BUDFOR

Main information

  • Trade name:
  • BUDFOR Powder for Inhalation 400/12 Microgram
  • Dosage:
  • 400/12 Microgram
  • Pharmaceutical form:
  • Powder for Inhalation
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • BUDFOR Powder for Inhalation 400/12 Microgram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0970/061/003
  • Authorization date:
  • 07-01-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Budfor400micrograms/12micrograms/Inhalation,Inhalationpowder

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachdelivereddose(thedosethatleavesthemouthpiece)contains:budesonide320micrograms/inhalationand

formoterolfumaratedihydrate9micrograms/inhalation.

Eachmetereddosecontains:budesonide400micrograms / inhalationandformoterolfumaratedihydrate

12micrograms/inhalation.

Excipient:Lactosemonohydrate491microgramsperdose.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Inhalationpowder

Whitepowder

4CLINICALPARTICULARS

4.1TherapeuticIndications

Asthma

Budforisindicatedintheregulartreatmentofasthmawhereuseofacombination(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

Budforisnotintendedfortheinitialmanagementofasthma.ThedosageofthecomponentsofBudforisindividualand

shouldbeadjustedtotheseverityofthedisease.Thisshouldbeconsiderednotonlywhentreatmentwithcombination

productsisinitiatedbutalsowhenthemaintenancedoseisadjusted.Ifanindividualpatientshouldrequirea

combinationofdosesotherthanthoseavailableinthecombinationinhaler,appropriatedosesof

adrenoceptor

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Recommendeddoses:

Adults(18yearsandolder):1inhalationtwicedaily.Somepatientsmayrequireuptoamaximumof2inhalations

twicedaily.

Adolescents(12 -17years):1inhalationtwicedaily.

Patientsshouldberegularlyreassessedbytheirprescriber/healthcareprovider,sothatthedosageofBudforremains

optimal.Thedoseshouldbetitratedtothelowestdoseatwhicheffectivecontrolofsymptomsismaintained.When

long-termcontrolofsymptomsismaintainedwiththelowestrecommendeddosage,thenthenextstepcouldincludea

testofinhaledcorticosteroidalone.

Inusualpracticewhencontrolofsymptomsisachievedwiththetwicedailyregimen,titrationtothelowesteffective

dosecouldincludeBudforgivenoncedaily,whenintheopinionoftheprescriber,along -actingbronchodilatorwould

berequiredtomaintaincontrol.

Increasinguseofaseparaterapid-actingbronchodilatorindicatesaworseningoftheunderlyingconditionandwarrants

areassessmentoftheasthmatherapy.

Children(6yearsandolder):Alowerstrengthisavailableforchildren6 -11years.

Childrenunder6years:Asonlylimiteddataareavailable,Budforisnotrecommendedforchildrenyoungerthan6

years.

Budfor400micrograms/12micrograms/inhalationshouldbeusedasBudformaintenancetherapyonly.Lower

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

Budformaintenanceandrelievertherapyregimen.

COPD

Recommendeddoses:

Adults:1inhalationtwicedaily.

Generalinformation

Specialpatientgroups:

Therearenospecialdosingrequirementsforelderlypatients.TherearenodataavailableforuseofBudforinpatients

withhepaticorrenalimpairment.Asbudesonideandformoterolareprimarilyeliminatedviahepaticmetabolism,an

increasedexposurecanbeexpectedinpatientswithseverelivercirrhosis.

InstructionsforcorrectuseofBudfor:

Theinhalerisinspiratoryflow-driven,whichmeansthatwhenthepatientinhalesthroughthemouthpiece,the

substancewillfollowtheinspiredairintotheairways.

Note:Itisimportanttoinstructthepatient

tocarefullyreadtheinstructionsforuseinthepatientinformationleafletwhichispackedtogetherwitheach

BudforInhaler.

tobreatheinforcefullyanddeeplythroughthemouthpiecetoensurethatanoptimaldoseisdeliveredtothelungs.

nevertobreatheoutthroughthemouthpiece.

toreplacethecoveroftheBudforInhalerafteruse.

torinsetheirmouthoutwithwaterafterinhalingthemaintenancedosetominimisetheriskoforopharyngeal

thrush.

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4.3Contraindications

Hypersensitivity(allergy)tobudesonide,formoterolorlactose(whichcontainssmallamountsofmilkprotein).

4.4Specialwarningsandprecautionsforuse

Itisrecommendedthatthedoseistaperedwhenthetreatmentisdiscontinuedandshouldnotbestoppedabruptly.

