COMBINEB

Main information

  • Trade name:
  • COMBINEB Nebuliser Solution 0.5mg/2.5m Milligrams per Ampule
  • Dosage:
  • 0.5mg/2.5m Milligrams per Ampule
  • Pharmaceutical form:
  • Nebuliser Solution
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • COMBINEB Nebuliser Solution 0.5mg/2.5m Milligrams per Ampule
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1518/002/001
  • Authorization date:
  • 17-10-2008
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Combineb0.5mg/2.5mgper2.5mlNebuliserSolution

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Each2.5mlsingledoseampoulecontains0.5mgofipratropiumbromide(asmonohydrate)and2.5mgofsalbutamol

(assulphate).

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

NebuliserSolution

A2.5mlampoulecontaining2.5mlofcolourlessnebulisersolution.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Combineb0.5mg/2.5mgper2.5mlnebulisersolutionisindicatedforthemanagementofbronchospasminpatients

sufferingfromchronicobstructivepulmonarydisease(COPD)whorequireregulartreatmentwithbothipratropium

bromideandsalbutamol.

4.2Posologyandmethodofadministration

Forinhalationuse.

Therecommendeddoseis:

Adults(includingelderlypatientsandchildrenover12years):1ampoulethreeorfourtimesdaily.

Childrenunder12years:ThereisnoexperienceoftheuseofCombineb0.5mg/2.5mgper2.5mlnebulisersolutionin

childrenunder12years.

Administration:

Combineb0.5mg/2.5mgper2.5mlnebulisersolutionmaybeadministeredfromasuitablenebuliseroranintermittent

positivepressureventilatorafterthesingledoseampoulehasbeenopenedanditscontentstransferredtothenebuliser

chamber.Administrationshouldbeinaccordancewiththemanufacturer’sinstructionsforthedevice.Thesolutionin

thesingledoseampoulesisintendedforinhalationuseonlyandshouldnotbetakenorallyoradministeredparenterally.

1.Preparethenebuliserbyfollowingthemanufacturer'sinstructionsandtheadviceofyourdoctor.

2.Carefullyseparateanewampoulefromthestrip.Neveruseanampoulethathasbeenopenedalready.

3.Opentheampoulebysimplytwistingoffthetop,alwaystakingcaretoholditinanuprightposition.

4.Unlessotherwiseinstructedbyyourdoctor,squeezeallthecontentsoftheplasticampouleintothenebuliser

chamber.

5.Assemblethenebuliseranduseitasdirectedbyyourdoctor.

6.Afternebulisation,cleanthenebuliseraccordingtothemanufacturer'sinstructions.Itisimportantthatthe

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 12/04/2011 CRN 2089036 page number: 1

Asthesingledoseunitscontainnopreservativesitisimportantthatthecontentsareusedimmediatelyafteropening

andafreshampouleisusedforeachadministrationtoavoidmicrobialcontamination.Partlyused,openedordamaged

singledoseunitsshouldbediscarded.

Anysolutionremaininginthenebuliserchambershouldbediscarded.

ItisstronglyrecommendedthatCombineb0.5mg/2.5mgper2.5mlnebulisersolutionshouldnotbemixedwithother

medicinesinthesamenebuliser.

4.3Contraindications

Patientswithhypertrophicobstructivecardiomyopathyortachyarrhythmia.

Patientswithknownhypersensitivitytoipratropiumbromide,salbutamol,atropineoritsderivativesortoanyofthe

excipients.

4.4Specialwarningsandprecautionsforuse

Patientsshouldbeinstructedtoconsultadoctorimmediatelyintheeventofacute,rapidlyworseningdyspnoeaorifa

reducedresponsetotreatmentbecomesapparent.

Immediatehypersensitivityreactionsmayoccurafteradministrationasdemonstratedbyrarecasesofurticaria,

angioedema,rash,bronchospasm,oropharyngealoedemaandanaphylaxis.

Aswithotherinhalationtherapythereisariskofinhalation-inducedbronchoconstrictionorparadoxical

bronchospasm.Ifthisoccursthepatientwillexperienceanimmediateincreaseinwheezingandshortnessofbreath

afterdosingwhichshouldbetreatedstraightawaywithanalternativepresentationordifferentfast-actinginhaled

bronchodilator.Combineb0.5mg/2.5mgper2.5mlnebulisersolutionshouldbediscontinuedimmediately,thepatient

shouldbeassessedand,ifnecessary,alternativetherapyinstituted.

