Combivent

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Ipratropium bromide monohydrate 21 µg; Salbutamol sulfate 120 µg
Available from:
Boehringer Ingelheim (NZ) Ltd
INN (International Name):
Ipratropium bromide monohydrate 21 µg
Dosage:
120µg/21µg per dose
Pharmaceutical form:
Aerosol inhaler, metered dose
Composition:
Active: Ipratropium bromide monohydrate 21 µg Salbutamol sulfate 120 µg Excipient: Dichlorodifluoromethane Lecithin Trichlorofluoromethane
Units in package:
Inhaler, metered, 200 dose units
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Boehringer Ingelheim Pharma GmbH & Co KG
Product summary:
Package - Contents - Shelf Life: Inhaler, metered, - 200 dose units - 36 months from date of manufacture stored at or below 30°C
Authorization number:
TT50-5212/1
Authorization date:
1993-07-30

NewZealandDatasheet

NameofMedicine

COMBIVENT ®

Salbutamol/Ipratropiumbromide

Presentation

Inhaler:100mcg /20mcg perinhalation.

COMBIVENTmetereddoseinhalerhasanopaqueshaftwithagreymouthpieceandcap.The

canistercontainsacreamy-whitehomogenoussuspensionofmicronisedsubstancesina

chlorofluorohydrocarbonpropellantmixturefilledinanaluminiumcanisterwithameteringvalve.

Eachmetereddosecontainssalbutamol100mcg(equivalentto120mcgsalbutamolsulphate),

and ipratropiumbromidemcg(equivalentto 21mcg ofipratropiumbromide monohydrate).

Uses

Actions

COMBIVENTcontains two active bronchodilatingsubstances,salbutamolsulphateand ipratropium

bromide.

Salbutamolsulphateisabeta

-adrenergicagentwhichactsonairwaysmoothmuscleresultingin

relaxation.Salbutamolrelaxesallsmoothmusclefromthetracheatotheterminalbronchiolesand

protectsagainstallbronchoconstrictorchallenges.

Ipratropiumbromideisa quaternaryammoniumcompound with anticholinergic(parasympatholytic)

properties.Inpreclinicalstudies,itappearstoinhibitvagallymediatedreflexesbyantagonisingthe

actionofacetylcholine,thetransmitteragentreleasedfromthevagusnerve.Anticholinergics

preventtheincreaseofintracellularconcentrationofCa ++ whichiscausedbyinteractionof

acetylcholinewithmuscarinicreceptorsonbronchialsmoothmuscle.Ca ++ releaseismediatedby

thesecondmessengersystemconsistingofIP3(inositoltriphosphate)andDAG(diacylglycerol).

Thebronchodilation followinginhalation ofipratropiumbromideisprimarilylocaland sitespecificto

thelungandnotsystemicin nature.

COMBIVENTprovidesthesimultaneousreleaseofipratropiumbromideandsalbutamolallowing

thesynergisticefficacyonthemuscarinicandbeta

-adrenergicreceptorsinthelungresultingina

bronchodilation which is superiortothatprovided byeach single agent.

ControlledstudiesinpatientswithreversiblebronchospasmhavedemonstratedthatCOMBIVENT

hasagreaterbronchodilatoreffectthaneitherofitscomponentsandtherewasnopotentiationof

adverseevents

Pharmacokinetics

Fromapharmacokineticperspective,theefficacyobservedintheCOMBIVENTInhalationAerosol

pulmonaryclinicaltrialsisdueto alocaleffectonthelungfollowinginhalation.

Followinginhalation10to39%ofadoseisgenerallydepositedinlungs,dependingonthe

formulation,inhalationtechniqueanddevice,whiletheremainderofthedelivereddoseis

depositedinthemouthpiece,mouthandtheupperpartoftherespiratorytract(oropharynx).The

portionofthedosedepositedinthelungsreachesthecirculationrapidly(withinminutes).The

amountoftheactivesubstancedepositedintheoropharynxisslowlyswallowedandpassesthe

gastrointestinaltract.Thereforethesystemicexposureisafunctionofbothoralandlung

bioavailability.