Ifpatientsfindthetreatmentineffective,orexceedthehighestrecommendeddoseofBudfor,medicalattentionmustbe

sought(seesection4.2).Increasinguseofrescuebronchodilatorsindicatesaworseningoftheunderlyingconditionand

warrantsareassessmentoftheasthmatherapy.SuddenandprogressivedeteriorationincontrolofasthmaorCOPDis

potentiallylifethreateningandthepatientshouldundergourgentmedicalassessment.Inthissituation,consideration

shouldbegiventotheneedforincreasedtherapywithcorticosteroids,e.g.acourseoforalcorticosteroids,orantibiotic

treatmentifaninfectionispresent.

Patientsshouldbeadvisedtohaverescueinhaleravailableatalltimes.

PatientsshouldberemindedtotaketheirBudformaintenancedoseasprescribed,evenwhenasymptomatic.

Onceasthmasymptomsarecontrolled,considerationmaybegiventograduallyreducingthedoseofBudfor.Regular

reviewofpatientsastreatmentissteppeddownisimportant.ThelowesteffectivedoseofBudforshouldbeused(see

section4.2).

PatientsshouldnotbeinitiatedonBudforduringanexacerbation,oriftheyhavesignificantlyworseningoracutely

deterioratingasthma.

Seriousasthma -relatedadverseeventsandexacerbationsmayoccurduringtreatmentwithBudfor.Patientsshouldbe

askedtocontinuetreatmentbuttoseekmedicaladviceifasthmasymptomsremainuncontrolledorworsenafter

initiationofBudfor.

Aswithotherinhalationtherapy,paradoxicalbronchospasmmayoccur,withanimmediateincreaseinwheezingand

shortnessofbreathafterdosing.IfthepatientexperiencesparadoxicalbronchospasmBudforshouldbediscontinued

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

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Potentialeffectsonbonedensityshouldbeconsidered,particularlyinpatientsonhighdosesforprolongedperiodsthat

havecoexistingriskfactorsforosteoporosis.Long -termstudieswithinhaledbudesonideinchildrenatmeandaily

dosesof400micrograms(metereddose)orinadultsatdailydosesof800micrograms(metereddose)havenotshown

anysignificanteffectsonbonemineraldensity.NoinformationregardingtheeffectofBudforathigherdosesis

available.

Ifthereisanyreasontosupposethatadrenalfunctionisimpairedfromprevioussystemicsteroidtherapy,careshould

betakenwhentransferringpatientstoBudfortherapy.

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.

DuringtransferfromoraltherapytoBudfor,agenerallylowersystemicsteroidactionwillbeexperiencedwhichmay

resultintheappearanceofallergicorarthriticsymptomssuchasrhinitis,eczemaandmuscleandjointpain.Specific

treatmentshouldbeinitiatedfortheseconditions.Ageneralinsufficientglucocorticosteroideffectshouldbesuspected

if,inrarecases,symptomssuchastiredness,headache,nauseaandvomitingshouldoccur.Inthesecasesatemporary

increaseinthedoseoforalglucocorticosteroidsissometimesnecessary.

Tominimisetheriskoforopharyngealcandidainfection,thepatientshouldbeinstructedtorinsetheirmouthoutwith

waterafterinhalingthemaintenancedose.

Concomitanttreatmentwithitraconazole,ritonavirorotherpotentCYP3A4inhibitorsshouldbeavoided(see

section4.5).Ifthisisnotpossiblethetimeintervalbetweenadministrationoftheinteractingdrugsshouldbeaslongas

possible.

Budforshouldbeadministeredwithcautioninpatientswiththyrotoxicosis,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.Particular

cautionisrecommendedinunstableasthmawithvariableuseofrescuebronchodilators,inacutesevereasthmaasthe

associatedriskmaybeaugmentedbyhypoxiaandinotherconditionswhenthelikelihoodforhypokalaemiais

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Asforall

adrenoceptoragonists,additionalbloodglucosecontrolsshouldbeconsideredindiabeticpatients.

Budforcontainslactosemonohydrate(<1mg/inhalation).Thisamountdoesnotnormallycauseproblemsinlactose

intolerantpeople.Theexcipientlactosecontainssmallamountsofmilkproteins,whichmaycauseallergicreactions.

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.Budforshouldthereforenotbegiventogether

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

ForBudforortheconcomitanttreatmentwithformoterolandbudesonide,noclinicaldataonexposedpregnanciesare

available.Datafromanembryo -fetaldevelopmentstudyintheratshowednoevidenceofanyadditionaleffectfrom

thecombination.

Therearenoadequatedatafromuseofformoterolinpregnantwomen.Inanimalstudies,formoterolhascaused

adverseeffectsinreproductionstudiesatveryhighsystemicexposurelevels(seesection5.3).

