ESMOCARD

Main information

  • Trade name:
  • ESMOCARD Concentrate for Soln for Inf 2500 Milligram
  • Dosage:
  • 2500 Milligram
  • Pharmaceutical form:
  • Concentrate for Soln for Inf
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ESMOCARD Concentrate for Soln for Inf 2500 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1353/001/002
  • Authorization date:
  • 07-03-2008
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Esmocard2500mg/10mlconcentrateforsolutionforinfusion.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachampouleof10mlconcentrateforsolutionforinfusioncontains2500mgesmololhydrochloride.

1mlaqueoussolutioncontains250mgesmololhydrochloride(250mg/ml).

Excipients:2010mgethanol96%and2590mgPropyleneglycolina10mlampoule.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Concentrateforsolutionforinfusion.

Thesolutionisclearandcolourless.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Esmololhydrochlorideisindicatedforsupraventriculartachycardia(exceptforpre-excitationsyndromes),andforthe

rapidcontrolofventricularrateinpatientswithatrialfibrillationoratrialflutterinperioperative,postoperative,orother

circumstanceswhereshort-termcontroloftheventricularratewithashortactingagentisdesirable.

Esmololhydrochlorideisalsoindicatedfortachycardiaandhypertensionoccuringintheperioperativephaseandnon-

compensatorysinustachycardiawhere,inthephysician’sjudgementtherapidheartraterequiresspecificintervention.

Esmololhydrochlorideisnotintendedforuseinchronicsettings.

4.2Posologyandmethodofadministration

ESMOCARD2500mg/10mlconcentrateforsolutionforinfusionmustbedilutedbeforeadministration,exact

instructionsforusearegiveninsection6.6.

Esmocard2500mg/10mlconcentrateforsolutionforinfusionmustbedilutedandusedimmediatelyafteropening(see

sections4.4and6).Dilutethecontentof2ampoulesto500mlwiththeappropriatesolutiontoobtainaconcentration

of10mg/ml,seealsosection6.6.TheadministrationofEsmocard2500mg/10mlconcentrateforsolutionforinfusion

undilutedorincorrectlydilutedmayresultindeath(seesection4.4).

SUPRAVENTRICULARTACHYARRHYTHMIA

Thedosageofesmololshouldbetitratedindividually.Astartingdoseisrequired,followedbyamaintenancedosage.

Theeffectivedoseofesmololhydrochlorideiswithintherangeof50to200micrograms/kg/min,althoughdosesas

highas300micrograms/kg/minhavebeenused.Inafewpatientstheaverageeffectivedosageof25

micrograms/kg/minhasbeenadequate.

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Asthedesiredheartrateorsafetyendpoint(e.g.loweredbloodpressure)isapproached,OMITtheloadinginfusionand

reducetheincrementaldoseinthemaintenanceinfusionfrom50micrograms/kg/minto25micrograms/kg/minor

lower.Ifnecessary,theintervalbetweenthetitrationstepsmaybeincreasedfrom5to10minutes.

NB:Maintenancedosesabove200micrograms/kg/minhavenotbeenshowntohavesignificantlyincreasedbenefits,

andthesafetyofdosesabove300micrograms/kg/minhasnotbeenstudied.

Intheeventofanadversereaction,thedosageofesmololmaybereducedordiscontinued.Pharmacologicaladverse

reactionsshouldresolvewithin30minutes.

Ifalocalinfusionsitereactiondevelops,analternativeinfusionsiteshouldbeusedandcautionshouldbetakento

preventextravasation.

Theadministrationofesmololinfusionsforlongerthan24hourshasnotbeenthoroughlyevaluated.Infusiondurations

greaterthan24hoursshouldonlybeusedwithcaution.

