BUDFOR

Main information

  • Trade name:
  • BUDFOR Powder for Inhalation 200/ 6 Microgram
  • Dosage:
  • 200/ 6 Microgram
  • Pharmaceutical form:
  • Powder for Inhalation
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • BUDFOR Powder for Inhalation 200/6 Microgram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0970/061/002
  • Authorization date:
  • 07-01-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Budfor200micrograms/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

Budforisindicatedintheregulartreatmentofasthma,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

Budforisnotintendedfortheinitialmanagementofasthma.ThedosageofthecomponentsofBudforisindividualand

shouldbeadjustedtotheseverityofthedisease.Thisshouldbeconsiderednotonlywhentreatmentwithcombination

productsisinitiatedbutalsowhenthemaintenancedoseisadjusted.Ifanindividualpatientshouldrequirea

combinationofdosesotherthanthoseavailableinthecombinationinhaler,appropriatedosesof

-adrenoceptor

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Thedoseshouldbetitratedtothelowestdoseatwhicheffectivecontrolofsymptomsismaintained.Patientsshouldbe

regularlyreassessedbytheirprescriber/healthcareprovidersothatthedosageofBudforremainsoptimal.Whenlong-

termcontrolofsymptomsismaintainedwiththelowestrecommendeddosage,thenthenextstepcouldincludeatestof

inhaledcorticosteroidalone.

ForBudfortherearetwotreatmentapproaches:

A.Budformaintenancetherapy:Budforistakenasregularmaintenancetreatmentwithaseparaterapid -acting

bronchodilatorasrescue.

B.Budformaintenanceandrelievertherapy:Budforistakenasregularmaintenancetreatmentandasneededin

responsetosymptoms.

A.Budformaintenancetherapy

Patientsshouldbeadvisedtohavetheirseparaterapid -actingbronchodilatoravailableforrescueuseatalltimes.

Recommendeddoses:

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

twicedaily.

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

Inusualpracticewhencontrolofsymptomsisachievedwiththetwicedailyregimen,titrationtothelowesteffective

dosecouldincludeBudforgivenoncedaily,whenintheopinionoftheprescriber,along-actingbronchodilatorwould

berequiredtomaintaincontrol.

Increasinguseofaseparaterapid-actingbronchodilatorindicatesaworseningoftheunderlyingconditionandwarrants

areassessmentoftheasthmatherapy.

Children(6yearsandolder):Alowerstrengthisavailableforchildren6 -11years.

Childrenunder6years:Asonlylimiteddataareavailable,Budforisnotrecommendedforchildrenyoungerthan6

years.

B.Budformaintenanceandrelievertherapy

PatientstakeadailymaintenancedoseofBudforandinadditiontakeBudforasneededinresponsetosymptoms.

PatientsshouldbeadvisedtoalwayshaveBudforavailableforrescueuse.

Budformaintenanceandrelievertherapyshouldespeciallybeconsideredforpatientswith:

inadequateasthmacontrolandinfrequentneedofrelievermedication.

asthmaexacerbationsinthepastrequiringmedicalintervention.

Closemonitoringfordose-relatedadverseeffectsisneededinpatientswhofrequentlytakehighnumbersofBudfor

-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:Budformaintenanceandrelievertherapyisnotrecommendedforchildren

andadolescents.

COPD

Recommendeddoses:

Adults:2inhalationstwicedaily.

Generalinformation

Specialpatientgroups:

Therearenospecialdosingrequirementsforelderlypatients.TherearenodataavailableforuseofBudforinpatients

withhepaticorrenalimpairment.Asbudesonideandformoterolareprimarilyeliminatedviahepaticmetabolism,an

increasedexposurecanbeexpectedinpatientswithseverelivercirrhosis.

InstructionsforcorrectuseofBudfor:

Theinhalerisinspiratoryflow -driven,whichmeansthatwhenthepatientinhalesthroughthemouthpiece,the

substancewillfollowtheinspiredairintotheairways.

Note:Itisimportanttoinstructthepatient

tocarefullyreadtheinstructionsforuseinthepatientinformationleafletwhichispackedtogetherwitheach

BudforInhaler.

tobreatheinforcefullyanddeeplythroughthemouthpiecetoensurethatanoptimaldoseisdeliveredtothelungs.

nevertobreatheoutthroughthemouthpiece.

toreplacethecoveroftheBudforInhalerafteruse.

torinsetheirmouthoutwithwaterafterinhalingthemaintenancedosetominimisetheriskoforopharyngeal

thrush.Iforopharyngealthrushoccurs,patientsshouldalsorinsetheirmouthwithwateraftertheas-neededinhalations.

ThepatientmaynottasteorfeelanymedicationwhenusingBudforInhalerduetothesmallamountofdrugdispensed.

