AMIODARONE

Main information

  • Trade name:
  • AMIODARONE Concentrate for Soln for Inj 50 Mg/ Ml
  • Dosage:
  • 50 Mg/ Ml
  • Pharmaceutical form:
  • Concentrate for Soln for Inj
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • AMIODARONE Concentrate for Soln for Inj 50 Mg/Ml
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0126/186/001
  • Authorization date:
  • 26-09-2008
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Amiodarone50mg/mlConcentrateforsolutionforinjectionorinfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachmlcontains50mgofamiodaronehydrochloride

Each3mlampoulecontains150mgamiodaronehydrochloride.

Excipient:60.6mgofbenzylalcohol/ampouleof3mlsterileconcentrate

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Concentrateforsolutionforinjectionorinfusion(Sterileconcentrate)

Clear,pale,yellowsolution

4CLINICALPARTICULARS

4.1TherapeuticIndications

Amiodaroneisindicatedonlyforthetreatmentofsevererhythmdisordersnotrespondingtoothertherapiesorwhen

othertreatmentscannotbeused.

TachyarrhythmiasassociatedwithWolff-Parkinson-Whitesyndrome.

Alltypesoftachyarrhythmiasincludingsupraventricular,nodalandventriculartachycardias;atrialflutterand

fibrillation;ventricularfibrillation;whenotherdrugshavebeenprovenineffectiveorcausedunacceptablesideeffects

orwheninvasiveanti-arrhythmicprocedureiscontraindicatedornoteffective.

4.2Posologyandmethodofadministration

Routesofadministration:

Intravenoususe

Treatmentshouldbeinitiatedandnormallymonitoredonlyunderhospitalorspecialistsupervision.

Amiodaronecanbeusedwherearapidresponseisrequiredorwhereoraladministrationisnotpossible.

Infusion:

Thestandardrecommendedloadingdoseis5mg/kgbodyweightin250mlof5%dextroseinfusedwithin20minutesto

2hours.Thismayberepeated2to3timesduringthefollowing24hours(upto1200mg/24hours[approximately15

mg/kgbodyweight]inupto500ml5%dextrose)andtherateofinfusionistobecontrolledaccordingtotheclinical

response.(Seesection4.4).

Injection:

Inextremeclinicalemergencythedrugmay,atthediscretionoftheclinician,begivenasaslowinjectionof150-300

mgin10-20ml5%dextroseoveraminimumof3minutes.Thesolutionispreparedbydrawing150mgofamiodarone

=1ampouletoa10mlinjectionsyringeandfillingitupwith5%dextrose.Plaindextroseshouldbeadministered

straightafterthelastinjecting,sinceamiodaroneisveryirritatingtotheveins.Thisshouldnotberepeatedforatleast

15minutesfollowingthefirstinjectioneventhoughonly1ampoulehasbeeninjected(possibilityofirreversible

collapse).PatientstreatedinthiswaywithAmiodaronemustbecloselymonitored,e.g.,inanintensivecareunit(see

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Changeoverfromintravenoustooraltherapy:

Assoonasanadequateresponsehasbeenobtained,oraltherapyshouldbeinitiatedconcomitantlyattheusualloading

dose(i.e.200mgthreetimesaday).Amiodaroneshouldthenbephasedoutgradually.

Paediatricpopulation

Thesafetyandefficacyofamiodaroneinchildrenhasnotbeenestablished.

Currentlyavailabledataaredescribedinsections5.1and5.2.

Duetothepresenceofbenzylalcohol,amiodaroneintravenousadministrationiscontraindicatedinneonates,infants

andchildrenupto3yearsold.

Elderly:

Aswithallpatientsitisimportantthattheminimumeffectivedoseisused.Whilstthereisnoevidencethatdosage

requirementsaredifferentforthisgroupofpatientstheymaybemoresusceptibletobradycardiaandconduction

defectsiftoohighadoseisemployed.Particularattentionshouldbepaidtomonitoringthyroidfunction(seesections

4.3,4.4and4.8).

Seesection6.2forinformationonincompatibilities.

