EDOFLO

Main information

  • Trade name:
  • EDOFLO Powder for Inhalation 100/6 Mcg/Dose
  • Dosage:
  • 100/6 Mcg/Dose
  • Pharmaceutical form:
  • Powder for Inhalation
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • EDOFLO Powder for Inhalation 100/6 Mcg/Dose
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0970/062/001
  • Authorization date:
  • 26-11-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Edoflo100micrograms/6micrograms/Inhalation,Inhalationpowder

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachdelivereddose(thedosethatleavesthemouthpiece)contains:budesonide80micrograms/inhalationand

formoterolfumaratedihydrate4.5micrograms/inhalation.

Each metered dose contains: budesonide 100micrograms/inhalation and formoterol fumarate dihydrate

6micrograms/inhalation.

Excipient:Lactosemonohydrate810microgramsperdose.

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Inhalationpowder.

Whitepowder.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Edofloisindicatedintheregulartreatmentofasthmawhereuseofacombination(inhaledcorticosteroidand

long -acting

adrenoceptoragonist)isappropriate:

patientsnotadequatelycontrolledwithinhaledcorticosteroidsand“asneeded”inhaledshort -acting

adrenoceptoragonists.

patientsalreadyadequatelycontrolledonbothinhaledcorticosteroidsandlong -acting

adrenoceptoragonists.

Note:Edoflo(100micrograms/6micrograms/inhalation)isnotappropriateinpatientswithsevereasthma.

4.2Posologyandmethodofadministration

Routeofadministration:Forinhalationuse

Edofloisnotintendedfortheinitialmanagementofasthma.

ThedosageofthecomponentsofEdofloisindividualandshouldbeadjustedtotheseverityofthedisease.Thisshould

beconsiderednotonlywhentreatmentwithcombinationproductsisinitiatedbutalsowhenthemaintenancedoseis

adjusted.Ifanindividualpatientshouldrequireacombinationofdosesotherthanthoseavailableinthecombination

inhaler,appropriatedosesof

adrenoceptoragonistsand/orcorticosteroidsbyindividualinhalersshouldbe

prescribed.

Thedoseshouldbetitratedtothelowestdoseatwhicheffectivecontrolofsymptomsismaintained.Patientsshouldbe

regularlyreassessedbytheirprescriber/healthcareprovidersothatthedosageofEdofloremainsoptimal.Whenlong-

termcontrolofsymptomsismaintainedwiththelowestrecommendeddosage,thenthenextstepcouldincludeatestof

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ForEdoflotherearetwotreatmentapproaches:

A.Edoflomaintenancetherapy:Edofloistakenasregularmaintenancetreatmentwithaseparaterapid-acting

bronchodilatorasrescue.

B.Edoflomaintenanceandrelievertherapy:Edofloistakenasregularmaintenancetreatmentandasneededin

responsetosymptoms.

A.Edoflomaintenancetherapy

Patientsshouldbeadvisedtohavetheirseparaterapid -actingbronchodilatoravailableforrescueuseatalltimes.

Recommendeddoses:

Adults(18yearsandolder):1 -2inhalationstwicedaily.Somepatientsmayrequireuptoamaximumof4inhalations

twicedaily.

Adolescents(12-17years):1 -2inhalationstwicedaily.

Children(6yearsandolder):2inhalationstwicedaily.

Inusualpracticewhencontrolofsymptomsisachievedwiththetwicedailyregimen,titrationtothelowesteffective

dosecouldincludeEdoflogivenoncedaily,whenintheopinionoftheprescriber,along-actingbronchodilatorwould

berequiredtomaintaincontrol.

Increasinguseofaseparaterapidactingbronchodilatorindicatesaworseningoftheunderlyingconditionandwarrants

areassessmentoftheasthmatherapy.

Childrenunder6years:Asonlylimiteddataareavailable,Edofloisnotrecommendedforchildrenyoungerthan6

years.

B.Edoflomaintenanceandrelievertherapy

PatientstakeadailymaintenancedoseofEdofloandinadditiontakeEdofloasneededinresponsetosymptoms.

PatientsshouldbeadvisedtoalwayshaveEdofloavailableforrescueuse.

Edoflomaintenanceandrelievertherapyshouldespeciallybeconsideredforpatientswith:

inadequateasthmacontrolandinfrequentneedofrelievermedication

asthmaexacerbationsinthepastrequiringmedicalintervention

Closemonitoringfordose-relatedadverseeffectsisneededinpatientswhofrequentlytakehighnumbersofEdofloas-

neededinhalations.