Ipratropium

Cumulativerenalexcretion(0-24hrs)ofipratropium(parentcompound)isapproximatedto46%of

anintravenouslyadministereddose,below1%ofanoraldoseandapproximately3-4%ofan

inhaleddose.Basedonthesedata,thetotalsystemicbioavailabilityoforalandinhaleddosesof

ipratropiumbromideisestimatedat2%and7to9%respectively.Takingthisintoaccount,

swalloweddose portionsofipratropiumbromidedo notrelevantlycontribute tosystemicexposure.

Kineticparametersdescribingthedispositionofipratropiumwerecalculatedfromplasma

concentrationsafteri.v.administration.Arapidbiphasicdeclineinplasmaconcentrationsis

observed.Theapparentvolumeofdistributionatsteady-state(Vdss)isappro ximately176L(≈2.4

L/kg).Thedrugisminimally(lessthan20%)boundtoplasmaproteins.Preclinicalstudieswithrats

and dogsrevealedthatthequarternaryamine ipratropiumdoesnotcrosstheblood-brain barrier.

Thehalf-lifeoftheterminaleliminationphaseisapproximately1.6hours.Ipratropiumhasatotal

clearanceof2.3L/minandarenalclearanceof0.9L/min.Afterintravenousadministration

approximately60%ofadose ismetabolisedprobablymainlyin theliverbyoxidation.

Inanexcretionbalancestudycumulativerenalexcretion(6days)ofdrug-relatedradioactivity

(includingparentcompoundandallmetabolites)accountedfor72.1%afterintravenous

administration,9.3%afteroraladministrationand3.2%afterinhalation.Totalradioactivityexcreted

viathefaeceswas6.3%followingintravenousapplication,88.5%followingoraldosingand69.4%

afterinhalation.Regardingtheexcretionofdrug-relatedradioactivityafterintravenous

administration,themainexcretionoccursviathekidneys.Thehalf-lifeforeliminationofdrug-

relatedradioactivity(parentcompoundandmetabolites)is3.6hours.Themainurinarymetabolites

bindpoorlytothemuscarinicreceptorand havetoberegardedas ineffective.

Salbutamolisrapidlyandcompletelyabsorbedfollowingadministrationeitherbytheinhaledor

gastricrouteandhasanoralbioavalabilityofapproximately50%.Meanpeakplasmasalbutamol

concentrationsof492pg/mloccurwithinthreehoursafterinhalationofCOMBIVENT.Following

thissingleinhaledadministration,approximately27%oftheestimatedmouthpiecedoseis

excretedunchangedinthe24hoururine.Kineticparameterswerecalculatedfromplasma

concentrationsafteri.v.administration.Theapparentvolumeofdistribution(Vz)isapproximately

156L(≈2.5L/kg).Only8%ofthedrugisboundtoplasmaproteins.Salbutamolwillcrossthe

bloodbrainbarrierreachingconcentrationsamountingtoabout5%oftheplasmaconcentrations

[90].Themeanterminalhalf-lifeisapproximately4hourswithameantotalclearanceof480

mL/min andameanrenalclearance of291mL/min.

Salbutamolisconjugativelymetabolisedtosalbutamol4'-O-sulphate.TheR(-)-enantiomerof

salbutamol(levosalbutamol)ispreferentiallymetabolisedandisthereforeclearedfromthebody

morerapidlythantheS(+)-enantiomer.Followingintravenousadministration,urinaryexcretionwas

completeafterapproximately24hours.Themajorityofthedosewasexcretedasparent

compound(64.2%)and12.0%wereexcretedassulphateconjugate.Afteroraladministration

urinaryexcretionofunchangeddrugandsulphateconjugatewere31.8%and48.2%ofthedose,

respectively.