Cardiopulmonaryresuscitation:

Therecommendeddoseforventricularfibrillations/pulselessventriculartachycardiaresistanttodefibrillationis300

mg(or5mg/kgbody-weight)dilutedin20ml5%dextroseandrapidlyinjectedfollowedbyadministrationofplain

dextroseafterthelastinjection,sinceamiodaroneisveryirritatingtotheveins.Anadditional150mg(or2.5mg/kg

body-weight)IVdosemaybeconsideredifventricularfibrillationpersists.

Seesection6.2forinformationonincompatibilities.

Hepaticandrenalimpairment:

Althoughnodosageadjustmentforpatientswithrenalorhepaticabnormalitieshasbeendefinedduringchronic

treatmentwithoralamiodarone,closeclinicalmonitoringisprudentforelderlypatientse.g.inanintensivecareunit.

4.3Contraindications

Hypersensitivitytoiodineortoamiodaronehydrochloride,ortoanyoftheexcipients.(Oneampoulecontains

approximately56mgiodine).

Sinusbradycardia,sinoatrialheartblockandsicksinussyndrome,unlessthepatienthasapacemaker(riskofsinus

arrest).Atrioventricularblock,bifascicularortrifascicularconductiondisturbance,ifthepatientdoesnothavea

pacemaker.

Evidenceorhistoryofthyroiddysfunction.

Severerespiratoryfailure,circulatorycollapse,orseverearterialhypotension.

Hypotension,heartfailureandcardiomyopathyarealsocontraindicationswhenusingAmiodaroneasbolusinjection.

ThecombinationofAmiodaronewithdrugswhichmayinduceTorsadesdePointesiscontra-indicated(seesection

4.5).

Duetothepresenceofbenzylalcohol,intravenousamiodaroneiscontraindicatedinneonates,infantsandchildrenup

to3yearsold.

Theabovementionedcontraindicationsarenotrelevantwhenamiodaroneisusedinthecardiopulmonaryresuscitation

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4.4Specialwarningsandprecautionsforuse

Onlytobeusedwhenotherantiarrhythmicshaveshowninsufficienteffect,andthatthepatientsmustbemonitored

closelyduringtreatmentforadversereactionsfromlungs,thyroidglandandliver.Theproductcanbeusedinpregnant

atlife-threateningandpregnancythreateningarrhythmias.Theneonateshouldbemonitoredcloselyforthyroid

dysfunction.

Intravenousinjectionisgenerallynotrecommendedduetothehaemodynamicrisk(severehypotension,circulatory

collapse),andintravenousinfusionistobepreferredwherepossible.Intravenousinjectionmustonlybegivenin

emergencysituationswherealternativetreatmenthasfailed,andonlyinacardiacunitundercontinuousmonitoring

(ECG,bloodpressure).Duetoinsufficientdocumentation,itisrecommendednottousethesolutionforinjection

withoutpriordilution.

Thedosageisabout5mg/kgbodyweightandisgiven–exceptincaseofcardiopulmonalresuscitationofshock

resistantventricularfibrillation–asaninjectionduringatleast3minutes.Otherproductsmustnotbeinjectedinthe

sameIVadmittance.Iftreatmentwithamiodaronehydrochlorideistobecontinued,itmustbeperformedvia

intravenousinfusion.

Paediatricpatients:

AmiodaroneStragencontainsbenzylalcohol(20mg/ml).Benzylalcoholmaycausetoxicreactionsandallergic

reactionsininfantsandchildrenupto3yearsold.

Cardiacdisorders:

Amiodaronehydrochloridehasalowpro-arrhythmiceffect.Onsetsofnewarrhythmiasorworseningoftreated

arrhythmias,sometimesfatal,havebeenreported.Itisimportant,butdifficult,todifferentiatealackofefficacyofthe

drugfromaproarrhythmiceffect,whetherornotthisisassociatedwithaworseningofthecardiaccondition.

Proarrhythmiceffectsgenerallyoccurinthecontextofdruginteractionsand/orelectrolyticdisorders(seesections4.5.

and4.8).

Toohighadosagemayleadtoseverebradycardiaandtoconductiondisturbanceswiththeappearanceofan

idioventricularrhythm,particularlyinelderlypatientsorduringdigitalistherapy.Inthese

circumstances,Amiodaronetreatmentshouldbewithdrawn.Ifnecessarybeta-adrenostimulantsorglucagonmaybe

given.Becauseofthelonghalf-lifeofamiodaronehydrochloride,ifbradycardiaissevereandsymptomaticthe

insertionofapacemakershouldbeconsidered.