Recommendeddoses:

Adults(18yearsandolder):Therecommendedmaintenancedoseis2inhalationsperday,giveneitherasone

inhalationinthemorningandeveningoras2inhalationsineitherthemorningorevening.Patientsshouldtake1

additionalinhalationasneededinresponsetosymptoms.Ifsymptomspersistafterafewminutes,anadditional

inhalationshouldbetaken.Notmorethan6inhalationsshouldbetakenonanysingleoccasion.

Atotaldailydoseofmorethan8inhalationsisnotnormallyneeded;however,atotaldailydoseofupto12inhalations

couldbeusedforalimitedperiod.Patientsusingmorethan8inhalationsdailyshouldbestronglyrecommendedto

seekmedicaladvice.Theyshouldbereassessedandtheirmaintenancetherapyshouldbereconsidered.

Childrenandadolescentsunder18years:Edoflomaintenanceandrelievertherapyisnotrecommendedforchildren

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Generalinformation

Specialpatientgroups:

Therearenospecialdosingrequirementsforelderlypatients.TherearenodataavailableforuseofEdofloinpatients

withhepaticorrenalimpairment.Asbudesonideandformoterolareprimarilyeliminatedviahepaticmetabolism,an

increasedexposurecanbeexpectedinpatientswithseverelivercirrhosis.

InstructionsforcorrectuseofEdoflo:

Edofloisinspiratoryflow-driven,whichmeansthatwhenthepatientinhalesthroughthemouthpiece,thesubstance

willfollowtheinspiredairintotheairways.

Note:Itisimportanttoinstructthepatient.

tocarefullyreadtheinstructionsforuseinthepatientinformationleafletwhichispackedtogetherwitheach

EdofloInhaler.

tobreatheinforcefullyanddeeplythroughthemouthpiecetoensurethatanoptimaldoseisdeliveredtothelungs.

nevertobreatheoutthroughthemouthpiece.

toreplacethecoveroftheEdofloInhalerafteruse.

torinsetheirmouthoutwithwaterafterinhalingthemaintenancedosetominimisetheriskoforopharyngeal

thrush.Iforopharyngealthrushoccurs,patientsshouldalsorinsetheirmouthwithwateraftertheas-neededinhalations.

ThepatientmaynottasteorfeelanymedicationwhenusingEdofloInhalerduetothesmallamountofdrugdispensed.

4.3Contraindications

Hypersensitivity(allergy)tobudesonide,formoterolorlactose(whichcontainssmallamountsofmilkproteins).

4.4Specialwarningsandprecautionsforuse

Itisrecommendedthatthedoseistaperedwhenthetreatmentisdiscontinuedandshouldnotbestoppedabruptly.

Ifpatientsfindthetreatmentineffective,orexceedthehighestrecommendeddoseofEdoflo,medicalattentionmustbe

sought(seesection4.2).Suddenandprogressivedeteriorationincontrolofasthmaispotentiallylifethreateningand

thepatientshouldundergourgentmedicalassessment.Inthissituationconsiderationshouldbegiventotheneedfor

increasedtherapywithcorticosteroids,e.g.acourseoforalcorticosteroids,orantibiotictreatmentifaninfectionis

present.

Patientsshouldbeadvisedtohavetheirrescueinhaleravailableatalltimes,eitherEdoflo(forpatientsusingEdofloas

maintenanceandrelievertherapy)oraseparaterapid -actingbronchodilator(forpatientsusingEdofloasmaintenance

therapyonly).

PatientsshouldberemindedtotaketheirEdoflomaintenancedoseasprescribed,evenwhenasymptomatic.The

prophylacticuseofEdoflo,e.g.beforeexercise,hasnotbeenstudied.TherelieverinhalationsofEdofloshouldbe

takeninresponsetoasthmasymptomsbutarenotintendedforregularprophylacticuse,e.g.beforeexercise.Forsuch

use,aseparaterapid -actingbronchodilatorshouldbeconsidered.

Onceasthmasymptomsarecontrolled,considerationmaybegiventograduallyreducingthedoseofEdoflo.Regular

reviewofpatientsastreatmentissteppeddownisimportant.ThelowesteffectivedoseofEdofloshouldbeused(see

section4.2).

PatientsshouldnotbeinitiatedonEdofloduringanexacerbation,oriftheyhavesignificantlyworseningoracutely

deterioratingasthma.

