DUOVENT UNIT DOSE VIALS

Main information

  • Trade name:
  • DUOVENT UNIT DOSE VIALS
  • Dosage:
  • 0.5mg/1.25 Mg/Dose
  • Pharmaceutical form:
  • Nebuliser Solution
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • DUOVENT UNIT DOSE VIALS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0007/034/004
  • Authorization date:
  • 04-12-1993
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

DuoventUDVs0.5mg/1.25mgper4mlNebuliserSolution

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Each4mlsingledoseunitcontains0.5mgofipratropiumbromide(asmonohydrate)and1.25mgoffenoterol

hydrobromide.

Forafulllistofexcipients,seeSection6.1.

3PHARMACEUTICALFORM

Nebulisersolution

Aclear,colourlessoralmostcolourlesssolution,freefromsuspendedparticles.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Themanagementofacutesevereasthmaorreversibleobstructiveairwaysdisordersrequiringtreatmentbynebuliser,in

patientswhohavenotrespondedsufficientlywelltoanticholinergictherapyorinsituationswherethebeta

agonist

alonehasproducedunacceptablelevelsofsideeffects.

4.2Posologyandmethodofadministration

Adults:

Therecommendeddoseforadultsandchildrenover14yearsisonevial(4ml)threeoratmaximumfourtimesdaily.

Children:

Useinchildrenbelowtheageof14yearsisnotrecommended.

Useinchildrenshouldbesupervisedbyaresponsibleadult.

Thedoseofnebulisersolutionmayneedtobedilutedinordertoobtainafinalvolumesuitablefortheparticular

nebuliserbeingused;ifdilutionisnecessaryuseonlysterilesodiumchloride0.9%solution.

4.3Contraindications

Hypertrophicobstructivecardiomyopathy,tachyarrhythmia.Hypersensitivitytofenoterolhydrobromideoratropine-

likesubstancesortoanyoftheexcipientsoftheproduct.

4.4Specialwarningsandprecautionsforuse

Itisdangeroustoexceedtherecommendeddose.

Inthecaseofacute,rapidlyworseningdyspnoea(difficultyinbreathing)adoctorshouldbeconsultedimmediately.

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evaluatedfortheadditionortheincreaseofanti-inflammatorytherapy(e.g.inhaledcorticosteroids)tocontrolairway

inflammationandtopreventdeteriorationofdiseasecontrol.

Theuseofincreasingamountsofbeta

-agonistcontainingproductssuchasDuoventonaregularbasistocontrol

symptomsofbronchialobstructionmaysuggestdecliningdiseasecontrol.Ifbronchialobstructiondeterioratesitis

inappropriateandpossiblyhazardoustosimplyincreasetheuseofbeta

-agonistcontainingproductssuchasDuovent,

beyondtherecommendeddoseoverextendedperiodsoftime.Inthissituation,thepatient'stherapyplan,andin

particulartheadequacyofanti-inflammatorytherapywithinhaledcorticosteroidsshouldbereviewedtoprevent

potentiallylifethreateningdeteriorationofdiseasecontrol.

OthersympathomimeticbronchodilatorsshouldonlybeusedwithDuoventundermedicalsupervision.

InthefollowingconditionsDuoventshouldonlybeusedaftercarefulrisk/benefitassessment,especiallywhendoses

higherthanrecommendedareused:Insufficientlycontrolleddiabetesmellitus,myocardialinsufficiency,angina,

cardiacdysrhythmias,hypertensionrecentmyocardialinfarction,hypertrophicsubvalvularaorticstenosis,severe

organicheartorvasculardisorders,hyperthyroidism,phaeochromocytoma.

Cardiovasculareffectsmaybeseenwithsympathicomimeticdrugs,includingDUOVENT.Thereissomeevidence

frompost-marketingdataandpublishedliteratureofrareoccurrencesofmyocardialischaemiaassociatedwithbeta-

agonists.Patientswithunderlyingsevereheartdisease(e.g.ischaemicheartdisease,arrhythmiaorsevereheartfailure)

whoarereceivingDUOVENT,shouldbewarnedtoseekmedicaladviceiftheyexperiencechestpainorother

symptomsofworseningheartdisease.Attentionshouldbepaidtoassessmentofsymptomssuchasdyspnoeaandchest

pain,astheymaybeeitherrespiratoryorcardiacorigin.