Conversiontable:microg/kg/min ml/min(esmololdilutedto10 mg/mlstrength)

500

µg/kg/min 50

µg/kg/min 100

µg/kg/min 150

µg/kg/min 200

µg/kg/min 250

µg/kg/min 300

µg/kg/min

1minute

only

kg ml/min ml/min ml/min ml/min ml/min ml/min ml/min

2,25 0,225 0,45 0,675 0,9 1,125 1,35

0,25 0,5 0,75 1 1,25 1,5

2,75 0,275 0,55 0,825 1,1 1,375 1,65

3,25 0,325 0,65 0,975 1,3 1,625 1,95

0,35 0,7 1,05 1,4 1,75 2,1

3,75 0,375 0,75 1,125 1,5 1,875 2,25

4,25 0,425 0,85 1,275 1,7 2,125 2,55

0,45 0,9 1,35 1,8 2,25 2,7

4,75 0,475 0,95 1,425 1,9 2,375 2,85

5,25 0,525 1,05 1,575 2,1 2,625 3,15

0,55 1,1 1,65 2,2 2,75 3,3

5,75 0,575 1,15 1,725 2,3 2,875 3,45

Conversiontable:microg/kg/min ml/h(esmololdiluted to 10mg/mlstrength)

500

µg/kg/min 50

µg/kg/min 100

µg/kg/min 150

µg/kg/min 200

µg/kg/min 250

µg/kg/min 300

µg/kg/min

1minute

only

kg ml/h ml/h ml/h ml/h ml/h ml/h ml/h

13,5 27 40,5 54 67,5 81

16,5 33 49,5 66 82,5 99

19,5 39 58,5 78 97,5 117

22,5 45 67,5 90 112,5 135

25,5 51 76,5 102 127,5 153

28,5 57 85,5 114 142,5 171

31,5 63 94,5 126 157,5 189

34,5 69 103,5 138 172,5 207

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Abruptdiscontinuationofesmololinpatientshasnotbeenreportedtoproducethewithdrawaleffectswhichmayoccur

withabruptwithdrawalofbeta-blockersfollowingchronicuseincoronaryarterydisease(CAD)patients.However,

cautionshouldstillbeusedindiscontinuingesmololinfusionsabruptlyinCADpatients.

PERIOPERATIVETACHYCARDIAANDHYPERTENSION

Whentreatingtachycardiaand/orhypertensionintheperioperativesetting,thefollowingdoseregimensmaybeused.

a)Fortheintraoperativetreatment-duringanaesthesiawhenimmediatecontrolisrequired,abolusinjectionof80mg

isgivenover15to30seconds,followedbya150micrograms/kg/mininfusion.Titratetheinfusionrateasrequired

upto300micrograms/kg/min.

b)Uponawakeningfromanaesthesiaadministeraninfusionof500micrograms/kg/minforupto4minutesfollowedby

aninfusionof300micrograms/kg/min.

c)Forpostoperativesituationswhentimefortitrationisavailable,givethe500micrograms/kg/minloadingdoseover

oneminutebeforeeachtitrationsteptoproducearapidonsetofaction.Usetitrationstepsof50,100,150,200,250

and300micrograms/kg/mingivenoverfourminutes,stoppingatthedesiredtherapeuticeffect.

Replacementofesmololtherapybyalternativedrugs

Afterachievinganadequatecontroloftheheartrateandastableclinicalstatus,transitiontoalternativedrugs

(antiarrhytmicsorcalciumantagonists)maybeaccomplished.

Whenesmololisreplacedbyalternativedrugs,thephysicianshouldcarefullyconsiderthelabellingofthealternative

drugandthedosageofesmololshouldbereducedasfollows:

1)Withinthefirsthourafterthefirstdoseofthealternativedrug,theinfusionrateofesmololshouldbereducedby

one-half(50%).

2)Afteradministrationoftheseconddoseoftheotheralternativedrug,thepatientresponseshouldbesupervised

andifsatisfactorycontrolismaintainedforthefirsthour,discontinuetheesmololinfusion.

Additionaldosinginformation:asthedesiredtherapeuticeffectorasafetyendpoint(e.g.loweredbloodpressure)is

approached,omittheloadingdoseandreducetheincrementalinfusionto12.5–25micrograms/kg/min.Also,if

desired,increasetheintervalbetweentitrationstepsfromfivetotenminutes.

Esmocardshouldbediscontinuedwhenheartrateorbloodpressurerapidlyapproachorexceedasafetylimit,andthen

restartedwithoutaloadinginfusionatalowerdoseaftertheheartrateorbloodpressurehasreturnedtoanacceptable

level.

Elderly

Specialstudiesofelderlyhavenotbeenperformedyet.However,ananalysisofdataof252patientsover65years

indicatedthatnovariationsinpharmacodynamiceffectsoccuredascomparedwithdataofpatientsyoungerthan65

years.

