EDOFLO

Main information

  • Trade name:
  • EDOFLO Powder for Inhalation 400/12 Mcg/Dose
  • Dosage:
  • 400/12 Mcg/Dose
  • Pharmaceutical form:
  • Powder for Inhalation
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • EDOFLO Powder for Inhalation 400/12 Mcg/Dose
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0970/062/003
  • Authorization date:
  • 26-11-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Edoflo400micrograms/12micrograms/Inhalation,Inhalationpowder

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachdelivereddose(thedosethatleavesthemouthpiece)contains:budesonide320micrograms/inhalationand

formoterolfumaratedihydrate9micrograms/inhalation.

Each metered dose contains: budesonide 400micrograms / inhalation and formoterol fumarate dihydrate

12micrograms / inhalation.

Excipient:Lactosemonohydrate491microgramsperdose.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Inhalationpowder

Whitepowder

4CLINICALPARTICULARS

4.1TherapeuticIndications

Asthma

Edofloisindicatedintheregulartreatmentofasthmawhereuseofacombination(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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Recommendeddoses:

Adults(18yearsandolder):1inhalationtwicedaily.Somepatientsmayrequireuptoamaximumof2inhalations

twicedaily.

Adolescents(12 -17years):1inhalationtwicedaily.

Patientsshouldberegularlyreassessedbytheirprescriber/healthcareprovider,sothatthedosageofEdofloremains

optimal.Thedoseshouldbetitratedtothelowestdoseatwhicheffectivecontrolofsymptomsismaintained.When

long-termcontrolofsymptomsismaintainedwiththelowestrecommendeddosage,thenthenextstepcouldincludea

testofinhaledcorticosteroidalone.

Inusualpracticewhencontrolofsymptomsisachievedwiththetwicedailyregimen,titrationtothelowesteffective

dosecouldincludeEdoflogivenoncedaily,whenintheopinionoftheprescriber,along -actingbronchodilatorwould

berequiredtomaintaincontrol.

Increasinguseofaseparaterapid-actingbronchodilatorindicatesaworseningoftheunderlyingconditionandwarrants

areassessmentoftheasthmatherapy.

Children(6yearsandolder):Alowerstrengthisavailableforchildren6 -11years.

Childrenunder6years:Asonlylimiteddataareavailable,Edofloisnotrecommendedforchildrenyoungerthan6

years.

Edoflo400micrograms/12micrograms/inhalationshouldbeusedasEdoflomaintenancetherapyonly.Lower

strengths,100micrograms/6micrograms/inhalationand200micrograms/6micrograms/inhalation,areavailableforthe

Edoflomaintenanceandrelievertherapyregimen.

COPD

Recommendeddoses:

Adults:1inhalationtwicedaily.

Generalinformation

Specialpatientgroups:

Therearenospecialdosingrequirementsforelderlypatients.TherearenodataavailableforuseofEdofloinpatients

withhepaticorrenalimpairment.Asbudesonideandformoterolareprimarilyeliminatedviahepaticmetabolism,an

increasedexposurecanbeexpectedinpatientswithseverelivercirrhosis.

InstructionsforcorrectuseofEdoflo:

Theinhalerisinspiratoryflow-driven,whichmeansthatwhenthepatientinhalesthroughthemouthpiece,the

substancewillfollowtheinspiredairintotheairways.

Note:Itisimportanttoinstructthepatient

tocarefullyreadtheinstructionsforuseinthepatientinformationleafletwhichispackedtogetherwitheachEdoflo

Inhaler.

tobreatheinforcefullyanddeeplythroughthemouthpiecetoensurethatanoptimaldoseisdeliveredtothelungs.

nevertobreatheoutthroughthemouthpiece.

toreplacethecoveroftheEdofloInhalerafteruse.

torinsetheirmouthoutwithwaterafterinhalingthemaintenancedosetominimisetheriskoforopharyngeal

thrush.

ThepatientmaynottasteorfeelanymedicationwhenusingEdofloInhalerduetothesmallamountofdrugdispensed.

