ATRACURIUM BESILATE, VIAL 10 Micromol Solution for Injection

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
ATRACURIUM BESILATE
Available from:
HOSPIRA UK Ltd
INN (International Name):
ATRACURIUM BESILATE
Dosage:
10 Micromol
Pharmaceutical form:
Solution for Injection
Prescription type:
Product subject to prescription which may not be renewed (A)
Authorization status:
Authorised
Authorization number:
PA0437/042/002
Authorization date:
0000-00-00

PACKAGE LEAFLET:INFORMATION FOR THE USER

AtracuriumBesilate 10 mg/ml Solution for Injection

The active substance is atracuriumbesilate

Read all of this leaflet carefully before you start taking this medicine.

- Keep this leaflet. You mayneed to read it again.

- If youhave anyfurtherquestions, ask your doctor.

- If anyof the side effects gets serious, or ifyou noticeanyside effects not listed inthis

leaflet, pleasetellyourdoctor or pharmacist.

In this leaflet:

1. What AtracuriumBesilateSolution for Injection is and what it is used for

2. Before youare given AtracuriumBesilateSolution forInjection

3. How you are given AtracuriumBesilate Solution for Injection

4. Possible side effects

5. How to store AtracuriumBesilate Solution for Injection

6.Further information

1. WHAT ATRACURIUMBESILATESOLUTIONFOR INJECTION IS AND

WHAT IT IS USED FOR

AtracuriumBesilate Solution for Injection isa medicine which actsas amuscle relaxant.

AtracuriumBesilateSolution for Injection isusedduring surgeryto relaxmusclesand to

assistwith inserting a breathing tube and with artificial breathing. It is also usedto help with

artificial breathing inpatients in intensive care.

2. BEFORE YOU ARE GIVEN ATRACURIUM BESILATE SOLUTIONFOR

INJECTION

You will notbe given AtracuriumBesilate Solution for Injection

- if you are allergic (hypersensitive) to atracurium besilateor any of the other

ingredients of this drug (see section 6)

Take special care with Atracurium Besilate Solution for Injection if you

- are pregnant or breast-feeding (see Pregnancyand breast-feeding)

- haveheart or circulation problems

- haveproblemswith your lungs

- have ahistory of allergyorasthma

- suffer frommyasthenia gravis, Eaton-Lambertsyndrome or other neuromuscular

diseases(thesemayresultin muscle weakness)

- havesevere electrolytedisorders(unusual levels of ions such as sodium, potassiumor

chloride inyour blood)

- aresuffering from burns

- have hadallergic reactions to other muscle relaxants(e.g. curares)

Using other medicines

Please tell your doctoror pharmacist if you are takingor have recently taken anyother

medicines, including medicines obtained without aprescription.

Somemedicines are known to interact with atracuriumbesilate,tell your doctor if youare

takinganyof thefollowing:

- antibiotics(e.g. aminoglycosides, polymyxins, spectinomycin, tetracyclines, lincomycin,

clindamycin andvancomycin)

- antiarrhythmic medicines(used to control the rhythmof the heart) (e.g. lidocaine,

procainamide, quinidine)

- diuretics(water tablets) (e.g. frusemide,thiazides, acetazolamide,mannitol)

- medicines used to control blood pressure or angina or other heart problems(e.g.

propranolol,oxprenolol, diltiazem, nicardipine,nifedipine, trimetaphan, hexamethonium

and verapamil)

- antiepileptic medicines(e.g. carbamazepine, phenytoin)

- drugs used totreat rheumatism(e.g. chloroquine,d-penicillamine)

- corticosteroidsadministered intoyourvein (usedin the treatmentof allergic

emergencies,severe asthma and septic shock)

- inhalation anaesthetics(drugs toputyou to sleep) (e.g. isoflurane, desflurane,

sevoflurane and enfluraneanaesthesia, halothane)

- others you mayrecognisebyname (e.g. dantrolene (used in anaesthesia),magnesium

sulphate (used to treat eclampsia and pre-eclampsia in pregnant women and some heart

problems), ketamine (usedin anaesthesia), lithium(used to treat bipolar disorder), quinine

(used to treat malaria and leg cramps)and chlorpromazine (used to treat somepsychiatric

disorders and nausea)).