Seriousasthma-relatedadverseeventsandexacerbationsmayoccurduringtreatmentwithEdoflo.Patientsshouldbe

askedtocontinuetreatmentbuttoseekmedicaladviceifasthmasymptomsremainuncontrolledorworsenafter

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Aswithotherinhalationtherapy,paradoxicalbronchospasmmayoccur,withanimmediateincreaseinwheezingand

shortnessofbreathafterdosing.IfthepatientexperiencesparadoxicalbronchospasmEdofloshouldbediscontinued

immediately,thepatientshouldbeassessedandanalternativetherapyinstituted,ifnecessary.Paradoxical

bronchospasmrespondstoarapid -actinginhaledbronchodilatorandshouldbetreatedstraightaway(seesection4.8).

Systemiceffectsmayoccurwithanyinhaledcorticosteroid,particularlyathighdosesprescribedforlongperiods.

Theseeffectsaremuchlesslikelytooccurwithinhalationtreatmentthanwithoralcorticosteroids.Possiblesystemic

effectsincludeCushing’ssyndrome,Cushingoidfeatures,adrenalsuppression,growthretardationinchildrenand

adolescents,decreaseinbonemineraldensity,cataractandglaucoma.

Itisrecommendedthattheheightofchildrenreceivingprolongedtreatmentwithinhaledcorticosteroidsisregularly

monitored.Ifgrowthisslowed,therapyshouldbere -evaluatedwiththeaimofreducingthedoseofinhaled

corticosteroidtothelowestdoseatwhicheffectivecontrolofasthmaismaintained,ifpossible.Thebenefitsofthe

corticosteroidtherapyandthepossiblerisksofgrowthsuppressionmustbecarefullyweighed.Inaddition

considerationshouldbegiventoreferringthepatienttoapaediatricrespiratoryspecialist.

Limiteddatafromlong -termstudiessuggestthatmostchildrenandadolescentstreatedwithinhaledbudesonidewill

ultimatelyachievetheiradulttargetheight.However,aninitialsmallbuttransientreductioningrowth(approximately

1cm)hasbeenobserved.Thisgenerallyoccurswithinthefirstyearoftreatment.

Long -termstudieswithinhaledbudesonideinchildrenatmeandailydosesof400micrograms(metereddose)orin

adultsatdailydosesof800micrograms(metereddose)havenotshownanysignificanteffectsonbonemineraldensity.

NoinformationregardingtheeffectofEdofloathigherdosesisavailable.

Ifthereisanyreasontosupposethatadrenalfunctionisimpairedfromprevioussystemicsteroidtherapy,careshould

betakenwhentransferringpatientstoEdoflotherapy.

Thebenefitsofinhaledbudesonidetherapywouldnormallyminimisetheneedfororalsteroids,butpatients

transferringfromoralsteroidsmayremainatriskofimpairedadrenalreserveforaconsiderabletime.Recoverymay

takeaconsiderableamountoftimeaftercessationoforalsteroidtherapyandhenceoralsteroid -dependentpatients

transferredtoinhaledbudesonidemayremainatriskfromimpairedadrenalfunctionforsomeconsiderabletime.In

suchcircumstancesHPAaxisfunctionshouldbemonitoredregularly.

Prolongedtreatmentwithhighdosesofinhaledcorticosteroids,particularlyhigherthanrecommendeddoses,mayalso

resultinclinicallysignificantadrenalsuppression.Thereforeadditionalsystemiccorticosteroidcovershouldbe

consideredduringperiodsofstresssuchassevereinfectionsorelectivesurgery.Rapidreductioninthedoseofsteroids

caninduceacuteadrenalcrisis.Symptomsandsignswhichmightbeseeninacuteadrenalcrisismaybesomewhat

vaguebutmayincludeanorexia,abdominalpain,weightloss,tiredness,headache,nausea,vomiting,decreasedlevelof

consciousness,seizures,hypotensionandhypoglycaemia.

Treatmentwithsupplementarysystemicsteroidsorinhaledbudesonideshouldnotbestoppedabruptly.

DuringtransferfromoraltherapytoEdoflo,agenerallylowersystemicsteroidactionwillbeexperiencedwhichmay

resultintheappearanceofallergicorarthriticsymptomssuchasrhinitis,eczemaandmuscleandjointpain.Specific

treatmentshouldbeinitiatedfortheseconditions.Ageneralinsufficientglucocorticosteroideffectshouldbesuspected

if,inrarecases,symptomssuchastiredness,headache,nauseaandvomitingshouldoccur.Inthesecasesatemporary

increaseinthedoseoforalglucocorticosteroidsissometimesnecessary.

