BUDESITAN 0.5MG/2ML NEBULISER SUSPENSION 0.5mg/2ml Nebuliser Suspension

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
BUDESONIDE
Available from:
Breath Limited
INN (International Name):
BUDESONIDE
Dosage:
0.5mg/2ml
Pharmaceutical form:
Nebuliser Suspension
Authorization status:
Authorised
Authorization number:
PA1831/001/001
Authorization date:
0000-00-00

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Budesitan0.5mg/2mlNebuliserSuspension.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Onemlofsuspensioncontains0.25mgbudesonide.

Oneampouleof2mlsuspensioncontains0.5mgbudesonide.

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Nebulisersuspension

Whitetooff-whitesuspension.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofpersistentbronchialasthmainpatientswhereuseofapressurisedinhalerordrypowderformulationis

unsatisfactoryorinappropriate.

4.2Posologyandmethodofadministration

Routeofadministration:Forinhalationuseonly.

Thedoseshouldbegiventwicedaily.

Administrationoncedailymaybeconsideredincasesofmildtomoderatestableasthma.

Initialdosage:

Theinitialdoseshouldbetailoredtotheseverityofthediseaseandthereaftershouldbeadjustedonanindividualbasis.

Thefollowingdosesarerecommendedbuttheminimumeffectivedoseshouldalwaysbesought:

Childrenaged6monthsandabove:

0.25–1.0mgdaily.Forpatientsinmaintenancetherapywithoralsteroidsahigherinitialdosageupto2.0mgdaily

shouldbeconsidered.

Adults(includingtheelderly)andchildren/adolescentsover12yearsofage:

0.5-2mgdaily.Inveryseverecasesthedosagemaybeincreasedfurther.

Maintenancedose:

Themaintenancedoseshouldbeadjustedtomeettherequirementsoftheindividualpatienttakingaccountofthe

severityofthediseaseandtheclinicalresponseofthepatient.Whenthedesiredclinicaleffecthasbeenobtained,the

maintenancedoseshouldbereducedtotheminimumrequiredforcontrolofthesymptoms.

Childrenaged6monthsandabove:

0.25-1.0mgdaily.

Adults(includingtheelderly)andchildren/adolescentsover12yearsofage:

0.5-2.0mgdaily.Inveryseverecasesthedosemaybefurtherincreased.

Administrationoncedaily:

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maintenancedosebetween0.25mgand1mgbudesonidedaily.Once-dailyadministrationmaybeinitiatedbothin

patientswhoarenotreceivingcorticosteroidtreatmentandinwell-controlledpatientswhoarealreadytakinginhaled

steroids.Thedosemaybegiveninthemorningorevening.Ifaworseningoftheasthmaoccurs,thedailydoseshould

beincreasedbyadministeringthedosetwicedaily.

Onsetofeffect:

Animprovementoftheasthmafollowingadministrationofbudesonidemayoccurwithin3daysafterinitiationof

therapy.Themaximumeffectwillonlybeobtainedafter2-4weeksoftreatment.

Patientsinmaintenancetherapywithoralglucocorticosteroids:

WithBudesitan0.5mg/2mlNebuliserSuspensionitispossibletoreplaceorconsiderablyreducethedoseoforal

glucocorticosteroidsandstillmaintainorimprovethecontrolofasthma.

Initially,ahighdoseofinhaledbudesonideshouldbeadministered.Itmaybeco-administeredwiththepreviouslyused

oralglucocorticosteroidforapproximately10days.Theoraldoseisthenreduced(byforexample2.5mgprednisolone

orequivalentdosepermonth)tothelowestpossiblelevel.Inmanypatientsitispossibletoreplacetheoral

glucocorticosteroidentirelywithinhaledbudesonide.

Whentaperingoffsystemiccorticosteroidssomepatientswillexperiencesteroidwithdrawalsymptoms,e.g.joint

and/ormusclepain,lackofenergyanddepressionorevenadecreasedlungfunction.Suchpatientsmustbeadvisedto

continuetheinhaledbudesonidetherapy,buttheyshouldalsobeexaminedforanyobjectivesignsofadrenocortical

insufficiency.Ifsuchsignsarepresent,thedoseofthesystemiccorticosteroidshouldbetemporarilyincreasedandthen

taperedoffevenmoreslowly.Inperiodsofstressorsevereasthmaattacks,patientsinthetransitionphasemayrequire

treatmentwithsystemiccorticosteroids.