Pregnancy and breast-feeding

Atracuriumbesilate should not be used during thefirst threemonths of pregnancy. It will not

be used during the secondand third trimesters unless your doctor advises that it is necessary.

Atracuriumbesilate can be used duringa caesarean section.

Your baby wouldbe closelymonitored ifyoubreast-feed within 24 hours of being given

atracuriumbesilate.

Ask your doctor for advicebefore takingany medicine.

Driving andusing machines

Do not driveor use machines within 24hours ofbeing given atracuriumbesilate.

3. HOW YOUARE GIVEN ATRACURIUM BESILATE SOLUTION FOR

INJECTION

Atracuriumbesilate is used duringprocedures which require you tobe anaesthetised

(unconscious) or heavilysedated. The amountgiven toyou willdepend uponthe length of

time you will be unconscious or heavilysedated and your bodyweight.

An initial dose of thismedicine will begivento you of approximately0.3 – 0.6mg/kg of

body weight, followed by a reduced dose at specific intervals. This standarddose will be

given to children and adults. The rate thismedicine isadministered mayvarydependingon

your age and if you suffer from anyheart problems. You will be monitored during use with

this medicine, and the dose will be adjusted if necessary.

Atracuriumbesilate will be given toyoubyan injection into avein.

Children less than 1 monthold should not have this medicine.

If you are given more Atracurium Besilate Solution for Injection thanyou should be

given

Atracuriumbesilate willonlybe used bydoctors who areappropriatelyskilled in its

administration. As this medicine will be given toyou whilstyouare in hospital it is unlikely

that you willbe given too little or too much, however tell your doctoror a healthcare

professional immediatelyifyouhave any concerns.

If youhave anyfurtherquestions on theuse of this product, askyour doctor.

4.POSSIBLE SIDE EFFECTS

Like all medicines, AtracuriumBesilate Solution forInjection can cause side effects, although

not everybody gets them.

If any of thefollowing happen, tell the doctor immediately:

- severe allergic reaction – you mayget a suddenitchyrash (hives), swelling of thehands,

feet, ankles, face, lips,mouth or throat(which maycause difficultyin swallowing or

breathing), andyou mayfeel you are going to faint

- seizures (fits)

- shock

- heart failure

- cardiac arrest

The above are rare or very rare serious side effects. You may need urgentmedical

attention.

If you experience any of the followingtell your doctor as soon as possible:

- Common sideeffects(may affect up to1 in 10people)rapid heart beat

- slow heart beat

- soreness at the injection site

- wheezing

- localised rashor itching ofthe skin

- low blood pressure (hypotension)

- high bloodpressure(hypertension)

- flushingof the skin

Uncommon side effects(mayaffect up to 1 in100 people)

- difficultybreathing

- generalised rash or redness of the skin

- hives

Rare side effects(mayaffect up to 1 in1,000 people)

- shortness of breath

- spasmof the vocal cords

- rapid swelling under the skin (angioneurotic oedema)

- itching

Very rareside effects(mayaffect up to1 in10,000people)

- low blood oxygen level (hypoxemia)

Not known(frequencycannotbe estimated fromthe available data)

- prolonged therapeutic action of the medicine

- insufficient therapeutic action of the medicine

- increasedmucous secretions in the lungs

- muscle weakness/tiredness or difficultycontrollingyour muscles

If any of theside effects gets serious, or if you noticeany side effects not listed in this

leaflet, please tell your doctor or pharmacist.

5. HOW TO STORE ATRACURIUMBESILATE SOLUTION FORINJECTION

Keep out of the reach and sight of children.

Do not use AtracuriumBesilate Solution for Injection after the expirydate which is stated on

the vial label and carton.

The vials should be storedin a refrigerator (2 –8°C) but not frozen.

The vials should be keptinthe outer carton (inorder toprotect fromlight).

6. FURTHER INFORMATION

What Atracurium Besilate Solution for Injection contains

The active substance is atracuriumbesilate

The other ingredients are benzenesulphonic acid andWater for Injections

What Atracurium Besilate Solution for Injection looks like and contents of the pack

Thismedicinal product is a solution for injection(a solutionwhich can be given as an

injection). It is a clear, colourless or faint yellow solution. Eachmillilitre (ml) of solution

contains 10milligrams(mg) of atracuriumbesilate.

Thismedicineis presented in glass containers (vials). The 25 ml vial is available in packs

containing1vial. Not allpresentations maybe marketed.