Tominimisetheriskoforopharyngealcandidainfection,thepatientshouldbeinstructedtorinsetheirmouthoutwith

waterafterinhalingthemaintenancedose.Iforopharyngealthrushoccurs,patientsshouldalsorinsetheirmouthwith

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Concomitanttreatmentwithitraconazole,ritonavirorotherpotentCYP3A4inhibitorsshouldbeavoided(see

section4.5).Ifthisisnotpossiblethetimeintervalbetweenadministrationoftheinteractingdrugsshouldbeaslongas

possible.InpatientsusingpotentCYP3A4inhibitors,Edoflomaintenanceandrelievertherapyisnotrecommended.

Edofloshouldbeadministeredwithcautioninpatientswiththyrotoxicosis,phaeochromocytoma,diabetesmellitus,

untreatedhypokalaemia,hypertrophicobstructivecardiomyopathy,idiopathicsubvalvularaorticstenosis,severe

hypertension,aneurysmorotherseverecardiovasculardisorders,suchasischaemicheartdisease,tachyarrhythmiasor

severeheartfailure.

CautionshouldbeobservedwhentreatingpatientswithprolongationoftheQTc -interval.Formoterolitselfmayinduce

prolongationoftheQTc -interval.

Theneedfor,anddoseofinhaledcorticosteroidsshouldbere -evaluatedinpatientswithactiveorquiescentpulmonary

tuberculosis,fungalandviralinfectionsintheairways.

Potentiallyserioushypokalaemiamayresultfromhighdosesof

adrenoceptoragonists.Concomitanttreatmentof

adrenoceptoragonistswithdrugs,whichcaninducehypokalaemiaorpotentiateahypokalaemiceffect,e.g.

xanthine -derivatives,steroidsanddiuretics,mayaddtoapossiblehypokalaemiceffectofthe

adrenoceptoragonist.

Particularcautionisrecommendedinunstableasthmawithvariableuseofrescuebronchodilators,inacutesevere

asthmaastheassociatedriskmaybeaugmentedbyhypoxiaandinotherconditionswhenthelikelihoodfor

hypokalaemiaisincreased.Itisrecommendedthatserumpotassiumlevelsaremonitoredduringthesecircumstances.

Asforall

adrenoceptoragonists,additionalbloodglucosecontrolsshouldbeconsideredindiabeticpatients.

Edoflocontainslactosemonohydrate(<1mg/inhalation).Thisamountdoesnotnormallycauseproblemsinlactose

intolerantpeople.Theexcipientlactosecontainssmallamountsofmilkproteins,whichmaycauseallergicreactions.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Pharmakokineticinteractions

PotentinhibitorsofCYP3A4(e.g.ketoconazole,itraconazole,voriconazole,posaconazole,clarithromycin,

telithromycin,nefazodoneandHIVproteaseinhibitors)arelikelytomarkedlyincreaseplasmalevelsofbudesonide

andconcomitantuseshouldbeavoided.Ifthisisnotpossiblethetimeintervalbetweenadministrationoftheinhibitor

andbudesonideshouldbeaslongaspossible(section4.4).InpatientsusingpotentCYP3A4inhibitors,Edoflo

maintenanceandrelievertherapyisnotrecommended.

ThepotentCYP3A4inhibitorketoconazole,200mgoncedaily,increasedplasmalevelsofconcomitantlyorally

administeredbudesonide(singledoseof3mg)onaveragesix-fold.Whenketoconazolewasadministered12hours

afterbudesonidetheconcentrationwasonaverageincreasedonlythree-foldshowingthatseparationofthe

administrationtimescanreducetheincreaseinplasmalevels.Limiteddataaboutthisinteractionforhigh-doseinhaled

budesonideindicatesthatmarkedincreaseinplasmalevels(onaveragefourfold)mayoccurifitraconazole,200mg

oncedaily,isadministeredconcomitantlywithinhaledbudesonide(singledoseof1000µg).

Pharmacodynamicinteractions

Beta -adrenergicblockerscanweakenorinhibittheeffectofformoterol.Edofloshouldthereforenotbegiventogether

withbeta -adrenergicblockers(includingeyedrops)unlesstherearecompellingreasons.

Concomitanttreatmentwithquinidine,disopyramide,procainamide,phenothiazines,antihistamines(terfenadine),

monoamineoxidaseinhibitorsandtricyclicantidepressantscanprolongtheQTc -intervalandincreasetheriskof

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InadditionL -Dopa,L-thyroxine,oxytocinandalcoholcanimpaircardiactolerancetowards

-sympathomimetics.