Therearealsorarereportsofanumberofocularcomplicationswhenaerosolisedipratropiumbromide,eitheraloneor

incombinationwithabeta

-adrenergicagonist,hasbeeninadvertentlysprayedintotheeye.Patientsmustthereforebe

instructedinthecorrectuseofCombineb0.5mg/2.5mgper2.5mlnebulisersolutionwiththeirnebuliserandmustbe

warnednottoallowthesolutionormisttoentertheeyes.

Suchocularcomplicationsmayincludeacuteangleglaucoma,mydriasis,blurringofvision,increasedintraocular

pressure,eyepainandnarrow-angleglaucoma.Patientswhomaybesusceptibletoglaucomashouldbewarned

specificallyabouttheneedforocularprotection.Antiglaucomatherapyiseffectiveinthepreventionofacutenarrow-

angleglaucomainsusceptibleindividuals.

Eyepainordiscomfort,blurredvision,visualhalosorcolouredspotstogetherwithredeyesfromconjunctival

congestionorcornealoedemamaybemanifestationsofacutenarrow-angleglaucoma.Ifacombinationofthese

symptomsdevelops,treatmentwithmioticeyedropsshouldbeinitiatedandthepatientshouldseekspecialistadvice

immediately.

InthefollowingconditionsCombineb0.5mg/2.5mgper2.5mlnebulisersolutionshouldonlybeusedaftercareful

risk/benefitassessment:inadequatelycontrolleddiabetesmellitus,recentmyocardialinfarctionand/orsevereorganic

heartorvasculardisorders,hyperthyroidism,pheochromocytoma,prostatichypertrophy,bladderoutflowobstruction

andriskofnarrow-angleglaucoma.

Potentiallyserioushypokalaemiamayresultfrombeta

-agonisttherapy.Particularcautionisadvisedinsevereairway

obstruction,asthiseffectmaybepotentiatedbyconcomitanttreatmentwithxanthinederivatives,diureticsand

steroids.Hypokalaemiacanbringaboutincreasedsensitivitytoarrhythmiasinpatientsbeingtreatedwithdigoxin.

Additionallyhypoxiamayaggravatetheeffectsofhypokalaemiaoncardiacrhythm.Itisrecommendedthatserum

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 12/04/2011 CRN 2089036 page number: 2

Patientswithcysticfibrosismaybemorepronetodisturbancesingastrointestinalmotilityandthereforeipratropium

bromide,aswithotheranticholinergics,shouldbeusedwithcautioninthesepatients.

Ifitisnecessarytousehigherdosesthanrecommendedtocontrolthesymptomsofbronchoconstriction(or

bronchospasm)thepatient’streatmentplanshouldbereassessed.

Cardiovasculareffectsmaybeseenwithsympathomimeticdrugs,includingsalbutamol.Thereissomeevidencefrom

post-marketingdataandpublishedliteratureofrareoccurrencesofmyocardialischaemiaassociatedwithsalbutamol.

Patientswithunderlyingsevereheartdisease(e.g.ischaemicheartdisease,arrhythmiaorsevereheartfailure)whoare

receivingsalbutamolshouldbewarnedtoseekmedicaladviceiftheyexperiencechestpainorothersymptomsof

worseningheartdisease.Attentionshouldbepaidtoassessmentofsymptomssuchasdyspnoeaandchestpain,asthey

maybeofeitherrespiratoryorcardiacorigin.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Concurrentuseofadditionalbeta

-agonists,corticosteroids,anticholinergicsandxanthinederivativesmayenhancethe

effectofCombineb0.5mg/2.5mgper2.5mlnebulisersolutiononairwayfunctionandmayincreasetheseverityofside

effects.Duetoopposingpharmacodynamicinteractionwiththesalbutamolelementapotentiallyseriousreductionin

effectmayoccurduringconcurrentadministrationofbeta-blockerssuchaspropranolol.

Salbutamolshouldbeadministeredwithcautiontopatientsbeingtreatedwithmonoamineoxidaseinhibitorsor

tricyclicantidepressantsasthesedrugscanenhancetheeffectofbetaadrenergicagonists.