4.3Contraindications

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4.4Specialwarningsandprecautionsforuse

Itisrecommendedthatthedoseistaperedwhenthetreatmentisdiscontinuedandshouldnotbestoppedabruptly.

Ifpatientsfindthetreatmentineffective,orexceedthehighestrecommendeddoseofEdoflo,medicalattentionmustbe

sought(seesection4.2).Increasinguseofrescuebronchodilatorsindicatesaworseningoftheunderlyingconditionand

warrantsareassessmentoftheasthmatherapy.SuddenandprogressivedeteriorationincontrolofasthmaorCOPDis

potentiallylifethreateningandthepatientshouldundergourgentmedicalassessment.Inthissituation,consideration

shouldbegiventotheneedforincreasedtherapywithcorticosteroids,e.g.acourseoforalcorticosteroids,orantibiotic

treatmentifaninfectionispresent.

Patientsshouldbeadvisedtohaverescueinhaleravailableatalltimes.

PatientsshouldberemindedtotaketheirEdoflomaintenancedoseasprescribed,evenwhenasymptomatic.

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.

Potentialeffectsonbonedensityshouldbeconsidered,particularlyinpatientsonhighdosesforprolongedperiodsthat

havecoexistingriskfactorsforosteoporosis.Long -termstudieswithinhaledbudesonideinchildrenatmeandaily

dosesof400micrograms(metereddose)orinadultsatdailydosesof800micrograms(metereddose)havenotshown

anysignificanteffectsonbonemineraldensity.NoinformationregardingtheeffectofEdofloathigherdosesis

available.

Ifthereisanyreasontosupposethatadrenalfunctionisimpairedfromprevioussystemicsteroidtherapy,careshould

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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.

Concomitanttreatmentwithitraconazole,ritonavirorotherpotentCYP3A4inhibitorsshouldbeavoided(see

section4.5).Ifthisisnotpossiblethetimeintervalbetweenadministrationoftheinteractingdrugsshouldbeaslongas

possible.

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(seesection4.4).

ThepotentCYP3A4inhibitorketoconazole,200mgoncedaily,increasedplasmalevelsofconcomitantlyorally

administeredbudesonide(singledoseof3mg)onaveragesix-fold.Whenketoconazolewasadministered12hours

afterbudesonidetheconcentrationwasonaverageincreasedonlythree-foldshowingthatseparationofthe

administrationtimescanreducetheincreaseinplasmalevels.Limiteddataaboutthisinteractionforhigh-doseinhaled

budesonideindicatesthatmarkedincreasesinplasmalevels(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 -adrenergicdrugsoranticholinergicdrugscanhaveapotentiallyadditive

bronchodilatingeffect.

Hypokalaemiamayincreasethedispositiontowardsarrhythmiasinpatientswhoaretreatedwithdigitalisglycosides.

Budesonideandformoterolhavenotbeenobservedtointeractwithanyotherdrugsusedinthetreatmentofasthma.

4.6Fertility,pregnancyandlactation

ForEdofloortheconcomitanttreatmentwithformoterolandbudesonide,noclinicaldataonexposedpregnanciesare

available.Datafromanembryo -fetaldevelopmentstudyintheratshowednoevidenceofanyadditionaleffectfrom

thecombination.

Therearenoadequatedatafromuseofformoterolinpregnantwomen.Inanimalstudies,formoterolhascaused

adverseeffectsinreproductionstudiesatveryhighsystemicexposurelevels(seesection5.3).

Dataonapproximately2000exposedpregnanciesindicatenoincreasedteratogenicriskassociatedwiththeuseof

inhaledbudesonide.Inanimalstudiesglucocorticosteroidshavebeenshowntoinducemalformations(seesection5.3).

Thisisnotlikelytoberelevantforhumansgivenrecommendeddoses.

Animalstudieshavealsoidentifiedaninvolvementofexcessprenatalglucocorticoidsinincreasedrisksforintrauterine

growthretardation,adultcardiovasculardiseaseandpermanentchangesinglucocorticoidreceptordensity,

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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

(mainlyinchildren)

Nervoussystemdisorders Common Headache,tremor

Uncommon Dizziness

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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.Adoseof90

microgramsadministeredduringthreehoursinpatientswithacutebronchialobstructionraisednosafetyconcerns.

