconsciousness.

Ifnocleareffectonawarenessandrespirationisobtainedafterrepeateddosing,itshouldbeconsideredthatthe

intoxicationisnotduetobenzodiazepines.

Infusionshouldbediscontinuedevery6hourstoverifywhetherresedationoccurs.

Toavoidwithdrawalsymptomsinpatientstreatedforalongperiodoftimewithhighdosesofbenzodiazepinesinthe

intensivecareunit,thedosageofflumazenilhastobetitratedindividuallyandtheinjectionhastobeadministered

slowly(seesection4.4).

Elderly

Intheabsenceofdataontheuseofflumazenilinelderlypatients,itshouldbenotedthatthispopulationisgenerally

moresensitivetotheeffectsofmedicinalproductsandshouldbetreatedwithduecaution.

Childrenandadolescents(from1to17years)

Forthereversalofconscioussedationinducedbybenzodiazepinesinchildrenolderthan1yeartherecommended

startingdoseis0.01mg/kg(upto0.2mg),administeredintravenouslyoveraperiodof15seconds.If,afterawaiting

periodof45seconds,therequiredlevelofconsciousnessisnotobtainedafollow-upinjectionof0.01mg/kg(upto0.2

mg)maybeadministeredandwherenecessaryrepeatedat60-secondintervals(uptoamaximumof4times)toa

maximumdoseof0.05mg/kgor1mg,dependingonwhichisthelowestdose.Thedoseshouldbeadjustedtothe

patient’sresponse.Therearenodataonsafetyandefficacyofrepeatedflumazeniladministrationinchildrenincaseof

resedation.

Childrenundertheageof1year

Thereareinsufficientdataontheuseofflumazenilinchildrenunder1year.

Thereforeflumazenilshouldonlybeadministeredinchildrenunder1yearifthepotentialbenefitstothepatient

outweighthepossiblerisk.

Patientswithrenalorhepaticimpairment

Inpatientswithimpairedhepaticfunction,theeliminationofflumazenilmaybedelayed(seesection5.2)andtherefore

carefultitrationofdosageisrecommended.Nodosageadjustmentsarerequiredinpatientswithrenalimpairment.

4.3Contraindications

Hypersensitivitytoflumazenilortoanyoftheexcipients.

Patientsreceivingbenzodiazepinesforcontrolofapotentiallylife-threateningcondition(e.g.controlofintracranial

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Inmixedintoxicationswithbenzodiazepinesandtricyclicand/ortetracyclicantidepressants,thetoxicityofthe

antidepressantscanbemaskedbyprotectivebenzodiazepineeffects.

Inthepresenceofautonomic(anticholinergic),neurological(motorabnormalities)orcardiovascularsymptomsof

severeintoxicationwithtricyclics/tetracyclics,Flumazenilshouldnotbeusedtoreversebenzodiazepineeffect.

4.4Specialwarningsandprecautionsforuse

Thepatientshouldbemonitoredforanadequateperiodoftime(ECG,pulse,oximetry,patientalertnessandother

vitalsignssuchasheartrate,respiratoryrateandbloodpressure).

Flumazenilspecificallyreversesbenzodiazepines.Thereforeifthepatientdoesnotwakeup,anotheraetiology

shouldbeconsidered.

Whenusedinanaesthesiologyattheendofsurgery,flumazenilshouldnotbegivenuntiltheeffectsofperipheral

musclerelaxantshavebeenfullyreversed.

Astheactionofflumazenilisusuallyshorterthanthatofbenzodiazepinesandsedationmaypossiblyrecurthe

patientshouldremaincloselymonitored,preferablyintheintensivecareunit,untiltheeffectofflumazenilhas

presumablywornoff.

Inpatientsatincreasedrisktheadvantagesofsedationbymeansofbenzodiazepinesshouldbeweighedagainstthe

drawbacksofrapidawakening.Inpatients(e.g.withcardiacproblems)maintenanceofacertainlevelofsedation

maybepreferabletobeingfullyawake.

Rapidinjectionofhighdoses(morethan1mg)flumazenilshouldbeavoidedinpatientswhoreceivechronic

treatmentwithbenzodiazepinesasthismaycausewithdrawalsymptoms.