Marketing AuthorisationHolder and Manufacturer

Hospira UKLimited

Queensway

Royal LeamingtonSpa

Warwickshire

CV31 3RW

United Kingdom

France AtracuriumHospira 10 mg/ml, solution injectable

Ireland AtracuriumBesilate 10mg/ml Solution for Injection

Portugal Faulcurium,10 mg/ml, Solução injectável

United Kingdom AtracuriumBesilate 10mg/ml Solution for Injection

This leafletwas last revised in 08/2013

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The following information is intended formedicalor healthcare professionals only:

Handlingandpreparation:

Do not use ifcloudiness orprecipitate isobserved.

AtracuriumBesilate Solution for Injection hasan acid pH and therefore should not be mixed

with alkaline solutions (e.g. barbiturate solutions)in the samesyringeoradministered

simultaneously during intravenous infusion through the same needle.

To avoid distress to thepatient, AtracuriumBesilate Injectionshouldnotbe administered

before unconsciousness has been induced.

AtracuriumBesilate Solution for Injection maybeadministered asan intravenous injection or

infusion.

Do not giveAtracuriumbesilate injection intramuscularly since this mayresult in tissue

irritation andthere are no clinical data to support this route of administration.

When a small vein is selected as the injectionsite, AtracuriumBesilate Injection shouldbe

flushed through the vein with physiological saline after injection.

AtracuriumBesilate Injection is hypotonic and must not be appliedinto the infusion line ofa

bloodtransfusion.

Where an infusion is required, atracuriumbesilate infusion solutions maybe prepared by

admixing AtracuriumBesilate Injection with anappropriate diluent (see below) to give an

atracuriumbesilate concentration of 0.5mg/ml to 5 mg/ml.

AtracuriumBesilate Injection diluted to0.5mg/mlwith the following infusion solutions, and

stored at 30 °C protected fromlight, wasshown tobe stable for the times stated below.

Infusion Solution Period of stability

SodiumChloride 0.9%Intravenous Infusion

Glucose 5%Intravenous Infusion

Glucose 4%and SodiumChloride 0.18%

Intravenous Infusion

Ringer’s Injection USP

Compound SodiumLactate Intravenous Infusion

(Hartmann’sSolution for Injection) 24 hours

24 hours

24 hours

24 hours

4 hours

AtracuriumBesilateInjectiondiluted to5 mg/ml with the following infusionsolutions, and

stored at 30 °C protected fromlight in50 ml plasticsyringes, was shown tobe stable for the

times stated below.

Infusion Solution Period of stability

SodiumChloride 0.9%Intravenous Infusion

Glucose 5%Intravenous Infusion

Glucose 4%and SodiumChloride 0.18%

Intravenous Infusion

Ringer’s Injection USP

Compound SodiumLactate Intravenous Infusion

(Hartmann’sSolution for Injection) 24 hours

24 hours

24 hours

24 hours

8 hours

The clinician must be prepared to assistofcontrol ventilation,and anticholinesteraseagents

shouldbe immediatelyavailable for reversal of neuromuscular blockade.

The potentialfor histaminerelease existsinsusceptible patients during administration of

atracuriumbesilate. Caution should be exercisedin patients with a historysuggestive of an

increased sensitivityto theeffects of histamine.

Disposal:

Discard residue immediately after use.

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.DonotgiveAtracurium

BesilateInjectionintramuscularlysincethismayresultintissueirritationandtherearenoclinicaldatatosupport

thisrouteofadministration.

Toavoiddistresstothepatient,AtracuriumBesilateInjectionshouldnotbeadministeredbeforeunconsciousness

hasbeeninduced.AtracuriumBesilateInjectionshouldnotbemixedinthesamesyringe,oradministered

simultaneouslythroughthesameneedle,withalkalinesolutions(e.g.barbituratesolutions).

Incommonwithallneuromuscularblockingagents,monitoringofneuromuscularfunctionisrecommendedduring

theuseofAtracuriumBesilateInjectioninordertoindividualisedosagerequirements.

Initialbolusdosesforintubation

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

anintravenousbolusinjection,isrecommended.Thiswillprovideadequaterelaxationforabout15to35minutes.

