CORDARONE X

Main information

  • Trade name:
  • CORDARONE X
  • Dosage:
  • 200 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CORDARONE X
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1500/044/001
  • Authorization date:
  • 07-01-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

CordaroneX200mgTablets.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

EachtabletcontainsAmiodaroneHydrochloride200mg.

Excipients:Alsocontainslactosemonohydrate.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablet

ProductimportedfromtheNetherlandsandHungary:

Round,whitetabletwithascorelineononesideandalogoand‘200’engravedoneithersideofthescoreline.

Thescorelineisonlytofacilitatebreakingforeaseofswallowingandnottodivideintoequaldoses.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentshouldbeinitiatedandnormallymonitoredonlyunderhospitalorspecialistsupervision.OralCordaroneX

isindicatedforthetreatmentofsevererhythmdisordersonlywhennotrespondingtoothertherapiesorwhenother

treatmentscannotbeused.

TachyarrhythmiasassociatedwithWolff-Parkinson-WhiteSyndrome.

Atrialflutterandfibrillationwhenotherdrugscannotbeused.

Alltypesoftachyarrhythmiasofparoxysmalnatureincluding:supraventricular,nodalandVentriculartachycardias,

ventricularfibrillation:whenotherdrugscannotbeused.

Cordaroneisindicatedforthepreventionofventriculararrhythmiasinhigh-riskpatientsfollowingmyocardial

infarctionorinpatientswithclinicalsignsofcongestivecardiacfailureand/orLVEFlessthan40%whoarereceiving

appropriatecardiacfailuretreatmentwhichincludesACE-inhibitors.Theminimumeffectivedosemustbeusedand

treatmentmustbeinitiatedandusedonlyunderhospital/specialistsupervision.

4.2Posologyandmethodofadministration

CordaroneX200Tabletsarefororaladministration.

Adults

Itisparticularlyimportantthattheminimumeffectivedosebeused.Inallcasesthepatient’smanagementmustbe

judgedontheindividualresponseandwellbeing.Thefollowingdosageregimenisgenerallyeffective.

InitialStabilisation

Treatmentshouldbestartedwith200mg,threetimesadayandmaybecontinuedfor1week.Thedosageshouldthen

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Maintenance

Aftertheinitialperiodthedosageshouldbereducedto200mgdaily,orlessifappropriate.Rarely,thepatientmay

requireahighermaintenancedose.Thescored100mgtabletshouldbeusedtotitratetheminimumdosagerequiredto

maintaincontrolofthearrhythmia.Themaintenancedoseshouldberegularlyreviewed,especiallywherethisexceeds

200mgdaily.

GeneralConsiderations

Initialdosing

Ahighdoseisneededinordertoachieveadequatetissuelevelsrapidly.

Maintenance

Toohighadoseduringmaintenancetherapycancausesideeffectswhicharebelievedtoberelatedtohightissuelevels

ofamiodaroneanditsmetabolites.

Amiodaroneisstronglyproteinboundandhasanaverageplasmahalflifeof50days(reportedrange20-100days).It

followsthatsufficienttimemustbeallowedforanewdistributionequilibriumtobeachievedbetweenadjustmentsof

dosage.Inpatientswithpotentiallylethalarrhythmiasthelonghalflifeisavaluablesafeguardasomissionofoccasional

dosesdoesnotsignificantlyinfluencetheoveralltherapeuticeffect.

Itisparticularlyimportantthattheminimumeffectivedosageisusedandthepatientismonitoredregularlytodetect

theclinicalfeaturesofexcessamiodaronedosage.Therapymaythenbeadjustedaccordingly.

Dosagereduction/withdrawal

Sideeffectsslowlydisappearasthetissuelevelsfall.Followingdrugwithdrawal,residualtissue-boundamiodarone

mayprotectthepatientforuptoamonth.However,thelikelihoodofrecurrenceofarrhythmiaduringthisperiod

shouldbeconsidered.