Dosageschedule:

*)Shouldbemixedwith0.9%salinetoavolumeof2ml.

Divisionofthedoseandmiscibility:

Thecontentsofthesingle-dosecontainermaybedividedforadjustmentofthedose.

Halftheampoulecontentsshouldbeplacedinthenebulisercupandmixedwithanequalvolumeof0.9%sodium

chloridesolution.Toensureaccuratedosingtheuseofameasuringsyringeisrecommended.

Budesitan0.5mg/2mlNebuliserSuspensionmaybemixedwith0.9%sodiumchloridesolutionandwithsolutionsfor

inhalationcontainingterbutaline,salbutamol,sodiumcromoglycateoripratropium.

Nebuliser:

Budesitan0.5mg/2mlNebuliserSuspensionmustbeadministeredwithajetnebulisersuppliedwithamouthpieceor

mask.Thenebulisershouldbeconnectedtoanaircompressorwithadequateairflow(5-8l/min),andthefilling

volumeshouldbe2-4ml.

Therecanbevariationintheperformance(dosedelivered)betweennebulizers,eventhoseofthesamemakeand

model.

Note!UltrasoundnebulisersarenotsuitablefornebulisationofBudesitan0.5mg/2mlNebuliserSuspensionand

Dosageinmg VolumeofBudesonide

NebuliserSuspension

0.25

0.75

1ml*

2ml

3ml

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Instructionforuse:

Thespraycontainershouldbeshakenbeforeuse.

Tominimisetheriskoforopharyngealcandidainfection,thepatientshouldrinsetheirmouthoutwithwaterafter

inhaling

Topreventirritationofthefacialskinthefaceshouldbewashedafterusingthenebuliserwithamask.

Thenebulisershouldbecleanedaftereachuse.

Washthenebulisercontainerandmouthpieceorface-maskinwarmwaterusingamilddetergentinaccordancewith

themanufacturer’sinstructions.Rinsewellanddryitbyconnectingthenebulisercontainertothecompressorortheair

inlet.

4.3Contraindications

Hypersensitivitytobudesonideoranyoftheexcipients.

4.4Specialwarningsandprecautionsforuse

Budesitan0.5mg/2mlNebuliserSuspensionisnotindicatedforthetreatmentofacutedyspnoeaorstatusasthmaticus.

Theseconditionsshouldbetreatedwithshortacting-sympathomimeticsandotherbronchodilators.

Thetransferofpatientstreatedwithoralcorticosteroidstotheinhaledcorticosteroidandtheirsubsequentmanagement

requiresspecialcare.Thepatientsshouldbeinareasonablystablestatebeforeinitiatingahighdoseofinhaled

corticosteroidinadditiontotheirusualmaintenancedoseofsystemiccorticosteroid.Afterabout10days,withdrawal

ofthesystemiccorticosteroidisstartedbyreducingthedailydosegradually(byforexample2.5milligrams

prednisoloneortheequivalenteachmonth)tothelowestpossiblelevel.Itmaybepossibletocompletelyreplacethe

oralcorticosteroidwithinhaledcorticosteroid.

Patientswhohaverequiredhighdoseemergencycorticosteroidtherapyorprolongedtreatmentatthehighest

recommendeddoseofinhaledcorticosteroids,mayalsobeatriskofimpairedadrenalfunction.Thesepatientsmay

exhibitsignsandsymptomsofadrenalinsufficiencywhenexposedtoseverestress.Additionalsystemiccorticosteroid

treatmentshouldbeconsideredduringperiodsofstressorelectivesurgery..

Duringtransferfromoraltherapytoinhaledbudesonide,symptomsmayappearthathadpreviouslybeensuppressedby

systemictreatmentwithglucocorticosteroids,forexamplesymptomsofallergicrhinitis,eczema,muscleandjoint

pain.Specifictreatmentshouldbeco-administeredtotreattheseconditions.