Potentiallyserioushypokalaemiamayresultfrombeta

-agonisttherapy.

Duoventshouldbeusedwithcautioninpatientswithprostatichyperplasiaorbladderneckobstructionorpredisposed

toorwithnarrow-angleglaucoma.

Usersmustbeadequatelyinstructedinthecorrectmethodofuseofthenebuliserandthemedication.Careshouldbe

takentopreventthesolutionormistfromenteringtheeyes.Itisrecommendedthatthenebulisedsolutionbe

administeredviaamouthpiece.Ifthisisnotavailableandanebulisermaskisused,itmustfitproperly.Patientswho

maybepredisposedtoglaucomashouldbewarnedspecificallytoprotecttheireyes.

Therehavebeenisolatedreportsofocularcomplications(i.e.mydriasis,increasedintraocularpressure,narrow-angle

glaucoma,eyepain)whenaerosolisedipratropiumbromideeitheraloneorincombinationwithanadrenergicbeta

agonist,wassprayedintotheeyes.

Eyepainordiscomfort,blurredvision,visualhalosorcolouredimagesinassociationwithredeyesfromconjunctival

congestionandcornealoedemamaybesignsofacutenarrow-angleglaucoma.Shouldanycombinationofthese

symptomsdevelop,treatmentwithmioticdropsshouldbeinitiatedandspecialistadvicesoughtimmediately.

Patientswithcysticfibrosismaybemorepronetogastro-intestinalmotilitydisturbances.

Ipratropiumbromidemaycausereducedsalivationleadingtodrymouth.

ImmediatehypersensitivityreactionsmayoccurafteradministrationofDUOVENT,asdemonstratedbyrarecasesof

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Otherbeta-adrenergicsandanticholinergicsandxanthinederivatives(suchastheophylline)mayenhancethe

bronchodilatoryeffect.Theconcurrentadministrationofotherbeta-mimetics,systemicallyavailableanticholinergics

andxanthinederivatives(e.g.theophylline)mayincreasetheadversereactions.

ß-adrenergicblockingagentsmayantagonisefenoterolhydrobromideandpotentiallyseriouslyreducethe

bronchodilatoreffectifadministeredconcurrently.

Beta-agonistinducedhypokalaemiamaybeincreasedbyconcomitanttreatmentwithxanthinederivatives,

corticosteroidsanddiuretics.Thisshouldbetakenintoaccountparticularlyinpatientswithsevereairwayobstruction.

Hypokalaemiamayresultinanincreasedsusceptibilitytoarrhythmiasinpatientsreceivingdigoxin.Additionally,

hypoxiamayaggravatetheeffectofhypokalaemiaoncardiacrhythm.Itisrecommendedthatserumpotassiumlevels

aremonitoredinsuchsituations.

Inthosepatientsreceivingsympathomimeticaminesandmonoamineoxidaseinhibitorsortricyclicantidepressants,the

productshouldbeadministeredwithcare.

Inhalationofhalogenatedhydrocarbonanaestheticssuchashalothane,trichloroethyleneandenfluranemayincreasethe

susceptibilitytothecardiovasculareffectsofbeta-agonists.

4.6Fertility,pregnancyandlactation

Thisproductshouldbeusedduringpregnancyonlyifconsideredessentialbythephysician.

Beta-adrenergicagentshavebeenshowntoprolongpregnancyandinhibitlabour.Theinhibitoryeffectoffenoterol

hydrobromideonuterinecontractionshouldbetakenintoaccount.

Preclinicalstudieshaveshownthatfenoterolhydrobromideissecretedinbreastmilk.Itisnotknownwhether

ipratropiumisexcretedintobreastmilk.Itisunlikelythatipratropiumwouldreachtheinfanttoanimportantextent,

howevercautionshouldbeexercisedwhenDUOVENTisadministeredtoanursingwoman.