Endotrachealintubationcanusuallybeaccomplishedwithin90to120secondsoftheintravenousinjectionof0.5to

0.6mg/kg.Maximumneuromuscularblockadeisgenerallyachievedapproximately3to5minutesafter

administration.Spontaneousrecoveryfromtheendoffullblockoccursinabout35minutesasmeasuredbythe

restorationofthetetanicresponseto95%ofnormalneuromuscularfunction.

Althoughatracuriumispotentiatedby(approximately35%)isofluraneorenfluraneanaesthesia,thesameinitial

atracuriumbesilatedose(0.3to0.6mg/kg)maybeusedforintubationifgivenpriortotheadministrationofthese

inhalationagents.Howeveriftheinitialatracuriumdoseisadministeredaftersteadystateanaesthesiawith

isofluraneorenfluranehasbeenachieved,thedoseofatracuriumshouldbereducedbyapproximatelyone-third.

Smallerdosagereductionsmaybeconsideredwithconcomitanthalothaneanaesthesiasinceithasonlyamarginal

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Maintenancedoses

IntermittentIVinjection:Duringprolongedsurgicalproceduresneuromuscularblockademaybemaintainedwith

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

maintenancedosesof0.1mg/kg,thefirstmaintenancedoseisrequiredwithin20to45minutesoftheinitialbolus

dose,thentypicallyat15to25minuteintervals,however,theneedformaintenancedosesshouldbedeterminedby

theindividualpatient’srequirementsandresponse.Successivesupplementarydosingdoesnotgiveriseto

accumulationofneuromuscularblockingeffect.

Useasaninfusion:Aftertheinitialatracuriumbolusdose,neuromuscularblockademaybemaintainedduring

prolongedsurgicalproceduresbyadministeringatracuriumbesilateasacontinuousintravenousinfusionatarateof

0.3to0.6mg/kg/hour.Theinfusionshouldnotbecommenceduntilearlyspontaneousrecoveryfromtheinitial

atracuriumbolusdoseisevident.

AtracuriumbesilateinfusionsolutionsmaybepreparedbyadmixingAtracuriumBesilateInjectionwithan

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

AtracuriumBesilateInjectioncanbeadministeredbyinfusionduringcardiopulmonarybypasssurgeryatthe

recommendedinfusionrates.Inducedhypothermiatoabodytemperatureof25to26 °

Creducestherateof

inactivationofatracurium,andthereforefullneuromuscularblockmaybemaintainedwithapproximatelyhalfthe

originalinfusionrateatthesetemperatures.

Compatibilitywithinfusionsolutions:AtracuriumBesilateInjectiondilutedto0.5mg/mlwiththefollowing

infusionsolutions,andstoredat30 °

Cprotectedfromlight,wasshowntobestableforthetimesstatedbelow.

AtracuriumBesilateInjectiondilutedto5mg/mlwiththefollowinginfusionsolutions,andstoredat30 °

Cprotected

fromlightin50mlplastic

syringes,wasshowntobestableforthetimesstatedbelow.

Reversalofneuromuscularblockade

Theneuromuscularblockadeinducedbyatracuriumcanbereversedwithananticholinesteraseagentsuchas

neostigmineorpyridostigmine,usuallyinconjunctionwithananticholinergicagentsuchasatropineor

InfusionSolution Periodofstability

SodiumChloride0.9%IntravenousInfusion

Glucose5%IntravenousInfusion

Glucose4%andSodiumChloride0.18%

IntravenousInfusion

Ringer’sInjectionUSP

CompoundSodiumLactateIntravenousInfusion

24hours

24hours

24hours

24hours

4hours

InfusionSolution Periodofstability

SodiumChloride0.9%IntravenousInfusion

Glucose5%IntravenousInfusion

Glucose4%andSodiumChloride0.18%

IntravenousInfusion

Ringer’sInjectionUSP

CompoundSodiumLactateIntravenousInfusion

24hours

24hours

24hours

24hours

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anaesthesia,reversalcanusuallybeattemptedapproximately20to35minutesaftertheinitialatracurium

dose,orapproximately10to30minutesafterthelastatracuriummaintenancedose,whenrecoveryofmuscle

twitchhasstarted.Completereversalofneuromuscularblockadeisusuallyachievedwithin8to10minutes

afteradministrationofthereversingagents.

