FUROSEMIDE PFIZER

Main information

  • Trade name:
  • FUROSEMIDE PFIZER
  • Dosage:
  • 10 Mg/Ml
  • Pharmaceutical form:
  • Solution for Injection
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • FUROSEMIDE PFIZER
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0822/026/001
  • Authorization date:
  • 21-12-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

FurosemidePfizer10mg/mlSolutionforInjection

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Each1mlsolutioncontains10mgfurosemide.

Each2mlampoulecontains20mgoffurosemide(20mg/2ml)

Each5mlampoulecontains50mgoffurosemide(50mg/5ml)

ExcipientsSodium0.3mmolper2ml.

Forafulllistofexcipients,seesection6

3PHARMACEUTICALFORM

Solutionforinjection.

Aclearandcolourlesssolution,essentiallyfreefromvisibleparticles.

pHofthesolutionisbetween8.00and9.30.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Whenapromptdiuresisisrequired.Useinemergenciesorwhenoraltherapyisprecluded.Indicationsinclude:

-Oedemaand/orascitescausedbycardiacorhepaticdiseases

-Oedemacausedbyrenaldiseases(incaseofnephroticsyndrome,treatmentoftheunderlyingdiseaseisessential)

-Pulmonaryoedema(e.g.incaseofacuteheartfailure)

-Hypertensivecrisis(inadditiontoothertherapeuticmeasures)

4.2Posologyandmethodofadministration

Routeofadministration:intravenousor(inexceptionalcases)intramuscular

General:

Theparenteraladministrationoffurosemideisindicatedincaseswhereoraladministrationisnotfeasibleornot

efficient(forexampleincaseofreducedintestinalabsorption)orwhenaquickeffectisrequired.Toachieveoptimum

efficacyandsuppresscounter-regulation,acontinuousfurosemideinfusionisgenerallytobepreferredtorepeated

bolusinjections.

Wherecontinuousfurosemideinfusionisnotfeasibleforfollow-uptreatmentafteroneorseveralacutebolusdoses,a

follow-upregimenwithlowdosesgivenatshortintervals(approx.4hours)istobepreferredtoaregimenwithhigher

bolusdosesatlongerintervals.

Therapyshouldbeindividualizedaccordingtopatientresponsetogainmaximaltherapeuticresponseandtodetermine

theminimaldoseneededtomaintainthatresponse.

Intravenousfurosemidemustbeinjectedorinfusedslowly;arateof4mgperminutemustnotbeexceededandshould

neverbegiveninassociationwithothermedicinalproductsinthesamesyringe.

Generally,Furosemideshouldbeadministeredintravenously.Intramuscularadministrationmustberestrictedto

exceptionalcaseswhereneitheroralnorintravenousadministrationisfeasible.Itmustbenotedthatintramuscular

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Adults:

Intheabsenceofconditionsrequiringareduceddose(seebelow)theinitialdoserecommendedforadultsand

adolescentsover15years,isof20mgto40mgfurosemide(1or2ampoules)byintravenous(orinexceptionalcases

intramuscular)administration;themaximumdosevaryingaccordingtoindividualresponse.

Iflargerdosesarerequired,theyshouldbegivenincreasingby20mgincrementsandnotgivenmoreoftenthanevery

twohours.

Inadults,therecommendedmaximumdailydoseoffurosemideadministrationis1500mg.

Theparenteraladministrationoffurosemideisindicatedincaseswhereoraladministrationisnotfeasibleornot

efficient(forexampleincaseofreducedintestinalabsorption)orwhenaquickeffectisrequired.Incaseswhere

parenteraladministrationisused,theswitchtooraladministrationisrecommended,assoonaspossible.

Childrenandadolescents(upto18yearsofage):

Theexperienceinchildrenandadolescentsarelimited.Theintravenousadministrationoffurosemidetochildrenand

adolescentsbelow15yearsisonlyrecommendedinexceptionalcases.

Thedosagewillbeadaptedtothebodyweight,andtherecommendeddoserangesfrom0.5to1mg/kgbodyweight

dailyuptoamaximumtotaldailydoseof20mg.

Thereshouldbeaswitchtooraltherapyassoonaspossible.

Renalimpairment:

Inpatientswithsevereimpairmentofrenalfunction(serumcreatinine>5mg/dl)itisrecommendedthataninfusion

rateof2.5mgfurosemideperminuteisnotexceeded.

Elderly:

Therecommendedinitialdoseis20mg/day,increasinggraduallyuntiltherequiredresponseisachieved.

Specialdosagerecommendations:

Foradults,thedoseisbasedonthefollowingconditions:

-Oedemaassociatedtochronicandacutecongestiveheartfailure

Therecommendedinitialdoseis20to40mgdaily.Thisdosecanbeadaptedtothepatient´sresponse,asnecessary.

Thedoseshouldbegivenintwoorthreeindividualdosesperdayforchroniccongestiveheartfailureandasabolus

foracutecongestiveheartfailure.

