ATRACURIUM BESILATE, VIAL

Main information

  • Trade name:
  • ATRACURIUM BESILATE, VIAL
  • Dosage:
  • 10
  • Pharmaceutical form:
  • Solution for Injection
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ATRACURIUM BESILATE, VIAL
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0437/042/002
  • Authorization date:
  • 15-06-1998
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

AtracuriumBesilate10mg/mlSolutionforInjection,vial.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Atracuriumbesilate10mg/ml(equivalenttoatracurium7.5mg/ml)

25mlofsolutioncontains250mgatracuriumbesilate.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Solutionforinjection

Aclearcolourlessorfaintyellowsolution.

4CLINICALPARTICULARS

4.1TherapeuticIndications

AtracuriumBesilateInjectionisindicatedasanadjuncttogeneralanaesthesiaduringsurgerytorelaxskeletalmuscles,

andtofacilitateendotrachealintubationandmechanicalventilation.Itisalsoindicatedtofacilitatemechanical

ventilationinintensivecareunit(ICU)patients.

4.2Posologyandmethodofadministration

Useasanadjuncttogeneralanaesthesia

AtracuriumBesilateInjectionshouldonlybeadministeredbyintravenousinjection.

DonotgiveAtracuriumBesilateInjectionintramuscularlysincethismayresultintissueirritationandthereareno

clinicaldatatosupportthisrouteofadministration.

Toavoiddistresstothepatient,AtracuriumBesilateInjectionshouldnotbeadministeredbeforeunconsciousnesshas

beeninduced.AtracuriumBesilateInjectionshouldnotbemixedinthesamesyringe,oradministeredsimultaneously

throughthesameneedle,withalkalinesolutions(e.g.barbituratesolutions).

Incommonwithallneuromuscularblockingagents,monitoringofneuromuscularfunctionisrecommendedduringthe

useofAtracuriumBesilateInjectioninordertoindividualisedosagerequirements.

Initialbolusdosesforintubation

Aninitialatracuriumbesilatedoseof0.3to0.6mg/kg(dependingonthedurationoffullblockrequired),givenasan

intravenousbolusinjection,isrecommended.Thiswillprovideadequaterelaxationforabout15to35minutes.

Endotrachealintubationcanusuallybeaccomplishedwithin90to120secondsoftheintravenousinjectionof0.5to0.6

mg/kg.Maximumneuromuscularblockadeisgenerallyachievedapproximately3to5minutesafteradministration.

Spontaneousrecoveryfromtheendoffullblockoccursinabout35minutesasmeasuredbytherestorationofthe

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Althoughatracuriumispotentiatedby(approximately35%)isofluraneorenfluraneanaesthesia,thesameinitial

atracuriumbesilatedose(0.3to0.6mg/kg)maybeusedforintubationifgivenpriortotheadministrationofthese

inhalationagents.Howeveriftheinitialatracuriumdoseisadministeredaftersteadystateanaesthesiawithisoflurane

orenfluranehasbeenachieved,thedoseofatracuriumshouldbereducedbyapproximatelyone-third.Smallerdosage

reductionsmaybeconsideredwithconcomitanthalothaneanaesthesiasinceithasonlyamarginal(approximately

20%)potentiatingeffectonatracurium.

Maintenancedoses

IntermittentIVinjection:Duringprolongedsurgicalproceduresneuromuscularblockademaybemaintainedwith

atracuriumbesilatemaintenancedosesof0.1to0.2mg/kg.Generally,underbalancedanaesthesia,usingmaintenance

dosesof0.1mg/kg,thefirstmaintenancedoseisrequiredwithin20to45minutesoftheinitialbolusdose,then

typicallyat15to25minuteintervals,however,theneedformaintenancedosesshouldbedeterminedbytheindividual

patient’srequirementsandresponse.

Successivesupplementarydosingdoesnotgiverisetoaccumulationofneuromuscularblockingeffect.

Useasaninfusion:Aftertheinitialatracuriumbolusdose,neuromuscularblockademaybemaintainedduring

prolongedsurgicalproceduresbyadministeringatracuriumbesilateasacontinuousintravenousinfusionatarateof0.3

to0.6mg/kg/hour.Theinfusionshouldnotbecommenceduntilearlyspontaneousrecoveryfromtheinitialatracurium

bolusdoseisevident.