ThepharmacologicalactionofamiodaronehydrochlorideinducesECGchanges:QTprolongation(relatedtoprolonged

repolarisation)withthepossibledevelopmentofU-wavesanddeformedT-waves;thesechangesdonotreflecttoxicity.

Pulmonarydisorders:

Veryrarecasesofinterstitialpneumonitishavebeenreportedwithintravenousamiodaronehydrochloride.Whenthe

diagnosisissuspected,achestX-rayshouldbeperformed.Amiodaronehydrochloridetherapyshouldbere-evaluated

sinceinterstitialpneumonitisisgenerallyreversiblefollowingearlywithdrawalofamiodaronehydrochloride,and

corticosteroidtherapyshouldbeconsidered(seesection4.8).

Veryrarecasesofsevererespiratorycomplications,sometimesfatal,havebeenobservedusuallyintheperiod

immediatelyfollowingsurgery(shocklung-adultacuterespiratorydistresssyndrome);apossibleinteractionwitha

highoxygenconcentrationmaybeimplicated(seesections4.5and4.8).

Liverdisorders:

Severehepatocellularinsufficiencymayoccurwithinthefirst24hoursofivamiodaronehydrochloride,andmay

sometimesbefatal.Closemonitoringoftransaminasesisthereforerecommendedassoonasamiodaronehydrochloride

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Cautionshouldbeexercisedinpatientswithhypotension,decompensatedcardiomyopathyandsevereheartfailure

(alsoseesection4.3).

Amiodaroneshouldonlybeusedinaspecialcareunitundercontinuousmonitoring(ECGandbloodpressure).

Repeatedorcontinuousinfusionviatheperipheralveinsmayleadtoinjectionsitereactions(seesection4.8).When

repeatedorcontinuousinfusionisanticipated,administrationbyacentralvenouscatheterisrecommended.

WhengivenbyinfusionAmiodaronemayreducedropsizeand,ifappropriate,adjustmentsshouldbemadetotherate

ofinfusion.

Anaesthesia:Beforesurgery,theanaesthetistshouldbeinformedthatthepatientistakingamiodaronehydrochloride

(seesection4.5).

Druginteractions(seesection4.5).

Concomitantuseofamiodaronewiththefollowingdrugsisnotrecommended;beta-blockers,heartratelowering

calciumchannelinhibitors(verapamil,diltiazem)whichmaycausehypokalaemia.

Inpatientstakingamiodaroneconcomitantlywithsimvastatin,thedoseofsimvastatinshouldnotexceed20mg/day.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Inviewofthelongandvariablehalf-lifeofamiodarone(approximately50days),potentialfordruginteractionsexists

notonlywithconcomitantmedicationbutalsowithdrugsadministeredafterdiscontinuationofamiodarone.

Combinationsthatarecontraindicated:

CombinedtherapywiththefollowingdrugswhichprolongtheQTintervaliscontra-indicated(seesection4.3)dueto

theincreasedriskofTorsadesdePointes;forexample:

ClassIaanti-arrhythmicdrugse.g.quinidine,procainamide,disopyramide.

ClassIIIanti-arrhythmicdrugse.g.sotalol,bretylium.

Intravenouserythromycin,co-trimoxazoleorpentamidineinjection.

Someanti-psychoticse.g.chlorpromazine,thioridazine,fluphenazine,pimozide,haloperidol,amisulpirideand

sertindole.

Lithiumandtricyclicanti-depressantse.g.doxepin,maprotiline,amitriptyline.

Certainantihistaminese.g.terfenadine,astemizole,mizolastine.

Anti-malarialse.g.quinine,mefloquine,chloroquine,halofantrine.

Combinationsthatarenotrecommended:

Combinedtherapywiththefollowingdrugsisnotrecommended:

Betablockersandcertaincalciumchannelinhibitors(diltiazem,verapamil);potentiationofnegativechronotropic

propertiesandconductionslowingeffectsmayoccur.

Stimulantlaxatives,whichmaycausehypokalaemiathusincreasingtheriskofTorsadesdePointes;othertypesof

laxativesshouldbeused.