Somepatientsmayfeelunwellinanon-specificwayduringthewithdrawalofsystemiccorticosteroidsdespite

maintenanceorevenimprovementinrespiratoryfunction.Suchpatientsshouldbeencouragedtocontinuetreatment

withinhaledbudesonideandwithdrawaloforalcorticosteroidunlessthereareclinicalsignstoindicatethecontrary,for

examplesignswhichmightindicateadrenalinsufficiency.

Aswithotherinhalationtherapiesparadoxicalbronchospasmmayoccur,manifestedbyanimmediateincreasein

wheezingandshortnessofbreathafterdosing.Paradoxicalbronchospasmrespondstoarapid-actinginhaled

bronchodilatorandshouldbetreatedstraightaway.Budesonideshouldbediscontinuedimmediately,thepatient

shouldbeassessedand,ifnecessary,alternativetreatmentinstituted.

Whenanacuteepisodeofdyspnoeaoccursdespiteawellmonitoredtreatment,arapid-actinginhaledbronchodilator

shouldbeusedandmedicalreassessmentshouldbeconsidered.Ifdespitemaximumdosesofinhaledcorticosteroids,

asthmasymptomsarenotadequatelycontrolled,patientsmayrequireshort-termtreatmentwithsystemic

corticosteroids.Insuchcases,itisnecessarytomaintaintheinhaledcorticosteroidtherapyinassociationwith

treatmentbythesystemicroute.

Systemiceffectsofinhaledcorticosteroidsmayoccur,particularlyathighdosesprescribedforprolongedperiods.

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syndrome,Cushingoidfeatures,adrenalsuppression,growthretardationinchildrenandadolescents,decreaseinbone

mineraldensity,cataract,glaucomaandmorerarely,arangeofpsychologicalorbehaviouraleffectsincluding

psychomotorhyperactivity,sleepdisorders,anxiety,depressionoraggression(particularlyinchildren).Itisimportant,

therefore,thatthedoseofinhaledcorticosteroidistitratedtothelowestdoseatwhicheffectivecontrolofasthmais

maintained.

Itisrecommendedthattheheightofchildrenreceivingprolongedtreatmentwithinhaledcorticosteroidsisregularly

monitored.Ifgrowthisslowed,therapyshouldbereviewedwiththeaimofreducingthedoseofinhaled

corticosteroid,ifpossible,tothelowestdoseatwhicheffectivecontrolofasthmaismaintained.Inaddition,

considerationshouldbegiventoreferringthepatienttoapaediatricrespiratoryspecialist.

Patientswhohavepreviouslybeendependentonoralcorticosteroidsmay,asaresultofprolongedsystemic

corticosteroidtherapy,experienceeffectsofimpairedadrenalfunction.Recoverymaytakeaconsiderableamountof

timeaftercessationoforalcorticosteroidtherapyandhenceoralsteroid-dependentpatientstransferredtobudesonide

mayremainatriskfromimpairedadrenocorticalfunctionforsomeconsiderabletime.Insuchcircumstances

hypothalamicpituitaryadrenocortical(HPA)axisfunctionshouldbemonitoredregularly.

Oralcandidiasismayoccurduringthetherapywithinhaledcorticosteroids.Thisinfectionmayrequiretreatmentwith

appropriateantifungaltherapyandinsomepatientsdiscontinuationoftreatmentmaybenecessary(seealsosection

4.2).

Exacerbationofclinicalsymptomsofasthmamaybeduetoacuterespiratorytractbacterialinfectionsandtreatment

withappropriateantibioticsmayberequired.Suchpatientsmayneedtoincreasethedoseofinhaledbudesonideanda

shortcourseoforalcorticosteroidsmayberequired.Arapid-actinginhaledbronchodilatorshouldbeusedas“rescue”

medicationtorelieveacuteasthmasymptoms.