4.7Effectsonabilitytodriveandusemachines

Nonestated.

4.8Undesirableeffects

Thefollowingsideeffectshavebeenreported.Thefrequenciesgivenbelowarebasedonclinicaltrialsinvolving2009

patientswhohavebeentreatedwithfenoterolandipratropiumcombinations.

Frequencies

Verycommon ≥1/10

Common ≥1/100<1/10

Uncommon ≥1/1,000<1/100

Rare ≥1/10,000<1/1000

Veryrare <1/10,000

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Immunesystemdisorders

Metabolismandnutritiondisorders

Hypokalaemia NotKnown

Psychiatricdisorders

NervousSystemDisorders

EyeDisorders

CardiacDisorders

Respiratory,ThoracicandMediastinalDisorders

Gastro-intestinalDisorders

Anaphylacticreaction (1)

Rare (1)

Allergictypereactions Rare

Angio-oedemaoftongue,lips,andface NotKnown

Psychologicalalterations Rare

Nervousness Rare

Headache Rare

Dizziness Rare

FineTremor Rare

NarrowangleGlaucoma (2) Rare

Ocularaccommodationdisturbances NotKnown

Increasedintraocularpressure (2) NotKnown

Eyepain (2) NotKnown

Mydriasis (2) NotKnown

Tachycardia,increasedheartrate Uncommon

Arrhythmias Uncommon

Atrialfibrillation Rare

Palpitations Rare

SupraventricularTachycardia Notknown

Decreaseindiastolicbloodpressure NotKnown

Increaseinsystolicbloodpressure NotKnown

Myocardialischaemia NotKnown

Cough

Common (3)

LocalIrritation

-Pharyngitis

Common (3)

-Throatirritation

Rare (3)

Laryngospasm (1)

Rare (1)

Inhalationinducedbronchospasm NotKnown

Drynessofmouth Uncommon

Nausea Uncommon

Gastro-intestinalmotilitydisturbances (4) Uncommon

Skinreactions Uncommon

Skinrash Rare

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MusculosceletalandConnectiveTissueDisorders

RenalandUrinaryDisorders

UrinaryRetention Rare

Observedintrialswiththemono-compoundipratropiumbromide

Therehavebeenisolatedreportsofocularcomplications(i.e.mydriasis,increasedintra-ocularpressure,narrow

angleglaucoma,eyepain)whenaerosolizedipratopiumbromideeitheraloneorincombinationwithanadrenergic

beta

-agonistwassprayedintotheeyes–seesection4.4.

verumfrequencyonlyforlocalsideeffects

e.g.constipation,diarrhoea,vomiting

4.9Overdose

Symptoms

Theeffectsofoverdosageareexpectedtobeprimarilyrelatedtofenoterol.Theexpectedsymptomswithoverdosage

arethoseofexcessivebeta-adrenergic-stimulation,themostprominentbeingtachycardia,palpitation,hypertension,

hypotension,wideningofthepulsepressure,anginalpain,arrhythmias,flushing,nausea,restlessness,dizziness,

headacheandtremor.Hypokalaemiamayoccurfollowingoverdosagewithfenoterol.Serumpotassiumlevelsshould

bemonitored.

Expectedsymptomsofoverdosagewithipratropiumbromide(suchasdrymouth,visualaccommodationdisorder)are

mildbecausethesystemicavailablilityofinhaledipratropiumisverylow.

Therapy

Theadministrationofsedatives/tranquillisersmaybenecessary,however,shouldonlybeperformedwhere

resuscitationequipmentisavailableduetotheriskofrespiratorydepression.Inseverecasesintensivetherapyinan

appropriateunitmaybenecessary.

Beta-selectivebeta-adrenergicblockingagentsshouldbechosenandbloodpressureshouldbemonitored.Shouldthe

administrationofabeta-adrenergicblockingagentbeconsiderednecessarytocounteracttheeffectsofoverdosage,its

useinapatientliabletobronchospasmshouldbecarefullymonitoredbecauseoftheriskofprecipitatingsevere

bronchospasm,whichmaybefatal.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

DUOVENTcontainstwoactivebronchodilatingingredients:ipratropiumbromide,exhibitingananticholinergiceffect

andfeneterolhydrobromideabeta-adrenergicagent.