Rareinstancesofbreathingdifficulties,possiblyrelatedtoincompletereversal,havebeenreportedfollowing

attemptedpharmacologicalantagonismofatracuriuminducedneuromuscularblockade.Aswithotheragents

inthisclass,thetendencyforresidualneuromuscularblockisincreasedifreversalisattemptedatdeeplevels

ofblockadeorifinadequatedosesofreversalagentsareemployed.

Facilitationofmechanicalventilationinintensivecareunit(ICU)patients

Afteranoptionalinitialbolusdoseof0.3to0.6mg/kg,neuromuscularblockmaybemaintainedby

administeringacontinuousatracuriumbesilateinfusionatratesofbetween11and13microgram/kg/min(0.65

to0.78mg/kg/hr).Theremaybewideinter-patientvariabilityindosagerequirementsandthesemayincrease

ordecreasewithtime.Infusionratesaslowas4.5microgram/kg/min(0.27mg/kg/hr)orashighas29.5

microgram/kg/min(1.77mg/kg/hr)arerequiredinsomepatients.

TherateofspontaneousrecoveryfromneuromuscularblockafterinfusionofatracuriumbesilateinICU

patientsisindependentofthedurationofadministration.

Spontaneousrecoverytoatrain-of-fourratio>0.75(theratiooftheheightofthefourthtothefirsttwitchina

train-of-four)canbeexpectedtooccurinapproximately60minutes.Arangeof32to108minuteshasbeen

observedinclinicaltrials.

Dosageconsiderations

Useinchildren:Thedosageinchildrenovertheageof1monthissimilartothatinadultsonabodyweight

basis,however,largeindividualvariabilityintheneuromuscularresponseinpaediatricpatientsindicatesthat

neuromuscularmonitoringisessential.

Useinneonates:Theuseofatracuriumisnotrecommendedinneonatessincethereareinsufficientdata

available(seesection5.1).

Useintheelderly:Thestandarddoseofatracuriummaybeusedinelderlypatients,however,itis

recommendedthatitbeadministeredslowly.

Useinpatientswithreducedrenaland/orhepaticfunction:Standarddosagesmaybeusedatalllevelsofrenal

orhepaticfunction,includingendstagefailure.

Useinpatientswithcardiovasculardisease:Inpatientswithsignificantcardiovasculardiseasetheinitialdose

ofatracuriumshouldbeadministeredoveraperiodofatleast60seconds.

Seealso“Specialwarningsandspecialprecautionsforuse”.

4.3Contraindications

Knownorsuspectedhypersensitivitytotheproduct.

4.4Specialwarningsandprecautionsforuse

AtracuriumBesilateInjectionshouldbeusedonlybythoseskilledinthemanagementofartificialrespirationandonly

whenfacilitiesareimmediatelyavailableforendotrachealintubationandforprovidingadequateventilationsupport,

includingtheadministrationofoxygenunderpositivepressureandtheeliminationofcarbondioxide.Theclinician

mustbepreparedtoassistorcontrolventilation,andanticholinesteraseagentsshouldbeimmediatelyavailablefor

reversalofneuromuscularblockade.

Atracuriumhasnoknowneffectonconsciousness,painthreshold,orcerebration.Insurgery,itshouldbeusedonly

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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

possiblewiththisproduct.

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.

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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

acutely,theneuromuscularblockingeffectsmaybeincreased.

Inprinciple,maintainingneuromuscularmonitoringuntilcompletereversalofneuromuscularblockadeshouldpermit

detectionofmostinteractions.

Nevertheless,recurrenceofneuromuscularblockademayoccur,forexample,upontreatmentwithpostsurgical

antibiotics.

4.6Fertility,pregnancyandlactation

Pregnancy

Atracuriumcrossestheplacentabuttherehavebeennodemonstratedadverseeffectsinthefoetusornewborninfant.

Animalstudieshaveindicatedthatatracuriumhasnoadverseeffectsonfoetaldevelopment.Aswithallneuromuscular

blockingagents,theuseofatracuriuminthefirstthreemonthsofpregnancyshouldbeavoidedanditshouldnotbe

usedduringthesecondandthirdtrimestersunlessclearlynecessary.

Atracuriumissuitableformaintenanceofmusclerelaxationduringcaesareansectionasitdoesnotcrosstheplacentain

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

administeredto26pregnantwomenduringdeliverybycaesareansection.Noharmfuleffectswereattributableto

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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

Theadverseeffectsarereportedindecreasingorderoffrequencywithineachsystemorderclass(SOC).

