ACCOLATE

Main information

  • Trade name:
  • ACCOLATE Film Coated Tablet 20 Milligram
  • Dosage:
  • 20 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ACCOLATE Film Coated Tablet 20 Milligram
    Ireland
  • Language:
  • English

Other information

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1328/044/001
  • Authorization date:
  • 06-10-2006
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage,interactions,side effects

IRISHMEDICINESBOARDACT1995

MEDICINALPRODUCTS(LICENSINGANDSALE)REGULATIONS,1998

(S.I.No.142of1998)

PPA1328/044/001

CaseNo:2034068

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrants

B&SHealthcare

Unit4,BradfieldRoad,Ruislip,Middlesex,HA40NU,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Accolate20mgFilm-CoatedTablets

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjectto

thegeneralconditionsasmaybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom26/03/2007until05/10/2010.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Accolate20mgFilm-coatedTablets.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains20mgofzafirlukast.

Excipientsincludelactose.

Forafulllistofexcipientsseesection6.1.

3PHARMACEUTICALFORM

Filmcoatedtablets(Tablets)

ProductimportedfromPortugal:

White,round,biconvexfilm-coatedtabletsintagliatedwith‘Accolate20’ononesideandplainonthe

reverse.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Accolateisindicatedfortheprophylaxisandchronictreatmentofasthma.

4.2Posologyandmethodofadministration

Accolateistakentopreventasthmaattacksandshouldthereforebetakencontinuously.

AdultsandChildrenaged12yearsandover:

Therapyshouldbeinitiatedat20mgtwicedaily.Theusualmaintenancedosageis20mgtwicedaily.

Increasingthedose,titratingtoamaximumof40mgtwicedaily,mayprovideadditionalbenefit.This

doseshouldnotbeexceededbecausehigherdosesmaybeassociatedwithhepatotoxicity.

Asfoodmayreducethebioavailabilityofzafirlukast,Accolateshouldnotbetakenwithmeals.

Elderly

Theclearanceofzafirlukastisreducedinelderlypatients>65yearsold),suchthatC

andAUCare

approximatelytwicethoseofyoungeradults.However,accumulationofzafirlukastisnotevidentin

elderlypatients.Inclinicaltrials,elderlypatientsreceivingadoseof20mgtwicedailywerenot

associatedwithanincreaseintheoverallincidenceofadverseeventsorwithdrawalsbecauseof

adverseevents.Therapymaybeinitiatedat20mgtwicedailyandadjustedaccordingtoclinical

response.

Children:

ThesafetyandefficacyofAccolateinchildrenunder12yearshasnotyetbeenestablished.Until

furtherinformationonuseinchildrenisavailable,zafirlukastisnotrecommendedinthisagegroup.

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Nodosageadjustmentisnecessaryinpatientswithrenalimpairment.

4.3Contraindications

Accolateshouldnotbegiventopatientswhohavepreviouslyexperiencedhypersensitivitytothe

productoranyofitsingredients.

Accolatehasnotbeenevaluatedinthetreatmentoflabile(brittleorunstable)asthma.

Accolateisnotrecommendedforpatientswithhepaticimpairmentincludinghepaticcirrhosis.

4.4Specialwarningsandprecautionsforuse

Accolateshouldbetakenregularlytoachievebenefit,evenduringsymptomfreeperiods.Accolate

therapyshouldnormallybecontinuedduringacuteexacerbationsofasthma.

Aswithinhaledsteroidsandcromones(disodiumcromoglycate,nedocromilsodium),Accolateisnot

indicatedforuseinthereversalofbronchospasminacuteasthmaattacks.

Accolateshouldnotbesubstitutedabruptlyforinhaledcorticosteroids.

Cautionisrequiredwhentreatingpatientswithsevereasthmawhensteroidreductionisbeing

considered.Rarely,suchpatientsmaypresentwithsystemiceosinophilia,eosinophilicpneumoniaor

withclinicalfeaturesofsystemicvasculitis,consistentwithChurg-Strausssyndrome.Presentations

mayinvolvevariousbodysystemsincludingvasculiticrash,worseningpulmonarysymptoms,cardiac

complicationsorneuropathy.Theseeventshaveusuallybeenassociatedwithreductionsinoral

steroidtherapy.AcausalrelationshipwithAccolatehasnotbeenestablished.Itisrecommendedthat

useofthismedicineinsevereasthmatics,especiallythosetakingoralsteroids,shouldberestrictedto

hospitalspecialistshavingfacilitiestomonitorusageofAccolateintheirpatients.

ElevationsinserumtransaminasescanoccurduringtreatmentwithAccolate.

