ARYTHMOL SR

Main information

  • Trade name:
  • ARYTHMOL SR
  • Dosage:
  • 225 Milligram
  • Pharmaceutical form:
  • Prolonged Release Capsules
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ARYTHMOL SR
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0038/079/004
  • Authorization date:
  • 10-03-2006
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

ArythmolSR225mgprolongedreleasecapsules

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachprolongedreleasecapsulecontains225mg,propafenonehydrochloride

Itcontains5.685µgsoyaoilpercapsule

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Prolongedreleasecapsule,hard

WhitetoalmostwhiteopaquecapsulestampedwithredAbbottlogoand“225”onthecap.

4CLINICALPARTICULARS

4.1TherapeuticIndications

ArythmolSR(sustained/prolongedrelease)isindicatedtoprolongthetimetorecurrenceofsymptomaticatrial

arrhythmiasinpatientswithoutsignificantstructuralheartdiseaseandwithahistoryofsymptomaticatrialfibrillation.

4.2Posologyandmethodofadministration

ThedoseofArythmolSRmustbeindividuallytitratedonthebasisofresponseandtolerance.Titrationtothe

individualmaintenancedoseshouldbesupervisedbyacardiologist(repeatedECGrecordingsandbloodpressure

measurements).Itisrecommendedthattherapybeinitiatedwith225mgpropafenonehydrochloride(asprolonged-

releasecapsules)giveneverytwelvehours.Thedosagemaybeincreasedataminimumintervalof5daysto325mg

propafenonehydrochloride(asprolonged-releasecapsules)giveneverytwelvehours.Ifadditionaltherapeuticeffectis

needed,thedoseofpropafenonehydrochloride(asprolonged-releasecapsules)maybeincreasedto425mggiven

everytwelvehoursafteraminimumofanother5dayinterval.Tofacilitatedosetitration,additionalstrengthsof

propafenoneSRareavailable.DirectcomparisonofpropafenoneSRcapsuleswithpropafenoneIR(immediate/instant

release)tabletshasnotbeenstudiedinclinicaltrials.

InthosepatientsinwhomsignificantwideningoftheQRScomplexorsecondorthirddegreeAVblockoccurs,adose

reductionshouldbeconsidered.

Dosageinimpairedliverfunction:propafenoneisextensivelymetabolisedviaasaturablehepaticoxidasepathway.In

viewoftheincreasedbioavailabilityandeliminationhalf-lifeofpropafenone,areductionintherecommendeddose

maybenecessary.

Dosageinimpairedrenalfunction:theeliminationofpropafenone’smajormetaboliteisaffectedbyrenalimpairment

thereforeArythmolSRshouldbeadministeredcautiously.

Elderly:Nooveralldifferencesinsafetyoreffectivenesswereobservedinthispatientpopulation,howevergreater

sensitivityofsomeolderindividualscannotberuledout,thereforethesepatientsshouldbecarefullymonitored.

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ArythmolSRshouldbetakenwithwater,eitherwithorwithoutfood.

Donotcrushorfurtherdividethecontentsofthecapsule.

ArythmolSRhasnotbeenstudiedinchildrenandadolescents.

4.3Contraindications

Hypersensitivitytopropafenonehydrochloride

Hypersensitivitytosoyaoranyoftheotherexcipients

Hypersensitivitytopeanut

KnownBrugadasyndrome

Significantstructuralheartdiseasesuchas:

Incidentofmyocardialinfarctionwithinthelast3months.

Uncontrolledcongestiveheartfailurewhereleftventricularoutputislessthan35%

Cardiogenicshock,unlessthisiscausedbyarrhythmia

Severesymptomaticbradycardia

Thepresenceofsinusnodedysfunction,atrialconductiondefects,seconddegreeorgreaterAVblock,

bundlebranchblockordistalblockintheabsenceofanartificialpacemaker.

Severehypotension

Manifestelectrolyteimbalance(e.g.,potassiummetabolismdisorders)

Severeobstructivepulmonarydisease

Myastheniagravis

Concomitanttreatmentwithritonavir

4.4Specialwarningsandprecautionsforuse

ItisessentialthateachpatientgivenArythmolSRbeevaluatedelectrocardiographicallyandclinicallypriorto,and

duringtherapytodeterminewhethertheresponsetoArythmolSRsupportscontinuedtreatment.

ABrugadasyndromemaybeunmaskedorBrugadalikeelectrocardiogram(ECG)changesmaybeprovokedafter

exposuretopropafenoneinpreviouslyasymptomaticcarriersofthesyndrome.Afterinitiatingtherapywith

propafenone,anECGshouldbeperformedtoruleoutchangessuggestiveofBrugadasyndrome.