Cautionisadvised:

Cautionshouldbeexercisedovercombinedtherapywiththefollowingdrugswhichmaycausehypokalaemiaand/or

hypomagnesaemia,e.g.diuretics,systemiccorticosteroids,tetracosactrin,intravenousamphotericin.

Incasesofhypokalaemia,correctiveactionshouldbetakenandQTintervalmonitored.IncaseofTorsadesdePointes,

antiarrhythmicagentsshouldnotbegiven;pacingmaybeinstitutedandIVmagnesiummaybeused.

Oralanticoagulants:

Amiodaronehydrochlorideraisestheplasmaconcentrationsoforalanticoagulants(warfarin)byinhibitionofCYP

2C9.Thedoseofwarfarinshouldbereducedaccordingly.Morefrequentmonitoringofprothrombintimebothduring

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Digoxin:

AdministrationofAmiodaronetoapatientalreadyreceivingdigoxinwillcauseanincreaseintheplasmadigoxin

concentrationandthusprecipitatesymptomsandsignsassociatedwithhighdigoxinlevels.Clinical,ECG,and

biologicalmonitoringarerecommendedanddigoxindosageusuallyhastobereduced.Asynergisticeffectonheart

rateandatrioventricularconductionisalsopossible.

Phenytoin:

AmiodaronehydrochlorideraisestheplasmaconcentrationsphenytoinbyinhibitionofCYP2C9.Phenytoindosage

shouldbereducedifsignsofoverdosageappear,andplasmalevelsmaybemeasured.

Flecainide:

Possibleincreaseofflecainideplasmalevels;dosageofflecainidebyinhibitionofCYP2D6;thedosageofflecainide

shouldbeadjusted.

DrugsmetabolisedbycytochromeP4503A4:

Whensuchdrugsareco-administeredwithamiodaronehydrochloride,aninhibitorofCYP3A4,thismayresultina

higherleveloftheirplasmaconcentrations,whichmayleadtoapossibleincreaseintheirtoxicity.

Cyclosporin:

Combinationwithamiodaronehydrochloridemayincreasecyclosporinplasmalevels.Dosageshouldbeadjusted.

Fentanyl:

Combinationwithamiodaronehydrochloridemayenhancethepharmacologiceffectsoffentanylandincreasetherisk

ofitstoxicity.

OtherdrugsmetabolisedbyCYP3A4:

Lidocaine,tacrolimus,sildenafil,ergotamine;simvastatinandotherstatinsmetabolisedbyCYP3A4(increasedriskof

musculartoxicity).

InteractionwithsubstratesofotherCYP450isoenzymes:

InvitrostudiesshowthatamiodaronealsohasthepotentialtoinhibitCYP1A2,CYP2C19andCYP2D6throughits

mainmetabolite.Whenco-administered,amiodaronewouldbeexpectedtoincreasetheplasmaconcentrationofdrugs

whosemetabolismisdependentuponCYP1A2,CYP2C19andCYP2D6.

Grapefruitjuice:

GrapefruitjuiceinhibitscytochromeP4503A4andmayincreasetheplasmaconcentrationofamiodarone

hydrochloride.Grapefruitjuiceshouldbeavoidedduringtreatmentwithamiodaronehydrochloride.

Generalanaesthesia:

Cautionisadvisedinpatientsundergoinggeneralanaesthesia,orreceivinghighdoseoxygentherapy.Thereissome

evidencethatthepresenceofamiodaronepossiblyincreasestheriskofcomplications(atropine-resistantbradycardia,

hypotension,decreasedcardiacoutput)duringgeneralanaesthesia.Afewcasesofadultrespiratorydistresssyndrome

mostoftenintheperiodimmediatelyaftersurgeryhavebeenobserved.Apossibleinteractionwithahighoxygen

concentrationmaybeimplicated.

4.6Fertility,pregnancyandlactation

Pregnancy:

Thereisonlyinsufficientexperienceonthesafetyofadministrationduringpregnancy.

Inviewoftheeffectofamiodaronehydrochlorideonthefoetalthyroidgland,amiodaronehydrochlorideshouldnotbe

usedduringpregnancyunlessclearlynecessary.

