CORDARONE X 200 MG TABLETS

Main information

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

Documents

Localization

  • Available in:
  • CORDARONE X 200 MG TABLETS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1328/058/001
  • Authorization date:
  • 21-12-2006
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PPA1328/058/001

CaseNo:2061197

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

B&SHealthcare

Unit4,BradfieldRoad,Ruislip,Middlesex,HA40NU,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

CordaroneX200mgTablets

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom24/02/2009until20/12/2011.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

CordaroneX200mgTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains200mgamiodaronehydrochloride.

Excipients:Lactosemonohydrate.

Forfulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablet

ProductimportedfromFrance,ItalyandtheNetherlands:

Round,whitetabletswithabreakline,ononesideimprinted‘200’andontheotheralogo.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentshouldbeinitiatedandnormallymonitoredonlyunderhospitalorspecialistsupervision.OralCordaroneX

isindicatedforthetreatmentofsevererhythmdisordersonlywhennotrespondingtoothertherapiesorwhenother

treatmentscannotbeused.

TachyarrhythmiasassociatedwithWolff-Parkinson-WhiteSyndrome.

Atrialflutterandfibrillationwhenotherdrugscannotbeused.

Alltypesoftachyarrhythmiasofparoxysmalnatureincluding:supraventricular,nodaland

Ventriculartachycardias,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

bereducedto200mg,twicedailyforafurtherweek.

Maintenance

Aftertheinitialperiodthedosageshouldbereducedto200mgdaily,orlessifappropriate.Rarely,thepatientmay

requireahighermaintenancedose.Thescored100mgtabletshouldbeusedtotitratetheminimumdosagerequiredto

maintaincontrolofthearrhythmia.

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GeneralConsiderations

Initialdosing

Ahighdoseisneededinordertoachieveadequatetissuelevelsrapidly.

Maintenance

Toohighadoseduringmaintenancetherapycancausesideeffectswhicharebelievedtoberelatedtohightissuelevels

ofamiodaroneanditsmetabolites.

Amiodaroneisstronglyproteinboundandhasanaverageplasmahalflifeof50days(reportedrange20-100days).It

followsthatsufficienttimemustbeallowedforanewdistributionequilibriumtobeachievedbetweenadjustmentsof

dosage.Inpatientswithpotentiallylethalarrhythmiasthelonghalflifeisavaluablesafeguardasomissionof

occasionaldosesdoesnotsignificantlyinfluencetheoveralltherapeuticeffect.

Itisparticularlyimportantthattheminimumeffectivedosageisusedandthepatientismonitoredregularlytodetect

theclinicalfeaturesofexcessamiodaronedosage.Therapymaythenbeadjustedaccordingly.

Dosagereduction/withdrawal

Sideeffectsslowlydisappearasthetissuelevelsfall.Followingdrugwithdrawal,residualtissue-boundamiodarone

mayprotectthepatientforuptoamonth.However,thelikelihoodofrecurrenceofarrhythmiaduringthisperiod

shouldbeconsidered.

Elderly

Aswithallpatientsitisimportantthattheminimumeffectivedoseisused.Whilstthereisnoevidencethatdosage

requirementsaredifferentforthisgroupofpatientstheymaybemoresusceptibletobradycardiaandconduction

defectsiftoohighadoseisemployed.Particularattentionshouldbepaidtomonitoringthyroidfunction.(seesections

4.3Contra-indications,4.4SpecialWarningsand4.8UndesirableEffects).

4.3Contraindications

Sinusbradycardiaandsinoatrialheartblock.Inpatientswithsevereconductiondisturbances(highGradeAVblock,

bifascicularortrifascicularblock),orsinusnodediseaseCordaroneXshouldonlybeusedinconjunctionwitha

pacemaker.

Evidenceorhistoryofthyroiddysfunction.

Knownhypersensitivitytoiodineortoamiodarone,ortoanyoftheexcipients.(One200mgtabletcontains

approximately75mgiodine).

ConcomitantadministrationofCordaroneXwithdrugswhichmayinducetorsadesdepointes(seesection4.5).

Pregnancy,exceptinexceptionalcircumstances(seesection4.6)

Lactation(seesection4.6).

4.4Specialwarningsandprecautionsforuse

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyofglucose-galactose

malabsorptionshouldnottakethismedicine.