Patientswithkidneyinsufficiency

Inpatientswithrenalinsufficiencycautionisneededwhenesmololisadministeredbyinfusion,sincetheacid

metaboliteisexcretedthroughthekidneys.Excretionoftheacidmetaboliteissignificantlydecreasedinpatientswith

renaldisease,withtheeliminationhalf-lifeincreasedtoabouttenfoldthatofnormals,andplasmalevelsconsiderably

elevated.

Patientswithliverinsufficiency

Incaseofliverinsufficiencynospecialprecautionsarenecessarysincetheesterasesintheredbloodcellshaveamain

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Paediatricpopulation(ageunder18years)

Therearelimiteddataavailableontheuseofesmololhydrochlorideinchildren(seesections5.1and5.2).The

availabledatadonotsupportsafetyandefficacyinthepaediatricpopulationandthereforesuchuseisnot

recommended.

4.3Contraindications

hypersensitivitytoesmololhydrochlorideortoanyoftheexcipients

severebradycardia(lessthan50beatsperminute)

“Sicksinus”-syndrome;severeAV-nodalconductancedisorders(withoutpacemaker);2ndor3rddegreeAV-

block

cardiogenicshock

severehypotension

overtheartfailure

Non-treatedphaeochromocytoma

pulmonaryhypertension

acuteasthmaticattack

metabolicacidosis

4.4Specialwarningsandprecautionsforuse

ESMOCARD2500MG/10MLCONCENTRATEFORSOLUTIONFORINFUSIONMUSTBEDILUTED

ANDUSEDIMMEDIATELYAFTEROPENING(seesection6)

IncorrectdilutionsofEsmocard2500mg/10mlconcentratemayresultinsevereoverdoses.Theseoverdosesmay

resultindeathorinpermanentdisability(seesection4.9).

Esmololhydrochloridecontainsethanol96%andpropyleneglycol.

Inthedilutedsolution,thecontentofethanolislessthan100mg.

Itisadvisedtoterminatetheinfusiongraduallybecauseoftheriskofreboundtachycardia.

Esmololhydrochlorideshouldbeusedwithcautionindiabeticsorincaseofhypoglycemia:Theseverityofthe

hypoglycemiaislessthantheoneobservedwithlesscardioselectivebetablockers.Thebetablockerscanmaskthe

prodromalsymptomsofahypoglycemiasuchastachycardia.Dizzinessandsweating,however,maynotbeaffected.

Themostfrequentlyobservedsideeffectishypotensionwhichisrapidlyreversiblewithdosagereductionor

discontinuation.Inpatientswithalowsystolicbloodpressure,extracautionisneededwhenadjustingthedosageand

duringthemaintenanceinfusion.

ItisadvisedtocontinuouslymonitorthebloodpressureandtheECGinallpatientstreatedwithesmolol.Intheevent

ofahypotensiveepisodetheinfusionrateshouldbereducedor,whennecessary,bediscontinued.

Duetoitsnegativeeffectonconductiontime,beta-blockersshouldonlybegivenwithcautiontopatientswithfirst

degreeheartblock.

Theelderlyshouldbetreatedwithcaution,startingwithalowerdosage,buttoleranceisusuallygoodintheelderly.

BetablockersmayincreasethenumberandthedurationofanginalattacksinpatientswithPrinzmetal’sanginadueto

unopposedalpha-receptormediatedcoronaryarteryvasoconstriction.Non-selectivebetablockersshouldnotbeused

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Sympatheticstimulationisnecessaryinsupportingcirculatoryfunctionincongestiveheartfailure,andbetablockade

carriesthepotentialhazardoffurtherdepressingmyocardialcontractilityandprecipitatingmoreseverefailure.

Continueddepressionofthemyocardiumwithbetablockingagentsoveraperiodoftimecan,insomecases,leadto

cardiacfailure.Atthefirstsignorsymptomofimpendingcardiacfailure,esmololshouldbewithdrawn.Although

withdrawalmaybesufficientbecauseoftheshorteliminationhalf-lifeofesmolol,specifictreatmentmayalsobe

considered(seesection4.9).

