EDOFLO

Main information

  • Trade name:
  • EDOFLO Powder for Inhalation 200/6 Mcg/Dose
  • Dosage:
  • 200/6 Mcg/Dose
  • Pharmaceutical form:
  • Powder for Inhalation
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • EDOFLO Powder for Inhalation 200/6 Mcg/Dose
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0970/062/002
  • Authorization date:
  • 26-11-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Edoflo200micrograms/6micrograms/Inhalation,Inhalationpowder

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachdelivereddose(thedosethatleavesthemouthpiece)contains:budesonide160micrograms/inhalationand

formoterolfumaratedihydrate4.5micrograms/inhalation.

Each metered dose contains: budesonide 200micrograms/inhalation and formoterol fumarate dihydrate

6micrograms / inhalation.

Excipient:Lactosemonohydrate730microgramsperdose.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Inhalationpowder

Whitepowder

4CLINICALPARTICULARS

4.1TherapeuticIndications

Asthma

Edofloisindicatedintheregulartreatmentofasthma,whereuseofacombination(inhaledcorticosteroidandlong-

acting

adrenoceptoragonist)isappropriate:

patientsnotadequatelycontrolledwithinhaledcorticosteroidsand“asneeded”inhaledshort -acting

adrenoceptoragonists.

patientsalreadyadequatelycontrolledonbothinhaledcorticosteroidsandlong-acting

adrenoceptoragonists.

COPD

SymptomatictreatmentofpatientswithsevereCOPD(FEV

<50%predictednormal)andahistoryofrepeated

exacerbations,whohavesignificantsymptomsdespiteregulartherapywithlong -actingbronchodilators.

4.2Posologyandmethodofadministration

Routeofadministration:Forinhalationuse

Asthma

Edofloisnotintendedfortheinitialmanagementofasthma.ThedosageofthecomponentsofEdofloisindividualand

shouldbeadjustedtotheseverityofthedisease.Thisshouldbeconsiderednotonlywhentreatmentwithcombination

productsisinitiatedbutalsowhenthemaintenancedoseisadjusted.Ifanindividualpatientshouldrequirea

combinationofdosesotherthanthoseavailableinthecombinationinhaler,appropriatedosesof

adrenoceptor

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Thedoseshouldbetitratedtothelowestdoseatwhicheffectivecontrolofsymptomsismaintained.Patientsshouldbe

regularlyreassessedbytheirprescriber/healthcareprovidersothatthedosageofEdofloremainsoptimal.Whenlong-

termcontrolofsymptomsismaintainedwiththelowestrecommendeddosage,thenthenextstepcouldincludeatestof

inhaledcorticosteroidalone.

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.

Inusualpracticewhencontrolofsymptomsisachievedwiththetwicedailyregimen,titrationtothelowesteffective

dosecouldincludeEdoflogivenoncedaily,whenintheopinionoftheprescriber,along-actingbronchodilatorwould

berequiredtomaintaincontrol.

Increasinguseofaseparaterapid-actingbronchodilatorindicatesaworseningoftheunderlyingconditionandwarrants

areassessmentoftheasthmatherapy.

Children(6yearsandolder):Alowerstrengthisavailableforchildren6 -11years.

Childrenunder6years:Asonlylimiteddataareavailable,Edofloisnotrecommendedforchildrenyoungerthan6

years.

B.Edoflomaintenanceandrelievertherapy

PatientstakeadailymaintenancedoseofEdofloandinadditiontakeEdofloasneededinresponsetosymptoms.

PatientsshouldbeadvisedtoalwayshaveEdofloavailableforrescueuse.

Edoflomaintenanceandrelievertherapyshouldespeciallybeconsideredforpatientswith:

inadequateasthmacontrolandinfrequentneedofrelievermedication

asthmaexacerbationsinthepastrequiringmedicalintervention

Closemonitoringfordose-relatedadverseeffectsisneededinpatientswhofrequentlytakehighnumbersofEdoflo

-neededinhalations.

Recommendeddoses:

Adults(18yearsandolder):Therecommendedmaintenancedoseis2inhalationsperday,giveneitherasone

inhalationinthemorningandeveningoras2inhalationsineitherthemorningorevening.Forsomepatientsa

maintenancedoseof2inhalationstwicedailymaybeappropriate.Patientsshouldtake1additionalinhalationas

neededinresponsetosymptoms.Ifsymptomspersistafterafewminutes,anadditionalinhalationshouldbetaken.Not

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Atotaldailydoseofmorethan8inhalationsisnotnormallyneeded;however,atotaldailydoseofupto12inhalations

couldbeusedforalimitedperiod.Patientsusingmorethan8inhalationsdailyshouldbestronglyrecommendedto

seekmedicaladvice.Theyshouldbereassessedandtheirmaintenancetherapyshouldbereconsidered.