Paediatricpatients

Thesafetyandefficacyofamiodaroneinpaediatricpatientshavenotbeenestablished.

Therefore,itsuseinpaediatricpatientsisnotrecommended.

Cardiacdisorders(seesection4.8):

Toohighadosagemayleadtoseverebradycardiaandtoconductiondisturbanceswiththeappearanceofan

idioventricularrhythm,particularlyinelderlypatientsorduringdigitalistherapy.Inthesecircumstances,CordaroneX

treatmentshouldbewithdrawn.Ifnecessarybeta-adrenostimulantsorglucagonmaybegiven.Becauseofthelonghalf-

lifeofamiodarone,ifbradycardiaissevereandsymptomatictheinsertionofapacemakershouldbeconsidered.

ThepharmacologicalactionofamiodaroneinducesECGchanges:QTprolongation(relatedtoprolonged

repolarisation)withthepossibledevelopmentofU-wavesanddeformedT-waves;thesechangesdonotreflecttoxicity.

Intheelderly,heartratemaydecreasemarkedly.

Treatmentshouldbediscontinuedincaseofonsetof2 nd

or3 rd

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block.

Amiodaronehasalowpro-arrhythmiceffect.Onsetsofnewarrhythmiasorworseningoftreatedarrhythmias,

sometimesfatal,havebeenreported.Itisimportant,butdifficult,todifferentiatealackofefficacyofthedrugfroma

proarrhythmiceffect,whetherornotthisisassociatedwithaworseningofthecardiaccondition.Proarrhythmiceffects

generallyoccurinthecontextofdruginteractionsand/orelectrolyticdisorders(seesections4.5.and4.8).

Hyperthyroidism(seesections4.4and4.8):

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):

Onsetofdyspnoeaornon-productivecoughmayberelatedtopulmonarytoxicity(hypersensitivitypneumonitis,

alveolar/interstitualpneumonitisorfibrosis,pleuritis,bronchiolitisobliteransorganisingpneumonitis).Presenting

featurescanincludedyspnoea(whichmaybesevereandunexplainedbythecurrentcardiacstatus),non-productive

coughanddeteriorationingeneralhealth(fatigue,weightlossandfever).Theonsetisusuallyslowbutmayberapidly

progressive.Whilstthemajorityofcaseshavebeenreportedwithlongtermtherapy,afewhaveoccurredsoonafter

startingtreatment.

PatientsshouldbecarefullyevaluatedclinicallyandconsiderationgiventochestX-raybeforestartingtherapy.During

treatment,ifpulmonarytoxicityissuspected,thisshouldberepeatedandassociatedwithlungfunctiontesting

includingwherepossiblemeasurementoftransferfactor.Initialradiologicalchangesmaybedifficulttodistinguish

frompulmonaryvenouscongestion.Pulmonarytoxicityhasusuallybeenreversiblefollowingearlywithdrawalof

amiodaronetherapy,withorwithoutcorticosteroidtherapy.Clinicalsymptomsoftenresolvewithinafewweeks

followedbyslowerradiologicalandlungfunctionimprovement.Somepatientscandeterioratedespitediscontinuing

CordaroneX.

Liverdisorders(seesection4.8):

Closemonitoringofliverfunctiontests(transaminases)isrecommendedassoonasamiodaroneisstartedandregurarly

duringtreatment.Acuteliverdisorders(includingseverehepatocellularinsufficiencyorhepaticfailure,sometimes

fatal)andchronicliverdisordersmayoccurwithoralandintravenousformswithinthefirst24hoursofIVamiodarone.

Thereforetheamiodaronedoseshouldbereducedorthetreatmentdiscontinuedofthetransaminasaincreaseexceeds

threetimesthenormalrange.Clinicalandbiologicalsignsofchronicliverdisordersduetooralamiodaronemaybe

minimal(hepatomegaly,transaminasesincreasedupto5timesthenormalrange)andreversibleafterwithdrawal,

howeverfatalcaseshavebeenreported.

Histologicalfindingsmayresemblepseudo-alcoholichepatitis,buttheycanbevariableandincludecirrhosis.

Althoughtherehavebeennoliteraturereportsonthepotentiationofhepaticadverseeffectsofalcohol,patientsshould

beadvisedtomoderatetheiralcoholintakewhiletakingCordaroneX.