Elderly

Aswithallpatientsitisimportantthattheminimumeffectivedoseisused.Whilstthereisnoevidencethatdosage

requirementsaredifferentforthisgroupofpatientstheymaybemoresusceptibletobradycardiaandconduction

defectsiftoohighadoseisemployed.Particularattentionshouldbepaidtomonitoringthyroidfunction.

(Seesection4.3,Contra-indications,4.4SpecialWarningsandprecautionsforuse,4.8UndesirableEffects).

4.3Contraindications

Sinusbradycardiaandsino-atrialheartblock.Inpatientswithsevereconductiondisturbances(highgradeAVblock,

bifascicularortrifascicularblock)orsinusnodedisease,CordaroneXshouldbeusedonlyinconjunctionwitha

pacemaker.

Evidenceorhistoryofthyroiddysfunction.

Knownhypersensitivitytoiodineortoamiodarone,oranyoftheexcipients.(One200mgtabletcontainsapproximately

75mgiodine).

ConcomitantadministrationofCordaroneXwithdrugswhichmayinducetorsadesdepointes(seesection4.5,Interaction

withothermedicinalproductsandotherformsofinteractions).

Pregnancy:exceptinexceptionalcircumstances(seesection4.6,Pregnancyandlactation).

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4.4Specialwarningsandprecautionsforuse

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

malabsorptionshouldnottakethismedicine.

Paediatricpatients:

Thesafetyandefficacyofamiodaroneinpaediatricpatientshavenotbeenestablished.Therefore,itsuseinpaediatric

patientsisnotrecommended.

Cardiacdisorders:(seesection4.8,Undesirableeffects)

Toohighadosagemayleadtoseverebradycardiaandtoconductiondisturbanceswiththeappearanceofan

idioventricularrhythm,particularlyinelderlypatientsorduringdigitalistherapy.Inthesecircumstances,CordaroneX

treatmentshouldbewithdrawn.Ifnecessarybeta-adrenostimulantsorglucagonmaybegiven.Becauseofthelong

half-lifeofamiodarone,ifbradycardiaissevereandsymptomatictheinsertionofapacemakershouldbeconsidered.

ThepharmacologicalactionofamiodaroneinducesECGchanges:QTprolongation(relatedtoprolonged

repolarisation)withthepossibledevelopmentofU-wavesanddeformedT-waves;thesechangesdonotreflecttoxicity.

Intheelderly,heartratemaydecreasemarkedly.

Treatmentshouldbediscontinuedincaseofonsetof2 nd

or3 rd

degreeA-Vblock,sino-atrialblock,orbifascicular

block.

Amiodaronehasalowpro-arrhythmiceffect.Onsetsofnewarrhythmiasorworseningoftreatedarrhythmias,

sometimesfatal,havebeenreported.Itisimportant,butdifficult,todifferentiatealackofefficacyofthedrugfroma

proarrhythmiceffect,whetherornotthisisassociatedwithaworseningofthecardiaccondition.Proarrhythmiceffects

generallyoccurinthecontextofdruginteractionsand/orelectrolyticdisorders(Seesection4.5,Interactionwith

othermedicinalproductsandotherformsofinteractions,section4.8,Undesirableeffects).

Hyperthyroidism:(seesection4.4,Specialwarningsandprecautionsforuse,Seesection4.8,Undesirableeffects)

Hyperthyroidismmayoccurduringamiodaronetreatment,or,uptoseveralmonthsafterdiscontinuation.Clinical

features,suchasweightloss,asthenia,restlessness,increaseinheartrate,onsetofarrhythmia,angina,congestiveheart

failureshouldalertthephysician.ThediagnosisissupportedbyadecreaseinserumultrasensitiveTSH(usTSH)level,

elevatedT

andareducedTSHresponsetothyrotropinreleasinghormone(TRH).ElevationofreverseT

)may

alsobefound.