Concomitanttreatmentwithmonoamineoxidaseinhibitorsincludingagentswithsimilarpropertiessuchas

furazolidoneandprocarbazinemayprecipitatehypertensivereactions.

Thereisanelevatedriskofarrhythmiasinpatientsreceivingconcomitantanaesthesiawithhalogenatedhydrocarbons.

Concomitantuseofotherbeta -adrenergicdrugsoranticholinergicdrugscanhaveapotentiallyadditive

bronchodilatingeffect.

Hypokalaemiamayincreasethedispositiontowardsarrhythmiasinpatientswhoaretreatedwithdigitalisglycosides.

Budesonideandformoterolhavenotbeenobservedtointeractwithanyotherdrugsusedinthetreatmentofasthma.

4.6Fertility,pregnancyandlactation

ForEdofloortheconcomitanttreatmentwithformoterolandbudesonide,noclinicaldataonexposedpregnanciesare

available.Datafromanembryo-fetaldevelopmentstudyintheratshowednoevidenceofanyadditionaleffectfromthe

combination.

Therearenoadequatedatafromuseofformoterolinpregnantwomen.Inanimalstudies,formoterolhascaused

adverseeffectsinreproductionstudiesatveryhighsystemicexposurelevels(seesection5.3).

Dataonapproximately2000exposedpregnanciesindicatenoincreasedteratogenicriskassociatedwiththeuseof

inhaledbudesonide.Inanimalstudiesglucocorticosteroidshavebeenshowntoinducemalformations(seesection5.3).

Thisisnotlikelytoberelevantforhumansgivenrecommendeddoses.

Animalstudieshavealsoidentifiedaninvolvementofexcessprenatalglucocorticoidsinincreasedrisksforintrauterine

growthretardation,adultcardiovasculardiseaseandpermanentchangesinglucocorticoidreceptordensity,

neurotransmitterturnoverandbehaviouratexposuresbelowtheteratogenicdoserange.

Duringpregnancy,Edofloshouldonlybeusedwhenthebenefitsoutweighthepotentialrisks.Thelowesteffective

doseofbudesonideneededtomaintainadequateasthmacontrolshouldbeused.

Budesonideisexcretedinbreastmilk.However,attherapeuticdosesnoeffectsonthesucklingchildareanticipatedIt

isnotknownwhetherformoterolpassesintohumanbreastmilk.Inrats,smallamountsofformoterolhavebeen

detectedinmaternalmilk.AdministrationofEdoflotowomenwhoarebreastfeedingshouldonlybeconsideredifthe

expectedbenefittothemotherisgreaterthananypossiblerisktothechild.

4.7Effectsonabilitytodriveandusemachines

Edoflohasnoornegligibleinfluenceontheabilitytodriveandusemachines.

4.8Undesirableeffects

SinceEdoflocontainsbothbudesonideandformoterol,thesamepatternofundesirableeffectsasreportedforthese

substancesmayoccur.Noincreasedincidenceofadversereactionshasbeenseenfollowingconcurrentadministration

ofthetwocompounds.Themostcommondrugrelatedadversereactionsarepharmacologicallypredictable

side -effectsof

adrenoceptoragonisttherapy,suchastremorandpalpitations.Thesetendtobemildandusually

disappearwithinafewdaysoftreatment.

Adversereactions,whichhavebeenassociatedwithbudesonideorformoterol,aregivenbelow,listedbysystemorgan

classandfrequency.Frequenciesaredefinedas:verycommon(1/10),common(1/100and<1/10),uncommon(1/1

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Table1

SOC Frequency AdverseDrugreaction

Infectionsand

infestations Common Candidainfectionsintheoropharynx

Immunesystemdisorders Rare Immediateanddelayedhypersensitivity

reactions,e.g.exanthema,urticaria,

pruritus,dermatitis,angioedemaand

anaphylacticreaction

Endocrinedisorders Veryrare Cushing’ssyndrome,adrenalsuppression,

growthretardation,decreaseinbone

mineraldensity

Metabolismandnutrition

disorders Rare Hypokalaemia

Veryrare Hyperglycaemia

Psychiatricdisorders Uncommon Agitation,restlessness,nervousness,sleep

disturbances

Veryrare Depression,behaviouraldisturbances

(mainlyinchildren)

