BEROTEC 100 INHALER CFC-FREE

Main information

  • Trade name:
  • BEROTEC 100 INHALER CFC-FREE
  • Dosage:
  • 100 Microgram
  • Pharmaceutical form:
  • Solution for Inhalation
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • BEROTEC 100 INHALER CFC-FREE
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0007/033/005
  • Authorization date:
  • 17-12-2004
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0007/033/005

CaseNo:2065924

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

BoehringerIngelheimLimited

EllesfieldAvenue,Bracknell,BerkshireRG128YS,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

BerotecInhalerCFC-Free100micrograms/metereddose,PressurisedInhalation,Solution.

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom11/06/2009until31/10/2010.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

BEROTECInhalerCFC-Free100micrograms/metereddose,pressurisedinhalation,solution.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

1metereddose(puff)contains100microgramsfenoterolhydrobromide.

Forfulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Pressurisedinhalation,solution.

Eachcontainerisfilledwith10mlofaclear,colourlessoralmostcolourlessliquid,freefromsuspendedparticlesand

issuppliedwithawhiteplasticoraladaptor(mouthpiece).

4CLINICALPARTICULARS

4.1TherapeuticIndications

Forthetreatmentofreversibleairwaysobstructioninbronchialasthmaandchronicobstructivepulmonarydisease.

4.2Posologyandmethodofadministration

Adults:Therecommendeddoseis1-2puffstobeinhaledasasingledose1-3timesdaily.Dosingshouldnotexceed

2puffseverysixhours,withuptoamaximumof8puffsperday.

Children(6-12years):Therecommendeddoseis1pufftobeinhaled1-3timesdaily.Dosingshouldnotexceed2

puffseverysixhours,withuptoamaximumof8puffsperday.Itisrecommendedthattheproductisadministered

underthesupervisionofaresponsibleadult.

Elderly:Nospecificinformationontheuseofthisproductintheelderlyisavailable.

Administration

Thecorrectadministrationofthemeteredaerosolisessentialforsuccessfultherapy.

Depressthevalvetwicebeforethemeteredaerosolisusedforthefirsttime.Whenevertheinhalerhasnotbeenused

for3daysormore,testfireitonceintotheairbeforeuse.

TheinhalercanbeusedwiththeAerochamber spacerdevice.Thismaybeusefulforpatientswhofinditdifficultto

synchroniseaerosolactuationandbreathingin.

WARNING.

TheplasticmouthpiecehasbeenspeciallydesignedforusewithBEROTECInhalerCFC-Freetoensurethatyou

alwaysgettherightamountofthemedicine.Themouthpiecemustneverbeusedwithanyothermeteredaerosolother

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Themouthpieceshouldalwaysbekeptclean.Tocleanthemouthpiece,thecanisteranddustcapmustberemoved.The

mouthpieceshouldthenbewashedinwarmsoapywater,rinsedanddried.Thesmallholeinthesideofthevalvestem

sometimesbecomesblockedduringuse.Thiscaneasilybeclearedwithapin.Thecanisteranddustcapshouldbe

replacedoncethemouthpieceisdry.

4.3Contraindications

Hypertrophicobstructivecardiomyopathy,tachyarrhythmia.Hypersensitivitytofenoterolhydrobromideortoinactive

ingredientsintheproduct.

4.4Specialwarningsandprecautionsforuse

WhenusingthenewformulationofBEROTECInhalerCFC-Freeforthefirsttime,somepatientsmaynoticethatthe

tasteisslightlydifferentfromthatoftheCFCcontainingformulation.Patientsshouldbemadeawareofthiswhen

changingfromoneformulationtotheother.Theyshouldalsobetoldthattheformulationshavebeenshowntobe

interchangeableforallpracticalpurposes.Thedifferenceintastehasnoconsequencesintermsofthesafetyorthe

efficacyofthenewformulation.