Co-administrationofipratropiumbromideandsalbutamolsulphatedoesnotpotentiatethe

systemicabsorptionofeithercomponentandthereforetheadditiveactivityofCOMBIVENTisdue

tothecombined localeffectonthelungfollowinginhalation.

Indications

COMBIVENTisindicatedforthetreatmentofreversiblebronchospasmassociatedwithobstructive

airwaydiseases inpatientswhorequiremorethan asingle bronchodilator.

DosageandAdministration

Becauseofinsufficientinformation inchildrenCOMBIVENTisnotindicatedforpediatricpatients.

COMBIVENThasnotbeenstudiedin patientswith hepaticorrenalinsufficiency.Itshould beused

with cautioninthosepatientpopulations.

Patientsshouldbeadvisedtoconsultadoctororthenearesthospitalimmediatelyinthecaseof

acuteorrapidlyworseningdyspnoea(difficultyinbreathing)ifadditionalinhalationsofCOMBIVENT

donotproduceanadequateimprovement.

In asthma,concomitantanti-inflammatorytherapyshould beconsidered.

Thefollowingdoses ofCOMBIVENTarerecommendedforadults(includingelderlypatients):

Adults(includingelderly): Two inhalations four times daily. The dose may be

increasedasrequireduptoamaximumof12inhalations

in 24hours.

Children: TherehasbeennoexperiencewiththeuseofCOMBIVENTin

childrenbelowtheage of12years.

Patientsshouldbeadvisedtoconsultadoctororthenearesthospitalimmediatelyinthecaseof

acuteorrapidlyworseningdyspnoeaifadditionalinhalationsdonotproduceanadequate

improvement.

Contraindications

COMBIVENTiscontraindicatedinpatientswithhypertrophicobstructivecardiomyopathyand

tachyarrhythmiaandinpatientswithahistoryofhypersensitivitytoatropineoritsderivatives,orto

anyothercomponentoftheproduct.

COMBIVENTmetereddoseaerosolisalsocontraindicatedinpatientswithasensitivitytosoya

lecithin orrelatedfoodproductssuchassoyabean and peanut.

WarningsandPrecautions

Inthecase ofacute,rapidlyworseningdyspnoeaa doctorshouldbeconsultedimmediately.

ImmediatehypersensitivityreactionsmayoccurafteradministrationofCOMBIVENTas

demonstratedbyrarecasesofurticaria,angioedema,rash,bronchospasmandoropharyngeal

oedema.

Therehavebeenisolatedreportsofocularcomplications(e.g.mydriasis,increasedintraocular

pressure,narrow-angleglaucoma,eyepain)whenaerosolisedipratropiumbromideeitheraloneor

incombinationwithanadrenergicbeta

-agonistcontainingipratropiumbromidehaveescapedinto

theeyes.

Eyepainordiscomfort,blurredvision,visualhalosorcolouredimagesin associationwithredeyes

fromconjunctivalcongestionandcornealoedemamaybesignsofacutenarrow-angleglaucoma.

Shouldanycombinationofthesesymptomsdevelop,treatmentwithmioticdropsshouldbe

initiatedandspecialistadvicesoughtimmediately.Patientsshouldbeinstructedinthecorrect

administrationofCOMBIVENTandcaremustbetakentopreventCOMBIVENTfromenteringthe

eye.Patientswhomaybepredisposedtoglaucomashouldbewarnedspecificallytoprotecttheir

eyes.

In thefollowingsituationsCOMBIVENTshould onlybeused aftercarefulrisk/benefitassessment,

especiallywhen doses higherthanrecommendedareused:

Insufficientlycontrolleddiabetesmellitus,recentmyocardialinfarction,severeorganicheartor

vasculardisorders,hyperthyroidism,phaeochromocytoma,riskofnarrow-angleglaucoma,

prostatichypertrophyorbladder-neckobstruction.