Nervoussystemdisorders Common Headache,tremor

Uncommon Dizziness

Veryrare Tastedisturbances

Eyedisorders Veryrare Cataractandglaucoma

Cardiacdisorders Common Palpitations

Uncommon Tachycardia

Rare Cardiacarrhythmias,e.g.atrialfibrillation,

supraventriculartachycardia,extrasystoles

Veryrare Anginapectoris.Prolongationof

-interval

Vasculardisorders Veryrare Variationsinbloodpressure

Respiratory,thoracicand

mediastinaldisorders Common Mildirritationinthethroat,coughing,

hoarseness

Rare Bronchospasm

Gastrointestinaldisorders Uncommon Nausea

Skinandsubcutaneous

tissuedisorders Uncommon Bruises

Musculoskeletaland

connectivetissue

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Candidainfectionintheoropharynxisduetodrugdeposition.Advisingthepatienttorinsethemouthoutwithwater

aftereachdosewillminimisetherisk.OropharyngealCandidainfectionusuallyrespondstotopicalanti -fungal

treatmentwithouttheneedtodiscontinuetheinhaledcorticosteroid.

Aswithotherinhalationtherapy,paradoxicalbronchospasmmayoccurveryrarely,affectinglessthan1in

10,000people,withanimmediateincreaseinwheezingandshortnessofbreathafterdosing.Paradoxicalbronchospasm

respondstoarapid-actinginhaledbronchodilatorandshouldbetreatedstraightaway.Edofloshouldbediscontinued

immediately,thepatientshouldbeassessedandanalternativetherapyinstitutedifnecessary(seesection4.4).

Systemiceffectsofinhaledcorticosteroidsmayoccur,particularlyathighdosesprescribedforprolongedperiods.

Theseeffectsaremuchlesslikelytooccurthanwithoralcorticosteroids.PossiblesystemiceffectsincludeCushing’s

Syndrome,Cushingoidfeatures,adrenalsuppression,growthretardationinchildrenandadolescents,decreaseinbone

mineraldensity,cataractandglaucoma.Increasedsusceptibilitytoinfectionsandimpairmentoftheabilitytoadaptto

stressmayalsooccur.Effectsareprobablydependentondose,exposuretime,concomitantandprevioussteroid

exposureandindividualsensitivity.

Treatmentwith

adrenoceptoragonistsmayresultinanincreaseinbloodlevelsofinsulin,freefattyacids,glycerol

andketonebodies.

4.9Overdose

Anoverdoseofformoterolwouldlikelyleadtoeffectsthataretypicalfor

adrenoceptoragonists:tremor,headache,

palpitations.Symptomsreportedfromisolatedcasesaretachycardia,hyperglycaemia,hypokalaemia,prolongedQTc

interval,arrhythmia,nauseaandvomiting.Supportiveandsymptomatictreatmentmaybeindicated.Adoseof

90microgramsadministeredduringthreehoursinpatientswithacutebronchialobstructionraisednosafetyconcerns.

Acuteoverdosagewithbudesonide,eveninexcessivedoses,isnotexpectedtobeaclinicalproblem.Whenused

chronicallyinexcessivedoses,systemicglucocorticosteroideffects,suchashypercorticismandadrenalsuppression,

mayappear.

IfEdoflotherapyhastobewithdrawnduetooverdoseoftheformoterolcomponentofthedrug,provisionof

appropriateinhaledcorticosteroidtherapymustbeconsidered.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Adrenergicsandotherdrugsforobstructiveairwaydiseases.

ATC-code:R03AK07

Mechanismsofactionandpharmacodynamiceffects

Edoflocontainsformoterolandbudesonide,whichhavedifferentmodesofactionandshowadditiveeffectsintermsof

reductionofasthmaexacerbations.Thespecificpropertiesofbudesonideandformoterolallowthecombinationtobe

usedeitherasmaintenanceandrelievertherapy,orasmaintenancetreatmentofasthma.

Budesonide

Budesonideisaglucocorticosteroidwhichwheninhaledhasadose-dependentanti-inflammatoryactionintheairways,

resultinginreducedsymptomsandfewerasthmaexacerbations.Inhaledbudesonidehaslesssevereadverseeffectsthan

systemiccorticosteroids.Theexactmechanismresponsiblefortheanti-inflammatoryeffectofglucocorticosteroidsis

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Formoterol

Formoterolisaselective

adrenoceptoragonistthatwheninhaledresultsinrapidandlong-actingrelaxationof

bronchialsmoothmuscleinpatientswithreversibleairwaysobstruction.Thebronchodilatingeffectisdosedependant,

withanonsetofeffectwithin1 -3minutes.Thedurationofeffectisatleast12hoursafterasingledose.