Theuseofesmololforcontrolofventricularresponseinpatientswithsupraventriculararrhythmiasshouldbe

undertakenwithcautionwhenthepatientiscompromisedhemodynamicallyoristakingotherdrugsthatdecreaseany

orallofthefollowing:peripheralresistance,myocardialfilling,myocardialcontractility,orelectricalimpulse

propagationinthemyocardium.Despitetherapidonsetandoffsetoftheeffectsofesmolol,severalcasesofdeathhave

beenreportedincomplexclinicalstateswhereesmololwaspresumablybeingusedtocontrolventricularrate.

Patientswithbronchospasticdiseaseshould,ingeneral,notreceivebetablockers.Becauseofitsrelativebeta1

selectivityandtitratability,esmololshouldbeusedwithcautioninpatientswithbronchospasticdiseases.However,

sincebeta1selectivityisnotabsolute,esmololshouldbecarefullytitratedtoobtainthelowestpossibleeffectivedose.

Intheeventofbronchospasm,theinfusionshouldbeterminatedimmediatelyandabeta2agonistshouldbe

administeredifnecessary.

Ifthepatientalreadyusesabeta-2-receptorstimulatingagent,itcanbenecessarytore-evaluatethedoseofthisagent.

Esmololshouldbeusedwithcautioninpatientswithahistoryofwheezingandasthma.

Inpatientswithpsoriasisorahistoryofpsoriasis,theadministrationofesmololhydrochlorideshouldbecarefully

weighedasitshouldbedoneinanyevent.

Inpatientswithperipheralcirculatorydisorders(Raynaud’sdiseaseorsyndrome,intermittentclaudication),beta

blockersshouldbeusedwithgreatcautionasaggravationofthesedisordersmayoccur.

Beta-blockersmayinducebradycardia.Ifthepulseratedecreasestolessthan50-55beatsperminuteatrestandthe

patientexperiencessymptomsrelatedtobradycardia,thedosageshouldbereduced.

Betablockersmayincreaseboththesensitivitytowardallergensandtheseriousnessofanaphylacticreactions.

Infusionofconcentrationsof20mg/mlhavebeenassociatedwithsignificantvenousirritationandthrombophlebitisin

animalsandman.Extravasationof20mg/mlmayleadtoaseriouslocalreactionandpossibleskinnecrosis.

Localreactionshavealsobeenreportedfollowinginfusionofconcentrationsof10mg/ml.Infusionintosmallveinsor

throughabutterflycathetershouldthereforebeavoided.

Useinthepaediatricpopulation(ageunder18years)

Thesafetyandeffectivenessofesmololhydrochlorideinchildrenhavenotbeenestablished.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Calciumantagonistssuchasverapamilandtoalesserextentdiltiazemhaveanegativeinfluenceoncontractilityand

AV-conduction.Aswithotherbeta-blockingagentsesmololshouldbeusedwithcautionincombinationwith

verapamilinpatientswithimpairedventricularfunction.Thecombinationshouldnotbegiventopatientswith

conductionabnormalitiesandesmololshouldnotbeadministeredwithin48hoursofdiscontinuingverapamil.

Calciumantagonistssuchasdihydropyridinederivatives(e.g.,nifedipine)mayincreasetheriskofhypotension.In

patientswithcardiacinsufficiencyandwhoarebeingtreatedwithacalciumantagonist,treatmentwithbeta-blocking

agentsmayleadtocardiacfailure.CarefultitrationofEsmocardandappropriatehaemodynamicmonitoringis

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ConcomitantuseofesmololandclassIantiarrhythmicagents(suchasdisopyramideandquinidine)andalso

amiodaronecanincreasetheactionofbothontheAV-conductancetimeandinducenegativeinotropiceffect.

Concomitantuseofesmololandinsulinororalantidiabeticdrugsmayintensifythebloodsugarloweringeffect

(especiallynon-selectivebeta-blockers).Beta-adrenergicblockademaypreventtheappearanceofsignsof

hypoglycemia(tachycardia).

Anaestheticdrugs

Insituationwherethepatient’svolumestatusisuncertainorconcomitantantihypertensivedrugsareutilized,theremay

beattenuationofthereflextachycardiaandanincreaseoftheriskofhypotension.