Inthecaseofhyperthyroidism,therapyshouldbewithdrawn.Clinicalrecoveryusuallyoccurswithinafewmonths,

althoughseverecases,sometimesresultinginfatalities,havebeenreported.Clinicalrecoveryprecedesthe

normalisationofthyroidfunctiontests.

Coursesofanti-thyroiddrugshavebeenusedforthetreatmentofseverethyroidhyperactivity;largedosesmaybe

requiredinitially.Thesemaynotalwaysbeeffectiveandconcomitanthighdosecorticosteroidtherapy(e.g.1mg/kg

prednisolone)mayberequiredforseveralweeks.

Pulmonarydisorders:(Seesection4.8,Undesirableeffects)

Onsetofdyspnoeaornon-productivecoughmayberelatedtopulmonarytoxicity(hypersensitivitypneumonitis,

alveolar/interstitualpneumonitisorfibrosis,pleuritis,bronchiolitisobliteransorganisingpneumonitis).Presenting

featurescanincludedyspnoea(whichmaybesevereandunexplainedbythecurrentcardiacstatus),non-productive

coughanddeteriorationingeneralhealth(fatigue,weightlossandfever).Theonsetisusuallyslowbutmayberapidly

progressive.Whilstthemajorityofcaseshavebeenreportedwithlongtermtherapy,afewhaveoccurredsoonafter

startingtreatment.

Amiodaronetherapyshouldbere-evaluatedsinceinterstitialpneumonitisisgenerallyreversiblefollowingearly

withdrawalofamiodarone.

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Duringtreatment,ifpulmonarytoxicityissuspected,thisshouldberepeatedandassociatedwithlungfunctiontesting

includingwherepossiblemeasurementoftransferfactor.Initialradiologicalchangesmaybedifficulttodistinguish

frompulmonaryvenouscongestion.

Pulmonarytoxicityhasusuallybeenreversiblefollowingearlywithdrawalofamiodaronetherapy,withorwithout

corticosteroidtherapy.

Clinicalsymptomsoftenresolvewithinafewweeksfollowedbyslowerradiologicalandlungfunctionimprovement.

SomepatientscandeterioratedespitediscontinuingCordaroneX.

Veryrarecasesofsevererespiratorycomplications,sometimesfatal,havebeenobservedusuallyintheperiod

immediatelyfollowingsurgery(adultacuterespiratorydistresssyndrom);apossibleinteractionwithahighoxygen

concentrationmaybeimplicated.

Liverdisorders:(Seesection4.8,Undesirableeffects)

Closemonitoringofliverfunctiontests(transaminases)isrecommendedassoonasamiodaroneisstartedandregularly

duringtreatment.acuteliverdisorders(includingseverehepatocellularinsufficiencyorhepaticfailure,sometimesfatal)

andchronicliverdisordersmayoccurwithoralandintravenousformswithinthefirst24hoursofIVamiodarone.

Thereforeamiodaronedoseshouldbereducedorthetreatmentdiscontinuedifthetransaminasesincreaseexceedsthree

timesthenormalrange.Clinicalandbiologicalsignsofchronicliverdisordersduetooralamiodaronemaybeminimal

(hepatomegaly,transaminasesincreasedupto5timesthenormalrange)andreversibleafterwithdrawal,howeverfatal

caseshavebeenreported.

Histologicalfindingsmayresemblepseudo-alcoholichepatitis,buttheycanbevariableandincludecirrhosis.

Althoughtherehavebeennoliteraturereportsonthepotentiationofhepaticadverseeffectsofalcohol,patientsshouldbe

advisedtomoderatetheiralcoholintakewhiletakingCordaroneX.

Neuromusculardisorders:(Seesection4.8,Undesirableeffects)

Amiodaronemayinduceperipheralsensorimotorneuropathyand/ormyopathy.Boththeseconditionsmaybesevere,

althoughrecoveryusuallyoccurswithinseveralmonthsafteramiodaronewithdrawal,butmaysometimesbe

incomplete.