Cardiovasculareffectsmaybeseenwithsympathomimeticdrugs,includingCOMBIVENT Thereis

someevidencefrompost-marketingdataandpublishedliteratureofrareoccurrencesof

myocardialischaemiaassociatedwithsalbutamol.Patientswithunderlyingsevereheartdisease

(e.g.ischaemicheartdisease,tachyarrhythmiaorsevereheartfailure)whoarereceiving

salbutamolforrespiratorydisease,shouldbewarnedtoseekmedicaladviceiftheyexperience

chestpainorothersymptomsofworseningheartdisease.Attentionshouldbepaidtoassessment

ofsymptomsasdyspnoea and chestpain,astheymaybeofeitherrespiratoryorcardiac origin.

Potentiallyserioushypokalaemiamayresultfromprolongedand/orhighdosebeta2-agonist

therapy.Additionally,hypoxia mayaggravatetheeffectsofhypokalaemiaoncardiacrhythm.

Patientswithcysticfibrosismaybemorepronetogastrointestinalmotilitydisturbances.

Ifhigherthan recommendeddosesofCOMBIVENTarerequiredto controlsymptoms,thepatient's

therapyplanshould bereviewedbya doctor.

TheuseofCOMBIVENTmayleadtopositiveresultswithregardstosalbutamolintestsfor

nonclinicalsubstance abuse,e.g.inthecontextofathletic performanceenhancement(doping).

Use inPregnancy

ThesafetyofCOMBIVENTduringhumanpregnancyhasnotbeenestablished.Theusual

precautionsregardingthe useofdrugsin pregnancy,especiallyduringthefirsttrimester,should be

observed.TheinhibitoryeffectofCOMBIVENTonuterinecontractionshouldbetakeninto

account.ThebenefitsofusingCOMBIVENTduringaconfirmedorsuspectedpregnancymustbe

weighed againstpossible hazardstotheunbornchild.

Foripratropiumbromide,preclinicalstudieshaveshownnoembryotoxicorteratogeniceffects

followinginhalationorintranasalapplicationatdosesconsiderablyhigherthanthose

recommendedinman.Forsalbutamolsulphate,non-inhalationpreclinicalstudiesdidnotindicate

directorindirectharmfuleffectsunlesstheinhalationMaximumRecommendedHumanDailyDose

(MRHDD)was exceeded(pleaserefertosectionToxicology).

NostudiesontheeffectonhumanfertilityhavebeenconductedforCOMBIVENT.Preclinical

studiesperformedwithipratropiumbromideandsalbutamolshowednoadverseeffectonfertility

(please refertosectionToxicology).

Usein Lactation

Itisnotknown whetheripratropiumbromideandsalbutamolsulphate areexcretedin breastmilk.

Althoughlipid-insolublequaternarycationspassintobreastmilk,itisconsideredunlikelythat

ipratropiumbromidewould reach theinfanttoanimportantextentwhenadministeredbyinhalation.

However,becausemanydrugsareexcretedinbreastmilk,cautionshouldbeexercisedwhen

COMBIVENTisadministeredto nursingmothers.

EffectsonAbilitytoDrive and Use Machines

No studies ontheeffectsontheabilityto drive and usemachineshave beenperformed.

However,patientsshouldbeadvisedthattheymayexperienceundesirableeffectssuchas

dizziness,accommodationdisorder,mydriasisandblurredvisionduringtreatmentwith

COMBIVENT.Therefore,cautionshouldberecommendedwhendrivingacaroroperating

machinery.Ifpatientsexperiencetheabovementionedsideeffectstheyshouldavoidpotentially

hazardous taskssuchasdrivingoroperatingmachinery.

AdverseEffects

Manyofthelistedundesirableeffectscanbeassignedtotheanticholinergicandbeta2-

sympathomimeticpropertiesofCOMBIVENT.AswithallinhalationtherapyCOMBIVENTmay

showsymptomsoflocalirritation.Adversedrugreactionswereidentifiedfromdataobtainedin

clinicaltrialsand pharmacovigilance duringpostapprovaluseofthedrug.