Aswithmostneuromuscularblockingagents,thepotentialexistsforundesirableeffectssuggestiveofhistaminerelease

insusceptiblepatients.Inclinicaltrials(875patients)reportsofskinflushingrangedfrom1%atdosesupto0.3mg/kg,

to29%atdosesof0.6mg/kgorgreater.Theincidenceoftransienthypotensionrangedfrom1to14%respectivelyfor

thecorrespondingdosages.

TableforfrequencyofadversereactionsforAtracuriumBesilate10mg/mlSolutionforinjection

SOC Very

common

(1/10) Common

(1/100to

<1/10) Uncommon

(1/1000to

<1/100) Rare

(1/10,000to

<1/1000 Veryrare

(<1/10,000) Not

known

(cannot

be

estimated

from

the

available

data).

Cardiac

disorders Tachycardia,

bradycardia

(observedin

1%of

patients) Severe

allergic

reactions

(e.g.shock,

cardiac

failure,

cardiacarrest)

General

disordersand

administration

sitecondition Reactionat

injectionsite

Immune

system

disorders Allergic

reactions(i.e.

anaphylactic

anaphylactoid

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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.

Anaphylactoid

reactions

Injury,

poisoningand

procedural

complications Prolonged

block

Respiratory,

thoracicand

mediastinal

disorders Wheezing, Broncospasm

(0.2%of

patients) Dysponea,

laryngospasm hypoxemia Bronchial

secretions

Skinand

subcutaneous

tissue

disorders Localized

skinreactions,

rash,itching, Generalized

Erythema,

Hives, Angioneurotic

oedema,

utricaria

Nervous

system

disorders Inadequate

block

Vascular

disorders Hypertension

(observedin

approximately

1%of

patients),

Hypotension,

vasodilatation

(flushing)-

eachoccurred

approximately

2-3%of

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5.1Pharmacodynamicproperties

Atracuriumbesilateisanon-depolarisingneuromuscularblockingagent(ATCcodeM03AC04)withanintermediate

durationofaction,administeredintravenouslytoproduceskeletalmusclerelaxation.

Non-depolarisingneuromuscularblockingagentsantagonisetheactionoftheneurotransmitteracetylcholineby

competitivelybindingwithcholinergicreceptorsitesonthemotorendplateofthemyoneuraljunction.Theseeffects

maybeinhibitedorreversedbytheadministrationofanticholinesterasessuchasneostigmineorpyridostigmine.

Aswithothernon-depolarisingneuromuscularblockingagents,thetimetoonsetorparalysisisreduced,andthe

durationofmaximumeffectprolonged,withincreasingatracuriumdoses.

Oncerecoveryfromatracurium’sneuromuscularblockingeffectbegins,itproceedsmorerapidlythanrecoveryfrom

tubocurarine,alcuronium,andpancuronium.Regardlessoftheatracuriumdose,thetimefromstartofrecovery(from

completeblock)tocompleterecovery(asmeasuredbyrestorationofthetetanicresponseto95%ofnormal)is

approximately30minutesunderbalancedanaesthesia,andapproximately40minutesunderhalothane,enfluraneor

isofluraneanaesthesia.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.

Paediatricpopulation:

Thelimiteddatainneonatesfromliteraturereportssuggestvariabilityinthetimetoonsetanddurationofactionof

atracuriuminthispopulationascomparedtochildren(seesection4.2).

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

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Date Printed 15/11/2013 CRN 2139384 page number: 8

5.3Preclinicalsafetydata

Carcinogenicity/Mutagenicity:Carcinogenicitystudieshavenotbeenperformed.

Atracuriumyieldednegativeresultsforgenemutationinbacteria,andchromosomaldamageinbonemarrowofrats.A

positiveresponseinthemouselymphomaassaywasobservedonlyathighlycytotoxicconcentrations.Thissingle

positiveresponseisnotconsideredtobeofclinicalrelevance.

Reproductivetoxicity:.Animalstudieshaveindicatedthatatracuriumhasnoadverseeffectonfoetaldevelopment.

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

Irish Medicines Board

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Date Printed 15/11/2013 CRN 2139384 page number: 9

CV313RW

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA0437/042/002

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation: 15June1998

Dateoflastrenewal: 15October2006

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 15/11/2013 CRN 2139384 page number: 10

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