Inpatientssufferingfrompre-operativeanxietyorhavingahistoryofchronicorepisodicanxietythedosageof

flumazenilshouldbeadjustedcarefully.

Postoperativepainmustbetakenintoaccount.

Inpatientstreatedforlongperiodswithhighdosesofbenzodiazepines,theadvantagesoftheuseofflumazenil

shouldbeweighedagainsttheriskofwithdrawalsymptoms.Ifwithdrawalsymptomsoccurdespitecarefuldosing

anindividuallytitrateddoseof5mgdiazepamor5mgmidazolamshouldbegivenbyslowintravenousinjection.

Becauseofthepotentialforresedationandrespiratorydepressionchildrenpreviouslysedatedwithmidazolam

shouldbemonitoredatleast2hoursafterflumazeniladministration.Incaseofothersedatingbenzodiazepines,the

monitoringtimemustbeadjustedaccordingtotheirexpectedduration.

Untilsufficientdataareavailableflumazenilshouldnotbeusedinchildrenof1yearoryoungerunlesstherisksfor

thepatient(especiallyincaseofaccidentaloverdose)havebeenweighedagainsttheadvantagesofthetherapy.

Useinchildrenforotherindicationsthanreversalofconscioussedationisnotrecommemdedasnocontrolled

studiesareavailable.Thesameappliesforchildrenbelowtheageof1year.

Theuseoftheantagonistisnotrecommendedinpatientswithepilepsy,whohavebeentreatedwith

benzodiazepinesforaprolongedperiodoftime.Althoughflumazenilhassomeintrinsicanti-epilepticeffects,the

abruptantagonisingeffectcancauseconvulsionsinpatientswithepilepsy.

Inpatientswithseriousbraindamage(and/orinstableintracranialpressure)receivingflumazenil–toreversethe

effectsofbenzodiazepines–anincreasedintracranialpressuremaydevelop.

Flumazenilisnotrecommendedforthetreatmentofbenzodiazepine-dependenceorforthetreatmentoflong-term

benzodiazepine-abstinence-syndromes.

Panicattackshavebeenreportedaftertheuseofflumazenilinpatientswithahistoryofpanicdisorder.

Duetotheincreasedfrequencyofbenzodiazepinestoleranceanddependenceinpatientswithalcoholismandother

drugdependencies,flumazenilshouldbeusedwithcautioninthispopulation.

Thismedicinalproductcontainsapproximately3.7mgsodiumpermlofflumazenilsolutionforinjection.This

shouldbetakenintoconsiderationbypatientsonacontrolledsodiumdiet.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Flumazenilreversesthecentraleffectsofbenzodiazepinesbymeansofcompetitiveinteractionatreceptorlevel:the

effectsofnon-benzodiazepineagonistsactingviathebenzodiazepinereceptor,suchaszopiclone,triazolopyridazine

andothers,arealsoantagonisedbyflumazenil.However,flumazenildoesnotblocktheeffectofmedicinalproducts

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Particularcautionisnecessarywhenusingflumazenilincasesofaccidentaloverdosesincethetoxiceffectsofother

psychotropicmedicinalproducts(especiallytricyclicantidepressants)takenconcurrentlymayincreasewiththe

subsidenceofthebenzodiazepineeffect.

Nochangeinthepharmacokineticsofflumazenilhasbeenobservedincombinationwiththebenzodiazepines

midazolam,flunitrazepamandlormetazepam.Flumazenildoesnotaffectthepharmacokineticsofthese

benzodiazepines.

4.6Fertility,pregnancyandlactation

Althoughstudiesinanimalshavenotshownevidenceofembryotoxicityorteratogenicity,thepossiblerisktohumans

causedbyflumazenilduringpregnancyhasnotbeendetermined(seesection5.3).Therefore,flumazenilshouldonlybe

usedduringpregnancyifthepossiblebenefittothepatientoutweighsthepotentialrisksforthefoetus.

Itisnotknownwhetherflumazenilisexcretedinhumanmilk.Forthisreason,breast-feedingshouldbeinterruptedfor

24hourswhenflumazenilisusedduringlactation.

Emergencyuseofflumazenilduringpregnancyandlactationisnotcontra-indicated.