Themostfrequentsideeffectsreportedinclinicaltrialswereheadache,throatirritation,cough,dry

mouth,gastro-intestinalmotilitydisorders(includingconstipation,diarrhoeaandvomiting),nausea,

and dizziness.

Immunesystemdisorders:

Anaphylactic reaction

Hypersensitivity

Metabolismand nutritiondisorders:

Hypokalaemia

Psychiatricdisorders:

Mentaldisorder

Nervousness

Nervoussystemdisorders:

Dizziness

Headache

Tremor

Eye disorders:

Accommodation disorder

Cornealoedema

Glaucoma

Eye pain

Intraocularpressure increased

Mydriasis

Visionblurred

Conjunctivalhyperaemia

Halo vision

Cardiac disorders:

Arrhythmia

Atrialfibrillation

Myocardialischaemia

Palpitations

Tachycardia

Supraventriculartachycardia

Respiratory,thoracicandmediastinaldisorders:

Bronchospasm

Bronchospasmparadoxical

Laryngospasm

Pharyngealoedema

Cough

Dysphonia

Drythroat

Gastrointestinaldisorders:

Oedemamouth

Drymouth

Throatirritation

Diarrhoea

Gastrointestinalmotilitydisorder

Constipation

Nausea

Vomiting

Stomatitis

Skin andsubcutaneoustissuedisorders:

Skinreactionssuchas:

Rash

Pruritus

Urticaria

Angioedema

Hyperhidrosis

Musculoskeletaland connective tissuedisorders

Muscle spasms

Muscularweakness

Myalgia

Renaland urinarydisorders:

Urinaryretention

Generaldisordersand administrationsiteconditions:

Asthenia

Investigations:

Blood pressurediastolicdecreased

Blood pressuresystolicincreased

Interactions

Theconcurrentadministrationofxanthinederivativesaswellasotherbeta-adrenergicsand

anticholinergicsmayincrease thesideeffects.

Beta-agonistinducedhypokalaemiamaybeincreasedbyconcomitanttreatmentwithxanthine

derivatives,glucocorticosteroidsanddiuretics.Thisshouldbetakenintoaccountparticularlyin

patientswith severeairwayobstruction.

Hypokalaemia mayresultin anincreasedsusceptibilityto arrhythmiasin patientsreceivingdigoxin.

Itisrecommendedthatserumpotassiumlevelsbe monitoredinsuchsituations.

Apotentiallyseriousreductioninbronchodilatoreffectmayoccurduringconcurrentadministration

ofbeta-blockers.

Beta-adrenergicagonistsshouldbeadministeredwithcautiontopatientsbeingtreatedwith

monoamineoxidaseinhibitorsortricyclicantidepressants,sincetheactionofbeta-adrenergic

agonistsmaybeenhanced.

Inhalationofhalogenatedhydrocarbonanaestheticssuchashalothane,trichloroethyleneand

enfluranemayincreasethesusceptibilityto thecardiovasculareffectsofbeta-agonists.

Overdosage

Symptoms

Theeffectsofoverdosageareexpectedtobeprimarilyrelatedtosalbutamol.Theexpected

symptomswithoverdosagearethoseofexcessivebeta-adrenergic-stimulation,themost

prominentbeingtachycardia,palpitation,tremor,hypertension,hypotension,wideningofthepulse

pressure,anginalpain,arrhythmias,andflushing.

Expectedsymptomsofoverdosagewithipratropiumbromide(suchasdrymouth,visual

accomodationdisorders)aremildandtransientinnatureinviewofthewidetherapeuticrangeand

topicaladministration.

Treatment

Administrationofsedatives,tranquillisers,in severecaseintensive therapy.