-Oedemaassociatedwithrenaldisease

Therecommendedinitialdoseis20to40mgdaily.Thisdosecanbeadaptedtotheresponseasnecessary.Thetotal

dailydosecanbeadministeredasasingledoseorasseveraldosesthroughouttheday.

Ifthisdoesnotleadtoanoptimalfluidexcretionincrease,furosemidemustbeadministeredincontinuous

intravenousinfusion,withaninitialrateof50mgto100mgperhour.

Beforebeginningtheadministrationoffurosemide,hypovolaemia,hypotensionandacid-baseandelectrolytic

imbalancesmustbecorrected.

Indialyzedpatients,theusualmaintenancedoserangesfrom250mgto1,500mgdaily.

Inpatientswithnephroticsyndromethedosagemustbedeterminedwithcaution,becauseoftheriskofahigher

incidenceofadverseevents.

-Oedemaassociatedwithhepaticdisease

Whenintravenoustreatmentisabsolutelyneeded,theinitialdoseshouldrangefrom20mgto40mg.Thisdosecan

beadaptedtotheresponseasnecessary.Thetotaldailydosecanbeadministeredasasingledoseorinseveral

doses.

Furosemidecanbeusedincombinationwithaldosteroneantagonistsincasesinwhichtheseagentsinmonotherapy

arenotsufficient.Inordertoavoidcomplicationssuchasorthostaticintoleranceoracid-baseandelectrolytic

imbalancesorhepaticencephalopathy,thedosemustbecarefullyadjustedtoachieveagradualfluidloss.Thedose

mayproduceinadultsadailybodyweightlossofapproximately0.5kg.

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-Pulmonaryoedema(inacuteheartfailure)

Theinitialdosetobeadministeredis40mgfurosemidebyintravenousapplication.Ifrequiredbytheconditionof

thepatient,anotherinjectionof20to40mgfurosemideisgivenafter30–60minutes.

Furosemideshouldbeusedinadditiontoothertherapeuticmeasures.

-Hypertensivecrisis(inadditiontoothertherapeuticmeasures)

Therecommendedinitialdoseinhypertensivecrisisis20mgto40mgadministratedinbolusbyintravenous

injection.Thisdosecanbeadaptedtotheresponseasnecessary.

4.3Contraindications

-Hypersensitivitytotheactivesubstance”furosemide”ortoanyoftheexcipients.

–Patientswithanuriaorrenalfailurewitholigoanurianotrespondingtofurosemide

–Renalfailureasaresultofpoisoningbynephrotoxicorhepatotoxicagents

–Renalfailureassociatedwithhepaticcoma

–Patientswithseverehypokalaemiaorseverehyponatraemia

–Patientswithhypovolaemia(withorwithouthypotension)ordehydration

–Patientsinpre-comatoseandcomatosestateassociatedwithhepaticencephalopathy

–Patientswithhypersensitivitytosulphonamides(e.g.Sulfonyureasorantibioticsofsulphonamidesgroup)mayshow

cross-sensitivitytofurosemide

–Lactation(seesection4.6)

4.4Specialwarningsandprecautionsforuse

Carefulmonitoringisrequiredincaseof:

-Patientswithpartialobstructionofurinaryoutflow(e.g.prostatichypertrophy,hydronephrosis,ureterostenosis).

Urinaryoutputmustbesecured

-Patientswithhypotensionoratincreasedriskfrompronouncedfallinbloodpressure(patientswithcoronaryartery

stenosisorcerebralarterystenosis)

-Patientswithmanifestorlatentdiabetesmellitusorvariationofglycaemia(regularmonitoringofbloodglucose

levelsnecessary)

-Patientswithgoutandhyperuricaemia(regularmonitoringofuricacidlevelsinserumnecessary)

-Patientswithhepaticdiseaseorhepatorenalsyndrome(renalimpairmentassociatedtoseverehepaticdisease)

-Hypoproteinaemia(associatedtonephroticsyndrome,furosemide´seffectmaybereducedanditsototoxicity

increased)

-Co-administrationwithlithiumsalts(monitoringoflithiumlevelsisrequired,seesection4.5)

-Acuteporphyria(theuseofdiureticsisconsideredtobeunsafeinacuteporphyriaandcautionshouldbeexercised)

-Incasesofasciteswithoedema,weightlossinducedbyenhanceddiuresisshouldnotexceed1kg/day

-Toovigorousdiuresismaycauseorthostatichypotensionoracutehypotensiveepisodes.

-NSAIDsmayantagonisethediureticeffectoffurosemideandotherdiuretics.UseofNSAIDswithdiureticsmay

increasetheriskofnephrotoxicity.

-Whereindicated,stepsshouldbetakentocorrecthypotensionorhypovolaemiabeforecommencingtherapy.