4.7Effectsonabilitytodriveandusemachines

Patientswhohavereceivedflumazeniltoreversetheeffectsofbenzodiazepinesedationshouldbewarnednottodrive,

tooperatemachineryortoengageinotheractivitiesdemandingphysicalormentalexertionforatleast24hours,since

theeffectofthebenzodiazepinemayreturn.

4.8Undesirableeffects

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),notknown(cannotbeestimatedfromtheavailabledata)

Immunesystems

disorders Allergicreactions. Common

Psychiatricdisorders Anxiety*,emotional

lability,insomnia,

somnolence. Common

Nervoussystem

disorders Vertigo,headache,

agitation*,tremor,dry

mouth,hyperventilation,

speechdisorder,paresthesia. Common

Convulsions(inpatients

sufferingepilepsyorsevere

hepaticinsufficiency,

mainlyafterlong-term

treatmentwith

benzodiazepinesormultiple

medicinalproductsabuse). Uncommon

Eardisorders Abnormalhearing. Uncommon

Eyedisorders Diplopia,strabismus,

lacrimationincreased. Common

Cardiacdisorders Palpitations*. Common

Tachycardiaorbradycardia,

extrasystole. Uncommon

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*:afterrapidinjection,notrequiringtreatment

Inpatientstreatedforlongperiodswithbenzodiazepinesflumazenilcaninducewithdrawalsymptoms.Thesymptoms

are:tension,agitation,anxiety,confusion,hallucinations,tremorandconvulsions.

Ingeneraltheundesirableeffectprofileinchildrendoesnotdiffermuchfromthatinadults.Whenusingflumazenilfor

thereversalofconscioussedationabnormalcrying,agitationandaggressivereactionshavebeenreported.

4.9Overdose

Evenwhenadministeredintravenouslyatdosesof100mg,nosymptomsofoverdoseattributabletoflumazenilhave

beenobserved.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Antidotes.

ATCcode:V03AB25

Flumazenil,animidazobenzodiazepine,isabenzodiazepineantagonistwhich,bycompetitiveinteraction,blocksthe

effectsofsubstancesactingviathebenzodiazepine-receptor.Neutralisationofparadoxalreactionsofbenzodiazepines

hasbeenreported.

Accordingtoexperimentsinanimals,theeffectsofsubstances,whicharenotactingviathebenzodiazepine-receptor

(likebarbiturates,GABA-mimeticsandadenosine-receptoragonists),arenotblockedbyflumazenil.Non-

benzodiazepine-agonists,likecyclopyrrolones(zopiclon)andtriazolopyridazines,areblockedbyflumazenil.The

hypnosedativeeffectsofbenzodiazepinesareblockedrapidly(within1-2minutes)afterintravenousadministration.

Dependingonthedifferenceineliminationtimebetweenagonistandantagonist,theeffectcanrecurafterseveral

hours.Flumazenilhaspossiblyaslightagonistic,anticonvulsiveeffect.Flumazenilcausedwithdrawal,including

convulsionsinanimalsreceivinglong-termflumazeniltreatment.

5.2Pharmacokineticproperties

Distribution

Flumazenilisalipophilicweakbase.Flumazenilisboundforapproximately50%toplasmaproteins,fromwhichtwo

thirdsareboundtoalbumin.Flumazenilisextensivelydividedoverextravascularspace.Duringthedistributionphase

plasmaconcentrationofflumazenildecreaseswithahalflifeof4-15minutes.Thedistributionvolumeundersteady-

Vasculardisorders orthostatichypotension,

transientincreasedblood

pressure(onawakening). Common

Respiratory,thoracic

andmediastinal

disorders Dyspnoea,cough,nasal

congestion,chestpain. Uncommon

Gastrointestinal

disorders Nausea(during

anaesthesia). Verycommon

Vomiting(during

anaesthesia),hiccup. Common

Skinandsubcutaneous

tissuedisorders Sweating. Common

Generaldisordersand

administrationsite

conditions Fatigue,injectionsitepain. Common

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Metabolism

Flumazenilismainlyeliminatedthroughhepaticmetabolism.Thecarboxylicacidmetabolitewasshowninplasma(in

freeform)andinurine(infreeandconjugatedform)tobethemostimportantmetabolite.