4.3Contraindications

Hypersensitivity(allergy)tobudesonide,formoterolorlactose(whichcontainssmallamountsofmilkproteins).

4.4Specialwarningsandprecautionsforuse

Itisrecommendedthatthedoseistaperedwhenthetreatmentisdiscontinuedandshouldnotbestoppedabruptly.

Ifpatientsfindthetreatmentineffective,orexceedthehighestrecommendeddoseofBudfor,medicalattentionmustbe

sought(seesection4.2).SuddenandprogressivedeteriorationincontrolofasthmaorCOPDispotentiallylife

threateningandthepatientshouldundergourgentmedicalassessment.Inthissituationconsiderationshouldbegivento

theneedforincreasedtherapywithcorticosteroids,e.g.acourseoforalcorticosteroids,orantibiotictreatmentifan

infectionispresent.

Patientsshouldbeadvisedtohavetheirrescueinhaleravailableatalltimes,eitherBudfor(forasthmapatientsusing

Budforasmaintenanceandrelievertherapy)oraseparaterapid -actingbronchodilator(forallpatientsusingBudforas

maintenancetherapyonly).

PatientsshouldberemindedtotaketheirBudformaintenancedoseasprescribed,evenwhenasymptomatic.The

prophylacticuseofBudfor,e.g.beforeexercise,hasnotbeenstudied.TherelieverinhalationsofBudforshouldbe

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Forsuchuse,aseparaterapid -actingbronchodilatorshouldbeconsidered.

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

1cm)hasbeenobserved.Thisgenerallyoccurswithinthefirstyearoftreatment.

Potentialeffectsonbonedensityshouldbeconsideredparticularlyinpatientsonhighdosesforprolongedperiodsthat

havecoexistingriskfactorsforosteoporosis.Long -termstudieswithinhaledbudesonideinchildrenatmeandaily

dosesof400micrograms(metereddose)orinadultsatdailydosesof800micrograms(metereddose)havenotshown

anysignificanteffectsonbonemineraldensity.NoinformationregardingtheeffectofBudforathigherdosesis

available.

Ifthereisanyreasontosupposethatadrenalfunctionisimpairedfromprevioussystemicsteroidtherapy,careshould

betakenwhentransferringpatientstoBudfortherapy.

Thebenefitsofinhaledbudesonidetherapywouldnormallyminimisetheneedfororalsteroids,butpatients

transferringfromoralsteroidsmayremainatriskofimpairedadrenalreserveforaconsiderabletime.Recoverymay

takeaconsiderableamountoftimeaftercessationoforalsteroidtherapyandhenceoralsteroid-dependentpatients

transferredtoinhaledbudesonidemayremainatriskfromimpairedadrenalfunctionforsomeconsiderabletime.In

suchcircumstancesHPAaxisfunctionshouldbemonitoredregularly.

Theprolongedtreatmentwithhighdosesofinhaledcorticosteroids,particularlyhigherthanrecommendeddoses,may

alsoresultinclinicallysignificantadrenalsuppression.Thereforeadditionalsystemiccorticosteroidcovershouldbe

consideredduringperiodsofstresssuchassevereinfectionsorelectivesurgery.Rapidreductioninthedoseofsteroids

caninduceacuteadrenalcrisis.Symptomsandsignswhichmightbeseeninacuteadrenalcrisismaybesomewhat

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

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Treatmentwithsupplementarysystemicsteroidsorinhaledbudesonideshouldnotbestoppedabruptly.

DuringtransferfromoraltherapytoBudfor,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,Budformaintenanceandrelievertherapyisnotrecommended.

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

adrenoceptoragonistswithdrugswhichcaninducehypokalaemiaorpotentiateahypokalaemiceffect,e.g.xanthine

derivatives,steroidsanddiuretics,mayaddtoapossiblehypokalaemiceffectofthe

adrenoceptoragonist.Particular

cautionisrecommendedinunstableasthmawithvariableuseofrescuebronchodilators,inacutesevereasthmaasthe

associatedriskmaybeaugmentedbyhypoxiaandinotherconditionswhenthelikelihoodforhypokalaemiais

increased.Itisrecommendedthatserumpotassiumlevelsaremonitoredduringthesecircumstances.

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(section4.4).InpatientsusingpotentCYP3A4inhibitors,Budfor

maintenanceandrelievertherapyisnotrecommended.