Childrenandadolescentsunder18years:Edoflomaintenanceandrelievertherapyisnotrecommendedforchildren

andadolescents.

COPD

Recommendeddoses:

Adults:2inhalationstwicedaily.

Generalinformation

Specialpatientgroups:

Therearenospecialdosingrequirementsforelderlypatients.TherearenodataavailableforuseofEdofloinpatients

withhepaticorrenalimpairment.Asbudesonideandformoterolareprimarilyeliminatedviahepaticmetabolism,an

increasedexposurecanbeexpectedinpatientswithseverelivercirrhosis.

InstructionsforcorrectuseofEdoflo:

Theinhalerisinspiratoryflow -driven,whichmeansthatwhenthepatientinhalesthroughthemouthpiece,the

substancewillfollowtheinspiredairintotheairways.

Note:Itisimportanttoinstructthepatient

tocarefullyreadtheinstructionsforuseinthepatientinformationleafletwhichispackedtogetherwitheachEdoflo

Inhaler.

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).SuddenandprogressivedeteriorationincontrolofasthmaorCOPDispotentiallylife

threateningandthepatientshouldundergourgentmedicalassessment.Inthissituationconsiderationshouldbegivento

theneedforincreasedtherapywithcorticosteroids,e.g.acourseoforalcorticosteroids,orantibiotictreatmentifan

infectionispresent.

Patientsshouldbeadvisedtohavetheirrescueinhaleravailableatalltimes,eitherEdoflo(forasthmapatientsusing

Edofloasmaintenanceandrelievertherapy)oraseparaterapid -actingbronchodilator(forallpatientsusingEdofloas

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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

initiationofEdoflo.

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.

Potentialeffectsonbonedensityshouldbeconsideredparticularlyinpatientsonhighdosesforprolongedperiodsthat

havecoexistingriskfactorsforosteoporosis.Long -termstudieswithinhaledbudesonideinchildrenatmeandaily

dosesof400micrograms(metereddose)orinadultsatdailydosesof800micrograms(metereddose)havenotshown

anysignificanteffectsonbonemineraldensity.NoinformationregardingtheeffectofEdofloathigherdosesis

available.

Ifthereisanyreasontosupposethatadrenalfunctionisimpairedfromprevioussystemicsteroidtherapy,careshould

betakenwhentransferringpatientstoEdoflotherapy.

Thebenefitsofinhaledbudesonidetherapywouldnormallyminimisetheneedfororalsteroids,butpatients

transferringfromoralsteroidsmayremainatriskofimpairedadrenalreserveforaconsiderabletime.Recoverymay

takeaconsiderableamountoftimeaftercessationoforalsteroidtherapyandhenceoralsteroid -dependentpatients

transferredtoinhaledbudesonidemayremainatriskfromimpairedadrenalfunctionforsomeconsiderabletime.In

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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

wateraftertheas -neededinhalations.

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

adrenoceptoragonistswithdrugswhichcaninducehypokalaemiaorpotentiateahypokalaemiceffect,e.g.

xanthine -derivatives,steroidsanddiuretics,mayaddtoapossiblehypokalaemiceffectofthe

adrenoceptoragonist.

Particularcautionisrecommendedinunstableasthmawithvariableuseofrescuebronchodilators,inacutesevere

asthmaastheassociatedriskmaybeaugmentedbyhypoxiaandinotherconditionswhenthelikelihoodfor

hypokalaemiaisincreased.Itisrecommendedthatserumpotassiumlevelsaremonitoredduringthesecircumstances.

Asforall

adrenoceptoragonists,additionalbloodglucosecontrolsshouldbeconsideredindiabeticpatients.

Edoflocontainslactosemonohydrate(<1mg/inhalation).Thisamountdoesnotnormallycauseproblemsinlactose

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Pharmacokineticinteractions

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

ventriculararrhythmias.

InadditionL -Dopa,L-thyroxine,oxytocinandalcoholcanimpaircardiactolerancetowards

-sympathomimetics.

Concomitanttreatmentwithmonoamineoxidaseinhibitorsincludingagentswithsimilarpropertiessuchas

furazolidoneandprocarbazinemayprecipitatehypertensivereactions.

Thereisanelevatedriskofarrhythmiasinpatientsreceivingconcomitantanaesthesiawithhalogenatedhydrocarbons.

Concomitantuseofotherbeta-adrenergicdrugsoranticholinergicdrugscanhaveapotentiallyadditivebronchodilating

effect.