Beta-receptorblockers,preferablybeta

-selective,aresuitableasspecificantidotes;however,a

possibleincreaseinbronchialobstructionmustbetakenintoaccountandthedoseshouldbe

adjustedcarefullyin patientssufferingfrombronchialasthma.

PharmaceuticalPrecautions

Storebelow30°C.

Shakewellbeforeuse.

Do notexposetheaerosolcanistertohightemperatures.

Do notforce openevenwhen apparentlyempty.

MedicineClassification

PrescriptionMedicine

PackageQuantities

Inhaler:10ml,200actuations.

FurtherInformation

COMBIVENT ® isa registeredtrademark.

Excipients

Aerosol:CFC(Freon11,12,114)soya lecithin

Source DocumentBPINo.:0178-02dated9.9.08

Instructions for Useof Inhaler

Whenusingtheaerosolforthefirsttimeitshouldbeshakenandthevalvedepressedonce

ortwiceto primethemeteringvalve beforeinitialuse.

Thecorrectoperationofthemeteredaerosolapparatusisessentialforsuccessfultherapy.

1) Remove theprotective cap.

2) Shakethemetereddoseaerosolwellbeforeeachuse.(SeeFig1)

3) Breatheoutdeeply.

4) Hold themetereddoseaerosol(asshown inFig 2),and closelips overthemouthpiece.

5) Breatheinasdeeplyaspossible,pressingthebaseofthecontainerfirmlyatthesame

time,thisreleasesonemetereddose.Holdthebreathforafewseconds,thenremovethe

mouthpiecefromthemouthandbreatheout.

6) Replacetheprotective capafteruse.

Note:Themouthpieceshouldalwaysbekeptcleanandcanbewashedinwarmwater.Ifsoapor

detergentisused,themouthpieceshould bethoroughlyrinsed inclearwater.

TheplasticmouthpiecehasbeenspeciallydesignedforusewithCOMBIVENTmetereddose

aerosoltoensurethatyoualwaysgettherightamountofthemedicine.Themouthpiecemust

neverbeusedwithanyothermetereddoseaerosolnormusttheCOMBIVENTmetereddose

aerosolbeused with anymouthpieceotherthantheone suppliedwith theproduct.

Thecontainerisunderpressureandshouldonnoaccountbeopenedbyforceorexposedto

temperatures exceeding50°C.

Testforremainingsolutionand cleaninginstructions

Thecontainerisnottransparent.Itisnotthereforepossibletoseewhenitisempty.The

inhalerwilldeliver200doses.Whenthesehaveallbeenusedthecanistermaystill

appeartocontainasmallamountoffluid.Theinhalershould,however,bereplaced

because youmaynotgettherightamountoftreatment.

Theamountoftreatmentin yourinhalercanbecheckedasfollows:

-Shakingthecanisterwillshowifthereis

anyremainingfluid.

-Alternativelyremovethecanisterfrom

theplasticmouthpieceandputitintoa

containerofwater.Thecontentsofthe

canistercanbeestimated byobservingits

positionin thewater.

(fig.3)

Clean yourinhaleratleastonceaweek.

Itisimportanttokeepthemouthpieceof

yourinhalercleantoensurethatmedicine

does notbuild upandblock thespray.

Forcleaning,firsttakeoffthedustcap

andremovethecanisterfromtheinhaler.

Rinsewarmwaterthroughtheinhaler

untilnomedicationbuild-upand/ordirtis

(fig.4)

Aftercleaningshakeouttheinhalerand

letitair-drywithoutusinganyheating

system.Oncethemouthpieceisdry,

replacethecanisterandthedustcap.

(fig.5)

Toxicology

TheacutetoxicityofCOMBIVENTaftersingleinhalationadministrationwastestedinratsand

dogs.Uptothehighesttechnicallyfeasibledose(rat:887/5397µg/kgipratropium

bromide/salbutamol,dog:164/861µg/kgipratropiumbromide/salbutamol)therewereno

indicationsofsystemictoxiceffects,thecombinationwaslocallywelltolerated.Theapproximate

afterintravenousadministrationwascalculatedfortheindividualsubstancestobebetween

12and20mg/kgforipratropiumbromideandbetween60and73mg/kgforsalbutamolsulphate

dependingonthespeciestested(mouse,rat,dog).