Cautiousdosetitrationisrequired:

-Electrolytevariations(e.g.hypokalaemia,hyponatraemia).Potassiumsupplementsand/ordietarymeasuresmaybe

neededtocontroloravoidhypokalemia

-Fluidvariations,dehydration,bloodvolumereductionwithcirculatorycollapseandpossibilityofthrombosisand

embolism,particularinelderly,withexcessiveuse

-Ototoxicity(ifadministeredfasterthan4mg/min-otherototoxiccompoundsadministeredconcomitantlycan

increasethisrisk,seesection4.5

-Administrationofhighdosages

-Administrationinprogressiveandsevererenaldisease

-Administrationwithsorbitol.Concomitantadministrationofbothsubstancesmayleadtoincreaseddehydratation

(sorbitolmightcauseadditionalfluidlossbyinducingdiarrhoea)

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-MedicationthatprolongtheQTinterval

Prematureinfants(possibledevelopmentofnephrocalcinosis/nephrolithiasis;renalfunctionmustbemonitoredand

renalultrasonographyperformed).Inprematureinfantswithrespiratorydistresssyndrome,diuretictreatmentwith

furosemideduringthefirstweeksoflifecanincreasetheriskofpersistentductusarteriosusBotalli.

Cautionshouldbeobservedinpatientsliabletoelectrolytedeficiency.

Regularmonitoringofserumsodium,potassiumandcreatinineisgenerallyrecommendedduringfurosemidetherapy;

particularlyclosemonitoringisrequiredinpatientsathighriskofdevelopingelectrolyteimbalancesorincaseof

significantadditionalfluidloss.(e.g.duetovomitingordiarrhoea).

Hypovolaemiaordehydrationaswellasanysignificantelectrolyteandacid-basedisturbancesmustbecorrected.This

mayrequiretemporarydiscontinuationoffurosemide.

Inpatientswhoareathighriskforradiocontrastnephropathy,furosemideisnotrecommendedtobeusedfordiuresis

aspartofthepreventativemeasuresagainstradiocontrast-inducednephropathy.

Concomitantusewithrisperidone

Inrisperidoneplacebo-controlledtrialsinelderlypatientswithdementia,ahigherincidenceofmortalitywasobserved

inpatientstreatedwithfurosemideplusrisperidone(7.3%;meanage89years,range75-97years)whencomparedto

patientstreatedwithrisperidonealone(3.1%;meanage84years,range70-96years)orfurosemidealone(4.1%;mean

age80years,range67-90years).Concomitantuseofrisperidonewithotherdiuretics(mainlythiazidediureticsusedin

lowdose)wasnotassociatedwithsimilarfindings.

Nopathophysiologicalmechanismhasbeenidentifiedtoexplainthisfinding,andnoconsistentpatternforcauseof

deathobserved.Nevertheless,cautionshouldbeexercisedandtherisksandbenefitsofthiscombinationorco-

treatmentwithotherpotentdiureticsshouldbeconsideredpriortothedecisiontouse.Therewasnoincreased

incidenceofmortalityamongpatientstakingotherdiureticsasconcomitanttreatmentwithrisperidone.Irrespectiveof

treatment,dehydrationwasanoverallriskfactorformortalityandshouldthereforebeavoidedinelderlypatientswith

dementia(seesection4.3Contraindications).

Photosensitivity:Casesofphotosensitivityreactionshavebeenreported.Ifphotosensitivityreactionoccursduring

treatment,itisrecommendedtostopthetreatment.Ifare-administrationisdeemednecessary,itisrecommendedto

protectexposedareastothesunortoartificialUVA.

Thismedicinalproductcontains0.6mmolsodiumperdoseof40mg.Tobetakenintoconsiderationbypatientsona

controlledsodiumdiet.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Notrecommendedcombinations

Lithium:

Lithiumexcretionlevelsmaybereducedbyfurosemide,resultinginincreasedcardiotoxiceffectandlithiumtoxicity.

Therefore,thiscombinationisnotrecommended(seesection4.4).Ifthiscombinationisdeemednecessarylithium

levelsshouldbecarefullymonitoredandlithiumdosageshouldbeadjusted.

Risperidone:

Cautionshouldbeexercisedandtherisksandbenefitsofthecombinationorco-treatmentwithfurosemideorwith

otherpotentdiureticsshouldbeconsideredpriortothedecisiontouse.Seesection4.4Specialwarningsand

precautionsforuseregardingincreasedmortalityinelderlypatientswithdementiaconcomitantlyreceivingrisperidone.

Combinationsrequiringacautionforuse

Ototoxicdrugs(e.g.aminoglycosides,cisplatin):

Furosemidemayintensifytheototoxicityofcertaindrugs,forexamplecisplatinoraminoglycosideantibioticssuchas

kanamycin,gentamicinandtobramycin,inparticularinpatientswithrenalimpairment.Sincethismayleadto

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ChloralHydrate:

Inisolatedcases,theintravenousadministrationoffurosemideina24hourperiodpriortochloralhydrate

administrationmayleadtoflush,hyperhidrosis,anxiety,nausea,increaseinbloodpressureandtachycardia.Therefore,

thesimultaneousadministrationoffurosemideandchloralhydrateisnotrecommended.