Eyedisorders:(Seesection4.8,Undesirableeffects)

Ifblurredordecreasedvisionoccurs,completeophthalmologicexaminationincludingfundoscopyshouldbepromptly

performed.

Appearanceofopticneuropathyand/oropticneuritisrequiresamiodaronewithdrawalduetothepotentialprogression

toblindness.Unlessblurredordecreasedvisionoccurs,opthamologicalexaminationisrecommendedannually.

Druginteractions:(Seesection4.5,Interactionwithothermedicinalproductsandotherformsofinteractions).

Concomitantuseofamiodaroneisnotrecommendedwiththefollowingdrugs:beta-blockers,heartratelowering

calciumchannelinhibitors(verapamil,diltiazem),stimulantlaxativeagentswhichmaycausehypokalaemia.

Amiodaronecancauseseriousadversereactionsaffectingtheeyes,heart,lung,liver,thyroidgland,skinandperipheral

nervoussystem(Seesection4.8,Undesirableeffects).

Becausethesereactionscanbedelayed,patientsonlong-termtherapyshouldbecarefullysupervised.Asundesirable

effectsareusuallydose-related,theminimumeffectivemaintenancedoseshouldbegiven.

Patientsshouldbeinstructedtoavoidexposuretosunandtouseprotectivemeasuresduringtherapyaspatientstaking

CordaroneXcanbecomeundulysensitivetosunlight,whichmaypersistafterseveralmonthsofdiscontinuationof

CordaroneX.Inmostcasessymptomsarelimitedtotingling,burninganderythemaofsun-exposedskinbutsevere

phototoxicreactionswithblisteringmaybeseen.(Seesection4.8,Undesirableeffects).

Monitoring:(seesection4.4,Specialwarningsandprecautionsforuse,Seesection4.8,Undesirableeffects)

Beforestartingamiodarone,itisrecommendedtoperformanECGandserumpotassiummeasurement.Monitoringof

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Asamiodaronemayinducehypothyroidismorhyperthyroidism,particularlyinpatientswithapersonalorfamily

historyofthyroiddisorders,clinicalandbiological(usTSH)monitoringshouldbeperformedbeforestarting

amiodarone.Thismonitoringshouldbecarriedoutduringtreatment,atsix-monthlyintervals,andforseveralmonths

followingitsdiscontinuation.Thisisparticularlyimportantintheelderly.Inpatientswhosehistoryindicatesan

increasedriskofthyroiddysfunction,regularassessmentisrecommended.SerumusTSHlevelshouldbemeasured

whenthyroiddysfunctionissuspected.

Inparticularinthecontextofchronicadministrationofantiarrhythmicdrugs,casesofincreaseintheventricular

fibrillationand/orpacingthresholdofthepacemakerorimplantablecardioverterdefibrillatiordevicehavebeen

reported,potentiallydffectingitsefficiency.Therefore,arepeatedverificationofthefunctioningofthedevicebefore

andduringamiodaronetreatmentisrecommended.

Thyroidabnormalities:(Seesection4.8,Undesirableeffects)

Amiodaronecontainsiodineandthusmayinterferewithradio-iodineuptake.However,thyroidfunctiontests(free-T

free-T

,usTSH)remaininterpretable.Amiodaroneinhibitsperipheralconversionofthyroxine(T

)totriiodothyronine

)andmaycauseisolatedbiochemicalchanges(increaseinserumfree-T

,free-T

beingslightlydecreasedoreven

normal)inclinicallyeuthyroidpatients.Thereisnoreasoninsuchcasestodiscontinueamiodaronetreatment.