Inhalationofanaestheticscontaininghalogenatedhydrocarbons,e.g.halothane,trichloroethyleneandenflurane,may

increasethesusceptibilitytocardiovascularsideeffectsofbeta

-agonists,whichshouldthereforebemonitoredclosely.

AlternativelydiscontinuationofCombineb0.5mg/2.5mgper2.5mlnebulisersolutionpriortooperationshouldbe

considered.

Potentiallyserioushypokalaemiamayresultfrombeta

-agonisttherapy.Particularcautionisadvisedinsevereairway

obstruction,asthiseffectmaybepotentiatedbyconcomitanttreatmentwithxanthinederivatives,diureticsandsteroids.

Hypokalaemiacanbringaboutincreasedsensitivitytoarrhythmiasinpatientsbeingtreatedwithdigoxin.

Theeffectofotheranticholinergiccompoundsmaybepotentiated.

4.6Fertility,pregnancyandlactation

Pregnancy

Therearenoadequatedatafromtheuseofipratropiumbromideandsalbutamoltogetherinpregnantwomen(inearly

stagesofpregnancy).Inanimalstudiestherehasbeenevidenceofsomeharmfuleffectsonthefetusatveryhighdose

levels.Thepotentialriskforhumansisunknown.Cautionshouldbeexercisedwhenprescribingtopregnantwomen

(especiallyinthefirsttrimester).

Lactation

Itisunknownwhetheripratropiumbromideandsalbutamolareexcretedinhumanbreastmilk.Adecisiononwhether

tocontinue/discontinuebreast-feedingortocontinue/discontinuetherapywithCombineb0.5mg/2.5mgper2.5ml

nebulisersolutionshouldbemadetakingintoaccountthebenefitofbreast-feedingtothechildandthebenefitof

Combineb0.5mg/2.5mgper2.5mlnebulisersolutiontherapytothewoman.

4.7Effectsonabilitytodriveandusemachines

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 12/04/2011 CRN 2089036 page number: 3

4.8Undesirableeffects

Common( ≥1/100and<1/10)

Uncommon( ≥1/1000and≤1/100)

Rare( ≥1/10000and<1/1000)

Notknown(cannotbeestimatedfromtheavailabledata)

SystemOrgan

Class Common Uncommon Rare Notknown

Metabolismand

nutrition

disorders Hypokalaemia

Psychiatric

disorders Nervousness Psychological

influence,e.g.

restlessness,

memory

disorders,

anxiety,

depression,

hyperactivityin

children

Eyedisorders Accommodation

disorders Paininthe

eyes,mydriasis,

increased

intraocular

pressure,

closed-angle

glaucoma.

Cardiac

disorders Palpitations,

tachycardia Increased

systolicblood

pressure,

arrhythmias Reduced

diastolicblood

pressure,

peripheral

vasodilatation Myocardial

ischaemia*(see

section4.4)

Respiratory,

thoracicand

mediastinal

disorders Coughing,

dysphonia Bronchospasm,

laryngospasm,

dyspnea,

paradoxical

bronchospasm

(i.e.inhalation-

induced

bronchoconstriction)

Gastrointestinal

disorders Drynessof

mouth,nausea Vomiting Mouthand

throatirritation,

motility

disorders

Skinand

subcutaneous

tissuedisorders Rash,itching,

urticaria,

angioedemaof

thetongue,lips

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 12/04/2011 CRN 2089036 page number: 4

*reportedspontaneouslyinpost-marketingdatathereforefrequencyregardedasunknown

4.9Overdose

Acuteeffectsofoverdosagewithipratropiumbromideareunlikelyduetoitspoorsystemicabsorptionaftereither

inhalationororaladministration.Anyeffectsofoverdosagearethereforelikelytoberelatedtothesalbutamol

component.

Manifestationsofoverdosagewithsalbutamolmayincludeanginalpain,hypertension,hypotension,hypokalaemia,

tachycardia,arrhythmia,chestpain,tremor,flushing,restlessnessanddizziness.Patientsshouldthereforebemonitored

closelyforthepotentialunwantedeffectsfromoverdosageofsalbutamol.