Ipratropiumbromideisaquaternaryammoniumcompoundwithanticholinergic(parasympatholytic)properties.In

preclinicalstudies,itappearstoinhibitvagallymediatedreflexesbyantagonisingtheactionofacetylcholine,the

transmitteragentreleasedfromthevagusnerve.Anticholinergicspreventtheincreaseinintracellularconcentrationof

cyclicguanosinemonophosphate(cyclicGMP)causedbyinteractionofacetylcholinewiththemuscarinicreceptoron

Sweating Notknown

Myalgia Rare

Musclecramps Rare

Weakness(muscle) NotKnown

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Incontrolledupto90daystudiesinpatientswithbronchospasmassociatedwithchronicobstructivepulmonarydisease

(chronicbronchitisandemphysema)significantimprovementsinpulmonaryfunction(FEV

andFEF

25-75% increases

of15%ormore)occurredwithin15minutes,reachedapeakin1-2hours,andpersistedinthemajorityofpatientsup

to6hours.

Incontrolledupto90daystudiesinpatientswithbronchospasmassociatedwithasthma,significantimprovementsin

pulmonaryfunction(FEV

increasesof15%ormore)occurredin40%ofthepatients.

Preclinicalandclinicalevidencesuggestnodeleteriouseffectofipratropiumbromideonairwaymucoussecretion,

mucociliaryclearanceorgasexchange.

Fenoterolhydrobromideisadirectactingsympathomimeticagent,selectivelystimulatingbeta

-receptorsinthe

therapeuticdoserange.Thestimulationofbeta

-receptorscomesintoeffectatahigherdoserange.Occupationof

beta

-receptorsactivatesadenylcyclaseviaastimulatoryG

-protein.TheincreaseincyclicAMPactivatesprotein

kinaseAwhichthenphosphorylatestargetproteinsinsmoothmusclecells.Thisinturnleadstothephosphorylationof

myosinlightchainkinase,inhibitionofphosphoinositidehydrolysis,andtheopeningoflarge-conductancecalcium-

activatedpotassiumchannels.

Fenoterolrelaxesbronchialandvascularsmoothmuscleandprotectsagainstbronchoconstrictingstimulisuchas

histamine,methacholine,coldair,andallergen(earlyresponse).Afteracuteadministrationthereleaseof

bronchoconstrictingandproinflammatorymediatorsfrommastcellsisinhibited.Further,anincreaseinmucocillary

clearancehasbeendemonstratedafteradministrationofhigherdosesoffenoterol.

Higherplasmaconcentrations,whicharemorefrequentlyachievedwithoral,orevenmoreso,withintravenous

administrationinhibituterinemotility.Alsoathigherdoses,metaboliceffectsareobserved:Lipolysis,glycogenolysis,

hyperglycemiaandhypokalemia,thelattercausedbyincreasedK +

uptakeprimarilyinskeletalmuscle.Beta-adrenergic

effectsontheheartsuchasincreaseinheartrateandcontractility,arecausedbythevasculareffectsoffenoterol,

cardiacbeta

-receptorstimulation,andatsupratherapeuticdoses,bybeta

-receptorstimulation.Aswithotherbeta-

adrenergicagents,QTcprolongationshavebeenreported.Forfenoterolthesewerediscreteandobservedatdoses

higherthanrecommended.Theclinicalsignificancehasnotbeenestablished.Tremorisamorefrequentlyobserved

effectofbeta-antagonists.Unliketheeffectsonthebronchialsmoothmuscle,thesystemiceffectsof-agonistsare

subjecttothedevelopmentoftolerance.

Inclinicalstudiesfenoterolwasshowntobehighlyefficaciousinmanifestbronchospasm.Itprevents

bronchoconstrictionfollowingexposuretovariousstimulisuchasexercise,coldair,andtheearlyresponsefollowing

allergenexposure.