AtracuriumbesilateinfusionsolutionsmaybepreparedbyadmixingAtracuriumBesilateInjectionwithanappropriate

diluent(seebelow)togiveanatracuriumbesilateconcentrationof0.5mg/mlto5mg/ml.

AtracuriumBesilateInjectioncanbeadministeredbyinfusionduringcardiopulmonarybypasssurgeryatthe

recommendedinfusionrates.Inducedhypothermiatoabodytemperatureof25to26°Creducestherateofinactivation

ofatracurium,andthereforefullneuromuscularblockmaybemaintainedwithapproximatelyhalftheoriginalinfusion

rateatthesetemperatures.

Compatibilitywithinfusionsolutions:AtracuriumBesilateInjectiondilutedto0.5mg/mlwiththefollowinginfusion

solutions,andstoredat30°Cprotectedfromlight,wasshowntobestableforthetimesstatedbelow.

AtracuriumBesilateInjectiondilutedto5mg/mlwiththefollowinginfusionsolutions,andstoredat30°Cprotected

InfusionSolution Periodofstability

SodiumChloride0.9%IntravenousInfusion 24hours

Glucose5%IntravenousInfusion 24hours

Glucose4%andSodiumChloride0.18%

IntravenousInfusion 24hours

Ringer’sInjectionUSP 24hours

CompoundSodiumLactateIntravenousInfusion

(Hartmann’sSolutionforInjection) 4hours

InfusionSolution Periodofstability

SodiumChloride0.9%IntravenousInfusion 24hours

Glucose5%IntravenousInfusion 24hours

Glucose4%andSodiumChloride0.18%

IntravenousInfusion 24hours

Ringer’sInjectionUSP 24hours

CompoundSodiumLactateIntravenousInfusion

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Reversalofneuromuscularblockade

Theneuromuscularblockadeinducedbyatracuriumcanbereversedwithananticholinesteraseagentsuchas

neostigmineorpyridostigmine,usuallyinconjunctionwithananticholinergicagentsuchasatropineor

glycopyrroniumtopreventtheadversemuscariniceffectsoftheanticholinesterase.Underbalancedanaesthesia,

reversalcanusuallybeattemptedapproximately20to35minutesaftertheinitialatracuriumdose,orapproximately10

to30minutesafterthelastatracuriummaintenancedose,whenrecoveryofmuscletwitchhasstarted.Complete

reversalofneuromuscularblockadeisusuallyachievedwithin8to10minutesafteradministrationofthereversing

agents.

Rareinstancesofbreathingdifficulties,possiblyrelatedtoincompletereversal,havebeenreportedfollowingattempted

pharmacologicalantagonismofatracuriuminducedneuromuscularblockade.Aswithotheragentsinthisclass,the

tendencyforresidualneuromuscularblockisincreasedifreversalisattemptedatdeeplevelsofblockadeorif

inadequatedosesofreversalagentsareemployed.

Facilitationofmechanicalventilationinintensivecareunit(ICU)patients

Afteranoptionalinitialbolusdoseof0.3to0.6mg/kg,neuromuscularblockmaybemaintainedbyadministeringa

continuousatracuriumbesilateinfusionatratesofbetween11and13microgram/kg/min(0.65to0.78mg/kg/hr).There

maybewideinter-patientvariabilityindosagerequirementsandthesemayincreaseordecreasewithtime.Infusion

ratesaslowas4.5microgram/kg/min(0.27mg/kg/hr)orashighas29.5microgram/kg/min(1.77mg/kg/hr)are

requiredinsomepatients.

TherateofspontaneousrecoveryfromneuromuscularblockafterinfusionofatracuriumbesilateinICUpatientsis

independentofthedurationofadministration.

Spontaneousrecoverytoatrain-of-fourratio>0.75(theratiooftheheightofthefourthtothefirsttwitchinatrain-of-

four)canbeexpectedtooccurinapproximately

60minutes.Arangeof32to108minuteshasbeenobservedinclinicaltrials.