Specialcareandadequatespecifictherapeuticcontrolofpatientswithactiveandquiescentpulmonarytuberculosisis

necessarybeforecommencingtreatmentwithinhaledbudesonide.Similarlypatientswithfungal,viralorother

infectionsoftheairwaysrequirecloseobservationandspecialcareandshouldusebudesonideonlyiftheyarealso

receivingadequatetreatmentforsuchinfections.

Inpatientswithexcessivemucoussecretionintherespiratorytract,short-termtherapywithoralcorticosteroidsmaybe

necessary.

Inpatientswithseverehepaticdysfunction,treatmentwithinhaledbudesonidecanresultinareducedeliminationrate

andhenceenhancedsystemicavailability.PossiblesystemiceffectsmaythenresultandthereforeHPAaxisfunctionin

thesepatientsshouldbemonitoredatregularintervals.

Concomitanttreatmentwithketoconazole,HIVproteaseinhibitorsorotherpotentCYP3A4inhibitorsshouldbe

avoided(seesection4.5).Ifthisisnotpossiblethetimeintervalbetweenadministrationofthetwodrugsshouldbeas

longaspossible.

RecentepidemiologicalstudiesshowthatthereisanincreasedincidenceofpneumoniainpatientswithChronic

ObstructivePulmonaryDisease(COPD)treatedwithinhaledcorticosteroids,withanadjustedoddsratioof1.7

(Reference).Careshouldbeexercisedinprescribingbudesonideforthosepatientswhoserespiratorydiseasemight

haveacomponentofCOPD.

Budesitan0.5mg/2mlNebuliserSuspensionshouldbeusedwithajetnebuliserdevice.Anultrasonicnebulisershould

notbeusedasthisisnotappropriatefornebulisersuspensions.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Budesitan0.5mg/2mlNebuliserSuspensioncanincreasetheefficacyofinhaledbeta-2-sympathomimetics.

ThemetabolismofbudesonideisprimarilymediatedbyCYP3A4.Inhibitorsofthisenzyme,e.g.,ketoconazoleand

itraconazole,canthereforeincreasesystemicexposuretobudesonideseveraltimes,seesection4.4.Sincethereareno

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treatmentsshouldbeaslongaspossibleandareductionofthebudesonidedosecouldalsobeconsidered.Limited

dataaboutthisinteractionforhigh-doseinhaledbudesonideindicatethatmarkedincreasesinplasmalevels(onaverage

four-fold)mayoccurifitraconazole,200mgoncedaily,isadministeredconcomitantlywithinhaledbudesonide

(singledoseof1000µg).

OtherpotentCYP3A4inhibitorssuchaserythromycin,clarithromycin,itraconazole,ketoconazole,ritonavirand

saquinavirarealsolikelytomarkedlyincreaseplasmaconcentrationsofbudesonide.

Cimetidinehadaweakbutclinicallyinsignificantinhibitingeffectonhepaticmetabolismofbudesonide.

Raisedplasmaconcentrationsofandenhancedeffectsofcorticosteroidshavebeenobservedinwomenalsotreated

withoestrogensandcontraceptivesteroids,butnoeffecthasbeenobservedwithbudesonideandconcomitantintakeof

lowdosecombinationoralcontraceptives.

Thesuppressiveeffectonadrenalfunctionisadditiveifusedconcomitantlywithsystemicorintranasalsteroids.

Becauseadrenalfunctionmaybesuppressed,anACTHstimulationtestfordiagnosingpituitaryinsufficiencymight

showfalseresults(lowvalues).

4.6Fertility,pregnancyandlactation

Pregnancy

Resultsfromalargeprospectiveepidemiologicalstudyandfromworld-widepostmarketingexperienceindicatethat

inhaledbudesonideduringpregnancyhasnoadverseeffectsonthehealthofthefoetus/newbornchild.

Aswithotherdrugstheadministrationofbudesonideduringpregnancyrequiresthatthebenefitsforthemotherare

weighedagainsttherisksforthefoetus.

Breastfeeding

Budesonideisexcretedinbreastmilk.However,attherapeuticdosesofbudesonidenoeffectsonthesucklingchildare

anticipated.Budesonidecanbeusedduringbreastfeeding.