Excessiveuseofsympathomimeticagentscancauseunwantedeffects.Theconcomitantuseofothersympathomimetic

drugsshouldbeavoidedoronlyusedunderstrictmedicalsupervision.ConcurrentadministrationofBEROTEC

InhalerCFC-Freewithanticholinergicbronchodilatorsinreversibleairwaysobstructionhasbeenshowntoproduce

greaterbronchodilatationthantheuseofeitheragentalone(butseesection4.5,Interactionwithothermedicinal

productsandotherinteractions).

InthefollowingconditionsBEROTECInhalerCFC-Freeshouldonlybeusedaftercarefulrisk/benefitassessment,

especiallywhendoseshigherthanrecommendedareused:

Insufficientlycontrolleddiabetesmellitus,recentmyocardialinfarction,severeorganicheartorvasculardisorders,

hyperthyroidism,pheochromocytoma.

Patientsmustbeinstructedinthecorrectuseofameteredaerosolandwarnednottoexceedtheprescribeddose.Inthe

caseofacute,rapidlyworseningdyspnoea(difficultyinbreathing)adoctorshouldbeconsultedimmediately.

Forprolongeduse,ondemand(symptom-oriented)treatmentmaybepreferabletoregularuse.Patientsshouldbe

evaluatedfortheadditionortheincreaseofanti-inflammatorytherapy(e.g.inhaledcorticosteroids)tocontrolairway

inflammationandtopreventlongtermlungdamage.

Ifbronchialobstructiondeterioratesitisinappropriateandpossiblyhazardoustosimplyincreasetheuseofbeta-

agonistcontainingdrugssuchasBEROTECInhalerCFC-Freebeyondtherecommendeddoseoverextendedperiodsof

time.Theuseofincreasingamountsofbeta-agonistcontainingproductslikeBEROTECInhalerCFC-Freeona

regularbasistocontrolsymptomsofbronchialobstructionmaysuggestdecliningdiseasecontrol.Inthissituation,the

patient'stherapyplan,andinparticulartheadequacyoftheanti-inflammatorytherapy,shouldbereviewedtoprevent

potentiallylifethreateningdeteriorationofdiseasecontrol.

Potentiallyserioushypokalaemiamayresultfromexcessivebeta-agonisttherapy.Thiseffectmaybepotentiatedby

concomitanttreatmentwithxanthinederivatives,glucocorticosteroidsanddiuretics.Additionally,hypoxiamay

aggravatetheeffectsofhypokalaemiaoncardiacrhythm.Itisrecommendedthatserumpotassiumlevelsare

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Beta-adrenergics,anticholinergics,xanthinederivatives(suchastheophylline)andcorticosteroidsmayenhancethe

bronchodilatoreffectoffenoterol.Theconcurrentadministrationofotherbeta-mimetics,systemicallyabsorbed

anticholinergicsandxanthinederivatives(e.g.theophylline)mayincreasethefrequencyandseverityofunwanted

effects.

Potentiallyseriousbronchospasmmayoccurduringconcurrentadministrationofbeta-blockerstopatientswith

reversibleairwaysobstruction.

Inviewofthepossibleinteractionbetweensympathomimeticaminesandmonoamineoxidaseinhibitorsortricyclic

antidepressants,careshouldbeexercisedifitisproposedtoadministerthesecompoundsconcurrentlywithBEROTEC

InhalerCFC-Free.

Inhalationofhalogenatedhydrocarbonanaestheticssuchashalothane,trichloroethyleneandenfluranemayincreasethe

susceptibilitytothecardiovasculareffectsofbeta-agonists.

4.6Pregnancyandlactation

Althoughfenoterolhydrobromidehasbeeningeneraluseforseveralyears,thereisnodefiniteevidenceofill-

consequencefollowingadministrationofthedrugduringhumanpregnancy;animalstudieshaveshownnohazard.

Nonetheless,theusualprecautionsregardingtheuseofdrugsduringpregnancy,especiallyduringthefirsttrimester,

shouldbeexercised.

Theinhibitoryeffectoffenoterolonuterinecontractionshouldbetakenintoaccount.