Dosageconsiderations

Useinchildren:Thedosageinchildrenovertheageof1monthissimilartothatinadultsonabodyweightbasis,

however,largeindividualvariabilityintheneuromuscularresponseinpaediatricpatientsindicatesthatneuromuscular

monitoringisessential.

Useinneonates:Thereareinsufficientdatatorecommendadoseinneonates,however,thispatientgroupisknownto

haveincreasedsensitivitytonon-depolarisingmusclerelaxants,andasaresultitisadvisabletoreducedosesinthis

patientgroup.

Useintheelderly:Thestandarddoseofatracuriummaybeusedinelderlypatients,however,itisrecommendedthatit

beadministeredslowly.

Useinpatientswithreducedrenaland/orhepaticfunction:Standarddosagesmaybeusedatalllevelsofrenalor

hepaticfunction,includingendstagefailure.

Useinpatientswithcardiovasculardisease:Inpatientswithsignificantcardiovasculardiseasetheinitialdoseof

atracuriumshouldbeadministeredoveraperiodofatleast

60seconds.

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4.3Contraindications

Knownorsuspectedhypersensitivitytotheproduct.

4.4Specialwarningsandprecautionsforuse

AtracuriumBesilateInjectionshouldbeusedonlybythoseskilledinthemanagementofartificialrespirationandonly

whenfacilitiesareimmediatelyavailableforendotrachealintubationandforprovidingadequateventilationsupport,

includingtheadministrationofoxygenunderpositivepressureandtheeliminationofcarbondioxide.Theclinician

mustbepreparedtoassistorcontrolventilation,andanticholinesteraseagentsshouldbeimmediatelyavailablefor

reversalofneuromuscularblockade.

Atracuriumhasnoknowneffectonconsciousness,painthreshold,orcerebration.Insurgery,itshouldbeusedonly

withadequategeneralanaesthesia.

Incommonwithotherneuromuscularblockingagents,thepotentialforhistaminereleaseexistsinsusceptiblepatients

duringadministrationofatracuriumbesilate.

Cautionshouldbeexercisedinpatientswithahistorysuggestiveofanincreasedsensitivitytotheeffectsofhistamine.

DonotgiveAtracuriumBesilateInjectionbyintramuscularadministration.

AtracuriumBesilateInjectionhasanacidpHandthereforeshouldnotbemixedwithalkalinesolutions(e.g.barbiturate

solutions)inthesamesyringeoradministeredsimultaneouslyduringintravenousinfusionthroughthesameneedle.

DependingontheresultantpHofsuchmixtures,AtracuriumBesilateInjectionmaybeinactivatedandafreeacidmay

beprecipitated.

Whenasmallveinisselectedastheinjectionsite,AtracuriumBesilateInjectionshouldbeflushedthroughthevein

withphysiologicalsalineafterinjection.Whenotheranaestheticdrugs

areadministeredthroughthesameindwellingneedleorcannulaasAtracuriumBesilateInjection,itisimportantthat

eachdrugisflushedthroughwithanadequatevolumeofphysiologicalsaline.

Atracuriummayhaveprofoundeffectsinpatientswithmyastheniagravis,Eaton-Lambertsyndrome,orother

neuromusculardiseasesinwhichpotentiationofnon-depolarisingagentshasbeennoted.Areduceddosageof

atracuriumandtheuseofaperipheralnervestimulatorforassessingneuromuscularblockadeisespeciallyimportantin

thesepatients.Similarprecautionsshouldbetakeninpatientswithsevereelectrolytedisorders.

Atracuriumdoesnothavesignificantvagalorganglionblockingpropertiesintherecommendeddosagerange.

Consequently,atracuriumwillnotcounteractthebradycardiaproducedbymanyanaestheticagentsorbyvagal

stimulationduringsurgery.Therefore,bradycardiaduringanaesthesiamaybemorecommonwithatracuriumthanwith

othermusclerelaxants.

Aswithothernon-depolarisingneuromuscularblockingagents,resistancetoatracuriummaydevelopinpatients

sufferingfromburns.Suchpatientsmayrequireincreaseddosesofatracuriumdependingonthetimeelapsedsincethe

burninjuryandtheextentoftheburn.