Theseareusuallyasymptomaticandtransientbutcouldrepresentearlyevidenceofhepatotoxicityand

haveveryrarelybeenassociatedwithmoreseverehepatocellularinjury,fulminanthepatitisandliver

failure,someofwhichresultedinafataloutcome.Extremelyrarely,casesoffulminanthepatitisand

liverfailurehavebeenreportedinpatientswhomnopreviousclinicalsignsorsymptomssuggestiveof

liverdysfunctionwerereported.

SerumtransaminasetestingshouldbedoneatbaselineandperiodicallyduringAccolatetreatment.

Periodicserumtransaminasetestinghasnotproventopreventseriousinjury,butitisgenerally

believedthatearlydetectionofdruginducedhepaticinjuryalongwithimmediatewithdrawalofthe

suspecteddrugmayenhancethelikelihoodforrecovery.Ifclinicalsymptomsorsignssuggestiveof

liverdysfunctionoccur(e.g.anorexia,nausea,vomiting,rightupperquadrantpain,fatigue,lethargy,

flu-likesymptoms,enlargedliver,pruritisandjaundice),Accolateshouldbediscontinued.Theserum

transaminases,inparticularserumALT,shouldbemeasuredimmediatelyandthepatientmanaged

accordingly.PatientsinwhomACCOLATEwaswithdrawnbecauseofhepatotoxicitywithnoother

attributablecauseshouldnotbere-exposedtoACCOLATE.

Accolateisnotrecommendedforpatientswithhepaticimpairmentincludinghepaticcirrhosis.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Accolatemaybeadministeredwithothertherapiesroutinelyusedinthemanagementofasthmaand

allergy.Inhaledsteroids,inhaledandoralbronchodilatortherapy,antibioticsandantihistaminesare

examplesofagents,whichhavebeenco-administeredwithAccolatewithoutadverseinteraction.

Accolatemaybeadministeredwithoralcontraceptiveswithoutadverseinteraction.

Co-administrationwithacetylsalicylicacid(“aspirin”)mayresultinincreasedplasmalevelsof

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clinicallyrelevanteffects.

Co-administrationwitherythromycinwillresultindecreasedplasmalevelsofzafirlukast,by

approximately40%.

Inclinicaltrialsco-administrationwiththeophyllineresultedindecreasedlevelsofzafirlukast,by

approximately30%,butwithnoeffectonplasmatheophyllinelevels.However,duringpost-

marketingsurveillance,therehavebeenrarecasesofpatientsexperiencingincreasedtheophylline

levelswhenco-administeredAccolate.

Co-administrationwithterfenadineresultedina54%decreaseinAUCforzafirlukast,butwithno

effectonplasmaterfenadinelevels.

Co-administrationwithwarfarinresultsinanincreaseinmaximumprothrombintimebyapproximately35%.Itis

thereforerecommendedthatifAccolateisco-administeredwithwarfarin,prothrombintimeshouldbeclosely

monitored.TheinteractionisprobablyduetoaninhibitionbyzafirlukastofthecytochromeP4502C9isoenzyme

system.

4.6Pregnancyandlactation

Inanimalstudies,zafirlukastdidnothaveanyapparenteffectonfertilityanddidnotappeartohave

anyteratogenicorselectivetoxiceffectonthefoetus.However,thesafetyofAccolateinhuman

pregnancyhasnotbeenestablished.Thepotentialrisksshouldbeweighedagainstthebenefitsof

continuingtherapyduringpregnancyandAccolateshouldbeusedduringpregnancyonlyifclearly

needed.

Zafirlukastisexcretedinhumanbreastmilk.Zafirlukastshouldnotbeadministeredtomotherswhoarebreastfeeding.

4.7Effectsonabilitytodriveandusemachines

ThereisnoevidencethatAccolateaffectstheabilitytodriveandusemachinery.

4.8Undesirableeffects

Accolateiswelltolerated.AdministrationofAccolatemaybeassociatedwith

thefollowingundesirableeffects.Thereactionsareclassifiedaccordingtofrequency

(common>1/100,<1/10;uncommon>1/1000,<1/100;rare>1/10000,<1/1000;veryrare<1/10000).

Gastrointestinal: Common:nausea,vomiting,diarrhoea,abdominal

pain

Hepatobiliary: Rare:symptomatichepatitiswithandwithout

hyperbilirubinaemia,hyperbilirubinaemia,without

elevatedliverfunctiontests.

Veryrare:hepaticfailure,fulminanthepatitis(see

section4.4).

Infectionsand

infestations: Common:infectionspredominantlyaffectingthe

respiratorytract.

General: Common:malaise.

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Theaboveeventshaveusuallyresolvedfollowingcessationoftherapy.Headacheandgastrointestinal

disturbancesareusuallymild.

ElevatedserumtransaminaselevelshavebeenobservedinclinicaltrialswithAccolate.Thechanges

usuallyresolvedduringcontinuedtreatmentorfollowingcessationoftherapy.