Neuromusculardisorders(seesection4.8):

Amiodaronemayinduceperipheralsensorimotorneuropathyand/ormyopathy.Boththeseconditionsmaybesevere,

althoughrecoveryusuallyoccurswithinseveralmonthsafteramiodaronewithdrawal,butmaysometimesbe

incomplete.

Eyedisorders(seesection4.8)

Ifblurredordecreasedvisionoccurs,completeophthalmologicexaminationincludingfundoscopyshouldbepromptly

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progressiontoblindness.Unlessblurredordecreasedvisionoccurs,opthamologicalexaminationisrecommended

annually.

Druginteractions(seesection4.5)

Concomitantuseofamiodaroneisnotrecommendedwiththefollowingdrugs:beta-blockers,heartratelowering

calciumchannelinhibitors(verapamil,diltiazem),stimulantlaxativeagentswhichmaycausehypokalaemia.

Amiodaronecancauseseriousadversereactionsaffectingtheeyes,heart,lung,liver,thyroidgland,skinandperipheral

nervoussystem(seesection4.8.).Becausethesereactionscanbedelayed,patientsonlong-termtherapyshouldbe

carefullysupervised.Asundesirableeffectsareusuallydose-related,theminimumeffectivemaintenancedoseshould

begiven.

Patientsshouldbeinstructedtoavoidexposuretosunandtouseprotectivemeasuresduringtherapyaspatientstaking

CordaroneXcanbecomeundulysensitivetosunlight,whichmaypersistafterseveralmonthsofdiscontinuationof

CordaroneX.Inmostcasessymptomsarelimitedtotingling,burninganderythemaofsun-exposedskinbutsevere

phototoxicreactionswithblisteringmaybeseen.(seesection4.8).

Monitoring(seesections4.4and4.8):

Beforestartingamiodarone,itisrecommendedtoperformanECGandserumpotassiummeasurement.Monitoringof

transaminases(seesection4.4.1)andECGisrecommendedduringtreatment.

Asamiodaronemayinducehypothyroidismorhyperthyroidism,particularlyinpatientswithapersonalhistoryof

thyroiddisorders,clinicalandbiological(usTSH)monitoringshouldbeperformedbeforestartingamiodarone.This

monitoringshouldbecarriedoutduringtreatment,atsix-monthlyintervals,andforseveralmonthsfollowingits

discontinuation.Thisisparticularlyimportantintheelderly.Inpatientswhosehistoryindicatesanincreasedriskof

thyroiddysfunction,regularassessmentisrecommended.SerumusTSHlevelshouldbemeasuredwhenthyroid

dysfunctionissuspected.

Inparticularinthecontexofchronicadministrationofantiarrhythmicdrugs,casesofincreaseintheventricular

fibrillationand/orpacingtresholdofthepacemakerorimplantiblecardioverterdefibrillatordevicehavebeenreported,

potentiallyaffectingitsefficacy.Therefore,arepeatedverificationofthefunctioningofthedevicebeforeandduring

amiodaronetreatmentisrecommended.

Thyroidabnormalities(seesection4.8)

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(seesections4.5and4.8):

Beforesurgery,theanaesthetistshouldbeinformedthatthepatientistakingamiodarone.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Someofthemoreimportantdrugsthatinteractwithamiodaroneincludewarfarin,digoxin,phenytoinandanydrug

whichprolongstheQTinterval.

Amiodaroneraisestheplasmaconcentrationsoforalanticoagulants(warfarin)andphenytoinbyinhibitionofCYP

2C9.Thedoseofwarfarinshouldbereducedaccordingly.Morefrequentmonitoringofprothrombintimebothduring

andafteramiodaronetreatmentisrecommended.Phenytoindosageshouldbereducedifsignsofoverdosageappear,

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AdministrationofCordaroneXtoapatientalreadyreceivingdigoxinwillbringaboutanincreaseintheplasma

digoxinconcentrationandthusprecipitatesymptomsandsignsassociatedwithhighdigoxinlevels.Clinical,ECGand

biologicalmonitoringisrecommendedanddigoxindosageusuallyhastobereduced.Asynergisticeffectonheartrate

andatrioventricularconductionisalsopossible.