Hypokalaemiamayincreasethedispositiontowardsarrhythmiasinpatientswhoaretreatedwithdigitalisglycosides.

Budesonideandformoterolhavenotbeenobservedtointeractwithanyotherdrugsusedinthetreatmentofasthma.

4.6Fertility,pregnancyandlactation

ForEdofloortheconcomitanttreatmentwithformoterolandbudesonide,noclinicaldataonexposedpregnanciesare

available.Datafromanembryo -fetaldevelopmentstudyintheratshowednoevidenceofanyadditionaleffectfrom

thecombination.

Therearenoadequatedatafromuseofformoterolinpregnantwomen.Inanimalstudies,formoterolhascaused

adverseeffectsinreproductionstudiesatveryhighsystemicexposurelevels(seesection5.3).

Dataonapproximately2000exposedpregnanciesindicatenoincreasedteratogenicriskassociatedwiththeuseof

inhaledbudesonide.Inanimalstudiesglucocorticosteroidshavebeenshowntoinducemalformations(seesection5.3).

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Animalstudieshavealsoidentifiedaninvolvementofexcessprenatalglucocorticoidsinincreasedrisksforintrauterine

growthretardation,adultcardiovasculardiseaseandpermanentchangesinglucocorticoidreceptordensity,

neurotransmitterturnoverandbehaviouratexposuresbelowtheteratogenicdoserange.

Duringpregnancy,Edofloshouldonlybeusedwhenthebenefitsoutweighthepotentialrisks.Thelowesteffective

doseofbudesonideneededtomaintainadequateasthmacontrolshouldbeused.

Budesonideisexcretedinbreastmilk.However,attherapeuticdosesnoeffectsonthesucklingchildareanticipated.It

isnotknownwhetherformoterolpassesintohumanbreastmilk.Inrats,smallamountsofformoterolhavebeen

detectedinmaternalmilk.AdministrationofEdoflotowomenwhoarebreastfeedingshouldonlybeconsideredifthe

expectedbenefittothemotherisgreaterthananypossiblerisktothechild.

4.7Effectsonabilitytodriveandusemachines

Edoflohasnoornegligibleinfluenceontheabilitytodriveandusemachines.

4.8Undesirableeffects

SinceEdoflocontainsbothbudesonideandformoterol,thesamepatternofundesirableeffectsasreportedforthese

substancesmayoccur.Noincreasedincidenceofadversereactionshasbeenseenfollowingconcurrentadministration

ofthetwocompounds.Themostcommondrugrelatedadversereactionsarepharmacologicallypredictable

side -effectsof

adrenoceptoragonisttherapy,suchastremorandpalpitations.Thesetendtobemildandusually

disappearwithinafewdaysoftreatment.Ina3 -yearclinicaltrialwithbudesonideinCOPD,skinbruisesand

pneumoniaoccurredatafrequencyof10%and6%,respectively,comparedwith4%and3%intheplacebogroup

(p<0.001andp<0.01,respectively).

Adversereactions,whichhavebeenassociatedwithbudesonideorformoterol,aregivenbelow,listedbysystemorgan

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

000and<1/100),rare(1/10000and<1/1000)andveryrare<1/10000).

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

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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

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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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

unknown.

Formoterol

Formoterolisaselective

adrenoceptoragonistthatwheninhaledresultsinrapidandlong -actingrelaxationof

bronchialsmoothmuscleinpatientswithreversibleairwaysobstruction.Thebronchodilatingeffectisdosedependant,

withanonsetofeffectwithin1 -3minutes.Thedurationofeffectisatleast12hoursafterasingledose.

Budesonide/formoterol

Asthma

Clinicalefficacyforbudesonide/formoterolmaintenancetherapy

Clinicalstudiesinadultshaveshownthattheadditionofformoteroltobudesonideimprovedasthmasymptomsand

lungfunction,andreducedexacerbations.Intwo12 -weekstudiestheeffectonlungfunctionofbudesonide/formoterol

wasequaltothatofthefreecombinationofbudesonideandformoterol,andexceededthatofbudesonidealone.All

treatmentarmsusedashort-acting

adrenoceptoragonistasneeded.Therewasnosignofattenuationoftheanti-

asthmaticeffectovertime.

Ina12 -weekpaediatricstudy,85childrenaged6-11yearsweretreatedwithamaintenancedoseof

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

adrenoceptoragonistasneeded.Lungfunctionwasimprovedandthetreatmentwaswelltoleratedcomparedtothe

correspondingdoseofbudesonidealone.