Propafenonehydrochloridemayalterbothpacingandsensingthresholdsofartificialpacemakers.Pacemakersshould

bemonitoredandprogrammedaccordinglyduringtherapy.

Thereisthepotentialforconversionofparoxysmalatrialfibrillationtoatrialflutterwithaccompanying2:1or1:1

conductionblock(seesection4.8).

AswithsomeotherClass1Canti-arrhythmicagents,patientswithsignificantstructuralheartdiseasemaybe

predisposedtoseriousadverseevents.ThereforeArythmolSRiscontraindicatedinthesepatients(seesection4.3).

Becauseofthebeta-blockereffect,careshouldbetakeninthetreatmentofpatientswithasthma.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

MedicinalproductsthatinhibitCYP2D6,CYP1A2andCYP3A4e.g.,ketoconazole,cimetidine, quinidine,

erythromycinandgrapefruitjuicemightleadtoincreasedlevelsofpropafenone.Whenpropafenoneisadministered

withinhibitorsoftheseenzymes,thepatientsshouldbecloselymonitoredandthedoseadjustedaccordingly.

Nosignificanteffectsonthepharmacokineticsofpropafenoneorlidocainehavebeenobservedfollowingtheir

concomitantuseinpatients.However,concomitantuseofpropafenoneandlidocainehasbeenreportedtoincreasethe

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Combinationtherapyofamiodaroneandpropafenonehydrochloridecanaffectconductionandrepolarizationandlead

toabnormalitiesthathavethepotentialtobeproarrythmic.

Doseadjustmentsofbothcompoundsbasedontherapeuticresponsemayberequired.

ElevatedlevelsofplasmapropafenonemayoccurwhenpropafenoneisusedconcomitantlywithSSRIs,suchas

fluoxetineandparoxetine.Concomitantadministrationofpropafenoneandfluoxetineinextensivemetabolisers

increasestheSpropafenoneCmaxandAUCby39and50%andtheRpropafenoneCmaxandAUCby71and50%.

Lowerdosesofpropafenonemaythereforebesufficienttoachievethedesiredtherapeuticresponse.

Potentialincreaseinadversereactionsmayoccurwhenpropafenoneistakeninconjunctionwithlocalanaesthetics

(e.g.,pacemakerimplantation,surgeryordentalwork)andothermedicinalproductswhichhaveaninhibitoryeffecton

theheartrateand/ormyocardialcontractility(e.g.,betablockers,tricyclicantidepressants).

CoadministrationofpropafenonehydrochloridewithdrugsmetabolizedbyCYP2D6(suchasvenlafaxine)mightlead

toincreasedlevelsofthesedrugs.Increasedplasmalevelsand/orbloodlevelsofpropranolol,metoprolol,desipramine,

cyclosporin,theophyllineanddigoxinhavebeenreportedduringpropafenonetherapy.Dosesofthesemedicinal

productsshouldbereduced,asappropriate,ifsignsofoverdoseareobserved.

Concomitantuseofpropafenoneandphenobarbitaland/orrifampicin(CYP3A4inducers)mayreducetheantiarrythmic

efficacyofpropafenoneasaresultofareductioninpropafenoneplasmalevels.Hence,responsetopropafenone

therapyshouldbemonitoredduringconcomitantchronicphenobarbitaland/orrifampicintreatment.

Closemonitoringoftheclottingstatusinpatientsreceivingconcomitantoralanticoagulants(e.g.,phenprocoumon,

warfarin)isrecommendedaspropafenonemayenhancetheplasmalevelsofthesemedicinalproductsresultinginan

increasedprothrombintime.Dosesofthesemedicinalproductsshouldbeadjustedifnecessary.

4.6Fertility,pregnancyandlactation

Pregnancy:

Therearenoadequateandwell-controlledstudiesinpregnantwomen.Propafenoneshouldbeusedduringpregnancy

onlyifthepotentialbenefitjustifiesthepotentialrisktothefoetus.

Propafenoneisknowntopasstheplacentalbarrierinhumans.Theconcentrationofpropafenoneintheumbilicalcord

hasbeenreportedtobeabout30%ofthatinthematernalblood.

Lactation:

Excretionofpropafenoneinhumanbreastmilkhasnotbeenstudied.Limiteddatasuggeststhatpropafenonemaybe

excretedinhumanbreastmilk.Propafenoneshouldbeusedwithcautioninnursingmothers.