Hypothyroidismshouldbesuspectedifthefollowingclinicalsignsoccur:weightgain,coldintolerance,reduced

activity,excessivebradycardia.ThediagnosisissupportedbyanincreaseinserumusTSHandanexaggeratedTSH

responsetoTRH.T

andT

levelsmaybelow.Euthyroidismisusuallyobtainedwithin3monthsfollowingthe

discontinuationoftreatment.Inlife-threateningsituations,amiodaronetherapycanbecontinued,incombinationwith

L-Thyroxine.ThedoseofL-ThyroxineisadjustedaccordingtoTSHlevels.

Anaesthesia:(Seesection4.5,Interactionwithothermedicinalproductsandotherformsofinteractions,section4.8,

Undesirableeffects).

Beforesurgery,theanaesthetistshouldbeinformedthatthepatientistakingamiodarone.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Someofthemoreimportantdrugsthatinteractwithamiodaroneincludewarfarin,digoxin,phenytoinandanydrug

whichprolongstheQTinterval.

Amiodaroneraisestheplasmaconcentrationsoforalanticoagulants(warfarin)andphenytoinbyinhibitionofCYP

2C9.Thedoseofwarfarinshouldbereducedaccordingly.Morefrequentmonitoringofprothrombintimebothduring

andafteramiodaronetreatmentisrecommended.Phenytoindosageshouldbereducedifsignsofoverdosageappear,

andplasmalevelsmaybemeasured.

AdministrationofCordaroneXtoapatientalreadyreceivingdigoxinwillbringaboutanincreaseintheplasmadigoxin

concentrationandthusprecipitatesymptomsandsignsassociatedwithhighdigoxinlevels.Clinical,ECGand

biologicalmonitoringisrecommendedanddigoxindosageusuallyhastobereduced.Asynergisticeffectonheartrate

andatrioventricularconductionisalsopossible.

CombinedtherapywiththefollowingdrugswhichprolongtheQTintervaliscontra-indicated(Seesection4.3,

Contraindications)duetotheincreasedriskoftorsadesdepointes;forexample:

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

ClassIIIanti-arrhythmicdrugse.g.sotalol,bretylium.

Intravenouserythromycin,co-trimoxazoleorpentamidineinjection(whenparenterallyadministered),asthereis

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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.

Combinedtherapywiththefollowingdrugsisnotrecommended:

betablockersandcertaincalciumchannelinhibitors(diltiazem,verapamil);potentiationofnegativechronotropic

propertiesandconductionslowingeffectsmayoccur.

stimulantlaxatives,whichmaycausehypokalaemiathusincreasingtheriskoftorsadesdepointes;othertypesof

laxativesshouldbeused.

Flouroquinolonesshouldbeavoidedinpatientsreceivingamiodarone.

Cautionshouldbeexercisedovercombinedtherapywiththefollowingdrugs

whichmaycausehypokalaemiaand/orhypomagnesaemiae.g.diuretics,systemiccorticosteroids,tetracosactride,

intravenousamphotericin.

GrapefruitjuiceinhibitscytochromeP4503A4andmayincreasetheplasmaconcentrationofamiodarone.Grapefruit

juiceshouldbeavoidedduringtreatmentwithoralamiodarone.

Incasesofhypokalaemia,correctiveactionshouldbetakenandQTintervalmonitored.Incaseoftorsadesdepointes,

antiarrhythmicagentsshouldnotbegiven;pacingmaybeinstitutedandIVmagnesiummaybeused.

Cautionisadvisedinpatientsundergoinggeneralanaesthesia,orreceivinghighdoseoxygentherapy.Potentially

severecomplicationshavebeenreportedinpatientstakingamiodaroneundergoinggeneralanaesthesia:bradycardia

unresponsivetoatropine,hypotension,disturbancesofconduction,decreasedcardiacoutput.Veryrarecasesofsevere

respiratorycomplications(adultacuterespiratorydistresssyndrome),sometimesfatal,havebeenobservedusuallyin

theperiodimmediatelyfollowingsurgery.Apossibleinteractionwithahighoxygenconcentrationmaybeimplicated.