Dataonapproximately2000exposedpregnanciesindicatenoincreasedteratogenicriskassociatedwiththeuseof

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Thisisnotlikelytoberelevantforhumansgivenrecommendeddoses.

Animalstudieshavealsoidentifiedaninvolvementofexcessprenatalglucocorticoidsinincreasedrisksforintrauterine

growthretardation,adultcardiovasculardiseaseandpermanentchangesinglucocorticoidreceptordensity,

neurotransmitterturnoverandbehaviouratexposuresbelowtheteratogenicdoserange.

Duringpregnancy,Budforshouldonlybeusedwhenthebenefitsoutweighthepotentialrisks.Thelowesteffective

doseofbudesonideneededtomaintainadequateasthmacontrolshouldbeused.

Budesonideisexcretedinbreastmilk.However,attherapeuticdosesnoeffectsonthesucklingchildareanticipated.It

isnotknownwhetherformoterolpassesintohumanbreastmilk.Inrats,smallamountsofformoterolhavebeen

detectedinmaternalmilk.AdministrationofBudfortowomenwhoarebreastfeedingshouldonlybeconsideredifthe

expectedbenefittothemotherisgreaterthananypossiblerisktothechild.

4.7Effectsonabilitytodriveandusemachines

Budforhasnoornegligibleinfluenceontheabilitytodriveandusemachines.

4.8Undesirableeffects

SinceBudforcontainsbothbudesonideandformoterol,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

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Candidainfectionintheoropharynxisduetodrugdeposition.Advisingthepatienttorinsethemouthoutwithwater

aftereachdosewillminimisetherisk.OropharyngealCandidainfectionusuallyrespondstotopicalanti-fungal

treatmentwithouttheneedtodiscontinuetheinhaledcorticosteroid.

Aswithotherinhalationtherapy,paradoxicalbronchospasmmayoccurveryrarely,affectinglessthan1in

10,000people,withanimmediateincreaseinwheezingandshortnessofbreathafterdosing.Paradoxicalbronchospasm

respondstoarapid-actinginhaledbronchodilatorandshouldbetreatedstraightaway.Budforshouldbediscontinued

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

(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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4.9Overdose

Anoverdoseofformoterolwouldlikelyleadtoeffectsthataretypicalfor

adrenoceptoragonists:tremor,headache,

palpitations.Symptomsreportedfromisolatedcasesaretachycardia,hyperglycaemia,hypokalaemia,prolongedQTc

interval,arrhythmia,nauseaandvomiting.Supportiveandsymptomatictreatmentmaybeindicated.Adoseof90

microgramsadministeredduringthreehoursinpatientswithacutebronchialobstructionraisednosafetyconcerns.

Acuteoverdosagewithbudesonide,eveninexcessivedoses,isnotexpectedtobeaclinicalproblem.Whenused

chronicallyinexcessivedoses,systemicglucocorticosteroideffects,suchashypercorticismandadrenalsuppression,

mayappear.

IfBudfortherapyhastobewithdrawnduetooverdoseoftheformoterolcomponentofthedrug,provisionof

appropriateinhaledcorticosteroidtherapymustbeconsidered.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Adrenergicsandotherdrugsforobstructiveairwaydiseases.

ATC-code:R03AK07

Mechanismsofactionandpharmacodynamiceffects

Budforcontainsformoterolandbudesonide,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

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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

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%

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

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BudesonideiseliminatedviametabolismmainlycatalysedbytheenzymeCYP3A4.Themetabolitesofbudesonideare

eliminatedinurineassuchorinconjugatedform.Onlynegligibleamountsofunchangedbudesonidehavebeen

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

half-lifeafteri.v.dosingaverages4hours.

Thepharmacokineticsofbudesonideorformoterolinchildrenandpatientswithrenalfailureareunknown.The

exposureofbudesonideandformoterolmaybeincreasedinpatientswithliverdisease.

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

Budforisaninspiratoryflowdriven,multidosepowderinhaler.Theinhaleriswhitewithayellowturninggrip.The

inhalerismadeofdifferentplasticmaterials(PP,PC,HDPE,LDPE,LLDPE,PBT).Ineachsecondarypackagethere

are1,2,3,10or18inhaler(s)containing60doses.Notallpack-sizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

AstraZenecaUKLimited

600CapabilityGreen

LutonLU13LU

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 10/04/2012 CRN 2104560 page number: 10

8MARKETINGAUTHORISATIONNUMBER

PA970/61/3

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:7thJanuary2011

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 10/04/2012 CRN 2104560 page number: 11