Concurrentuseofthesetwoactiveingredientsdilatesthebronchibyaffectingdifferentpharmacologicalsitesofaction.

Thetwoactivesubstancesthuscomplementeachotherintheirspasmolyticactiononthebronchialmusclesandallowa

broadtherapeuticuseinthefieldofbronchopulmonarydisordersassociatedwithconstrictionoftherespiratorytract.

Thecomplementaryactionissuchthatonlyaverylowproportionofthe-adrenergiccomponentisneededtoobtain

thedesiredeffect,facilitatingindividualdosagesuitedtoeachpatientwithaminimumofadversereactions.

InpatientswithasthmaandwithCOPDstudieswiththemeteredaerosolhaveshownthatDUOVENTisasefficacious

asdoublethedoseoffenoteroladministeredwithoutipratropiumbutisbettertoleratedincumulativedoseresponse

studies.InadequatelysizedstudiesinpatientswithasthmaorCOPDbetterefficacycomparedtoitscomponents

ipratropiumorfenoterolwasdemonstrated.

Inacuteasthmathecombinationoffenoterolandipratropiumiseffectiveshortlyafteradministrationandhasbeen

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5.2Pharmacokineticproperties

About16%ofthedosearedepositedintherespiratorytractfollowinginhalationbymeteredaerosol.Theremaining

portionisbeingswallowed.

Theactiveingredients(fenoterolhydrobromideandipratropiumbromide)areabsorbedveryquicklyfromthe

respiratorytract.Thepeakplasmaconcentrationsarereachedonlyminutesafterinhalation.Thereisnoevidencethat

thepharmacokineticsofbothingredientsinthecombinationdifferfromthoseofthemonosubstance.

Fenoterolhydrobromide

Theswallowedportionismainlymetabolisedtosulfateconjugates.Theabsolutebioavailabilityfollowingoral

administrationislow(approx.1.5%).Followingintravenousadministrationthreephaseswereobserved,wherebythe

terminalhalf-lifewasapproximately3hours.Fenoterolanditsconjugatesarerapidlyexcretedrenally(renalclearance:

267ml/min).About40%ofthedrugisboundtoplasmaproteins.Initsnon-metabolisedstate,fenoterolhydrobromide

canslowlypassthroughtheplacentaandenterthematernalmilk.

Ipratropiumbromide

Theabsolutebioavailabilityafteroraladministrationislow(approx.2%).Followingintravenousadministrationarapid

biphasicdeclineinplasmaisnotedforipratropium.Theterminalhalf-lifewasabout1.6hours.Thetotalclearanceof

theactiveingredientis2.3L/min.Approximately40%oftheclearanceisrenal(0.9L/min)and60%non-renali.e.

mainlyhepato-metabolic.Themainmetabolitesfoundinurinebindpoorlytothemuscarinicreceptor.Forty-six

percentoftheactiveingredientareexcretedrenallyafterintravenousadministration,4.4%-13.1%afterinhalation

fromametereddoseinhalerareexcretedasunchangedcompoundinurine.Thedrugisminimally(lessthan20%)

boundtoplasmaproteins.Theipratropiumiondoesnotcrosstheblood-brainbarrier.Itisnotknowniftheplacental

barrieriscrossed.

5.3Preclinicalsafetydata

Nonestated.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Sodiumchloride

Hydrochloricacid

Purifiedwater

6.2Incompatibilities

Notapplicable.

6.3Shelflife

3years.

Astheproductcontainsnopreservative,afreshvialshouldbeusedforeachdoseandthevialshouldbeopened

immediatelybeforeadministration.Anysolutionleftinthevialshouldbediscarded.

6.4Specialprecautionsforstorage

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6.5Natureandcontentsofcontainer

Lowdensitypolyethylene(LDPE)vialsformedinstripsof10packedintocartonscontaining20or60vials.Eachvial

contains4mlofsolution.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

BoehringerIngelheimLimited

EllesfieldAvenue

Bracknell,Berkshire

RG128YS

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA7/34/4

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:4 th

December1993

Dateoflastrenewal:2 nd

October2007

10DATEOFREVISIONOFTHETEXT

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