Lactation:

Amiodaronehydrochlorideisexcretedinthebreastmilkinsignificantquantities.Iftherapyisrequiredduringthe

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4.7Effectsonabilitytodriveandusemachines

Someoftheundesirableeffectsmentionedinsection4.8mayimpairabilitytodriveandusemachines.Howeverthis

sectionisnotrelevantas

Amiodaroneisonlygiveninahospitaloremergencymedicinesurroundings.

4.8Undesirableeffects

Systemorganclass Common

(>1/100,<1/10) Rare

(>1/10,000<1/1,000) VeryRare

(<1/10,000,notknown

(cannotbeestimatedfrom

theavailabledata))

Immunesystemdisorders: Theexcipientbenzyl

alcoholmaycause

hypersensitivityreactions Anaphylacticshock

Nervoussystemdisorder: Benignintra-cranial

hypertension(pseudo

tumourcerebri),headache

Cardiacdisorder: Bradycardia,generally

moderate Markedbradycaria,sinus

arrestrequiring

discontinuationof

amiodaronehydrochloride,

especiallyinpatientswith

sinusnodedysfunction

and/orinelderlypatients.

Onsetorworseningof

arrhythmia,sometimes

followedbycardiacarrest

Vasculardisorders: Decreaseinblood

pressure,usuallymoderate

andtransient.Casesof

severehypotensionor

collapsehavebeen

reportedfollowing

overdosageoratoorapid

injection.

Respiratory,thoracicand

mediastinaldisorder: Interstitialpneumonitis.

Severerespiratory

complications(adultacute

respiratorydistress

syndrome),sometimes

fatal.

Bronchospasmand/or

apnoeaincaseofsevere

respiratoryfailure,

especiallyinasthmatic

patients

Gastrointestinaldisorder: Nausea

Hepatobiliarydisorder: Isolatedincreaseinserum

transaminases,whichis

usuallymoderate(1.5to3

timesnormalrange)atthe

beginningoftherapy.They

mayreturntonormalwith

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4.9Overdose

Someinformationregardingacuteoverdosagewithamiodaronehydrochlorideisavailable.Fewcasesofsinus

bradycardia,heartblock,attacksofventriculartachycardia,TorsadesdePointes,circulatoryfailureandhepaticinjury

havebeenreported.

Symptoms:

Dizziness,headache,AVblock,bradycardia,arrhythmias,heartfailure,fallinbloodpressure,nausea,vomiting(see

alsosection4.8).

Treatment:

Intheeventofoverdosetreatmentshouldbesymptomatic,inadditiontogeneralsupportivemeasures.Thepatient

shouldbemonitoredandifbradycardiaoccurs,beta-adrenostimulantsorglucagonmaybegiven.Spontaneously

resolvingattacksofventriculartachycardiamayalsooccur.Duetothepharmacokineticsofamiodaronehydrochloride,

adequateandprolongedsurveillanceofthepatient,particularlycardiacstatus,isrecommended.

Incaseofsuspectedoverdose,theinfusionmustbestopped.

spontaneously.

Acuteliverdisorderswith

highserumtransaminases

and/orjaundice,including

hepaticfailure,sometimes

fatal

Skinandsubcutaneous

tissuedisorders: Sweating

Generaldisordersand

administrationsite

conditions: Injectionsitereactions

suchaspain,erythema,

oedema,necrosis,

extravasation,infiltration,

inflammation,induration,

thrombophlebitis,

phlebitis,cellulitis,

infection,pigmentation

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Antiarrythmic(ClassIII),ATCcode:C01BD01

Amiodaroneisadi-iodinatedbenzofuranderivativeandisclassifiedasaclassIIIantiarrhythmicagentowingtoits

abilitytoincreasethecardiacactionpotentialdurationinbothatrialandventricularmyocytesviablockofcardiacK+

channels(mainlyofboththerapidandslowcomponentsofthedelayedrectifierK+current,IKrandIKs,respectively).