ContinuationofBeta-blockadesreducestheriskofarrhythmiaduringinductionandintubation.Theanaesthesiologist

shouldbeinformedwhenthepatientisreceivingabeta-blockingagentinadditiontoesmolol.Thehypotensiveeffects

ofinhalationanaestheticagentsmaybeincreasedinthepresenceofesmolol.Thedosageofeitheragentmaybe

modifiedasneededtomaintainthedesiredhaemodynamics.

ThecombinationofEsmocardwithganglionblockingagentscanenhancethehypotensiveeffect.

NSAIDsmaydecreasethehypotensiveeffectsofbeta-blockers.

Specialcautionmustbetakenwhenusingfloctafenineoramisulprideconcomitantlywithbeta-blockers.

Concomitantadministrationoftricyclicantidepressants,barbituratesandphenothiazinesaswellasother

antihypertensiveagentsmayincreasethebloodpressureloweringeffect.DosingofEsmocardshouldbeadjusted

downwardtoavoidunexpectedhypotension.

Sympathomimeticagentsmaycounteracttheeffectofbeta-adrenergicblockingagents.

Catecholamine-depletingagents,e.g.,reserpine,mayhaveanadditiveeffectwhengivenwithbeta-blockingagents.

PatientstreatedconcurrentlywithEsmocardandacatecholaminedepletorshouldthereforebecloselyobservedfor

evidenceofhypotensionormarkedbradycardia,whichmayresultinvertigo,syncopeorposturalhypotension.

Concomitantuseofclonidineandbeta-blockersincreasetheriskof“rebound”hypertension.Whenclonidineisusedin

conjunctionwithnon-selectivebeta-blockers,suchaspropranolol,treatmentwithclonidineshouldbecontinuedfor

sometimeaftertreatment,whenthebeta-blockerhasbeendiscontinued.

DatafromaninteractionstudybetweenEsmocardandwarfarinshowedthatconcomitantadministrationofEsmocard

andwarfarindoesnotalterwarfarinplasmalevels.Esmocardconcentrations,however,wereequivocallyhigherwhen

givenwithwarfarin.

WhendigoxinandEsmocardwereconcomitantlyadministeredintravenouslytonormalvolunteers,therewasa10-20%

increaseindigoxinbloodlevelsatsometimepoints.ThecombinationofdigitalisglycosidesandEsmocardmay

increaseAVconductiontime.DigoxindidnotaffectEsmocardpharmacokinetics.

WhenintravenousmorphineandEsmocardinteractionwasstudiedinnormalsubjects,noeffectonmorphineblood

levelswasseen.TheEsmocardsteady-statebloodlevelswereincreasedby46%inthepresenceofmorphine,butno

otherpharmacokineticparameterswerechanged.

TheeffectofEsmocardonthedurationofsuxamethoniumchloride-inducedneuromuscularblockadehasbeenstudied

inpatientsundergoingsurgery.Theonsetofneuromuscularblockadebysuxamethoniumchloridewasunaffectedby

Esmocard,butthedurationofneuromuscularblockadewasprolongedfrom5minutesto8minutes.

Althoughtheinteractionsobservedinstudiesofwarfarin,digoxin,morphineorsuxamethoniumchloridearenotof

majorclinicalimportance,Esmocardshouldbetitratedwithcautioninpatientsbeingtreatedconcurrentlywith

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4.6Fertility,pregnancyandlactation

Pregnancy

Esmololisnotrecommendedinpregnancy.

Thereareinsufficientdatatodeterminethepossibleharmfuleffectsofesmololduringpregnancy.Todate,thereareno

indicationsforanincreasedriskonbirthdefectsinhumans.Animalstudieshaveshownreproductivetoxicity(see

section5.3).Thepotentialriskforhumansisunknown.Basedonthepharmacologicalaction,inthelaterperiodof

pregnancy,sideeffectsonthefoetusandneonate(especiallyhypoglycemia,hypotensionandbradycardia)shouldbe

takenintoaccount.

Beta-blockersreducetheplacentacirculation.

Iftreatmentwithesmololisconsiderednecessary,theuteroplacentalbloodflowandfoetalgrowthshouldbe

monitored.Thenewborninfantmustbecloselymonitored.

Lactation

Itisunknownwhetheresmololisexcretedinthebreastmilk.Lactationisnotadvisedduringtheuseofesmolol.

4.7Effectsonabilitytodriveandusemachines

Notrelevant.