Pre-clinicalstudieshaveshownthatfenoterolisexcretedintobreastmilk.Safetyinbreast-fedinfantshasnotbeen

established.

4.7Effectsonabilitytodriveandusemachines

Nonestated.

4.8Undesirableeffects

FrequentundesirableeffectsofBEROTECInhalerCFC-Freearetremor,nervousness,headache,dizziness,

tachycardia,palpitationsandoropharyngealirritation.

Potentiallyserioushypokalaemiamayresultfrombeta-agonisttherapy.

Aswithotherinhaledbronchodilators,coughandparadoxicalbronchospasmhavebeenreported.

Aswithotherbeta-mimetics,nausea,vomiting,sweating,weaknessandmyalgia/musclecrampsmayoccur.Inrare

casesdecreaseindiastolicbloodpressure,increaseinsystolicbloodpressure,arrhythmias,particularlyafterhigher

doses,mayoccur.

Inrarecasesskinreactionsorallergicreactionshavebeenreported,especiallyinhypersensitivepatients.

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4.9Overdose

Symptoms

Theexpectedsymptomswithoverdosagearethoseofexcessivebeta-adrenergicstimulation,includingexaggerationof

theknownpharmacologicaleffectse.g.flushing,tremor,nausea,restlessness,tachycardia,palpitation,dizziness,

headache,increaseinsystolicbloodpressure,fallindiastolicbloodpressure,afeelingofpressureinthechest,

excitationandextrasystoles.Hypokalemiamayoccurfollowingoverdosewithfenoterol.Serumpotassiumlevels

shouldbemonitored.

Therapy

Treatmentofoverdosageshouldprimarilybesupportiveandsymptomoriented.

Ifspecifictherapyisconsiderednecessary,cardioselectivebeta-blockersaretobepreferred.Theseshouldbe

administeredwithextremecautiontopatientswithasthmabecauseoftheriskofprecipitatingseverebronchospasm.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

TrialswithatreatmentdurationofuptothreemonthsinvolvingadultasthmaticsandCOPDpatients,andasthmatic

children,inwhichtheCFC-FreeformulationandtheCFCformulationhavebeencompared,haveshownthetwo

formulationstobetherapeuticallyequivalent.

Fenoterolhydrobromideisadirectactingsympathomimeticagent,selectivelystimulatingbeta-receptorsinthe

therapeuticdoserange.Thestimulationofbeta-receptorscomesintoeffectatahigherdoserange.Occupationof

beta-receptorsactivatesadenylcyclaseviaastimulatoryG-protein.TheincreaseincyclicAMPactivatesprotein

kinaseAwhichthenphosphorylatestargetproteinsinsmoothmusclecells.Thisinturnleadstothephosphorylationof

myosinlightchainkinase,inhibitionofphosphoinositidehydrolysis,andtheopeningoflarge-conductancecalcium-

activatedpotassiumchannels.Thereissomeevidencethatthe'maxi-Kchannel'canbedirectlyactivatedviatheG-

protein.

Fenoterolrelaxesbronchialandvascularsmoothmuscleandprotectsagainstbroncho-constrictingstimulisuchas

histamine,methacholine,coldair,andallergen(earlyresponse).Afteracuteadministrationthereleaseofbroncho-

constrictingandproinflammatorymediatorsfrommastcellsisinhibited.Further,anincreaseinmucociliaryclearance

hasbeendemonstratedafteradministrationofhigherdosesoffenoterol.Higherplasmaconcentrations,whicharemore

frequentlyachievedwithoral,orevenmoreso,withintravenousadministrationinhibituterinemotility.Alsoathigher

doses,metaboliceffectsareobserved:lipolysis,glycogenolysis,hyperglycaemiaandhypokalaemia,thelattercaused

byincreasedpotassiumionuptakeprimarilyintoskeletalmuscle.Beta-adrenergiceffectsontheheartsuchasincrease

inheartrateandcontractility,arecausedbythevasculareffectsoffenoterol,cardiacbeta-receptorstimulation,andat

supratherapeuticdoses,bybeta-receptorstimulation.Tremorisamorefrequentlyobservedeffectofbeta-agonists.