Two13-weekinhalationtoxicitystudiesinratsanddogshavebeenperformedwiththe

combinationofipratropiumbromideandsalbutamolsulphate.Inthesestudies,theheartprovedto

bethetargetorgan.Intheratatdosagesof34/197to354.5/2604µg/kg/dayipratropium

bromide/salbutamolsulphate,anondosedependentincreaseinheartweightswaspresent,

howeverwithoutanyhistopathologicalcorrelate.Inthedogatdosesof32/198to129/790

µg/kg/dayipratropiumbromide/salbutamolsulphate,slightlyincreasedheartratesand,athigher

dosages,histopathologicallydetectablescarsand/orfibrosisinthepapillarymuscleoftheleft

ventricle,sometimesaccompaniedwith mineralisation,wereobserved.

Thecardiovascularfindingsobtainedintheabovementionedstudiesmustberegardedaswell

knowneffectsofß-adrenergicssuchassalbutamol.Thetoxicologicalprofileofipratropium

bromideisalsowellknownformanyyearsandcharacterisedbytypicalanticholinergiceffectsas

drynessofthemucosalmembranesofthehead,mydriasis,keratoconjunctivitissicca(dryeye)in

dogsonly,reductionintoneand inhibitionofmotilityin thegastrointestinaltract(rat).

Reproductiontoxicitystudies are availableforthetwo individualcomponentsofCOMBIVENT.

Salbutamolsulphatecausedcleftpalatesathighsubcutaneousdosagesinmice,startingat

dosagesintherangeoftheinhalationMRHDD(basedonmg/m 2 ).Howeverthisphenomenonis

wellknownandoccursalsoaftertheadministrationofotherbeta-adrenergiccompounds.Todayit

isassumedthatthiseffectiscausedbyanincreaseinthematernalcorticosteronelevelandmight

beregardedasaresultofgeneralstressnotrelevantforotherspecies.Apartfromthesefindings,

thestudiesperformedwithsalbutamolsulphateandwithipratropiumbromiderevealedonly

marginaleffects,ifany,onembryos,foetusesandpupsandtheseonlyintherangeofmaternal

toxicity.

Bothindividualsubstancesweretestedinnumerousin-vivoandin-vitrogenotoxicitytests.Neither

salbutamolsulphatenoripratropiumbromideshowedanyevidenceofmutagenicproperties.In

additionCOMBIVENTdid notshowgenotoxicactivityinin vitroassays.

Salbutamolsulphateandipratropiumbromideweretestedindividuallyforneoplasticpropertiesin

severalcarcinogenicitystudies.Afteroraladministrationofsalbutamolsulphateinrats,butnotin

mice,hamstersanddogs,anincreasedincidenceofleiomyomasofthemesovariumwas

observedatdosagesabout20-foldhigherthaninhalationMRHDD.Thedevelopmentofthe

leiomyomaswasfoundtobepreventablebysimultaneousadministrationofbeta-blockers.These

findingswereassessedtobespeciesspecificandthereforewithoutclinicalrelevance,

consequentlynotleading toanyrestrictionoftheclinicaluseofsalbutamolsulphate.

Ipratropiumbromiderevealednocarcinogenicpotentialwhen testedorallyin miceandrats.

NoevidencewasfoundofanyimmunotoxicologicaleffectcausedbyCOMBIVENToritsindividual

active ingredients.

NameandAddress

BoehringerIngelheim(N.Z.)Limited

POBox76-216

ManukauCity

Auckland

NEWZEALAND

Telephone:(09)274-8664

Facsimile:(09)271-0629

DateofPreparation

8October2010.

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