4.8Undesirableeffects

Incaseofanadversereaction,thedoseofesmololcanbereducedordiscontinued.

Mostoftheadversereactionsobservedhavebeenmildandtransient.Themostimportantadversereactionis

hypotension.

Thefollowingterminologieshavebeenusedinordertoclassifytheoccurrenceofundesirableeffects:

Verycommon(1/10)

Common(1/100to<1/10)

Uncommon(1/1,000to<1/100)

Rare(1/10,000to<1/1.000)

Veryrare(<1/10,000)

Nervoussystemdisorders

Common:paraesthesiae,disturbanceinattention,dizziness1,somnolence,headache

Uncommon:convulsions,syncope,dysgeusia,speechdisorder

Cardiacdisorders

Uncommon:bradycardia,atrioventricularblock

Veryrare:sinusarrest,asystole

Eyedisorders

Uncommon:Visualimpairment

Respiratory,thoracicandmediastinaldisorders

Uncommon:bronchospasm,wheezing,dyspnoea,nasalcongestion,pulmonaryoedema,rhonchi,rales

Gastrointestinaldisorders

Common:nausea,vomiting

Uncommon:dyspepsia,constipation,mouthdryness,abdominalpain

Renalandurinarydisorders

Uncommon:urinaryretention

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Verycommon:Diaphoresis

Uncommon:erythema 2

,skindiscolouration 2

Veryrare:skinnecrosisduetoextravasation 2

Notknown:psoriasis 3

Musculoskeletalandconnectivetissuedisorders

Uncommon:Musculoskeletalpain

Metabolismandnutritiondisorders

Common:anorexia

Vasculardisorders

Verycommon:hypotension

Uncommon:peripheralischaemia,pallor,flushing

Veryrare:thrombophlebitis 2

Generaldisordersandadministrationsiteconditions

Common:asthenia,fatigue,injectionsitereaction,infusionsitereaction,infusionsiteinflammation,infusionsite

induration

Uncommon:chestpain,oedema 2

,pain 2

,infusionsiteburning,feverandchills

Psychiatricdisorders:

Common:depression,anxiety,confusionalstate,agitation

Uncommon:thinkingabnormal

Dizzinessanddiaphoresisareinassociationwithsymptomatichypotension.

InassociationwithInjectionandInfusionsitereactions.

Betablockersasadrugclasscancausepsoriasisinsomesituationsorworsenit.

4.9Overdose

Casesofmassiveaccidentaloverdosesofesmololhaveoccurred.Someoftheseoverdoseshavebeenfatalwhileothers

resultedinpermanentdisability.Bolusdosesintherangeof625mgto2.5g(12.5-50mg/kg)havebeenfatal.

Symptoms

Incaseofoverdosethefollowingsymptomscanoccur:severehypotension,sinusbradycardia,atrioventricularblock,

heartinsufficiency,cardiogenicshock,cardiacarrest,bronchospasm,respiratoryinsufficiency,lossofconsciousnessto

coma,convulsions,nausea,vomiting,hypoglycemiaandhyperkalemia.

Becauseoftheshorteliminationhalf-lifeofESMOCARDpowderforconcentrateforsolutionforinfusion

(approximately9minutes),thefirststepinthemanagementoftoxicityshouldbetodiscontinuetheadministrationof

thedrug.ThetimetakenforsymptomstodisappearfollowingoverdosingwilldependontheamountofESMOCARD

administered.Thismaytakelongerthanthe30minutesseenwithdiscontinuationattherapeuticdoselevels.Artificial

respirationmaybenecessary.Basedontheobservedclinicaleffects,thefollowinggeneralmeasuresshouldalsobe

considered:

Bradycardia:atropineoranotheranticholinergicdrugshouldbegiveni.v.Whenthebradycardiacannotbetreated

sufficientlyapacemakermaybenecessary.

Bronchospasm:nebulisedbeta-2-sympathomimeticsshouldbegiven.Ifthisisnotsufficientintravenousbeta-2-

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Symptomatichypotension:fluidsand/orpressoragentsshouldbegiveni.v.

Cardiovasculardepressionorcardiacshock:diureticsorsympathomimeticscanbeadministered.Thedoseof

sympathomimetics(dependingonthesymptoms:dobutamine,dopamine,noradrenaline,isoprenaline,etc.)dependson

thetherapeuticeffect.