Thus,itprolongstherefractoryperiodoftheactionpotentialleadingtodepressionofectopiesandre-entry-arrhythmias

andtoprolongationoftheQTcintervalintheECG.Furthermore,amiodaronealsoblockscardiacNa+currents(classI

effect)andCa2+currents(classIVeffect).Thelattermayleadtoslowingofconductionthroughthesinoatrialand

atrioventricularnodes.Duringlong-termadministration,amiodaronealsoseemstoinhibitthetraffickingofion

channelsfromtheendoplasmicreticulumtotheplasmamembraneincardiacmyocytes,andtheseeffectsmay

contributetocardiacelectrophysiologicalactionsofamiodaroneunderchronicadministration.Furthermore,

amiodaroneisanon-competitiveantagonistatbothß-and-adrenoceptorsand,therefore,hashaemodynamiceffects:

dilatationofcoronaryarteriesandperipheralvasodilationleadingtoareductionofsystemicbloodpressure.Negative

inotropic,negativechronotropicandnegativedromotropiceffectsseemtobeinducedbytheß-adrenergicantagonistic

effectsinducedbyamiodarone.Amiodaroneisapotentinhibitorofiodothyronine-5´-monodeiodinaseactivity(the

mainT4-T3convertingenzyme).Someeffectsofamiodaronearecomparablewithhypothyroidism,whichmightbe

duetoinhibitionofthyroidhormonesynthesis.Inrats,increasesinserumthyroid-stimulatinghormone(TSH),

thyroxine(T4)andreversetriiodothyronine(rT3),anddecreasesinserumtriiodothyronine(T3)asaresultof

deiodinationofT4toT3havebeenobserved.Theseantithyroidactionsofamiodaronemightcontributetoitscardiac

electrophysiologicaleffects.Themainmetabolitedesethylamiodaronehaseffectsoncardiacelectrophysiologysimilar

tothoseoftheparentcompound.

Nocontrolledpaediatricstudieshavebeenundertaken.

Inpublishedstudiesthesafetyofamiodaronewasevaluatedin1118paediatricpatientswithvariousarrhythmias.The

followingdoseswereusedinpaediatricclinicaltrials.

Oral

-Loadingdose:10to20mg/kg/dayfor7to10days(or500mg/m/dayifexpressedpersquaremeter)

-Maintenancedose:theminimumeffectivedosageshouldbeused;accordingtoindividualresponse,itmayrange

between5to10mg/kg/day(or250mg/m/dayifexpressedpersquaremeter)

Intravenous

-Loadingdose:5mg/kgbodyweightover20minutesto2hours,

-Maintenancedose:10to15mg/kg/dayfromfewhourstoseveraldays

Ifneededoraltherapymaybeinitiatedconcomitantlyattheusualloadingdose.

5.2Pharmacokineticproperties

Pharmacokineticsofamiodaronehydrochlorideisunusualandcomplex,andhasnotbeencompletelyelucidated.

Absorptionfollowingoraladministrationisvariableandmaybeprolonged,withenterohepaticcycling.Themajor

metaboliteisdesethylamiodarone.Amiodaronehydrochlorideishighlyproteinbound>95%).Renalexcretionis

minimalandfaecalexcretionisthemajorroute.Astudyinbothhealthyvolunteersandpatientsafterintravenous

administrationofamiodaronehydrochloridereportedthatthecalculatedvolumesofdistributionandtotalblood

clearanceusingatwo-compartmentopenmodelweresimilarforbothgroups.Eliminationofamiodaronehydrochloride

afterintravenousinjectionappearedtobebiexponentialwithadistributionphaselastingabout4hours.Theveryhigh

volumeofdistributioncombinedwitharelativelylowapparentvolumeforthecentralcompartmentsuggestsextensive

tissuedistribution.Abolusivinjectionof400mggaveaterminalT

ofapprox11hours.

Nocontrolledpaediatricstudieshavebeenundertaken.Inthelimitedpublisheddataavailableinpaediatricpatients,

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5.3Preclinicalsafetydata

Inchronictoxicitystudies,amiodaroneledtopulmonarydamage(fibrosis,phospholipidosis;inhamsters,rats

anddogs)aswellasCNSdisorders(inrats).Pulmonarydamageappearstobepredominantlycausedby

oxidativestressandfreeradicals.Inaddition,amiodaronecausedliverdamageinrats.Theactionof

amiodaroneonserumlipidsmayindirectlyresultfromalteredplasmaconcentrationsofthyroidgland

hormones.