Unliketheeffectsonthebronchialsmoothmuscle,thesystemiceffectsofbeta-agonistsaresubjecttothedevelopment

oftolerance.

Inclinicalstudiesfenoterolwasshowntobehighlyefficaciousinmanifestbronchospasm.Itprevents

bronchoconstrictionfollowingexposuretovariousstimulisuchasexercise,coldairandtheearlyresponsefollowing

allergenexposure.

5.2Pharmacokineticproperties

ThetherapeuticeffectofBEROTECisproducedbyatopicalactionintheairway.Thereforethepharmacodynamicsof

bronchodilationandthepharmacokineticsofplasmaconcentrationsproducedbyBEROTECdonotexhibitparallel

timecourses.ThoughpharmacokineticcomparisonoftheCFC-FreeformulationandtheconventionalCFC

formulationhasshowndifferencesofexposuretofenoterolthetwopreparationscanbeconsideredtherapeutically

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Followinginhalationoffenoterolhydrobromideinobstructivelungdiseases,bronchodilatationoccurswithinafew

minutes.Thebronchodilatoreffectslast3-5hours.

Followinginhalation,dependinguponthemethodofinhalationandthesystemused,about10-30%oftheactive

ingredientreleasedfromtheaerosolpreparationreachesthelowerrespiratorytract,whereastheremainderisdeposited

intheupperrespiratorytractandinthemouth.Asaresult,someofthefenoterolwhichhasbeenadministeredby

inhalationentersthegastro-intestinaltract.AfterinhalationofonepufffromaBEROTEC100meteredaerosol,an

absorptionrateof17%ofthedosehasbeendetermined.Absorptionthenfollowsabiphasiccourse,30%offenoterol

hydrobromidebeingrapidlyabsorbedwithahalf-lifeof11minutes,70%beingslowlyabsorbedwithahalf-lifeof120

minutes.

Thereisnocorrelationbetweenplasmalevelsandthepharmacodynamictimeresponsecurvefollowinginhalation.

Thelongbronchodilatoractionfollowinginhalationcomparedwiththatfollowingintravenousadministrationisnot

supportedbythesystemicplasmalevels.

Afteroraladministration,approximately60%ofthefenoterolhydrobromideisabsorbed.Thepercentagewhichhas

beenabsorbedundergoesthoroughfirst-passmetabolismwiththeresultthatoralbioavailabilityfallstoabout1.5%.

Thisiswhytheswallowedportionoftheactiveingredientcontributespracticallynothingtothesystemicplasmalevel

followinginhalation.

Systemicallyadministeredfenoterolhydrobromideiseliminatedaccordingtoa3-compartmentmodelwithhalflivesof

=0.42minutes,t =14.3minutesandt =3.2hours.Metabolictransformationoffenoterol

hydrobromideinmanoccursalmostexclusivelybysulphation,predominantlyintheintestinalwall.

Initsnon-metabolisedstate,fenoterolhydrobromidecanpassthroughtheplacentaandenterthematernalmilk.

Thereisinsufficientdataontheeffectsoffenoterolhydrobromideinthediabeticmetabolicstate.

5.3Preclinicalsafetydata

ToxicitystudieswithrepeateddosesofBEROTEChaveshownthetoxicologicalprofilesoftheCFC-Freeformulation

andtheconventionalCFCformulationtobesimilar.

Acutetoxicitystudieshavebeenundertakeninthemouse,rat,dogandmonkeybyoralIV,SC,IPandinhalation

routes.TheoralLD50wasevaluatedtobeintherangeof1600to7400mg/kgbodyweight(BW)inadultrodentsand

rabbitsandindogsbetween150and433mg/kgBW.IntravenousLD50formouse,rat,rabbitanddogwasbetween34

and81mg/kgBW.Whenadministeredbyinhalation,toxicitywasverylow.Upto670mg/kgBW,dependenton

speciesandexperimentalsetup,nomortalitywasobserved.