Incasefurthertreatmentisnecessary,thefollowingagentscanbegiveni.v.:

-Atropine:0.5-2mg

-Inotropicagents

-Calciumions

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Beta-blockingagents,selective

ATCcode:C07AB09

Esmololisaparenteraladministered,cardioselectivebeta-inhibitor.

Intherapeuticdosesesmololdoesnothaveintrinsicsympathicomimeticactivity(ISA)ofimportanceandnomembrane

stabilising(localanaesthetic)properties.

Basedonthepharmacologicalpropertiesesmololhasafastandshortactionbywhichthedosecanbequicklyadjusted:

Afterahighstartingdoseasteadystateplasmaconcentrationisreachedwithin5minutes(withoutstartingdose

in30minutes).However,thetherapeuticeffectissoonerobtainedthanthestabileplasmaconcentration.The

infusionratecanthenbeadjustedtoobtainthedesiredpharmacologicaleffect.

Esmololhydrochloridehastheknownhemodynamicandelectrophysiologiceffectofbeta-blockers:

Reductionoftheheartfrequencyduringrestandexercise

Reductionoftheisoprenalinecausedincreaseoftheheartfrequency

IncreaseoftherecoveringtimeoftheSA-node

DelayoftheAV-conductance

ProlongingtheAV-intervalwithnormalsinusrhythmandduringatriumstimulationwithoutdelayintheHis-

Purkinjetissue

ProlongingofPQtime,inductionofAVblockgradeII

Prolongingthefunctionalrefractoryperiodofatriaandventricles

Negativeinotropeeffectwithdecreasedejectionfraction

Decreaseinbloodpressure

PaediatricUse

Anuncontrolledpharmacokinetic/efficacystudywasundertakenin26paediatricpatientsaged2-16yearswith

supraventriculartachycardia(SVT).Aloadingdoseof1000micrograms/kgofesmololwasadministeredfollowedbya

continuousinfusionof300micrograms/kg/min.SVTwasterminatedin65%ofpatientswithin5minutesofthe

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Inarandomisedbutuncontrolleddosecomparisonstudy,efficacywasassessedin116paediatricpatientsaged1week

–7yearswithhypertensionfollowingrepairofcoarctationoftheaorta.Patientsreceivedaninitialinfusionofeither

125micrograms/kg,250micrograms/kg,or500micrograms/kg,followedbyacontinuousinfusionof125

micrograms/kg/min,250micrograms/kg/min,or500micrograms/kg/minrespectively.Therewasnosignificant

differenceinhypotensiveeffectbetweenthe3dosagegroups.54%ofpatientsoverallrequiredmedicationotherthan

esmololtoachievesatisfactorybloodpressurecontrol.Nodifferencewasapparentinthisregardbetweenthedifferent

dosegroups.

5.2Pharmacokineticproperties

Thekineticsofesmololarelinearinhealthyadults,theplasmaconcentrationisproportionaltothedose.Ifaloading

doseisnotusedthensteady-statebloodconcentrationsarereachedwithin30minuteswithdosesof50to300

micrograms/Kgperminute.

Thedistributionhalf-lifeofesmololhydrochlorideisveryfast,about2minutes.

Thevolumeofdistributionis3.4l/kg.

Esmololhydrochlorideismetabolisedbyesterasesintoanacidmetabolite(ASL-8123)andmethanol.Thisoccurs

throughhydrolysisoftheestergroupbyesterasesintheredbloodcells.

Themetabolismofesmololhydrochlorideisindependentwhenthedoseisbetween50and300micrograms/kg/minute.

Esmololhydrochlorideis55%boundtohumanplasmaproteincomparedwithonly10%fortheacidmetabolite.

Theeliminationhalf-lifeafterintravenousadministrationisapproximately9minutes.

Thetotalclearanceis285ml/kg/minute;thisisindependentofthecirculationoftheliveroranyotherorgan.Esmolol

hydrochlorideisexcretedbythekidneys,partlyunchanged(lessthan2%oftheadministeredamount),partlyasacid

metabolitethathasaweak(lessthan0.1%ofesmolol)beta-blockingactivity.Theacidmetaboliteisexcretedinthe

urineandhasahalf-lifeofabout3.7hours.