Inplacebo-controlledclinicaltrials,anincreasedincidenceofinfectionhasbeenobservedinelderlypatientsgiven

Accolate.Infectionswereusuallymild,predominantlyaffectingtherespiratorytractandnotnecessitatingwithdrawal

fromtherapywithAccolate.

4.9Overdose

ReportsofoverdosewithACCOLATEhavebeenreceived.InreportswithexcessiveACCOLATE

dosesnosignificantsymptomshavebeenobserved.

Removalofexcessmedicationbygastriclavagemaybehelpful.Managementshouldbesupportive.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

TheATCCodeisRO3DC

Leukotriene(LT)productionandreceptoroccupationhasbeenimplicatedinthepathophysiologyof

asthma.Effectsincludesmoothmusclecontraction,airwayoedemaandalteredcellactivityassociated

withtheinflammatoryprocessincludingeosinophilinfluxtothelung.Theseeffectscontributetoand

correlatewiththesignsandsymptomsofasthma.Accolateactsasananti-inflammatoryagent,

reducingtheeffectofthesepro-inflammatorymediators.

AccolateisahighlyselectiveandpotentoralpeptidecompetitiveantagonistofLTC

,and

,componentsofslowreactingsubstanceofanaphylaxis.Invitrostudieshaveshownthat

Accolateantagonisesthecontractileactivityofallthreepeptideleukotrienes(leukotrieneC

,D

Musculoskeletal

andconnective

tissue: Rare:arthralgia,myalgia.

Immunesystem: Rare:hypersensitivityreactionsincludingurticaria

andangioedema.

Epidermaland

dermal

conditions: Uncommon:rash(includingblistering),pruritus.

Neurological: Common:insomnia,headache

Bloodand

lymphatic

system: Rare:bruising,bleedingdisorders.

Veryrare:agranulocytosis.

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)inhumanconductingairwaysmoothmuscletothesameextent.Animalstudieshaveshown

Accolatetobeeffectiveinpreventingpeptideleukotriene-inducedincreasesinvascularpermeability,

whichgivesrisetooedemaintheairways,andtoinhibitpeptideleukotriene-inducedinfluxof

eosinophilsintotheairways.

ThespecificityofAccolatehasbeenshowninclinicalstudies,byitsactiononleukotrienereceptors

andnotprostaglandin,thromboxane,cholinergicandhistaminereceptors.

Inclinicaltrials,Accolatehasbeenshowntohaveanti-inflammatoryproperties.DosingwithAccolate

forfivedaysreducedcellularandnon-cellularcomponentsofinflammationintheairwayinducedby

antigenchallenge.Inaplacebo-controlledstudywheresegmentalbronchoprovocationwithallergen

wasfollowedbybronchoalveolarlavage48hourslater,zafirlukastdecreasedtheriseinbasophils,

lymphocytesandhistamine,andreducedthestimulatedproductionofsuperoxidebyalveolar

macrophages.Accolateattenuatedtheincreaseinbronchialhyperresponsivenessthatfollowsinhaled

allergenchallengeandthebronchoconstrictioninducedbyplateletactivatingfactor.

Further,methacholinesensitivitywasdiminishedbylong-termdosingwithAccolate20mgtwice

daily.Further,inclinicaltrialsevaluatingchronictherapywithAccolatethelungfunctionmeasured

whenplasmalevelswereattroughshowedimprovementsoverbaselinethatwereconsistentwitha

sustaineddecreaseinobstructionduetoinflammatorycomponents.

Accolateshowsadosedependentinhibitionofbronchoconstrictioninducedbyinhaledleukotriene

.Asthmaticpatientsareapproximately10-foldmoresensitivetothebronchoconstrictingactivityof

inhaledleukotrieneD

.AsingleoraldoseofAccolatecanenableanasthmaticpatienttoinhale100

timesmoreleukotrieneD

andshowssignificantprotectionat12and24hours.

Accolateinhibitsthebronchoconstrictioncausedbyseveralkindsofchallenge,suchastheresponseto

sulphurdioxide,exerciseandcoldair.Accolateattenuatestheearlyandlatephaseinflammatory

reactioncausedbyvariousantigenssuchasgrass,catdander,ragweedandmixedantigens.Insome

patients,Accolatecompletelypreventstheonsetofasthmaattacksinducedbyexerciseandallergens.

Inasthmaticpatientsnotadequatelycontrolledbybeta-agonisttherapy(givenasrequired),Accolateis

indicatedasfirstlinemaintenancetherapy.InsymptomaticpatientsAccolateimprovessymptoms

(reducingdaytimeandnocturnalasthmaticsymptoms),improveslungfunction,reducestheneedfor

concomitantbeta-agonistmedicationandreducesincidenceofexacerbations.Similarbenefitshave

beenseeninpatientswithmoresevereasthmareceivinghighdoseinhaledsteroids.