AtracuriumBesilateInjectionshouldbeadministeredoveraperiodofatleast60secondstopatientswhomaybe

unusuallysensitivetofallsinarterialbloodpressure,forexamplethosewhoarehypovolaemic.

AtracuriumBesilateInjectionishypotonicandmustnotbeappliedintotheinfusionlineofabloodtransfusion.

Monitoringofserialcreatinephosphokinase(CPK)valuesshouldbeconsideredinasthmaticpatientsreceivinghigh

dosecorticosteroidsandneuromuscularblockingagentsinintensivecareunits.

Specialprecautionsshouldbetakeninpatientswithknownanaphylacticreactionstocurares,ascross-reactivitymaybe

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Aswithothernon-depolarisingneuromuscularblockingagents,themagnitudeand/ordurationofatracurium’seffects

maybeincreasedasaresultofaninteractionwiththefollowingagents.

Inhalationanaesthetics:atracuriumispotentiatedbyisoflurane,desflurane,sevofluraneandenfluraneanaesthesia,and

onlymarginallypotentiatedbyhalothaneanaesthesia.

Antibiotics:includingtheaminoglycosides,polymyxins,spectinomycin,tetracyclines,lincomycin,clindamycinand

vancomycin.

Anticonvulsants(acuteadministrationonly):phenytoin,carbamazepine.

Antiarrhythmicdrugs:localanaestheticssuchaslidocaine,procainamide,quinidine.

Beta-blockers:propranolol,oxprenolol

Antirheumaticdrugs:chloroquine,d-penicillamine

Calciumchannelblockers:diltiazem,nicardipine,nifedipine,verapamil.

Diuretics:frusemide,thiazides,acetazolamideandpossiblymannitol.

Ganglionblockingagents:trimetaphan,hexamethonium.

Others:dantrolene,parenteralmagnesiumsulphate,chlorpromazine,steroids,

ketamine,lithiumsaltsandquinine.

Rarely,someoftheabovedrugsmayaggravateorunmasklatentmyastheniagravisoractuallyinduceamyasthenic

syndrome.Inthesesituationsaconsequentincreasedsensitivitytoatracuriumwouldbeexpected.

Theadministrationofcombinationsofnon-depolarisingneuromuscularblockingagentsinconjunctionwithatracurium

mayproduceadegreeofneuromuscularblockadeinexcessofthatwhichmightbeexpectedwereanequipotenttotal

doseofatracuriumadministered.Anysynergisticeffectmayvarybetweendifferentdrugcombinations.

Adepolarisingmusclerelaxantsuchassuxamethoniumchlorideshouldnotbeadministeredtoprolongthe

neuromuscularblockingeffectsofnondepolarisingblockingagentssuchasatracurium,asthismayresultina

prolongedandcomplexblockwhichcanbedifficulttoreversewithanticholinesterasedrugs.

Theprioruseofsuxamethoniumreducestheonset(tomaximumblockade)byapproximately2to3minutesandmay

increasethedepthofneuromuscularblockadeinducedbyatracurium.Therefore,theinitialatracuriumdoseshouldbe

reducedandthereduceddoseshouldnotbeadministereduntilthepatienthasrecoveredfromtheneuromuscular

blockingeffectsofsuxamethonium.

Theuseofintravenouscorticosteroidswithneuromuscularblockingagentshasbeenreportedtoantagonise

neuromuscularblockades.Inaddition,prolongedco-administrationoftheseagentsmayincreasetheriskand/or

severityofmyopathyresultinginprolongedflaccidparalysisfollowingdiscontinuationoftheneuromuscularblocking

agent.Themyopathyisusuallyreversiblewithrecoveryinseveralmonths.

Theonsetofneuromuscularblockadeislikelytobelengthenedandthedurationofblockadeshortenedinpatients

receivingchronicanticonvulsanttherapy(e.g.carbamazepine,phenytoin).However,iftheanticonvulsantsaregiven

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Inprinciple,maintainingneuromuscularmonitoringuntilcompletereversalofneuromuscularblockadeshouldpermit

detectionofmostinteractions.

Nevertheless,recurrenceofneuromuscularblockademayoccur,forexample,upontreatmentwithpostsurgical

antibiotics.