4.7Effectsonabilitytodriveandusemachines

Blurredvision,dizziness,fatigueandposturalhypotensionmayaffectthepatient’sspeedofreactionandimpairthe

individual’sabilitytooperatemachineryormotorvehicles.

4.8Undesirableeffects

a.Summaryofthesafetyprofile

ThemostfrequentandverycommonadversereactionsrelatedtoArythmolSRtherapyaredizziness,cardiac

conductiondisordersandpalpitations.

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Thefollowingtabledisplaysadversereactionsreportedinclinicaltrialsandfrompost-marketingexperiencewith

ArythmolSRprolongedreleasehardcapsules.

ThereactionsconsideredatleastpossiblyrelatedtoArythmolSRaredisplayedbysystemorganclassandfrequency

usingthefollowingconvention:verycommon( ≥1/10),common(≥1/100to<1/10),uncommon(≥1/1,000to<1/100)

andnotknown(adversereactionsfrompost-marketingexperience;cannotbeestimatedfromtheavailabledata).

Withineachfrequencygrouping,adversereactionsarepresentedinorderofdecreasingseriousnesswhenthe

seriousnesscouldbeassessed.

1Maybemanifestedbycholestasis,blooddyscrasiasandrash

2Excludingvertigo

3Includingsinoatrialblock,atrioventricularblockandintraventricularblock

SystemOrganClass Verycommon

1/10 Common

1/100to<1/10 Uncommon

1/1,000to<1/100 NotKnown

(cannotbeestimated

fromtheavailable

data)

Bloodandlymphaticsystem

disorders Thrombocytopenia Agranulocytosis

Leukopenia

Granulocytopenia

Immunesystemdisorders Hypersensitivity 1

Metabolismandnutrition

disorders Decreasedappetite

Psychiatricdisorders Anxiety

Sleepdisorders Nightmare Confusionalstate

Nervoussystemdisorders

Dizziness 2 Headache

Dysgeusia Syncope

Ataxia

Paraesthesia Convulsion

Extrapyramidal

symptoms

Restlessness

Eyedisorders Visionblurred

Earandlabyrinthdisorders Vertigo

Cardiacdisorders Cardiacconduction

disorders 3

Palpitations Sinusbradycardia

Bradycardia

Tachycardia

Atrialflutter Ventricular

tachycardia

Arrhythmia 4 Ventricularfibrillation

Cardiacfailure 5

Heartratereduced

Vasculardisorders Hypotension Orthostatichypotension

Respiratory,thoracicand

mediastinaldisorders Dyspnoea

Gastrointestinaldisorders Abdominalpain

Vomiting

Nausea

Diarrhoea

Constipation

Drymouth Abdominal

distension

Flatulence Retching

Gastrointestinal

disturbance

Hepatobiliarydisorders Hepaticfunction

abnormal 6 Hepatocellularinjury

Cholestasis

Hepatitis

Jaundice

Skinandsubcutaneoustissue

disorders Urticaria

Pruritus

Rash

Erythema

Musculoskeletalandconnective

tissuedisorders Lupus-likesyndrome

Reproductivesystemandbreast

disorders Erectiledysfunction Spermcountdecreased 7

Generaldisordersand

administrationsiteconditions Chestpain

Asthenia

Fatigue

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orventricularfibrillation.Someofthesearrhythmiascanbelife-threateningandmayrequireresuscitationtopreventa

potentiallyfataloutcome

5Anaggravationofpreexistingcardiacinsufficiencymayoccur

6Thistermcoversabnormalliverfunctiontests,suchasaspartateaminotransferaseincreased,alanineaminotransferase

increased,gamma-glutamyltransferaseincreasedandbloodalkalinephosphataseincreased

7Decreasedspermcountisreversibleupondiscontinuationofpropafenone

c.Descriptionofselectedadversereactions

Conductiondisorders

Themostfrequentpresentationisatrioventricularblockfirstdegreewhichisusuallyasymptomaticbutmayrequire

monitoringandreductionofdosetopreventhighergradeconductionblocks.

Doserelatedadversereactions

Dysgeusiaandnauseamaybedoserelated.

4.9Overdose

Symptomsofoverdosing:

Myocardialsymptoms:Theeffectsofpropafenoneoverdoseinthemyocardiummanifestasimpulsegenerationand

conductiondisorderssuchasPQprolongation,QRSwidening,suppressionofsinusnodeautomaticity,AVblock,

ventriculartachycardiaandventricularfibrillation.Reductionofcontractility(negativeinotropiceffect)cancause

hypotensionwhich,inseverecases,canleadtocardiovascularshock.