Maintenancetreatmentwithinhaledbudesonide(200or400microgramstwicedaily)inasthmaticnursingwomen

resultsinnegligiblesystemicexposuretobudesonideinbreast-fedinfants.

Inapharmacokineticstudy,theestimateddailyinfantdosewas0.3%ofthedailymaternaldoseforbothdoselevels,

andtheaverageplasmaconcentrationininfantswasestimatedtobe1/600thoftheconcentrationsobservedinmaternal

plasma,assumingcompleteinfantoralbioavailability.Budesonideconcentrationsininfantplasmasampleswereall

lessthanthelimitofquantification.

BasedondatafrominhaledbudesonideandthefactthatbudesonideexhibitslinearPKpropertieswithinthetherapeutic

dosageintervalsafternasal,inhaled,oralandrectaladministrations,attherapeuticdosesofbudesonide,exposuretothe

sucklingchildisanticipatedtobelow.

4.7Effectsonabilitytodriveandusemachines

Inhaledbudesonidehasnoornegligibleinfluenceontheabilitytodriveandusemachines.

4.8Undesirableeffects

Tabulatedlistofadversereactions

Thefollowingdefinitionsapplytotheincidenceofundesirableeffects:Verycommon(1/10);common(1/100,

<1/10);uncommon(1/1,000,<1/100);rare(1/10,000,<1/1,000);veryrare(<1/10,000),notknown(cannotbe

estimatedfromtheavailabledata).

Infectionsand

infestations Common Oropharyngealcandidiasis

Immunesystemdisorders Rare Immediateanddelayedhypersensitivity

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*refertoDescriptionofselectedadversereactions:facialskinirritation,below

**refertoPaediatricpopulation,below

Descriptionofselectedadversereactions

Facialirritation,asanexampleofahypersensitivityreaction,hasoccurredinsomecaseswhenanebuliserwithaface

maskhasbeenused.Topreventirritationthefacialskinshouldbewashedwithwaterafteruseofthefacemask.

ThereisanincreasedriskofpneumoniainpatientswithnewlydiagnosedCOPDstartingtreatmentwithinhaled

corticosteroids.Howeveraweightedassessmentof8pooledclinicaltrialsinvolving4643COPDpatientstreatedwith

budesonideand3643patientsrandomizedtonon-ICStreatmentsdidnotdemonstrateanincreasedriskforpneumonia.

Theresultsfromthefirst7ofthese8trialshavebeenpublishedasameta-analysis.

Treatmentwithinhaledbudesonidemayresultincandidainfectionintheoropharynx.Experiencehasshownthat

candidainfectionoccurslessoftenwheninhalationisperformedbeforemealsand/orwhenthemouthisrinsedafter

inhalation.Inmostcasesthisconditionrespondstotopicalanti-fungaltherapywithoutdiscontinuingtreatmentwith

inhaledbudesonide.

Coughingcanusuallybepreventedbyinhalingabeta-2agonist(e.g.terbutaline)5-10minutesbeforeadministrationof

Budesitan0.5mg/2mlNebuliserSuspension.

Systemiceffectsofinhaledcorticosteroidsmayoccur,particularlyathighdosesprescribedforprolongedperiods.

Thesemayincludeadrenalsuppression,growthretardationinchildrenandadolescents,decreaseinbonemineral

density,cataractandglaucoma,andsusceptibilitytoinfections.Theabilitytoadapttostressmaybeimpaired.The

systemiceffectsdescribed,however,aremuchlesslikelytooccurwithinhaledbudesonidethanwithoral

corticosteroids.

Paediatricpopulation

Duetotheriskofgrowthretardationinthepaediatricpopulation,growthshouldbemonitoredasdescribedinsection

urticaria,angioedemaandanaphylactic

reaction.