4.6Pregnancyandlactation

Pregnancy

Atracuriumcrossestheplacentabuttherehavebeennodemonstratedadverseeffectsinthefoetusornewborninfant.

Animalstudieshaveindicatedthatatracuriumhasnoadverseeffectsonfoetaldevelopment.Aswithallneuromuscular

blockingagents,theuseofatracuriuminthefirstthreemonthsofpregnancyshouldbeavoidedanditshouldnotbe

usedduringthesecondandthirdtrimestersunlessclearlynecessary.

Atracuriumissuitableformaintenanceofmusclerelaxationduringcaesareansectionasitdoesnotcrosstheplacentain

clinicallysignificantamountsfollowingrecommendeddoses.Inanopenstudy,atracuriumbesilate(0.3mg/kg)was

administeredto26pregnantwomenduringdeliverybycaesareansection.Noharmfuleffectswereattributableto

atracuriuminanyofthenewborninfants,althoughsmallamountsofatracuriumwereshowntocrosstheplacental

barrier.Thepossibilityofrespiratorydepressioninthenewborninfantshouldalwaysbeconsideredfollowing

caesareansectionduringwhichaneuromuscularblockingagenthasbeenadministered.

AnaesthesiaduringthethirdtrimesterofpregnancyexposesthemothertoMendelsonsyndrome(acidpneumopathy

duetogastricacidaspiration).Ifamusclerelaxantisusedatinductionofanaesthesia,oneshouldbechosenwitha

shortonsetanddurationofactionandlowplacentaltransferandusedinthelowestdoserequiredtoinduceadequate

neuromuscularrelaxation.Inpatientsreceivingmagnesiumsulphate,thereversalofneuromuscularblockademaybe

unsatisfactoryandtheatracuriumdoseshouldbeloweredasindicated.

Breastfeeding

AtracuriumhasarelativelyhighmolecularweightandishighlyionizedatphysiologicpH,bothfactorsthatmarkedly

reducetransferintomilk.Inaddition,eventhoughmilkisslightlymoreacidicthanplasma,anyatracuriumtransferred

intomilkwouldberapidlydegraded.Nevertheless,inviewofthepotentialrespiratorydepressanteffectontheneonate,

especiallyifpremature,itisrecommendedthatifbreastfeedingisstartedwithin24hoursafteradministrationof

atracurium,theneonateiscloselymonitored.

4.7Effectsonabilitytodriveandusemachines

Itisnotrecommendedtousepotentiallydangerousmachineryordriveacarwithin24hoursafterfullrecoveryfrom

theneuromuscularblockingactionofatracurium.

4.8Undesirableeffects

Aswithmostneuromuscularblockingagents,thepotentialexistsforundesirableeffectssuggestiveofhistaminerelease

insusceptiblepatients.Inclinicaltrialsinvolving875patients,reportsofskinflushingrangedfrom1%atdosesupto

0.3mg/kg,to29%atdosesof0.6mg/kgorgreater.Theincidenceoftransienthypotensionrangedfrom1to14%

respectivelyforthecorrespondingdosages.

Otherundesirableeffectsreportedincludedbronchospasm,tachycardiaandrarelyanaphylactoidreactions.

Inlargescaleatracuriumsurveillancestudies,undesirableeffectsconsideredpossiblyorprobablyrelatedtoatracurium

wereobservedinapproximately10%ofpatients.

Localisedskinreactions,generalisedflushingandhypotensioneachoccurredinapproximately2to3%ofpatients.

Hypertension,tachycardiaandbradycardiawereobservedinapproximately1%ofpatients.Bronchospasmwas

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Thefollowingundesirableeffectshavebeenreportedforatracurium:

General:Allergicreactions(i.e.anaphylacticoranaphylactoidresponses)whichinrareinstancesweresevere(e.g.

shock,cardiacfailure,cardiacarrest),angioneuroticoedema.

Musculoskeletal:Inadequateblock,prolongedblock.

Cardiovascular:Hypotension,hypertension,vasodilatation(flushing),tachycardia,bradycardia,hypoxaemia.

Respiratory:Dyspnoea,bronchospasm,laryngospasm,wheezing.