Non-cardiacsymptoms:Headache,dizziness,blurredvision,paraesthesia,tremor,nausea,constipationanddrymouth

mayoccurfrequently.Inextremelyrarecases,convulsionshavebeenreportedonoverdose.Deathhasalsobeen

reported.

Inseverecasesofpoisoning,clonic-tonicconvulsions,paraesthesia,somnolence,comaandrespiratoryarrestmay

occur.

Treatment:

Inadditiontogeneralemergencymeasures,thepatient'svitalparametersshouldbemonitoredinanintensivecare

setting,andrectified,asappropriate.

Defibrillationaswellasinfusionofdopamineandisoproterenolhavebeeneffectiveincontrollingrhythmandblood

pressure.Convulsionshavebeenalleviatedwithintravenousdiazepam.Generalsupportivemeasuressuchas

mechanicalrespiratoryassistanceandexternalcardiacmassagemaybenecessary.

Attemptstoachieveeliminationviahaemoperfusionareoflimitedefficacy.

Owingtohighproteinbinding(>95%)andthelargevolumeofdistribution,haemodialysisisineffective.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Antiarrhythmics,classIC

ATCcodeC01BC03.

Propafenoneisanantiarrhythmicagentwithmembrane-stabilising,sodiumchannelblockingproperties(Vaughan

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Propafenonereducestherateofriseoftheactionpotentialtherebyslowingdownimpulseconduction(negative

dromotropiceffect):Therefractoryperiodsintheatrium,AVnodeandventriclesareprolonged.Propafenoneprolongs

therefractoryperiodsintheaccessorypathwaysinpatientswithWolff-Parkinson-Whitesyndrome(WPWsyndrome).

In2double-blindPhaseIIItrialsArythmolSRhasbeenevaluatedinpatientswithrecurrentepisodesofsymptomatic

atrialfibrillation.

InoneUSmulticentrestudy(RAFT),3dosesofArythmolSR(225mgbid,325mgbidand425mgbid)andplacebo

werecomparedin523patients.Thepatientshadamedianhistoryofatrialfibrillationof13monthsanddocumented

symptomaticatrialfibrillationwithin12monthsofstudyentry.Over90%wereNYHAClassIand21%hadaprior

electricalcardioversion.AllthreedosesofArythmolSRadministeredforupto39weekswereshowntobesuperiorto

placeboforthetimetothefirstrecurrenceofsymptomaticatrialarrhythmiafromday1ofrandomisation.(p<0.014for

225mgbidand<0.001for325mgand425mgbid).

Figure1:Tachycardia-freeperiod(absenceofsymptomaticAF,atrialflutterorPSVT)fromDay1ofrandomisation

(fullanalysisset);RAFT(log-ranktest)

Adose-responsetoArythmolSRwasprominentforthefollowinganalyses:timetorecurrenceofsymptomaticatrial

arrhythmiafromDay1ofrandomisationandtimetorecurrenceofsymptomaticatrialarrhythmiafromDay5of

randomisation.Therewasacleardoseresponseobservedinthetachycardia-freeperiodwith425mgbidgroup

demonstratingthelongesttimetorecurrence.Nevertheless,regardingthesafetyparameters,itappearsthatpropafenone

SR425mgbidhasalessfavourablesafetyprofilethanpropafenone325mgand225mgbid.

InaEuropeanmulticentretrial(ERAFT),2dosesofArythmolSR(325mgbidand425mgbid)andplacebowere

comparedin293patients.Patientshadamediandurationofatrialfibrillationof3.3years,37%hadahistoryofminor

structuralheartdiseaseand61%weretakingmedicationsthatloweredheartrate.Duringaqualifyingperiodofupto28

days,patientshadtohave1documentedincidentofsymptomaticatrialfibrillation.Thedouble-blindtreatmentphase

consistedofa4-dayloadingperiodfollowedbya91-dayefficacyperiod.Symptomaticarrhythmiasweredocumented

byelectrocardiogrammonitoringArythmolSRwasshowntoprolongthetimetothefirstrecurrenceofsymptomatic

atrialarrhythmiafromDay5ofrandomisation(primaryefficacyanalysis)inadosedependentmanner:9daysinthe

placebogroup,35daysinthepropafenoneSR325mgbidgroup(p=0.004)and44daysinthepropafenoneSR425mg

bidgroup(p=0.003).