Flecainide

AmiodaroneraisesplasmaconcentrationsofflecainidebyinhibitionofCYP2D6;thedosageofflecainideshouldbe

adjusted

DrugsmetabolisedbycytochromeP4503A4

Whensuchdrugsareco-administeredwithamiodarone,aninhibitorofCYP3A4,thismayresultinahigherlevelof

theirplasmaconcentrations,whichmayleadtoapossibleincreaseintheirtoxicity.

Ciclosporincombinationwithamiodaronemayincreaseciclosporinplasmalevels.Dosageshouldbeadjusted.

Fentanylcombinationwithamiodaronemayenhancethepharmacologiceffectsoffentanylandincreasetherisk

ofitstoxicity.

Statins:Theriskofmusculartoxicityisincreasedbyconcomitantadministrationofamiodaronewithstatins

metabolizedbyCYP3A4suchassimvastatin,torvastatinandlovastatin.Itisrecommendedtouseastatinnot

metabolizedbyCYP3A4whengivenwithamiodarone.

OtherdrugsmetabolisedbyCYP3A4:lidocaine,tacrolimus,sildenafil,midazolam,triazolam,

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4.6Fertility,pregnancyandlactation

Pregnancy

Inviewofitseffectonthefoetalthyroidgland,amiodaroneiscontraindicatedduringpregnancy,exceptinexceptional

circumstances.

If,becauseofthelonghalflifeofCordaroneX,discontinuationofthedrugisconsideredpriortoplannedconception,

therealriskofrecurrenceoflifethreateningarrhythmiasshouldbeweighedagainsttheunknownpossiblehazardfor

thefoetus.

Lactation

Amiodaroneisexcretedintothebreastmilkinsignificantquantitiesandbreast-feedingiscontraindicated.

4.7Effectsonabilitytodriveandusemachines

Accordingtothesafetydataforamiodarone,thereisnoevidencethatamiodaroneimpairstheabilitytodriveavehicle

oroperatemachinery.

4.8Undesirableeffects

Thefollowingadversereactionsareclassifiedbysystemorganclassandrankedunderheadingoffrequencyusingthe

followingconvention:verycommon(>=10%),common(>=1%and<10%);uncommon(>=0.1%and<1%);rare

(>=0.01%and<0.1%),veryrare(<0.01%).

Bloodandlymphaticsystemdisorders:

Veryrare:

haemolyticanaemia

aplasticanaemia

thrombocytopenia.

Cardiacdisorders:

Common:bradycardia,generallymoderateanddose-related.

Uncommon:

onsetorworseningofarrhythmia,sometimesfollowedbycardiacarrest(seesection4.4,Specialwarnings

andprecautionsforuse,seesection4.5,Interactionwithothermedicinalproductsandotherformsof

interactions).

conductiondisturbances(sinoatrialblock,AVblockofvariousdegrees)(seesection4.4,Specialwarnings

andprecautionsforuse).

Veryrare:markedbradycardiaorsinusarrestinpatientswithsinusnodedysfunctionand/orinelderlypatients.

Endocrinedisorders(seesection4.4,Specialwarningsandprecautionsforuse):

Common:

hypothyroidism

hyperthyroidism,sometimesfatal.

Veryrare:syndromeofinappropriateantidiuretichormonesecretion(SIADH).

Eyedisorders:

Verycommon:cornealmicrodepositsusuallylimitedtotheareaunderthepupil , whichareusuallyonly

discernablebyslit-lampexaminations.Theymaybeassociatedwithcoloredhalosindazzlinglightor

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discontinuationoftreatment.Thedepositsareconsideredessentiallybenignanddonotrequirediscontinuationof

amiodarone.

Veryrare:opticneuropathy/neuritisthatmayprogresstoblindness(seesection4.4,Specialwarningsand

precautionsforuse).