Dermatological:Rash,urticaria,generalisederythema,skinflushing,reactionatinjectionsite.

Afterprolongedadministrationofatracuriumbesilateinseverelyillpatientsunderintensivecare,someincidencesof

muscleweaknessand/ormyopathyoccurred.Mostpatientswereconcomitantlytreatedwithcorticosteroids.Acausal

relationshipwithatracuriumtherapyhasnotbeenestablished.

TherehavebeenrarereportsofseizuresinICUpatientswhohavebeenreceivingatracuriumconcurrentlywithseveral

otheragents.Thesepatientsusuallyhadoneormoremedicalconditionspredisposingtoseizures(e.g.cranialtrauma,

cerebraloedema,viralencephalitis,hypoxicencephalopathy,uraemia).Inclinicaltrials,thereappearstobeno

correlationbetweenplasmalaudanosineconcentrationandtheoccurrenceofseizures.

4.9Overdose

Prolongedmuscleparalysisanditsconsequencesarethemainsignsofoverdose.

Thereislimitedexperiencewithatracuriumoverdosagefollowingparenteraladministration.Thepossibilityof

iatrogenicoverdosagecanbeminimisedbycarefullymonitoringmuscletwitchresponsetoperipheralnerve

stimulation.

Excessivedosesofatracuriumarelikelytoproducesymptomsconsistentwithextensionsoftheusualpharmacological

effects.Overdosagemayincreasetheriskofhistaminereleaseandadversecardiovasculareffects,especially

hypotension.Ifcardiovascularsupportisnecessary,thisshouldincludeproperpositioning,fluidadministration,andthe

useofvasopressoragentsifnecessary.Itisessentialtomaintainapatentairwaywithassistedpositivepressure

ventilationuntilspontaneousrespirationisadequate.Fullsedationwillberequiredsinceconsciousnessisnotimpaired.

Thedurationofneuromuscularblockademaybeprolongedandaperipheralnervestimulatorshouldbeusedtomonitor

recovery.Recoverymaybehastenedbytheadministrationofananticholinesteraseagentsuchasneostigmineor

pyridostigmineinconjunctionwithananticholinergicagentsuchasatropine,onceevidenceofspontaneousrecoveryis

present.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Atracuriumbesilateisanon-depolarisingneuromuscularblockingagent(ATCcodeM03AC04)withanintermediate

durationofaction,administeredintravenouslytoproduceskeletalmusclerelaxation.

Non-depolarisingneuromuscularblockingagentsantagonisetheactionoftheneurotransmitteracetylcholineby

competitivelybindingwithcholinergicreceptorsitesonthemotorendplateofthemyoneuraljunction.Theseeffects

maybeinhibitedorreversedbytheadministrationofanticholinesterasessuchasneostigmineorpyridostigmine.

Aswithothernon-depolarisingneuromuscularblockingagents,thetimetoonsetorparalysisisreduced,andthe

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Oncerecoveryfromatracurium’sneuromuscularblockingeffectbegins,itproceedsmorerapidlythanrecoveryfrom

tubocurarine,alcuronium,andpancuronium.

Regardlessoftheatracuriumdose,thetimefromstartofrecovery(fromcompleteblock)tocompleterecovery(as

measuredbyrestorationofthetetanicresponseto95%ofnormal)isapproximately30minutesunderbalanced

anaesthesia,andapproximately40minutesunderhalothane,enfluraneorisofluraneanaesthesia.

Repeateddoseshavenocumulativeeffectonrecoveryrate.

Withinitialatracuriumbesilatedosesupto0.5mg/kg,plasmahistaminelevelswereshowntoincreaseby15%ina

dosedependantway,buthaemodynamicchangeswereminorwithinthisdoserange.Followingtheadministrationof

0.6mg/kgofatracuriumbesilate,histaminelevelswereshowntoincreaseby92%,andwereshowntocorrelatewitha

transient(5minutes)decreaseinbloodpressureandabrief(2to3minutes)episodeofskinflushing.Whilethese

effectsareoflittleclinicalsignificanceinmostpatients,thepossibilityofsubstantialhistaminereleaseatrecommended

dosesmustbeconsideredinsensitiveindividuals,orinpatientsinwhomsubstantialhistaminereleasewouldbe

especiallyhazardous(e.g.patientswithsignificantrespiratoryorcardiovasculardisease).