Acuteoverdosagewithbudesonide,eveninexcessivedoses,isnotexpectedtobeaclinicalproblem.Whenused

chronicallyinexcessivedoses,systemicglucocorticosteroideffects,suchashypercorticismandadrenalsuppression,

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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IfEdoflotherapyhastobewithdrawnduetooverdoseoftheformoterolcomponentofthedrug,provisionof

appropriateinhaledcorticosteroidtherapymustbeconsidered.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Adrenergicsandotherdrugsforobstructiveairwaydiseases.

ATC-code:R03AK07

Mechanismsofactionandpharmacodynamiceffects

Edoflocontainsformoterolandbudesonide,whichhavedifferentmodesofactionandshowadditiveeffectsintermsof

reductionofasthmaexacerbations.Themechanismsofactionofthetwosubstances,respectivelyarediscussedbelow.

Budesonide

Budesonideisaglucocorticosteroidwhichwheninhaledhasadose-dependentanti -inflammatoryactionintheairways,

resultinginreducedsymptomsandfewerasthmaexacerbations.Inhaledbudesonidehaslesssevereadverseeffectsthan

systemiccorticosteroids.Theexactmechanismresponsiblefortheanti-inflammatoryeffectofglucocorticosteroidsis

unknown.

Formoterol

Formoterolisaselective

adrenoceptoragonistthatwheninhaledresultsinrapidandlong-actingrelaxationof

bronchialsmoothmuscleinpatientswithreversibleairwaysobstruction.Thebronchodilatingeffectisdose-dependant,

withanonsetofeffectwithin1 -3minutes.Thedurationofeffectisatleast12hoursafterasingledose.

Budesonide/formoterol

Asthma

Clinicalstudiesinadultshaveshownthattheadditionofformoteroltobudesonideimprovedasthmasymptomsand

lungfunction,andreducedexacerbations.Intwo12-weekstudiestheeffectonlungfunctionofbudesonide/formoterol

wasequaltothatofthefreecombinationofbudesonideandformoterol,andexceededthatofbudesonidealone.All

treatmentarmsusedashort -acting

adrenoceptoragonistasneeded.Therewasnosignofattenuationoftheanti-

asthmaticeffectovertime.

Ina12-weekpaediatric,study85childrenaged6 -11yearsweretreatedwithamaintenancedoseof

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

adrenoceptoragonistasneeded.Lungfunctionwasimproved,andthetreatmentwaswelltoleratedcomparedtothe

correspondingdoseofbudesonidealone.

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

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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.Instudiesthemeanlungdepositionofformoterolafterinhalationviathepowderinhalerrangedfrom28%to

49%ofthedelivereddose.Thesystemicbioavailabilityisabout61%ofthedelivereddose.

Distributionandmetabolism

Plasmaproteinbindingisapproximately50%forformoteroland90%forbudesonide.Volumeofdistributionisabout

4L/kgforformoteroland3L/kgforbudesonide.Formoterolisinactivatedviaconjugationreactions(active

-demethylatedanddeformylatedmetabolitesareformed,buttheyareseenmainlyasinactivatedconjugates).

Budesonideundergoesanextensivedegree(approximately90%)ofbiotransformationonfirstpassagethroughtheliver

tometabolitesoflowglucocorticosteroidactivity.Theglucocorticosteroidactivityofthemajormetabolites,

-beta-hydroxy--udesonideand16-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.

Thepharmacokineticsofbudesonideorformoterolinchildrenandpatientswithrenalfailureareunknown.The

exposureofbudesonideandformoterolmaybeincreasedinpatientswithliverdisease.

5.3Preclinicalsafetydata

Thetoxicityobservedinanimalstudieswithbudesonideandformoterol,givenincombinationorseparately,were

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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)containing60doses..Notallpack-sizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

AstraZenecaUKLimited

600CapabilityGreen

Luton

LU13LU

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

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9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:26November2010

10DATEOFREVISIONOFTHETEXT

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