Budesonide/formoterol

Clinicalefficacyforbudesonide/formoterolmaintenancetherapy

Clinicalstudiesinadults,haveshownthattheadditionofformoteroltobudesonideimprovedasthmasymptomsand

lungfunction,andreducedexacerbations.Intwo12 -weekstudiestheeffectonlungfunctionofbudesonide/formoterol

wasequaltothatofthefreecombinationofbudesonideandformoterol,andexceededthatofbudesonidealone.All

treatmentarmsusedashort-acting

adrenoceptoragonistasneeded.Therewasnosignofattenuationofthe

anti -asthmaticeffectovertime.

Ina12 -weekpaediatricstudy,85childrenaged6-11yearsweretreatedwithamaintenancedoseof

budesonide/formoterol(2inhalationsof80micrograms/4.5micrograms/inhalationtwicedaily),andashort-acting

adrenoceptoragonistasneeded.Lungfunctionwasimproved,andthetreatmentwaswelltoleratedcomparedtothe

correspondingdoseofbudesonidealone.

Clinicalefficacyforbudesonide/formoterolmaintenanceandrelievertherapy

Atotalof12076asthmapatientswereincludedin5double -blindefficacyandsafetystudies(4447wererandomisedto

budesonide/formoterolmaintenanceandrelievertherapy)for6or12months.Patientswererequiredtobesymptomatic

despiteuseofinhaledglucocorticosteroids.

Budesonide/formoterolmaintenanceandrelievertherapyprovidedstatisticallysignificantandclinicallymeaningful

reductionsinsevereexacerbationsforallcomparisonsinall5studies.Thisincludedacomparisonwith

budesonide/formoterolatahighermaintenancedosewithterbutalineasreliever(study735)andbudesonide/formoterol

atthesamemaintenancedosewitheitherformoterolorterbutalineasreliever(study734)(Table2).InStudy735,lung

function,symptomcontrol,andrelieveruseweresimilarinalltreatmentgroups.InStudy734,symptomsandreliever

usewerereducedandlungfunctionimproved,comparedwithbothcomparatortreatments.Inthe5studiescombined,

patientsreceivingbudesonide/formoterolmaintenanceandrelievertherapyused,onaverage,norelieverinhalationson

57%oftreatmentdays.Therewasnosignofdevelopmentoftoleranceovertime.

Table2 Overviewofsevereexacerbationsinclinicalstudies

Study

No.

Duration Treatmentgroups n Severe

exacerbations a

Events Events/

patient -year

Study

735

6

months Budesonide/formoterol 160/4.5µg

bd+asneeded 1103 125

0.23 b

budesonide/formoterol 320/9µg

bd+terbutaline0.4mgasneeded 1099 173

0.32

Salmeterol/fluticasone2x25/125µg

bd+terbutaline0.4mgasneeded 1119 208

0.38

Study

734

12

months Budesonide/formoterol 160/4.5µg

bd+asneeded 1107 194

0.19 b

budesonide/formoterol 160/4.5µg

bd+formoterol4.5µgasneeded 1137 296

0.29

budesonide/formoterol 160/4.5µg

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Reductioninexacerbationrateisstatisticallysignificant(P -value<0.01)forbothcomparisons

In2otherstudieswithpatientsseekingmedicalattentionduetoacuteasthmasymptoms,budesonide/formoterol

providedrapidandeffectivereliefofbronchoconstrictionsimilartosalbutamolandformoterol.

5.2Pharmacokineticproperties

Absorption

Thefixed-dosecombinationofbudesonideandformoterol,andthecorrespondingmonoproductshavebeenshownto

bebioequivalentwithregardtosystemicexposureofbudesonideandformoterol,respectively.Inspiteofthis,asmall

increaseincortisolsuppressionwasseenafteradministrationofthefixed-dosecombinationcomparedtothe

monoproducts.Thedifferenceisconsiderednottohaveanimpactonclinicalsafety.

Therewasnoevidenceofpharmacokineticinteractionsbetweenbudesonideandformoterol.

Pharmacokineticparametersfortherespectivesubstanceswerecomparableaftertheadministrationofbudesonideand

formoterolasmonoproductsorasthefixed-dosecombination..Forbudesonide,AUCwasslightlyhigher,rateof

absorptionmorerapidandmaximalplasmaconcentrationhigherafteradministrationofthefixedcombination.For

formoterol,maximalplasmaconcentrationwassimilarafteradministrationofthefixedcombination.Inhaled

budesonideisrapidlyabsorbedandthemaximumplasmaconcentrationisreachedwithin30minutesafterinhalation.