Carbamazepineandaminoglutethimide:

Concomitantadministrationofcarbamazepineoraminoglutethimidemayincreasetheriskofhyponatraemia.

Otheranti-hypertensiveagents:

Theeffectofothercertainanti-hypertensiveagents(diureticsandotherdrugsthatlowbloodpressure)maybe

potentiatedbyconcurrentadministrationoffurosemide.

Inhibitorsoftheangiotensinconvertingenzyme(ACE)andAngiotensinIIreceptorantagonists:

Theeffectsofotherantihypertensivescanbepotentiatedbyconcomitantadministrationoffurosemide.Severefallin

bloodpressurewithshockinextremecasesanddeteriorationofrenalfunction(acuterenalfailureinisolatedcases)

havebeenobservedincombinationwithACEinhibitors,whentheACEinhibitorwasadministeredforthefirsttime,or

forthefirsttimeathighdosage(firstdosehypotension).Ifpossible,furosemidetherapyshouldbetemporarily

discontinued(oratleastthedosereduced)forthreedaysbeforetherapywithanACEinhibitororanAngiotensinII

receptorantagonistsisinitiatedorthedoseofanACEinhibitororAngiotensinIIreceptorantagonistsisincreased.

Patientstakingdiureticsmaysufferaccentuatedhypotensionanddeteriorationofrenalfunction;renalimpairmentmay

alsooccurduringthefirstconcurrentadministration,orwiththefirstadministrationofhighdosesofACEorofan

antagonistoftheangiotensinIIreceptor.

Thiazides:

Asynergeticeffectofdiuresisoccursasresultofinteractionoffurosemideandthiazides.

Anti-diabeticagents:

Adecreaseinglucosetolerancemayoccur,sincefurosemidemayreducethesedrugsaction.

Metformin:

Thebloodlevelsofmetforminmaybeincreasedbyfurosemide.Inversely,metforminmayreducefurosemide

concentration.Theriskislinkedtoanincreasedoccurrenceoflacticacidosisincaseoffunctionalrenalinsufficiency.

Cardiacglycosides(e.g.digoxin)andothermedicinalproductsthatmaycauseprolongationoftheQT-interval:

Adecreaseofpotassiumlevelsmayincreasedigitalistoxicity;forthisreason,potassiumlevelsshouldbemonitored.

Someelectrolytedisturbancesmayincreasethetoxicityofcertainconcomitantlyadministereddrugsthatmaycause

prolongationoftheQTinterval.e.g.(classIaantiarrhythmicsandclassIIIantiarrhythmicslikeamiodarone,sotalol,

dofetilide,ibutilideandquinolones).MonitoringofpotassiumplasmalevelsandECGarerecommended.

Fibrates:

Bloodlevelsoffurosemideandoffibricacidderivates(forexampleclofibrateandfenofibrate)maybeincreasedduring

concurrentadministration(particularlyincaseofhypoalbuminaemia).Theincreaseofitseffect/toxicityshouldbe

monitored.

Non-steroidalanti-inflammatoryagentsandhighdosesofsalicylates:

Non-steroidalanti-inflammatoryagents(includingcoxibs)mayinduceacuterenalfailureincasesofpre-existing

hypovolaemiaandreduceitsdiuretic,natriureticandantihypertensiveeffect.Whenco-administeredwithhighdosesof

salicylates,

thepredispositionforsalicylictoxicitymaybeincreasedduetoareducedrenalexcretionortoamodifiedrenal

function.

Nephrotoxicdrugs(e.g.polymyxins,aminoglycosides,cephalosporinsorganoplatins,immunosuppressants,iodinated

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Furosemidemayintensifythenephrotoxiceffectsofnephrotoxicdrugs.

Antibioticslikecephalosporins-impairmentofrenalfunctionmaydevelopinpatientsreceivingtreatmentwith

furosemideandhighdosesofcertaincephalosporins.

Thereisariskofcytotoxiceffectsifcisplatinandfurosemidearegivenconcomitantly.

Inaddition,Nephrotoxicityofcisplatinmaybeenhancediffurosemideinnotgiveninlowdoses(e.g.40mginpatients

withnormalrenalfunction)andwithpositivefluidbalance,whenusedtoachieveforceddiuresisduringcisplatin

treatment.

Drugsthatundergosignificantrenaltubularsecretion:

Probenecid,methotrexateandotherdrugswhich,likefurosemide,undergosignificantrenaltubularsecretionmay

reducetheeffectoffurosemide.Conversely,furosemidemaydecreaserenaleliminationoftheseproducts.Incaseof

high-dosetreatment(inparticular,ofbothfurosemideandtheothermedicinalproducts),thismayleadtoincreased

serumlevelsandanincreasedriskofadverseeffectsduetofurosemideortheconcomitantmedication.