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5.2Pharmacokineticproperties

Metabolism

Propafenoneisknowntoundergoextensiveandsaturablepresystemicbiotransformation(CYP2D6hepaticfirstpass

effect),whichresultsinadoseanddosageformdependentabsolutebioavailability.

Asaresultoftheincreasedfirstpasseffect,higherdailydosesofpropafenonearerequiredfromtheSRformulation

relativetotheimmediatereleaseformulation,toobtainsimilarexposuretopropafenonehydrochloride.

Therearetwogeneticallydeterminedpatternsofpropafenonemetabolism.Inover90%ofpatients,thedrugisrapidly

andextensivelymetabolisedwithaneliminationhalf-lifefrom2-10hours.Thesepatientsmetabolisepropafenoneinto

twoactivemetabolites:5-hydroxypropafenonewhichisformedbyCYP2D6andN-depropylpropafenone

(norpropafenone)whichisformedbybothCYP3A4andCYP1A2.Inlessthan10%ofpatients,metabolismof

propafenoneisslowerbecausethe5-hydroxymetaboliteisnotformedorisminimallyformed.

Maximalplasmalevelsofpropafenonearereachedbetween3-8hoursfollowingtheadministrationofArythmolSR.

Theestimatedpropafenoneeliminationhalf-liferangesfrom10-32hours.

Inextensivemetabolisers,thesaturablehydroxylationpathway(CYP2D6)resultsinnonlinearpharmacokinetics.The

effectivedoseofpropafenoneappearstobethesameregardlessofthemetabolicstatus(poorvs.rapidmetaboliser)of

thepatient.Inaddition,sincesteady-stateconditionsarereachedby5daysinbothgroupsofpatientsnochangeinthe

dosingtitrationstrategyisrequired.

Datafromrelativebioavailabilityassessmentscontainedinapharmacokineticstudycomparingdifferentdosagesand

formulationsofprolongedrelease(SR)andimmediaterelease(IR)propafenonedemonstratedthatcomparable

exposures(AUCs)ofpropafenoneoccurredwith150mgpropafenoneIRtabletsadministeredthreetimesadayand

325mgArythmolSRcapsulesadministeredtwiceaday,aswellas300mgpropafenoneIRtabletsadministeredtwice

adayand425mgArythmolSRcapsulesadministeredtwiceaday.AswitchtoArythmolSRcapsulesinpatients

beingtreatedwithpropafenoneIRtablets,however,hasnotbeenexplicitlystudiedinaclinicaltrial.

Thedosagemustbeadjustedinpatientswithliverdisease.ArythmolSRshouldbeadministeredcautiouslyinpatients

withrenaldisorder.Pleaseseesection4.2.

Althoughfoodincreasedbioavailabilityinasingledosestudy,duringmultipledoseadministrationofpropafenoneSR

tohealthyvolunteers,fooddidnothaveamajorimpactontheabsorptionofpropafenoneSR.

Inter/IntraSubjectVariability

Withpropafenone,thereisaconsiderabledegreeofinterindividualvariabilityinpharmacokineticswhichisduein

largeparttothefirstpasshepaticeffectandnon-linearpharmacokineticsinextensivemetabolisers.Thelarge

intersubjectvariabilityinbloodlevelsrequirethatthedoseofthedrugbetitratedcarefullyinpatientswithclose

attentionpaidtoclinicalandECGevidenceoftoxicity.

5.3Preclinicalsafetydata

Preclinicaldatarevealnospecialhazardforhumansbasedonconventionalstudiesofsafetypharmacology,repeated

dosetoxicity,genotoxicity,carcinogenicpotentialortoxicitytoreproduction.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Capsulecontents

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Magnesiumstearate

Capsuleshell

Gelatin

TitaniumdioxideE171

Sodiumlaurilsulfate

Printingink

Shellac

RedferricoxidesE172

Soyalecithin

Dimeticone

Simeticone

Mono-andDiglycerides

Methylcellulose

Macrogolstearate

Xanthangum

BenzoicacidE210

Macrogol

SorbicacidE200

6.2Incompatibilities

NotApplicable

6.3Shelflife

5years

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

PVC/aluminiumorPolypropylene/aluminiumblistercontaining20,50,60and100capsules.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

AbbottLaboratoriesIrelandLtd

4051KingswoodDrive

CitywestBusinessCampus

Dublin24

Ireland

8MARKETINGAUTHORISATIONNUMBER

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9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:10March2006

Dateoflastrenewal:2October2009

10DATEOFREVISIONOFTHETEXT

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