Endocrinedisorders Rare Signsandsymptomsofsystemic

corticosteroideffects,includingadrenal

suppressionandgrowthretardation**

Eyedisorders Notknown Cataracts,glaucoma

Psychiatricdisorders Rare Restlessness,nervousness,depression,

behaviouralchanges(predominantlyin

children)

Notknown Sleepdisorders,anxiety,psychomotor

activity,aggression,

Respiratory,thoracicand

mediastinaldisorders Common Hoarseness,cough,throatirritation

Rare Bronchospasm

Gastrointestinaldisorders Common Oralmucosalirritation,difficultyin

swallowing

Skinandsubcutaneous

disorders Rare Bruising,skinreactions,pruritus,erythema

Musculoskeletaland

connectivetissue

disorders Rare Growthretardation

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4.9Overdose

Symptoms:

Acuteoverdosewithbudesonideusuallydoesnotconstituteaclinicalproblem.Theonlyharmfuleffectafteralarge

amountofspraysduringashortperiodisasuppressionofthecortexfunction.

Ifitisamatterofchronicuseofveryhighdoses,effectssuchasadegreeofcortexatrophyinadditionto

adrenocorticalsuppressionmayoccur.

Treatment:

Acuteoverdosage:Thereisnoneedforacutemeasures.Thetreatmentwithbudesonideshouldbecontinuedwiththe

lowestpossibleeffectivemaintenancedose,andtheadrenocorticalfunctionwillrepairitselfautomaticallywithin1-2

days.

Chronicoverdosage:Thepatientshouldbetreatedasasteroiddependentandbetransferredtoasuitablemaintenance

dosewithasystemicsteroid,forexampleprednisolone.Whentheconditionisstabilized,thepatientshouldcontinue

thetreatmentwiththeinhalationofbudesonideattherecommendeddose.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Otherdrugsforobstructiveairwaysdiseases,inhalant,Glucocorticoids

ATCcode:R03BA02

Budesonideisaglucocorticosteroidwithapowerfullocalanti-inflammatoryaction.

Theprecisemechanismofactionofglucocorticosteroidsinthetreatmentofasthmaisnotfullyunderstood.Anti-

inflammatoryeffects(includingT-cells,eosinophiliccellsandmastcells)suchasinhibitionofthereleaseof

inflammatorymediatorsandinhibitionofcytokine-mediatedimmuneresponse,areprobablyimportant.Thestrengthof

budesonide,measuredasaffinityforglucocorticoidreceptors,isapproximately15timesstrongerthanthatof

prednisolone.

Aclinicaltrialwithasthmapatientsinwhichinhaledandoralbudesonidewascomparedwithplacebo,showed

statisticallysignificanteffectsofinhaledbudesonide,butnotoforalbudesonide.Thetherapeuticeffectofnormally

useddosesofinhaledbudesonidemaythereforechieflybeexplainedbyadirecteffectontheairways.

Budesonidehasdemonstratedananti-anaphylacticandanti-inflammatoryeffectinchallengetestsinexperimental

animalsandinpatients.Thiseffecthasmanifesteditselfasreducedbronchialobstructioninboththeimmediateandthe

laterallergicreaction.

Itwasalsodemonstratedthatbudesonidereducestheairways’reactivitytohistamineandmetacholineinhyperreactive

patients.Treatmentwithinhaledbudesonidehasbeenusedtoeffectivelypreventexercise-inducedasthma.

InrecommendeddosesBudesonideNebuliserSuspensionhasasignificantlysmallerinfluenceontheadrenalfunction

than10mgprednisone,shownbytheACTHtest.Noclinicallyrelevantchangesintheplasmacortisolvaluesor

responsetoACTHstimulationwereobservedwhenbudesonidewasgivenindosesupto1600µgdailyfor3monthsto

adultsandupto800µgdailytochildren.Long-termmonitoringforupto52weeksconfirmedthattheHPAaxiswas

notsuppressed.

Bothasthmaandinhaledglucocorticosteroidsmayaffectthegrowthinlength.TheeffectofBudesonideNebuliser

Suspensiononthegrowthinlengthwasstudiedin519children(from8monthsto9years)inthreeprospective,

randomised,open,non-blindedstudies.Thestudiesdidnotshowanysignificantdifferenceinthegrowthinlengthof

childrentreatedeitherwithBudesonideNebuliserSuspensionorwithconventionalasthmatherapy.Twostudies(N=

239and72patients,respectively)showed7mmand8mmgreatergrowthafteroneyearoftreatmentwithBudesonide

NebuliserSuspensioncomparedwithtraditionalasthmatherapy(notstatisticallysignificant),whileonestudy(N=

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thaninthegroupofconventionalasthmatreatment(statisticallysignificantdifference).