Peripheraladrenergicinhibitors:

Theseagents´effectsmaybeenhancedbythesimultaneousadministrationoffurosemide.

Phenobarbitalandphenytoin:

Attenuationoftheeffectoffurosemidemayoccurfollowingconcurrentadministrationofthesedrugs.

Tubocurarine,curarinederivativesandsuccinylcholine:

Themusclerelaxingeffectoftheseagentsmaybeenhancedorprolongedbyfurosemide.

Glucocorticoids,carbenoxolone,AmphotericinB,PenicillinG,ACTH,laxativesandliquorice:

Co-administrationoffurosemidewithglucocorticoids,carbenoxolone,largeamountofliquoriceorprolongeuseof

laxativesmayincreasepotassiumloss.Intheassociationwithglucocorticoids,hypokalaemiashouldbeconsideredand

itsaggravationwiththeoveruseoflaxatives.Since,thismayleadtoirreversiblehearingdamages,thiscombination

shouldonlybeusediftherearecompellingmedicalreasons.

Potassiumlevelsshouldbemonitored.

Sucralfate:

Simultaneousadministrationofsucralfateandfurosemidemayreducethenatriureticandantihypertensiveeffectsof

furosemide.Patientsreceivingbothdrugsshouldbeobservedcloselytodetermineifthedesireddiureticand/or

antihypertensiveeffectoffurosemideisachieved.Theintakeoffurosemideandsucralfateshouldbeseparatedbyat

leasttwohours.

Oralanticoagulants:

Furosemidincreasestheeffectsoforalanticoagulants.

Theophylline:

Theeffectsoftheophyllineandofcurare-typemusclerelaxantsmaybepotentiated.

Pressoramines(e.g.adrenaline(epinephrine),noradrenaline(norepinephrine)):

Concomitantuseoffurosemidemayattenuatetheeffectsofpressoramines.

Otherinteractions:

Concomitantuseofciclosporinandfurosemideisassociatedwithincreasedriskofgoutyarthritis.

4.6Fertility,pregnancyandlactation

Useduringpregnancy

Furosemideshouldnotbegivenduringpregnancyunlesstherearecompellingmedicalreasons.Furosemidecrossesthe

placentalbarrier,andcanthereforecauseadiuresisofthefetus.Treatmentduringpregnancyrequiresmonitoringof

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Treatmentofpregnancyhypertensionandoedemaisingeneralnotrecommended,asphysiologicalhypovolemiacanbe

inducedwhichcausesreductionofplacentalperfusion.

Ifuseoffurosemideisessentialforthetreatmentofcardiacorrenalinsufficiencyduringpregnancy,carefulmonitoring

ofelectrolytes,haematocritandfetalgrowthisessential.Possibledisplacementofbilirubinfromalbuminbindingand

thuselevatedriskofnuclearicterusinhyperbilirubinaemiaisdiscussedforfurosemide.Furosemidecanpredisposethe

fetustohypercalciuria,nephrocalcinosis,andsecondaryhyperparathyroidism.

Furosemidereaches100%ofthematernalserumconcentrationincordblood.Nomalformationsinhumanswhich

mightbeassociatedwithexposuretofurosemidehavebeenreportedtodate.However,thereislimitedexperienceto

allowaconclusiveevaluationofapotentialdamagingeffectintheembryo/fetus.

Useduringlactation

Furosemidepassesintobreastmilkandmayinhibitlactation.Womenmustnotbreast-feediftheyaretreatedwith

furosemide(seesection4.3).

4.7Effectsonabilitytodriveandusemachines

Furosemidehasnegligibleinfluenceontheabilitytodriveandusemachines.

PatientsrespondindividuallytoFurosemide.

Theabilitytodriveoroperatemachinescanincidentallybereducedbecauseoftreatmentwithfurosemide,especiallyat

thestartoftherapy,changeofmedicationorincombinationwithalcohol.

4.8Undesirableeffects

Theevaluationofadversereactionsisbasedonthefollowingdefinitionoffrequency:

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);notknown(cannotbeestimatedfromtheavailabledata).

Bloodandlymphaticsystemdisorders

Uncommon:thrombocytopenia;thrombocytopeniamaybecomemanifest,especiallywithanincreaseofhaemorrhage

tendency.

Rare:eosinophilia,leukopenia,bonemarrowdepression;occurrenceofthissymptomnecessitateswithdrawalof

treatment.

Veryrare:haemolyticanaemia,aplasticanaemia,agranulocytosis.

Severefluiddepletionmayleadtohaemoconcentrationwithatendencyforthrombosestodevelopespeciallyinelder

patients.

Immunesystemdisorders

Rare:severeanaphylacticandanaphylactoidreactionssuchasanaphylacticshock(fortreatmentseesection4.9).