Studiesinmalignanthyperthermia-susceptiblepigsindicatedthatatracuriumbesilatedoesnottriggerthissyndrome.

Clinicalstudiesinpatientswithahistoryofmalignanthyperthermiarevealedthesameresults.

Atracuriumbesilatedoesnotappeartoaffectintraocularpressure,therefore,itisasuitableagentforophthalmic

surgery.

5.2Pharmacokineticproperties

Thepharmacokineticsofatracuriumbesilateinhumansareessentiallylinearwithinthedoserangeof0.3to0.6mg/kg.

Theeliminationhalf-lifeisapproximately20minutes.Theproteinbindingofatracuriumisapproximately82%.The

volumeofdistributionofatracuriumis0.16l/kgandplasmaclearanceofatracuriumisabout6.5ml/min/kg.Some

placentaltransferoccursinhumans.Theumbilicalvenoustomaternalvenousdrugconcentrationratiosarebetween

0.03and0.33(mean0.12+/-0.04).

Thedurationofneuromuscularblockadeproducedbyatracuriumdoesnotcorrelatewithplasmapseudocholinesterase

levelsandisnotalteredbytheabsenceofrenalfunction.Thisisconsistentwiththeresultsofinvitrostudieswhich

haveshownthatatracuriumisinactivatedinplasmaviatwonon-oxidativepathways:esterhydrolysis,catalysedby

non-specificesterases;andHofmannelimination,anon-enzymaticchemicalprocesswhichoccursatphysiologicalpH

andbodytemperature.TherateofHofmannelimination,whichistheprincipalrouteofeliminationforatracurium,is

increasedatahigherpHorathighertemperatures,andreducedatalowerpHorlowertemperatures.

Limitedclinicalexperienceonlongtermadministrationofatracuriumbesilateshowonlyminimaleffectsof

haemofiltrationorhaemodialysisonplasmalevelsofatracuriumanditsmetabolites.Theeffectsofhaemoperfusionon

plasmalevelsofatracuriumanditsmetabolitesarenotknown.

5.3Preclinicalsafetydata

Carcinogenicity/Mutagenicity:Carcinogenicitystudieshavenotbeenperformed.

Atracuriumyieldednegativeresultsforgenemutationinbacteria,andchromosomaldamageinbonemarrowofrats.A

positiveresponseinthemouselymphomaassaywasobservedonlyathighlycytotoxicconcentrations.Thissingle

positiveresponseisnotconsideredtobeofclinicalrelevance.

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Benzenesulphonicacid

WaterforInjections.

6.2Incompatibilities

AtracuriumBesilateSolutionforInjectionhasanacidpHandthereforeshouldnotbemixedwithalkalinesolutions

(e.g.barbituratesolutions)inthesamesyringeoradministeredsimultaneouslyduringintravenousinfusionthroughthe

sameneedle.

6.3ShelfLife

Aspackagedforsale–18months.

Inuse–seesection4.2,Posologyandmethodofadministrationforinformationonchemicalandphysicalstability

followingdilutionwithanumberofinfusionsolutions.However,fromamicrobiologicalpointofview,theproduct

shouldbeusedimmediately.Ifnotusedimmediately,inusestoragetimesandconditionspriortousearethe

responsibilityoftheuser.

Discardresidueimmediatelyafteruse.

6.4Specialprecautionsforstorage

Storeinarefrigerator(2°Cto8°C).

Donotfreeze.

Keepcontainerintheoutercarton.

6.5Natureandcontentsofcontainer

25ml:TypeIglassvialwithrubberstopperinpacksof1vial.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Containsnopreservative.Discardresidueimmediatelyafteruse.Donotuseifcloudinessorprecipitateisobserved.

7MARKETINGAUTHORISATIONHOLDER

HospiraUKLimited

Queensway

RoyalLeamingtonSpa

Warwickshire

CV313RW

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8MARKETINGAUTHORISATIONNUMBER

PA0437/042/002

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation: 15June1998

Dateoflastrenewal: 15October2006

10DATEOFREVISIONOFTHETEXT

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