Clinicalefficacyforbudesonide/formoterolmaintenanceandrelievertherapy

Atotalof12076asthmapatientswereincludedin5double -blindefficacyandsafetystudies(4447wererandomisedto

budesonide/formoterolmaintenanceandrelievertherapy)for6or12months.Patientswererequiredtobesymptomatic

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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

Hospitalisation/emergencyroomtreatmentortreatmentwithoralsteroids

Reductioninexacerbationrateisstatisticallysignificant(P -value<0.01)forbothcomparisons

In2otherstudieswithpatientsseekingmedicalattentionduetoacuteasthmasymptoms,budesonide/formoterol

providedrapidandeffectivereliefofbronchoconstrictionsimilartosalbutamolandformoterol.

COPD

Intwo12 -monthstudies,theeffectonlungfunctionandtherateofexacerbation(definedascoursesoforalsteroids

and/orcourseofantibioticsand/orhospitalisations)inpatientswithsevereCOPDwasevaluated.MedianFEV

inclusioninthetrialswas36%ofpredictednormal.Themeannumberofexacerbationsperyear(asdefinedabove)was

significantlyreducedwithbudesonide/formoterolascomparedwithtreatmentwithformoterolaloneorplacebo(mean

rate1.4comparedwith1.8 -1.9intheplacebo/formoterolgroup).Themeannumberofdaysonoral

corticosteroids/patientduringthe12monthswasslightlyreducedinthebudesonide/formoterolgroup(7 -8

days/patient/yearcomparedwith11 -12and9-12daysintheplaceboandformoterolgroups,respectively).For

changesinlungfunctionparameters,suchasFEV

,budesonide/formoterolwasnotsuperiortotreatmentwith

formoterolalone.

5.2Pharmacokineticproperties

Absorption

Thefixed-dosecombinationofbudesonideandformoterol,andthecorrespondingmonoproductshavebeenshownto

bebioequivalentwithregardtosystemicexposureofbudesonideandformoterol,respectively.Inspiteofthis,asmall

increaseincortisolsuppressionwasseenafteradministrationofthefixed-dosecombinationcomparedtothe

StudyNo.

Duration Treatmentgroups n Severe

exacerbations a

Events Events/

patient-

year

Study735

6months Budesonide/formoterol 160/4.5µg

bd+asneeded 1103 125

0.23 b

Budesonide/formoterol 320/9µg

bd+terbutaline0.4mgasneeded 1099 173 0.32

Salmeterol/fluticasone2x25/125µgbd+

terbutaline0.4mgasneeded 1119 208

0.38

Study734

12months 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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Therewasnoevidenceofpharmacokineticinteractionsbetweenbudesonideandformoterol.

Pharmacokineticparametersfortherespectivesubstanceswerecomparableaftertheadministrationofbudesonideand

formoterolasmonoproductsorasthefixed-dosecombination.Forbudesonide,AUCwasslightlyhigher,rateof

absorptionmorerapidandmaximalplasmaconcentrationhigherafteradministrationofthefixedcombination.For

formoterol,maximalplasmaconcentrationwassimilarafteradministrationofthefixedcombination.

Inhaledbudesonideisrapidlyabsorbedandthemaximumplasmaconcentrationisreachedwithin30minutesafter

inhalation.Instudies,meanlungdepositionofbudesonideafterinhalationviatheinhalerrangedfrom32%to44%of

thedelivereddose.Thesystemicbioavailabilityisapproximately49%ofthedelivereddose.Inchildren6-16yearsof

agethelungdepositionfallsinthesamerangeasinadultsforthesamegivendose.Theresultingplasma

concentrationswerenotdetermined.

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.

Thepharmacokineticsofbudesonideorformoterolinpatientswithrenalfailureareunknown.Theexposureof

budesonideandformoterolmaybeincreasedinpatientswithliverdisease.

5.3Preclinicalsafetydata

Thetoxicityobservedinanimalstudieswithbudesonideandformoterol,givenincombinationorseparately,were

effectsassociatedwithexaggeratedpharmacologicalactivity.

Inanimalreproductionstudies,corticosteroidssuchasbudesonidehavebeenshowntoinducemalformations(cleft

palate,skeletalmalformations).However,theseanimalexperimentalresultsdonotseemtoberelevantinhumansatthe

recommendeddoses.Animalreproductionstudieswithformoterolhaveshownasomewhatreducedfertilityinmale

ratsathighsystemicexposureandimplantationlossesaswellasdecreasedearlypostnatalsurvivalandbirthweightat

considerablyhighersystemicexposuresthanthosereachedduringclinicaluse.However,theseanimalexperimental

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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

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA970/62/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:26November2010

10DATEOFREVISIONOFTHETEXT

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