Gastrointestinaldisorders:

Verycommon:benigngastrointestinaldisorders(nausea,vomiting,dysgeusia)usuallyoccurringwithloading

dosageandresolvingwithdosereduction.

Hepato-biliarydisorders:(seesection4.4,Specialwarningsandprecautionsforuse).

Verycommon:isolatedincreaseinserumtransaminases,whichisusuallymoderate(1.5to3timesnormal

range),occurringatthebeginningoftherapy.Itmayreturntonormalwithdosereductionoreven

spontaneously.

Common:acuteliverdisorderswithhighserumtransaminasesand/orjaundice,includinghepaticfailure,which

aresometimesfatal.

Veryrare:chronicliverdisease(pseudoalcoholichepatitis,cirrhosis),sometimesfatal.

Investigations:

Veryrare:increasedinbloodcreatinine.

Nervoussystemdisorders:

Common

extrapyramidaltremor,forwhichregressionusuallyoccursafterreductionofdoseorwithdrawal

nightmares

sleepdisorders.

Uncommon:peripheralsensorimotorneuropathyand/ormyopathy,usuallyreversibleonwithdrawalofthedrug

(seesection4.4,Specialwarningsandprecautionsforuse).

Veryrare:

cerebellarataxia,forwhichregressionusuallyoccursafterreductionofdoseorwithdrawal

benignintracranialhypertension(pseudo-tumorcerebri)

headache

vertigo.

Reproductivesystemandbreastdisorders:

Veryrare:

epididymo-orchitis

impotence.

Respiratory,thoracicandmediastinaldisorders:

Common:pulmonarytoxicity[hypersensitivitypneumonitis,alveolar/interstitialpneumonitisorfibrosis,

pleuritis,bronchiolitisobliteransorganisingpneumonia(BOOP)],sometimesfatal(seesection4.4,Special

warningsandprecautionsforuse).

Pulmonaryhaemorrage(Frequency:Notknown).

Veryrare:

bronchospasminpatientswithsevererespiratoryfailureandespeciallyinasthmaticpatients

adultacuterespiratorydistresssyndrome,sometimesfatal,mostoftenimmediatelyaftersurgery(possible

interactionwithahighoxygenconcentration)(seesection4.4,Specialwarningsandprecautionsforuse,

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Skinandsubcutaneoustissuedisorders:

Verycommon:photosensitivity(seesection4.4,Specialwarningsandprecautionsforuse).

Common:slategreyorbluishpigmentationsoflight-exposedskin,particularlytheface,incaseofprolonged

treatmentwithhighdailydosages;suchpigmentationsslowlydisappearfollowingtreatment

discontinuation.

Veryrare:

erythemaduringthecourseofradiotherapy

skinrashes,usuallynon-specific

exfoliativedermatitis

alopecia.

Frequencynotknown:

urticaria.

Vasculardisorders:

Veryrare:vesculitis.

Immunesystemdisorders:

Angioneuroticoedema(Quincke’soedema)(Frequency:Notknown)

4.9Overdose

Littleinformationisavailableregardingacuteoverdosagewithamiodarone.Fewcasesofsinusbradycardia,heart

block,attacksofventriculartachycardia,torsadesdepointes,circulatoryfailureandhepaticinjuryhavebeenreported.

Intheeventofoverdosetreatmentshouldbesymptomatic,gastriclavagemaybeemployedtoreduceabsorptionin

additiontogeneralsupportivemeasures.

Thepatientshouldbemonitoredandifbradycardiaensues,beta-adrenostimulantsorglucagonmaybegiven.

Spontaneouslyresolvingattacksofventriculartachycardiamayalsooccur.Duetothepharmacokineticsofamiodarone,

adequateandprolongedsurveillanceofthepatient,particularlycardiacstatus,isrecommended.

Neitheramiodaroneoritsmetabolitesisdialysable.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

ATCcode:CO1BD01

Pharmacotherapeuticgroup:Antiarrhythmics,ClassIII.