5.2Pharmacokineticproperties

Absorption:

InadultsthesystemicbioavailabilityofbudesonidefollowingadministrationofBudesonideNebuliserSuspensionviaa

jetnebuliserisapproximately15%ofthedeclareddoseand40-70%ofthedosedeliveredtothepatient.Asmallpart

ofthesystemicallyavailabledosecomesfrominhalationsuspensionthatisswallowed.Thepeakplasmaconcentration

followingadministrationofasingledoseof2mgisachieved10-30minutesafterthebeginningofinhalationandis

approximately4nmol/l.Inchildren(4-6years),thesystemicbioavailabilityofbudesonideafteradministrationof

BudesonideNebuliserSuspensionviaajetnebuliserisapproximately6%ofthedeclareddoseand26%ofthedose

administeredtothepatient.Thepeakplasmaconcentrationfollowingadministrationofasingledoseof1mgis

reachedapproximately20minutesafterthebeginningofinhalationandisapproximately2.4nmol/l.

Distribution:

Thevolumeofdistributioninadultsisapproximately3l/kg.Plasmaproteinbindingisapproximately85-90%.

Metabolism:

Budesonideundergoesextensive(~90%)firstpassbiotransformationintheliverviaCYP3A4tometaboliteswitha

lowglucocorticosteroidactivity.Thein-vitroactivityofthemainmetabolites,6--hydroxybudesonideand16--

hydroxyprednisolone,islessthan1%ofthatofbudesonide.

Excretion:

Themetabolitesareexcretedinunchangedorconjugatedformpredominantlyviathekidneys.Nounchanged

budesonideisfoundintheurine.Budesonidehasahighsystemicclearance(approximately1.2litres/min)inhealthy

adults,andtheeliminationhalf-lifefollowingintravenousadministrationisapproximately2-3hours.Budesonidehasa

systemicclearanceofapproximately0.5l/minin4to6-year-oldasthmaticchildren.Childrenhaveanapproximately50

%higherclearanceperkgbodyweightthanadults.Thehalf-lifeofbudesonidefollowinginhalationisabout2.3hours

inasthmaticchildren,whichisroughlythesameasinhealthyadults.

5.3Preclinicalsafetydata

Preclinicaldatarevealednospecialhazardforhumansinthetherapeuticdoserangebasedonstudiesofchronic

toxicity,genotoxicityandcarcinogenicity.

Glucocorticoids,includingbudesonide,haveproducedteratogeniceffectsinanimals,includingcleftpalateandskeletal

abnormalities.Similareffectsareconsideredunlikelytooccurinhumansattherecommendeddoselevels.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Disodiumedetate

Sodiumchloride

Polysorbate80

Citricacid

Sodiumcitrate

Waterforinjection

6.2Incompatibilities

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6.3Shelflife

3years.

Afterfirstopeningofthefoilsachet,theampoulemaybestoredunopenedforthreemonths.

Useampoulewithin12hoursofopening.

6.4Specialprecautionsforstorage

Storeintheoriginalpackageinordertoprotectfromlightandmoisture.

6.5Natureandcontentsofcontainer

Lowdensitypolyethyleneampoulecontaining2mlnebulisersuspension.

Packsizes:Tri-laminatefoilsachetscontaining5,20,24,40(2x20)and60ampoules(instripsof4,5,8,10or12

ampoules).

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Budesonidenebulisersuspensioncanbemixedwith0.9%salineandwithsolutionsofterbutaline,salbutamol,sodium

chromoglycate,oripratropiumbromide.

Forsingleuseonly.Anyunusedsolutionshouldbediscarded.

7MARKETINGAUTHORISATIONHOLDER

BreathLimited

WhiddonValley,

Barnstaple,

Devon

EX328NS

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA1831/001/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:21October2005

Dateoflastrenewal:24February2009

10DATEOFREVISIONOFTHETEXT

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