Inclinicalstudies,therewasasignificantfirst-doseeffectonbaselinebronchomotortoneobserved

within2hoursofdosing,whenpeakplasmaconcentrationshadnotyetbeenachieved.Initial

improvementsinasthmasymptomsoccurredwithinthefirstweekandoftenwithinthefirstfewdays

oftreatmentwithAccolate.

Accolateisadministeredasatwice-dailyoraltherapyandmay,therefore,beofparticularvalueinpatientswhomay

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5.2Pharmacokineticproperties

Peakplasmaconcentrationsofzafirlukastareachievedapproximately3hoursafteroraladministration

ofAccolate.

Followingtwice-dailyadministrationofAccolate(30-80mgbd),accumulationofzafirlukastinplasma

waslow(notdetectable-2.9timesfirstdosevalues;mean1.45;median1.27).Theterminalhalf-life

ofzafirlukastisapproximately10hours.Steadystateplasmaconcentrationsofzafirlukastwere

proportionaltothedoseandpredictablefromsingle-dosepharmacokineticdata.

Pharmacokineticsofzafirlukastinadolescentsandadultswithasthmaweresimilartothoseofhealthy

adultmales.Whenadjustedforbodyweight,thepharmacokineticsofzafirlukastarenotsignificantly

differentbetweenmenandwomen.

AdministrationofAccolatewithfoodincreasedthevariabilityinthebioavailabilityofzafirlukastand

reducedbioavailabilityinmost(75%)subjects.Thenetreductionwasapproximately40%.

Followingaradiolabelleddoseofzafirlukastapproximately10%oftheradioactivitywasrecoveredin

theurineand89%wasrecoveredinthefaeces.Zafirlukastisextensivelymetabolised.Four

metabolitesaccountforthe10%ofdoserecoveredinurine,zafirlukastitselfisnotfoundinurine.In

additiontozafirlukast,threeofthesemetaboliteshavebeenidentifiedinhumanplasmaandina

standardin-vitrotestofactivitywerefoundtobeatleast90-foldlesspotentthanzafirlukast.

Elderlysubjectsandsubjectswithstablealcoholiccirrhosisdemonstratedanapproximatelytwofold

increaseinC

andAUCcomparedtonormalsubjectsgiventhesamedosesofAccolate.

Therearenosignificantdifferencesinthepharmacokineticsofzafirlukastinrenallyimpairedpatients

andnormalsubjects.

Zafirlukastisapproximately99%proteinboundtohumanplasmaproteins,predominantlyalbumin,overthe

concentrationrange0.25-4.0microgram/ml.

5.3Preclinicalsafetydata

Aftermultipledosesofgreaterthan40mg/kg/dayforupto12months,liverenlargementassociated

withdegenerative/fattychangeorglycogendepositionwasseeninrats,miceanddogs.Histiocytic

aggregateswereseeninanumberoftissuesofdogs.

Malemicegiven300mg/kgzafirlukastdailyhadanincreasedincidenceofhepatocellularadenomas

comparedtocontrolanimals.Ratsgiven2000mg/kgzafirlukastdailyhadanincreasedincidenceof

urinarybladderpapillomacomparedtocontrolanimals.Zafirlukastwasnotmutagenicinarangeof

tests.TheclinicalsignificanceofthesefindingsduringthelongtermuseofAccolateinmanis

unknown.

Inanimalstudies,zafirlukastdidnothaveanyeffectontheoffspringoffemaleratsthatreceivedthe

drugduringlactation,butneonatal/juvenileratsanddogswereparticularlysensitivetotheadverse

effectsofzafirlukast,includingfatnecrosis.Therelevanceofthesefindingstohumansisunknown.

Zafirlukastshouldnotbeadministeredtomotherswhoarebreastfeeding.

Therewerenoothernotablefindingsfromthepreclinicaltesting.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

CroscarmelloseSodium

LactoseMonohydrate

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Povidone

MagnesiumStearate

Hypromellose

TitaniumDioxide(E171)

6.2Incompatibilities

Notapplicable

6.3ShelfLife

Theshelf-lifeexpirydateofthisproductshallbethedateshownonthecountainerandouterpackage

oftheproductonthemarketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove30°C

6.5Natureandcontentsofcontainer

Cartoncontaining60tabletsinaluminiumlaminate/foilblisterpacks.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerials

derivedfromsuchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7ParallelProductAuthorisationHolder

B&SHealthcare

Unit4

BradfieldRoad

Ruislip

Middlesex

HA40NU

UnitedKingdom

8ParallelProductAuthorisationNumber

PPA1328/44/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:6thOctober2006.

10DATEOFREVISIONOFTHETEXT

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