Inpharmacologicalteststhismetabolitehasprovedtobeinactiveasbenzodiazepineagonistorantagonist.

Elimination

Almostnounchangedflumazenilisexcretedintheurine.Thisindicatesacompletemetabolicdegradationoftheactive

substanceinthebody.Radiolabelledmedicinalproductiscompletelyeliminatedwithin72hours,with90to95%of

theradioactivityappearingintheurineand5to10%inthefaeces.Eliminationisrapid,asisshownbytheshorthalf

lifeof40to80minutes.Thetotalplasmaclearanceofflumazenilis0.8to1.0l/hour/kgandcanalmostcompletelybe

attributedtohepaticmetabolism.

Thepharmacokineticsofflumazenilisdose-proportionalwithinthetherapeuticdose-rangeandupto100mg.

Theintakeoffoodduringtheintravenousinfusionofflumazenilresultsinanincreaseof50%oftheclearance

probablyduetopostprandialincreaseinliverperfusion.

Pharmacokineticsinspecialpatientgroups

Elderly

Thepharmacokineticsofflumazenilinelderlyisnotdifferentfromthatinyoungadults.

Patientswithimpairedhepaticfunction

Inpatientswithamoderatelytoseverelyimpairedliverfunctionthehalflifeofflumazenilisincreased(increaseof70

–210%)andthetotalclearanceislower(between57and74%)comparedtonormalhealthyvolunteers.

Patientswithimpairedrenalfunction

Pharmacokineticsofflumazenilisnotdifferentinpatientswithimpairedrenalfunctionorpatientsundergoing

haemodialysiscomparedtonormalhealthyvolunteers.

Children

Thehalflifeofflumazenilinchildrenovertheageofoneisalittleshorterandvariesmorethaninadultsandamounts

toanaverageof40minutes(ingeneralvaryingfrom20to75minutes).Theclearanceandthedistributionvolume,

correctedforbodyweight,arethesameasinadults.

5.3Preclinicalsafetydata

Lateprenatalaswellasper-andpostnatalexposuretoflumazenilinducedbothbehaviouralalterationsandanincrease

ofhippocampalbenzodiazepinereceptordensityintheratoffspring.Theeffectofthesefindingsisnotconsidered

relevantiftheproductisusedforaveryshorttimeasinstructed.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Disodiumedetate

Glacialaceticacid

Sodiumchloride

Sodiumhydroxidesolution4%forpHadjustment

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6.2Incompatibilities

Thismedicinalproductmustnotbemixedwithothermedicinalproductsexceptforthosementionedinsection6.6.

6.3Shelflife

3years.

Shelflifeafterfirstopening:

Afterfirstopeningthemedicinalproductshouldbeusedimmediately.

Shelflifeafterdilution:

Chemicalandphysicalin-usestabilityhasbeendemonstratedfor24hoursat25°C.

Fromamicrobiologicalpointofview,theproductshouldbeusedimmediately.Ifnotusedimmediately,in-usestorage

timesandconditionspriortousearetheresponsibilityoftheuserandwouldnormallynotbelongerthan24hoursat2

to8°C,unlessdilutionhastakenplaceincontrolledandvalidatedasepticconditions.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.

6.5Natureandcontentsofcontainer

Cartonboxeswith5or10ampoules(colourlessglassTypeI)containing5mlsolutionforinjection.

Cartonboxeswith5or10ampoules(colourlessglassTypeI)containing10mlsolutionforinjection.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Anyunusedsolutionshouldbediscarded.

Whenflumazenilistobeusedininfusion,itmustbedilutedpriortoinfusion.Flumazenilshouldonlybedilutedwith

sodiumchloride9mg/ml(0.9%)solution,dextrose50mg/ml(5%)solutionorsodiumchloride4.5mg/ml(0.45%)+

dextrose25mg/ml(2.5%)solution.

Compatibilitybetweenflumazenilandothersolutionsforinjectionhasnotbeenestablished.

Intravenousinfusionsolutionsshouldbediscardedafter24hours.

7MARKETINGAUTHORISATIONHOLDER

B.BraunMelsungenAG

Carl-Braun-Strasse1

34212Melsungen

Germany

8MARKETINGAUTHORISATIONNUMBER

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9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:9thNovember2007

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