Amiodaroneslowssinoatrial,atrialandnodalconductionandincreasestherefractoryperiodattheatrial,nodaland

ventricularlevelsbutdoesnotalterintraventricularconduction.Thereisalsoslowinginconductionandprolongation

ofrefractoryperiodsinaccessoryatrioventricularpathways.

Amiodaronehasanti-adrenergic(non-competitivealphaandbetablocker)effects.Itinhibitsthemetabolicand

biochemicaleffectsofcatecholaminesontheheartandinhibitsNa+andK+activatedATP-ase.

Amiodaronehasanti-ischaemicandhaemodynamiceffects.Itcausesamoderatedropinperipheralresistanceand

decreaseinheartrateleadingtoareductioninoxygenintake.Itcausesanincreaseincoronaryoutputduetoadirect

effectonthesmoothmuscleofthemyocardialarteries.Cardiacoutputismaintainedduetoadecreaseinaortic

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Aunivariateanalysis(EMIAT)suggestedthatall-causemortalityisreducedonamiodaronetreatmentinpatientswith

anejectionfractionlessthan30%,witharrhythmiaontheinitialHolter,onbeta-blockertreatment,andwithan

increasedinitialheartrate.

5.2Pharmacokineticproperties

Followingoraladministrationabsorptionisslowandvariablewithanapproximatemeanof50%,andmaybe

prolongedduetoenterohepaticcycling.Followingsingleadministration,peakplasmaconcentrationsarereachedafter

3-7hours.Therapeuticeffectsareusuallyobservedafteroneweek(fromafewdaystotwoweeksdependingonthe

loadingdose).Duetotheabovecharacteristics,loadingdosesshouldbeusedinordertoobtainrapidlythetissuelevels

necessarytohaveatherapeuticeffect.

Amiodaronehasalargebutvariablevolumeofdistributionbecauseofextensiveaccumulationinvarioussites(adipose

tissue,highlyperfusedorganssuchastheliver,lungandspleen).Amiodaroneishighlyproteinbound(>95%).

Themajormetaboliteisdesethylamiodarone.Amiodaronehasalonghalf-lifeandshowsconsiderableindividual

variability(from20to100days).Duringthefirstdaysoftherapy,thedrugaccumulatesinalmostalltissues,

especiallytheadiposetissue.Eliminationoccursafterafewdaysandsteady-stateplasmaconcentrationisreached

betweenoneandseveralmonthsdependingupontheindividualpatient.

Renalexcretionisminimal;excretionismainlyviathebileandthefaeces.

Aftertreatmentdiscontinuation,theeliminationcontinuesoverseveralmonths;thepersistenceofapharmacodynamic

effectover10daystoonemonthshouldbetakenintoaccount.

5.3Preclinicalsafetydata

Therearenopreclinicaldataofrelevancetotheprescriberwhichareadditionaltothatalreadyincludedinother

sectionsoftheSPC.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactosemonohydrate

Maizestarch

Povidone

Silica,colloidalanhydrous

Magnesiumstearate

6.2Incompatibilities

Notapplicable.

6.3Shelflife

Theshelflifeexpirydateofthisproductisthedateshownonthecartonandblistersoftheproductasmarketedinthe

Irish Medicines Board

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Date Printed 13/03/2012 CRN 2101838 page number: 10

6.4Specialprecautionsforstorage

Donotstoreabove25°C.Keeptheblisterintheoutercartoninordertoprotectfromlight.

6.5Natureandcontentsofcontainer

OverlabelledcardboardcartoncontainingPVC/aluminiumblisterstrips.

Packsize:30or60tablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

ProfindWholesaleLtd

Unit625,KilshaneAvenue

NorthwestBusinessPark

Dublin15

Ireland

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1500/44/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:7thofJanuary2011.

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 13/03/2012 CRN 2101838 page number: 11