Endocrinedisorders

Glucosetolerancemaydecreasewithfurosemide.Inpatientswithdiabetesmellitusthismayleadtoadeteriorationof

themetaboliccontrol;latentdiabetesmellitusmaybecomemanifest.

Metabolismandnutritiondisorders

Hypokalaemia,hyponatraemiaandmetabolicalkalosismayoccur,especiallyafterprolongedtherapyorwhenhigh

dosesareadministered.Regularmonitoringofserumelectrolytes(especiallypotassium,sodiumandcalcium)is

thereforeindicated.

Potassiumdepletionmayoccur,especiallyduetopoorpotassiumdiet.Particularywhenthesupplyofpotassiumis

concomitantlyreducedand/orextrarenalpotassiumlossesareincreased(e.g.invomitingorchronicdiarrhoea)

hypokalaemiamayoccurasaresultofincreasedrenalpotassiumlosses.

Underlyingdisorders(e.g.cirrhoticdiseaseorheartfailure),concomitantmedication(seesection4.5)andnutrition

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substitution.

Asaresultofincreasedrenalsodiumlosses,hyponatraemiawithcorrespondingsymptomsmayoccur,particularlyif

thesupplyofsodiumchlorideisrestricted.

Increasedrenalcalciumlossescanleadtohypocalcaemia,whichmayinducetetaniainrarecases.

Inpatientswithincreasedrenalmagnesiumlosses,tetaniaorcardiacarrhythmiaswereobservedinrarecasesasa

consequenceofhypomagnesaemia.

Uricacidlevelsmayincreaseandgoutattacksmayoccur.

Metabolicalkalosismaydevelop,orpre-existingmetabolicalkalosis(fore.g.decompensatedhepaticcirrhosis)may

becomemoreseverewithfurosemide.

Nervoussystemdisorders

Rare:paraesthesia,vertigo,dizziness,sleepiness,confusion,sensationsofpressureinthehead.

Eyedisorders

Rare:aggravationofmyopia,blurredvision;disturbancesofvisionwithhypovolaemiasymptoms.

Earandlabyrinthdisorders

Rare:dysacusisand/orsyrigmus(tinnitusaurium)duetofurosemidearerareandusuallytransitory;incidenceishigher

inrapidintravenousadministration,particularlyinpatientswithrenalfailureorhypoproteinaemia(e.g.innephrotic

syndrome).

Cardiacdisorders

Inparticular,attheinitialstateoftreatmentandinelderly,averyintensediuresismaycauseareductioninblood

pressurewhich,ifpronouncedmaycausesignsandsymptomssuchasorthostatichypotension,acutehypotension,

sensationsofpressureinthehead,dizziness,circulatorycollapse,thrombophlebitisorsuddendeath(withi.m.ori.v.

administration).

Gastrointestinaldisorders

Rare:nausea,vomiting,diarrhoea,anorexia,gastricdistress,constipation,drymouth.

Hepato-biliarydisorders

Veryrare:acutepancreatitis,intrahepaticcholestasis,cholestasisjaundice,hepaticischaemia,increasesinhepatic

transaminases.

Skinandsubcutaneoustissuedisorders

Uncommon:pruritus,dermalandmucosalreactions(e.g.bullousexanthema,rash,urticaria,purpura,erythema

multiforme,exfoliativedermatitis,photosensitivity)

Rare:vasculitis,lupuserythematosusexacerbationoractivation.

Musculoskeletalandconnectivetissuedisorders

Rare:legmusclecramps,asthenia.chronicarthritis.

Renalandurinarydisorders

Diureticsmayexacerbateorrevealacuteretentionofurinesymptoms(bladder-emptyingdisorders,prostatic

hyperplasiaornarrowingoftheurethra),vasculitis,glycosuria,transitorilyincreaseofbloodcreatinineandurealevels.

Rare:interstitialnephritis.

Pregnancy,puerperiumandperinatalconditions

Prematureinfantstreatedwithfurosemidemaydevelopnephrocalcinosisand/ornephrolithiasis;duetocalciumdeposit

inrenaltissue.

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increasetheriskofpersistentductusarteriosusBotalli.

Generaldisordersandadministrationsiteconditions

Rare:febrileconditions;followingi.m.injectionlocalreactionssuchaspainmayappear.

Investigations

Rare:serumcholesterolandtriglyceridelevelsmayriseduringfurosemidetreatment.

4.9Overdose

Theclinicalpictureinacuteorchronicoverdosedependsprimarilyontheextentandconsequencesofelectrolyteand

fluidloss(e.g.hypovolaemia,dehydration,haemoconcentration,cardiacarrhythmias-includingAVblockageand

ventricularfibrillation)duetoexcessivediuresis.

Symptoms:

Symptomsofthesedisturbancesincludeseverehypotension(progressingtoshock),acuterenalfailure,thrombosis,

deliriousstates,flaccidparalysis,apathyandconfusion.