CombinedtherapywiththefollowingdrugswhichprolongtheQTintervaliscontra-indicated(seesection4.3)dueto

theincreasedriskoftorsadesdepointes;forexample:

ClassIaanti-arrhythmicdrugse.g.quinidine,procainamide,disopyramide

ClassIIIanti-arrhythmicdrugse.g.sotalol,bretylium

intravenouserythromycin,co-trimoxazoleorpentamidineinjection(whenparenterallyadministered),asthereisan

incresedriskofpotentiallylethal"torsadesdepointes",vincamine,someneurolepticagents,cisapride

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

Cautionshouldbeexercisedovercombinedtherapywiththefollowingdrugswhichmaycausehypokalaemiaand/or

hypomagnesaemiae.g.diuretics,systemiccorticosteroids,tetracosactrin,intravenousamphotericin.

GrapefruitjuiceinhibitscytochromeP4503A4andmayincreasetheplasmaconcentrationofamiodarone.Grapefruit

juiceshouldbeavoidedduringthetreatmentwithoralamiodarone.

Incasesofhypokalaemia,correctiveactionshouldbetakenandQTintervalmonitored.Incaseoftorsadesdepointes,

antiarrhythmicagentsshouldnotbegiven;pacingmaybeinstitutedandIVmagnesiummaybeused.

Cautionisadvisedinpatientsundergoinggeneralanaesthesia,orreceivinghighdoseoxygentherapy.Potentiallysevere

complicationshavebeenreportedinpatientstakingamiodaroneundergoinggeneralanaesthesia:bradycardia

unresponsivetoatropine,hypotension,disturbancesofconduction,decreasedcardiacoutput.Afewcasesofadult

respiratorydistresssyndromemostoftenintheperiodimmediatelyaftersurgeryhavebeenobserved.Apossible

interactionwithahighoxygenconcentrationmaybeimplicated

Flecainide

AmiodaroneraisesplasmaconcentrationsofflecainidebyinhibitionofCYP2D6;thedosageofflecainideshouldbe

adjusted.

DrugsmetabolisedbycytochromeP4503A4

Whensuchdrugsareco-administeredwithamiodarone,aninhibitorofCYP3A4,thismayresultinahigherlevelof

theirplasmaconcentrations,whichmayleadtoapossibleincreaseintheirtoxicity.

Ciclosporin:combinationwithamiodaronemayincreaseciclosporinplasmalevels.Dosageshouldbeadjusted.

Fentanyl:combinationwithamiodaronemayenhancethepharmacologiceffectsoffentanylandincreasetheriskof

itstoxicity.

OtherdrugsmetabolisedbyCYP3A4:lidocaine,tacrolimus,sildenafil,midazolam,ergotamine;simvastatinand

otherstatinsmetabolisedbyCYP3A4(increasedriskofmusculartoxicity).

4.6Pregnancyandlactation

Pregnancy

Inviewofitseffectonthefoetalthyroidgland,amiodaroneiscontraindicatedduringpregnancy,exceptinexceptional

circumstances.

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therealriskofrecurrenceoflifethreateningarrhythmiasshouldbeweighedagainsttheunknownpossiblehazardfor

thefoetus.

Lactation

Amiodaroneisexcretedinthebreastmilkinsignificantquantitiesandbreast-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:

-haemolyticanemia

-aplasticanaemia

-thrombocytopenia.

Cardiacdisorders:

Common:bradycardia,generallymoderateanddose-related.

Uncommon:

-onsetorworseningofarrhythmia,sometimesfollowedbycardiacarrest(seesections4.4and4.5.)

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

Veryrare:markedbradycardiaorsinusarrestinpatientswithsinusnodedysfunctionand/orinelderlypatients.

Endocrinedisorders(seesection4.4):

Common:

-hypothyroidism

-hyperthyroidism,sometimesfatal

Veryrare:

-syndromeofinappropriateantidiuretichormonesecretion(SIADH).

Eyedisorders:

Verycommon:cornealmicrodepositsusuallylimitedtotheareaunderthepupil,whichareusuallyonlydiscernable

byslit-lampexaminations.Theymaybeassociatedwithcoloredhalosindazzlinglightorblurredvision.Corneal

micro-depositsconsistofcomplexlipiddepositsandarereversiblefollowingdiscontinuationoftreatment.Thedeposits

areconsideredessentiallybenignanddonotrequirediscontinuationofamiodarone.

Veryrare:opticneuropathy/neuritisthatmayprogresstoblindness(seesection4.4).