Instudies,meanlungdepositionofbudesonideafterinhalationviathepowderinhalerrangedfrom32%to44%ofthe

delivereddose.Thesystemicbioavailabilityisapproximately49%ofthedelivereddose.Inchildren6-16yearsofage

thelungdepositionfallsinthesamerangeasinadultsforthesamegivendose.Theresultingplasmaconcentrations

werenotdetermined.

Inhaledformoterolisrapidlyabsorbedandthemaximumplasmaconcentrationisreachedwithin10minutesafter

inhalation.Instudies,themeanlungdepositionofformoterolafterinhalationviathepowderinhalerrangedfrom28%

to49%ofthedelivereddose.Thesystemicbioavailabilityisabout61%ofthedelivereddose.

Distributionandmetabolism

Plasmaproteinbindingisapproximately50%forformoteroland90%forbudesonide.Volumeofdistributionisabout

4L/kgforformoteroland3L/kgforbudesonide.Formoterolisinactivatedviaconjugationreactions(active

-demethylatedanddeformylatedmetabolitesareformed,buttheyareseenmainlyasinactivatedconjugates).

Budesonideundergoesanextensivedegree(approximately90%)ofbiotransformationonfirstpassagethroughtheliver

tometabolitesoflowglucocorticosteroidactivity.Theglucocorticosteroidactivityofthemajormetabolites,

-beta-hydroxy-budesonideand16-alfa-hydroxy-prednisolone,islessthan1%ofthatofbudesonide.Thereareno

indicationsofanymetabolicinteractionsoranydisplacementreactionsbetweenformoterolandbudesonide.

Elimination

Themajorpartofadoseofformoterolistransformedbylivermetabolismfollowedbyrenalelimination.After

inhalation,8%to13%ofthedelivereddoseofformoterolisexcretedunmetabolisedintheurine.Formoterolhasahigh

systemicclearance(approximately1.4L/min)andtheterminaleliminationhalf-lifeaverages17hours.

BudesonideiseliminatedviametabolismmainlycatalysedbytheenzymeCYP3A4.Themetabolitesofbudesonideare

eliminatedinurineassuchorinconjugatedform.Onlynegligibleamountsofunchangedbudesonidehavebeen

detectedintheurine.Budesonidehasahighsystemicclearance(approximately1.2L/min)andtheplasmaelimination

half-lifeafteri.v.dosingaverages4hours.

Thepharmacokineticsofformoterolinchildrenhavenotbeenstudied.Thepharmacokineticsofbudesonideand

formoterolinpatientswithrenalfailureareunknown.Theexposureofbudesonideandformoterolmaybeincreasedin

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5.3Preclinicalsafetydata

Thetoxicityobservedinanimalstudieswithbudesonideandformoterol,givenincombinationorseparately,were

effectsassociatedwithexaggeratedpharmacologicalactivity.

Inanimalreproductionstudies,corticosteroidssuchasbudesonidehavebeenshowntoinducemalformations(cleft

palate,skeletalmalformations).However,theseanimalexperimentalresultsdonotseemtoberelevantinhumansatthe

recommendeddoses.Animalreproductionstudieswithformoterolhaveshownasomewhatreducedfertilityinmale

ratsathighsystemicexposureandimplantationlossesaswellasdecreasedearlypostnatalsurvivalandbirthweightat

considerablyhighersystemicexposuresthanthosereachedduringclinicaluse.However,theseanimalexperimental

resultsdonotseemtoberelevantinhumans.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactosemonohydrate(whichcontainsmilkproteins).

6.2Incompatibilities

Notapplicable.

6.3Shelflife

2years.

6.4Specialprecautionsforstorage

Donotstoreabove30 °

C.Keepthecontainertightlyclosed,inordertoprotectfrommoisture.

6.5Natureandcontentsofcontainer

Edofloisaninspiratoryflowdriven,multidosepowderinhaler.Theinhaleriswhitewitharedturninggrip.Theinhaler

ismadeofdifferentplasticmaterials(PP,PC,HDPE,LDPE,LLDPE,PBT).Ineachsecondarypackagethereare1,2,

3,10or18inhaler(s)containing60(or120)doses.Notallpack-sizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

AstraZenecaUKLimited

600CapabilityGreen

Luton

LU13LU

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8MARKETINGAUTHORISATIONNUMBER

PA970/62/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:26November2010

10DATEOFREVISIONOFTHETEXT

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