ThepotentCYP3A4inhibitorketoconazole,200mgoncedaily,increasedplasmalevelsofconcomitantlyorally

administeredbudesonide(singledoseof3mg)onaveragesix-fold.Whenketoconazolewasadministered12hours

afterbudesonidetheconcentrationwasonaverageincreasedonlythree-foldshowingthatseparationofthe

administrationtimescanreducetheincreaseinplasmalevels.Limiteddataaboutthisinteractionforhigh-doseinhaled

budesonideindicatesthatmarkedincreaseinplasmalevels(onaveragefourfold)mayoccurifitraconazole,200mg

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Pharmacodynamicinteractions

Beta -adrenergicblockerscanweakenorinhibittheeffectofformoterol.Budforshouldthereforenotbegiventogether

withbeta -adrenergicblockers(includingeyedrops)unlesstherearecompellingreasons.

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

monoamineoxidaseinhibitorsandtricyclicantidepressantscanprolongtheQTc -ntervalandincreasetheriskof

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

inhaledbudesonide.Inanimalstudiesglucocorticosteroidshavebeenshowntoinducemalformations(seesection5.3).

Thisisnotlikelytoberelevantforhumansgivenrecommendeddoses.

Animalstudieshavealsoidentifiedaninvolvementofexcessprenatalglucocorticoidsinincreasedrisksforintrauterine

growthretardation,adultcardiovasculardiseaseandpermanentchangesinglucocorticoidreceptordensity,

neurotransmitterturnoverandbehaviouratexposuresbelowtheteratogenicdoserange.

Duringpregnancy,Budforshouldonlybeusedwhenthebenefitsoutweighthepotentialrisks.Thelowesteffective

doseofbudesonideneededtomaintainadequateasthmacontrolshouldbeused.

Budesonideisexcretedinbreastmilk.However,attherapeuticdosesnoeffectsonthesucklingchildareanticipated.It

isnotknownwhetherformoterolpassesintohumanbreastmilk.Inrats,smallamountsofformoterolhavebeen

detectedinmaternalmilk.AdministrationofBudfortowomenwhoarebreastfeedingshouldonlybeconsideredifthe

expectedbenefittothemotherisgreaterthananypossiblerisktothechild.

4.7Effectsonabilitytodriveandusemachines

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4.8Undesirableeffects

SinceBudforcontainsbothbudesonideandformoterol,thesamepatternofundesirableeffectsasreportedforthese

substancesmayoccur.Noincreasedincidenceofadversereactionshasbeenseenfollowingconcurrentadministration

ofthetwocompounds.Themostcommondrugrelatedadversereactionsarepharmacologicallypredictablesideeffects

adrenoceptoragonisttherapy,suchastremorandpalpitations.Thesetendtobemildandusuallydisappearwithin

afewdaysoftreatment.Ina3 -yearclinicaltrialwithbudesonideinCOPD,skinbruisesandpneumoniaoccurredata

frequencyof10%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

Veryrare Tastedisturbances

Eyedisorders Veryrare Cataractandglaucoma

Cardiacdisorders Common Palpitations

Uncommon Tachycardia

Rare Cardiacarrhythmias,e.g.atrialfibrillation,

supraventriculartachycardia,extrasystoles

Veryrare Anginapectoris.Prolongationof

-interval

Vasculardisorders Veryrare Variationsinbloodpressure

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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

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.

IfBudfortherapyhastobewithdrawnduetooverdoseoftheformoterolcomponentofthedrug,provisionof

mediastinaldisorders hoarseness

Rare Bronchospasm

Gastrointestinaldisorders Uncommon Nausea

Skinandsubcutaneous

tissuedisorders Uncommon Bruises

Musculoskeletaland

connectivetissue

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Adrenergicsandotherdrugsforobstructiveairwaydiseases.

ATC-code:R03AK07

Mechanismsofactionandpharmacodynamiceffects

Budforcontainsformoterolandbudesonide,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

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

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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

monoproducts.Thedifferenceisconsiderednottohaveanimpactonclinicalsafety.

Study

No.

Duration Treatmentgroups n Severe

exacerbations a

Events Events/

patient-

year

Study

735

6months Budesonide/formoterol160/4.5µgbd+as

needed 1103 125 0.23 b

Budesonide/formoterol320/9µg

bd+terbutaline0.4mgasneeded 1099 173

0.32

Salmeterol/fluticasone2x25/125µgbd+

terbutaline0.4mgasneeded 1119 208 0.38

Study

734

12

months Budesonide/formoterol160/4.5µgbd+as

needed 1107 194

0.19 b

Budesonide/formoterol160/4.5µg

bd+formoterol4.5µgasneeded 1137 296

0.29

Budesonide/formoterol160/4.5µg

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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.

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

Budforisaninspiratoryflowdriven,multidosepowderinhaler.Theinhaleriswhitewithayellowturninggrip.The

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

are1,2,3,10or18inhaler(s)containing60(or120)doses.Notallpack-sizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

AstraZenecaUKLimited

600CapabilityGreen

LutonLU13LU

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA970/61/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:7thJanuary2011

10DATEOFREVISIONOFTHETEXT

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