Hypokalaemiamayoccurfollowingoverdosewithsalbutamolandthereforeserumpotassiumlevelsshouldbe

monitored.Thepreferredantidoteforoverdosagewithsalbutamolisacardioselectivebeta-blockingagent,butcaution

shouldbeusedinadministeringthesedrugstopatientswithahistoryofbronchospasm.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:

ATCCode:R03AK04Adrenergicsandotheranti-asthmatics

Ipratropiumbromideisananticholinergicagentwhichinhibitsvagally-mediatedreflexesbyantagonisingthe

muscarinicactionofacetylcholine.

Thebronchodilationfollowinginhalationofipratropiumbromideisprimarilylocalandsitespecifictothelungandnot

systemicinnature.

Salbutamolsulphateisabeta

-adrenergicagentwhichactsonairwaysmoothmuscleresultinginrelaxation.

Salbutamolrelaxesallsmoothmusclesfromthetracheatotheterminalbronchiolesandprotectsagainst

bronchoconstrictorchallenges.

Combineb0.5mg/2.5mgper2.5mlnebulisersolutionprovidesthesimultaneousdeliveryofipratropiumbromideand

salbutamolsulphateproducingeffectsonbothmuscarinicandbeta2-adrenergicreceptorsinthelung.Thisprovides

enhancedbronchodilationoverthatprovidedbyeachagentsingly.

5.2Pharmacokineticproperties

Ipratropiumbromideisquicklyabsorbedafterinhalationhoweversystemicbioavailabilityisestimatedtobelessthan

10%oftheadministereddose.Renalexcretionis46%ofthedoseandterminaleliminationhalf-lifeisabout1.6hours

afterintravenousadministrationandthehalflifeis3.6hoursfortotaldrugandmetabolitesafterradiolabelling.

Musculoskeletal,

connectivetissue

andbone

disorders Tremor Myalgia,

muscular

cramp,

muscular

weakness

Renaland

urinarydisorders Urinary

retention

General

disordersand

administration

siteconditions Headache Dizziness Anaphylactic

reaction,

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 12/04/2011 CRN 2089036 page number: 5

Salbutamolsulphateisrapidlyandcompletelyabsorbedfollowinginhalation.Peakplasmasalbutamolconcentrations

areseenwithinthreehoursofadministrationandthedrugisexcretedunchangedintheurineafter24hours.The

eliminationhalf-lifeis3-7hours.Salbutamolwillcrossthebloodbrainbarrierreachingconcentrationsamountingto

about5%oftheplasmaconcentrations.

Co-nebulisationofipratropiumbromideandsalbutamolsulphatedoesnotpotentiatethesystemicabsorptionofeither

component.TheincreasedpharmacodynamicactivityofCombineb0.5mg/2.5mgper2.5mlnebulisersolutionisdueto

thecombinedlocaleffectofbothdrugsonthelung.

Impairedorganfunction

Ipratropiumbromideandsalbutamolareeliminatedthroughrenalexcretion.Increasedsystemicexposuresof

ipratropiumbromideandsalbutamolareexpectedinpatientswithimpairedrenalfunction.Increasedsystemicexposure

ofsalbutamolisexpectedinpatientswithimpairedhepaticfunction.

5.3Preclinicalsafetydata

Theindividualactiveingredients,ipratropiumbromideandsalbutamolsulphate,havebeenextensivelyinvestigatedin

animalmodelsandtherearenoclinicallyrelevantsafetyissueswhenCombineb0.5mg/2.5mgper2.5mlnebuliser

solutionisusedattherecommendeddosesbypatients.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Sodiumchloride

Hydrochloricacid

Waterforinjections

6.2Incompatibilities

Combineb0.5mg/2.5mgper2.5mlnebulisersolutionshouldnotbemixedwithotherdrugsinthesamenebuliser.

6.3ShelfLife

2years.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.Donotfreeze.Storeintheoriginalpackageinordertoprotectfromlight.

6.5Natureandcontentsofcontainer

Singledosepolyethyleneampouleswithatwist-offtopcontaining2.5mlofsolution.

Theampoulesarepackedinstripsofteninafoilsachetwhichispackedincartons.Theavailablepacksizesare10,20,

40,60,80,100or120ampoules.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 12/04/2011 CRN 2089036 page number: 6

7MARKETINGAUTHORISATIONHOLDER

BreathePharmaceuticalsLimited

Unit20ABeckettWay

ParkWestBusinessPark

Dublin12

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA1518/2/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:1 st

February2008

Dateoflastrenewal:13thMarch2011

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 12/04/2011 CRN 2089036 page number: 7