Treatment:

Atthefirstsignsofshock(hypotension,sudoresis,nausea,cyanosis)theinjectionshouldbeimmediatelyinterrupted,

placethepatientheaddownandallowfreebreathing.

Fluidreplacementandcorrectionoftheelectrolyteimbalance;monitoringofmetabolicfunctions,andmaintenanceof

urinaryflux.

Medicinaltreatmentincaseofanaphylacticshock:dilute1mlof1:1000adrenalinesolutionin10mlandinjectslowly

1mlofthesolution(correspondingto0.1mgofadrenaline),controlpulseandtensionandmonitoreventual

arrhythmias.Adrenalineadministrationmayberepeated,ifnecessary.Subsequently,injectintravenouslya

glucocorticoid(forexample250mgofmethylprednisolone),repeatingifnecessary.

Adapttheabove-mentioneddosagesforchildren,accordingbodyweight.

Correcthypovolaemiawithavailablemeansandcomplementwithartificialventilation,oxygenandincaseof

anaphylacticshockwithanti-histamines.

Nospecificantidotetofurosemideisknown.Ifoverdoseduringparenteraltreatmenthastakenplace,inprinciplethe

treatmentconsistsonfollowupandsupportivetherapy.Haemodialysisdoesnotacceleratefurosemideelimination.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Diuretic,Sulfonamides,plain

ATCcode:CO3CA01

Furosemideisastrongdiureticagentoffastaction.Fromapharmacologicalpointofview,furosemideinhibitstheco-

transportsystem(reabsorption)ofthefollowingelectrolytesNa,Kand2CL,locatedontheluminalcellmembrane

ontheascendinglimboftheloopofHenle.Consequently,furosemide´sefficiencydependsonthedrugreachingthe

tubularlumenthroughananionictransportmechanism.Thediureticeffectresultsontheinhibitionofsodiumchloride

reabsorptioninthissegmentoftheloopofHenle.Asaresult,thefractionofexcretedsodiummayascendto35%of

sodiumglomerularfiltration.Thesecondaryeffectsofincreasedeliminationofsodiumare:increaseofurinary

excretionandincreaseofpotassiumdistalsecretionatthedistaltube.Excretionofcalciumandmagnesiumsaltsisalso

increased.

Furosemideinhibitsthefeedbackmechanisminthedensemaculaandinducesdose-dependentstimulationoftherenin-

angiotensin-aldosteronesystem.

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bloodvesselscapacity).Thisearlyvasculareffectseemstobemediatedbyprostaglandinsandassumesanadequate

renalfunctionwithactivationoftherenin-angiotensinsystemandanintactsynthesisofprostaglandins.Duetoits

natriureticeffect,furosemidereducesthevascularreactivitytocatecholaminethatisincreasedinhypertensivepatients.

Thediureticeffectoffurosemideisestablishedwithin15minutesofanintravenousadministration.

Adose-dependentincreaseindiuresisandnatriuresiswasfoundinhealthyindividualstowhomfurosemidewas

administerd(dosesbetween10and100mg).Thedurationofactioninhealthyindividualsaftertheadministrationofan

intravenous20mgdoseoffurosemideisapproximately3hoursand3to6hours,whenanoral40mgdoseisgiven.

Inillpatients,therelationbetweentubularconcentrationoffreefurosemideandboundfurosemide(determinedthrough

theurineexcretionrate)anditsnatriureticeffectistranslatedinasigmoidgraphic,withaminimumeffectiveexcretion

rateofapproximately10microgramsperminute.Consequently,acontinuousinfusionoffurosemideismoreeffective

thanrepeatedbolusinjections.Aboveacertainbolusadministrationdose,thedrugseffectsdonotsignificantly

increase.Theefficacyoffurosemideisdecreasedincasesofreducedtubularsecretionorincasesofintra-tubular

bindingofthedrugtoalbumin.

5.2Pharmacokineticproperties

Distribution

Furosemidedistributionvolumeis0.1to1.2litresperkgofbodyweight.Thedistributionvolumemaybeincreased

dependingontheconcomitantillness.

Proteinbinding(mostlytoalbumin)ishigherthan98%.

Elimination

Furosemideismostlyeliminatedasthenon-conjugatedform,mainlythroughsecretionattheproximaltube.After

intravenousadministration,60%to70%offurosemideiseliminatedbythismanner.Theglucuronicmetaboliteof

furosemiderepresents10%to20%oftherecoveredsubstancesintheurine.Theremainingdoseiseliminatedinthe

faeces,probablyafterbiliarysecretion.Afterintravenousadministration,theplasmahalf-lifeoffurosemideranges

from1to1.5hours.

Furosemideisexcretedinbreastmilk.Itcrossestheplacentalbarriertransferringitselfslowlytothefoetus.

Furosemideachievessimilarconcentrationsinthemother,foetusandnewborn.