Children

Apharmacokineticstudywasundertakenin22paediatricpatientsaged3-16years.Aloadingdoseof1000

micrograms/kgofesmololwasadministeredfollowedbyacontinuousinfusionof300micrograms/kg/min.The

observedmeantotalbodyclearancewas119mL/kg/min,themeanvolumeofdistribution283mL/kgandthemean

terminaleliminationhalf-life6.9min,indicatingthatesmololkineticsinchildrenaresimilartothoseinadults.

However,largeinter-individualvariabilitywasobserved.

5.3Preclinicalsafetydata

Noteratogeniceffecthasbeenobservedinanimalstudies.Inrabbitsanembryotoxiceffecthasbeenobserved

(increaseinfetalresorption)whichwasprobablycausedbyesmolol.Thiseffectwasobservedatdosesatleast10times

higherthanthetherapeuticdose.Nostudieshavebeendoneontheeffectofesmololonthefertilityandonperi-and

postnataleffects.Esmololwasfoundtobenotmutagenicinseveralinvitroandinvivotestsystems.Thesafetyof

esmololhasnotbeenexaminedinlong-termstudies.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Sodiumacetatetrihydrate

Aceticacid99%

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Ethanol96%

Hydrochloricacid10%(forpHadjustment)

Waterforinjections

6.2Incompatibilities

Esmocard2500mg/10mlconcentrateforsolutionforinfusionmustbedilutedbeforeuse.

Esmocard2500mg/10mlconcentrateforsolutionforinfusionMUSTNOTbemixedwithothermedicinalproductsor

sodiumcarbonatesolutionsexceptthosementionedinsection6.6.

6.3Shelflife

18months.

Chemicalandphysicalinusestabilityhasbeendemonstratedfor24hoursat2to8°C.

Fromamicrobiologicalpointofview,theproductshouldbeusedimmediately.Ifnotusedimmediately,in-usestorage

timesandconditionsaretheresponsibilityoftheuserandwouldnormallynotbelongerthan24hoursat2to8°C

unlessopeninganddilutionhavetakenplaceincontrolledandvalidatedasepticconditions.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.

Keeptheampouleintheoutercartoninordertoprotectfromlight.

Forstorageconditionsofthereconstitutedsolutionseesection6.3.

6.5Natureandcontentsofcontainer

Eachampouleof10mlsolutioncontains2500mgesmololhydrochloride(250mg/ml).

Aclear,colourlessglassampoulewithabreakring,containing10mlconcentrateforsolutionforinfusion.The

ampouleispackedinanoutercardboardcarton.

Packsize:1ampoulepercarton.

6.6Specialprecautionsfordisposalandotherhandling

THE2500mg/10mlAMPOULEISNOTFORDIRECTINTRAVENOUSINJECTION!

Dilutethecontentof2ampoulesto500mlinabottlewiththeappropriatesolutiontoobtainaconcentrationof

10mg/ml.

Esmocard2500mg/10mlconcentrateforsolutionforinfusioncanbeadministeredinnormalglassorPVCsets,after

dilution.

Esmocard2500mg/10mlconcentrateforsolutionforinfusionappearedtobesuitableforcombinationwiththe

followingcommonlyusedintravenouslyadministeredliquids,inglassaswellasinPVCbottles,whenthe

concentrationofesmololhydrochlorideis10mg/ml.

Glucose5%solution

Glucose5%inRinger’ssolution

Glucose5%inNaCl0.45%solution

Glucose5%inNaCl0.9%solution

Glucose5%inRinger-lactatesolution

Ringer-lactatesolution

NaCl(0.45%)solution

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KCl(40mEq/l)inglucosesolution

Thereconstitutedsolutionshouldbeexaminedvisuallyforparticulatematteranddiscolorationpriortoadministration.

Onlyaclearandcolourlesssolutionshouldbeused.Anyunusedsolutionandthecontainersshouldbedisposedofin

accordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

Orpha-DevelHandelsundVertriebsGmbH

Wintergasse85/1B

A-3002Purkersdorf

Austria

8MARKETINGAUTHORISATIONNUMBER

PA1353/1/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:7thMarch2008

Dateoflastrenewal:31stAugust2010

10DATEOFREVISIONOFTHETEXT

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