Amiodaroneisamarkedphototoxicsubstance.ThereisevidencethatUVradiationcancausecytotoxicallyactingfree

radicalsinthepresenceofamiodarone.Thismaynotonlyleadtoacutephototoxicreactions,butalsotodamageofthe

DNA(photomutagenicity)andsubsequentphotocancerogenicactions.Uptonowthesepotentiallyseveresideeffects

ofamiodaronehavenotbeeninvestigatedexperimentally.Thusthephotomutagenicandthephotocancerogenic

potentialofamiodaronearenotknown.Inacarcinogenicitystudyinrats,amiodaronecausedfolliculartumoursofthe

thyroidglandtoanincreasedextent(atdosesfrom>5mg/kg/dieinmaleanimalsand>16mg/kg/dieinfemale

animals).Theseeffectsseemtobebasedoneffectsofamiodaroneonthesynthesisand/orreleaseofthyroidgland

hormones.Hencenocancerogenicpotentialcanbededucedfromtheseinvestigationsforthetherapeuticadministration

ofamiodaroneinhumans.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Benzylalcohol

Polysorbate80

Waterforinjections

Hydrochloricacid(pHadjustment)

Sodiumhydroxide(pHadjustment)

6.2Incompatibilities

Thismedicinalproductmustnotbemixedwithothermedicinalproductsexceptthosementionedinsection6.6.

Amiodaroneisincompatiblewithsalinesolutionandshouldbeadministeredsolelyin5%dextrosesolution.Solutions

containinglessthan2ampoulesAmiodaronein500mldextrose5%areunstableandshouldnotbeused.

Thefollowingactivesubstancesorsolutionforreconstitution/dilutionorequipment/devicesshouldnotbeadministered

simultaneously:

TheuseofadministrationequipmentordevicescontainingplasticizerssuchasDEHP(di-2-ethylhexylphthalate)inthe

presenceofamiodaronehydrochloridemayresultinleachingoutofDEHP.Inordertominimisepatients’exposureto

DEHP,thefinalamiodaronehydrochloridedilutionforinfusionshouldpreferablybeadministeredthroughnonDEHP-

containingsets.

6.3Shelflife

2years.

Reconstituted/dilutedsolution:Afterdilutionindextrose5%,chemicalandphysicalin-usestabilityhasbeen

demonstratedfor36hoursat25°Cwhenexposedtolight.

Fromamicrobiologicalpointofview,thedilutedsolutionshouldbeusedimmediately.Ifnotusedimmediately,in-use

storagetimesandconditionspriortousearetheresponsibilityoftheuserandwouldnormallynotbelongerthan

24hoursat2°Cto8°Cunlessdilutionhastakenplaceincontrolledandvalidatedasepticconditions.

6.4Specialprecautionsforstorage

Donotstoreabove30ºC.Storeintheoriginalpackageinordertoprotectfromlight.

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6.5Natureandcontentsofcontainer

Clear,typeIglassampoulescontaining3mlsolution.

Packsize:5x1ampoule,10x1ampoule.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Forsingleuseonly.Discardanyunusedsolution.

Thedilutionistobemadeunderasepticconditions.Thesolutionistobeinspectedvisuallyforparticulatematterand

discolorationpriortoadministration.Thesolutionshouldonlybeusedifthesolutionisclearandfreefromparticles.

Solutionscontaininglessthan300mgofamiodarone(twoampoules)in500mlofdextrosearenotstableandmustnot

beused.Itshouldalsobestressedthatnoothercompoundsaretomixedtoamiodaroneinfusionsolution.

Amiodaroneshouldbeadministeredsolelyin5%dextrosesolution.

Amiodaronemustnotbemixedwithothermedicinalproductsinthesamesyringe.

Intravenousinfusion:

Thecalculateddoseisdilutedwith250ml5%dextrose.Seesextion4.2

Intravenousinjection:

150-300mg(correspondingto3-6mlAmiodarone)isdilutedwith10-20ml5%dextrose.Seesection4.2

7MARKETINGAUTHORISATIONHOLDER

ClonmelHealthcareLtd

WaterfordRoad

Clonmel

Co.Tipperary

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA126/186/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

19thDecember2007

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 15/03/2012 CRN 2111061 page number: 10