Gastrointestinaldisorders:

Verycommon:benigngastrointestinaldisorders(nausea,vomiting,dysgeusia)usuallyoccurringwithloadingdosage

andresolvingwithdosereduction.

Hepato-biliarydisorders:(seesection4.4).

Verycommon:isolatedincreaseinserumtransaminases,whichisusuallymoderate(1.5to3timesnormalrange),

occurringatthebeginningoftherapy.Itmayreturntonormalwithdosereductionorevenspontaneously.

Common:acuteliverdisorderswithhighserumtransaminasesand/orjaundice,includinghepaticfailure,whichare

sometimesfatal

Veryrare:chronicliverdisease(pseudoalcoholichepatitis,cirrhosis),sometimesfatal.

Investigations:

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Nervoussystemdisorders:

Common:

-extrapyramidaltremor,forwhichregressionusuallyoccursafterreductionofdoseorwithdrawal

-nightmares

-sleepdisorders.

Uncommon:peripheralsensorimotorneuropathyand/ormyopathy,usuallyreversibleonwithdrawalofthedrug(see

section4.4).

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).

Pulmonaryhaemorrhage

(Frequency:Notknown)

Veryrare:

-bronchospasminpatientswithsevererespiratoryfailureandespeciallyinasthmaticpatients

-adultacuterespiratorydistresssyndrome,sometimesfatal,mostoftenimmediatelyaftersurgery(possibleinteraction

withahighoxygenconcentration)(seesections4.4and4.5).

Skinandsubcutaneoustissuedisorders:

Verycommon:photosensitivity(seesection4.4),

Common:slategreyorbluishpigmentationsoflight-exposedskin,particularlytheface,incaseofprolonged

treatmentwithhighdailydosages;suchpigmentationsslowlydisappearfollowingtreatmentdiscontinuation.

Veryrare:

-erythemaduringthecourseofradiotherapy

-skinrashes,usuallynon-specific

-exfoliativedermatitis

-alopecia.

Vasculardisorders:

Veryrare:vasculitis.

Immunesystemdisorders:

Angioneuroticedema(Quincke'soedema)

(Frequency:Notknown)

4.9Overdose

Littleinformationisavailableregardingacuteoverdosagewithamiodarone.Fewcasesofsinusbradycardia,heart

block,attacksofventriculartachycardia,torsadesdepointes,circulatoryfailureandhepaticinjuryhavebeenreported.

Intheeventofoverdosetreatmentshouldbesymptomatic,gastriclavagemaybeemployedtoreduceabsorptionin

additiontogeneralsupportivemeasures.Thepatientshouldbemonitoredandifbradycardiaensues,beta-

adrenostimulantsorglucagonmaybegiven.

Spontaneouslyresolvingattacksofventriculartachycardiamayalsooccur.Duetothepharmacokineticsofamiodarone,

adequateandprolongedsurveillanceofthepatient,particularlycardiacstatus,isrecommended.

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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

pressureandperipheralresistance.

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,especially

theadiposetissue.Eliminationoccursafterafewdaysandsteady-stateplasmaconcentrationisreachedbetweenone

andseveralmonthsdependingupontheindividualpatient.

Renalexcretionisminimal;excretionismainlyviathebileandthefaeces.

Aftertreatmentdiscontinuation,theeliminationcontinuesoverseveralmonths;thepersistenceofapharmacodynamic

effectover10daystoonemonthshouldbetakenintoaccount.

5.3Preclinicalsafetydata

Therearenopreclinicaldataofrelevancetotheprescriberwhichareadditionaltothatalreadyincludedinother

sectionsoftheSPC.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactosemonohydrate

Maizestarch

Povidone

Colloidalanhydroussilica

Irish Medicines Board

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Date Printed 24/02/2009 CRN 2061197 page number: 9

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

Theshelf-lifeexpirydateofthisproductshallbethedateshownonthecontainerandouterpackageoftheproducton

themarketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.Storeintheoriginalpackage.

6.5Natureandcontentsofcontainer

PVC/aluminiumblisterpacksof20or30tabletspackedincardboardcartons.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7ParallelProductAuthorisationHolder

B&SHealthcare

Unit4

BradfieldRoad

Ruislip

Middlesex

HA40NU

UnitedKingdom

8ParallelProductAuthorisationNumber

PPA1328/58/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:21stDecember2006

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 24/02/2009 CRN 2061197 page number: 10