Renalimpairment

Incaseofrenalimpairment,furosemide´seliminationissloweranditshalf-lifeisincreased.Inpatientswithend-stage

renaldiseasetheaveragehalf-lifeis9.7hours.Inseveralmulti-organfailurethehalflifemayrangefrom20-24hours.

Incaseofnephroticsyndrome,thelowerconcentrationofplasmaproteinsleadstohigherconcentrationsofunbound

furosemide.Ontheotherhand,theefficiencyoffurosemideisreducedinthesepatients,duetointratubularalbumin

bindingandtoreducedtubularsecretion.

Furosemideexhibitslowdialysisinpatientsundergoinghaemodialysis,peritonealdialysisorCAPD(Chronic

AmbulatoryPeritonealDialysis).

Hepaticimpairment

Incaseofhepaticimpairment,furosemide´shalf-lifeincreases30%to90%,mainlyduetothehigherdistribution

volume.Biliaryeliminationmightbereduced(upto50%).Inthisgroupofpatients,thereisawidervariabilityofthe

pharmacokineticparameters.

Congestiveheartfailure,severehypertension,elderly

Furosemideeliminationisslowerduetoreducedrenalfunctioninpatientswithcongestiveheartfailure,severe

hypertensionorinelderly.

Prematureinfantsandnew-born

Dependingonthematurityofthekidney,eliminationoffurosemidemaybeslow.Incaseofchildrenwithinsufficient

capacityofglucuronidation,themetabolismofthedrugisalsoreduced.Intermneonatesthehalf-lifeisgenerallyless

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5.3Preclinicalsafetydata

Chronictoxicitystudiesintheratanddogledtorenalalterations(amongothersfibrousdegenerationandrenal

calcification).Furosemidedidnotshowgenotoxicorcarcinogenicpotential.

Inreproductivetoxicologystudies,areducednumberofdifferentiatedglomeruli,skeletalanomaliesofthescapulae,

humerusandribs(inducedbyhypokalaemia)wereseeninfetalrats,aswellashydronephrosisthatoccurredinfetal

miceandrabbitsafteradministrationofhighdoses.Theresultsofamousestudyandoneofthethreerabbitstudies

showedanincreasedincidenceandseverityofhydronephrosis(distentionoftherenalpelvisand,insomecases,ofthe

ureters)infetusesderivedfromthetreateddamsascomparedwiththosefromthecontrolgroup.

Pretermrabbitsgivenfurosemidehadahigherincidenceofintraventricularhaemorrhagethansaline-treatedlittermates,

possiblyduetofurosemide-inducedintracranialhypotension.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Sodiumhydroxide

Sodiumchloride

Hydrochloricacid

WaterforInjections

6.2Incompatibilities

FurosemidemayprecipitateoutofsolutioninfluidsoflowpH(e.g.dextrosesolutions).Thismedicinalproductshould

notbemixedwithothermedicinalproductsexceptthosementionedinsection6.6.

6.3Shelflife

Shelflifeofthefinishedmedicinalproduct:4years

Afterfirstopening:Onceopenedtheproductshouldbeusedimmediately.

Afterdilution:Chemicalandphysicalin-usestabilityhasbeendemonstratedfor24hoursat25ºCprotectedfromlight.

Fromamicrobiologicalpointofview,theproductshouldbeusedimmediately.Ifnotusedimmediately,in-usestorage

timesandconditionspriortousearetheresponsibilityoftheuserandwouldnormallynotbelongerthan24hoursat2

to8°C,unlessdilutionhastakenplaceincontrolledandvalidatedasepticconditions.

6.4Specialprecautionsforstorage

Keepintheoutercartoninordertoprotectfromlight.

Forstorageconditionsofthedilutedmedicinalproduct,seesection6.3.

6.5Natureandcontentsofcontainer

2mlor5ml,TypeIamberglassampoules.

Packsizes:

5,100x2mlampoules

5,50x5mlampoules

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6.6Specialprecautionsfordisposal

FurosemideInjectiondilutedto0.6mg/mliscompatiblewith0.90%NaClInfusion,andCompoundSodiumLactate

Infusionfor24hrs.Thedilutionofthesolutionforinjectionistobemadeunderasepticconditions.

Thesolutionistobeinspectedvisuallyforparticulatematteranddiscolorationpriortoadministration.Thesolution

shouldonlybeusedifthesolutionisclearandfreefromparticles.Anyunusedproductorwastematerialshouldbe

disposedofinaccordancewithlocalrequirements.Forsingleuseonly,discardanyremainingcontentsafteruse.

Furosemide10mg/mlSolutionforInjectionsolutionshouldnotbemixedwithanyotherdrugsintheinjectionbottle.

7MARKETINGAUTHORISATIONHOLDER

PfizerHealthcareIreland

9Riverwalk

NationalDigitalPark

CitywestBusinessCampus

Dublin24

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA822/26/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:21stDecember2011

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