Repeateddosetoxicitystudiesincludethechronictestinginmice,ratsanddogsforperiodsofupto78weeksandby

varyingroutesofadministration,PO,SC,IV,IPandbyinhalation.Summarising,thetoxicitystudiesrevealedfindings

indog,rabbit,mouseandrat,typicallyobservedafteradministrationofbeta-sympathomimetics(e.g.depletionofliver

glycogen,reducedglycogencontentofmuscle,reducedserumpotassiumlevels,tachycardia).

Athigherdosages,myocardialhypertrophyand/orlesionswereobservedinrat,mouse,andrabbitatvarious

administrationroutesfrom1mg/kgBW/donwards,e.g.rabbitsafterIVadministrationoveraperiodof4weeks.In

thedog-mostsensitivespeciestobeta-adrenergics-theselesionswerediscernedfrom0.019mg/kgBW/donwards.

Subacuteinhalationstudiesinmonkeysrevealednodirectsubstancerelatedtoxiceffects.

Inreproductiontoxicitystudies,ratsandrabbitsrevealednoteratogenicorembryotoxicchanges,whenadministeredby

inhalation.Fertilityandrearingwerenotimpairedbyfenoterolhydrobromide.Whenadministeredper-orally,doses

upto40mg/kgBW/dhadnodeleteriouseffectsonfertilityofmaleorfemalerats.Dailyoraldosesupto25mg/kg

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Inratstocolyticeffectswereobservedatdosesof3.5mg/kgBW/d.At25mg/kgBW/daslightlyincreasedfoetal

and/orneonatalmortalityoccurred.Extremelyhighdosesof300mg/kgBW/dPOand20mg/kgBW/dIVrevealedan

increasedrateofmalformations.

Mutagenicactivitywasnotobservedwhenfenoterolhydrobromidewastestedin-vitroandin-vivo.

Carcinogenicitystudiesinmice(PO18months)andrats(POandinhalation24months)revealedatoraldoselevelsof

25mg/kgBW/dfenoterolhydrobromideinducedanincreasedincidenceofuterineleiomyomaswithvariablemitotic

activityinmiceandmesovarialleiomyomasinrats,recognisedeffectscausedbythelocalactionofbeta-adrenergic

agentsontheuterinesmoothmusclecellinmiceandrats.Takingintoaccountthepresentlevelofresearch,these

resultsarenotapplicabletoman.Allotherneoplasiasfoundwereconsideredtobecommontypesofneoplasia

spontaneouslyoccurringinthestrainsusedanddidnotshowabiologicallyincreasedincidenceresultingfrom

treatmentwithfenoterol.

BEROTECInhalerCFC-FreeandBEROTEC100MDI(CFC-containing)havebeenshowntobeequallywelltolerated

intherespiratorytract.LocaltolerancestudieswithIV,IAocclusiveandsemiocclusivedermaladministrationto

rabbitsandinstillationofa0.05or0.1%solutionintotheconjunctivalsacofrabbitswerewelltolerated.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Norflurane(HFA134a)

Ethanol,anhydrous

Water,purified

Citricacidanhydrous

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

36months.

6.4Specialprecautionsforstorage

Donotstoreabove25ºC.

Protectfromdirectsunlightandheat.Donotfreeze.

Thecanistercontainsapressurisedliquid.Donotexposetotemperatureshigherthan50ºC.Donotpiercethecanister.

6.5Natureandcontentsofcontainer

17mlstainlesssteelpressurisedcontainercontaining10mlofsolutionwitha50microlitremeteringvalveandwhite

plasticoraladaptor.

Eachmeteredaerosolcontains200metereddoses.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

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7MARKETINGAUTHORISATIONHOLDER

BoehringerIngelheimLimited

EllesfieldAvenue

Bracknell

Berkshire

RG128YS

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA0007/033/005

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation: 17December2004

DateofLastrenewal: 01November2005

10DATEOFREVISIONOFTHETEXT

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