COLOMYCIN

Main information

  • Trade name:
  • COLOMYCIN Pdr for Soln Inj/ Inf 500000 International Unit
  • Dosage:
  • 500000 International Unit
  • Pharmaceutical form:
  • Pdr for Soln Inj/Inf
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • COLOMYCIN Pdr for Soln Inj/Inf 500000 International Unit
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0100/001/007
  • Authorization date:
  • 07-06-2005
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0100/001/007

CaseNo:2045705

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

ForestLaboratoriesUKLtd

BourneRoad,Bexley,KentDA51NX,England

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

ColomycinInjection500000InternationalUnits.Powderforsolutionforinjection,infusionorinhalation.

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom24/02/2009.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

ColomycinInjection500000InternationalUnits.

Powderforsolutionforinjection,infusionorinhalation.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachvialcontains500,000InternationalUnitsColistimethateSodium.

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Powderforsolutionforinjection,infusionorinhalation.

Sterilewhitepowderina10mlcolourlessglassvialwithablue‘flip-off’cap.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Colomycinisindicatedinthetreatmentofthefollowinginfectionswheresensitivitytestingsuggeststhattheyare

causedbysusceptiblebacteria:

TreatmentbyinhalationofPseudomonasaeruginosalunginfectioninpatientswithcysticfibrosis(CF).

IntravenousadministrationforthetreatmentofsomeseriousinfectionscausedbyGram-negativebacteria,including

thoseofthelowerrespiratorytractandurinarytract,whenmorecommonlyusedsystemicantibacterialagentsmaybe

contra-indicatedormaybeineffectivebecauseofbacterialresistance.

4.2Posologyandmethodofadministration

SYSTEMICTREATMENT

Colomycincanbegivenasa50mlintravenousinfusionoveraperiodof30minutes.Patientswithatotallyimplantable

venousaccessdevice(TIVAD)inplacemaytolerateabolusinjectionofupto2millionunitsin10mlgivenovera

minimumof5minutes(seesection6.6,Specialprecautionsfordisposalofausedmedicinalproductorwaste

materialsderivedfromsuchaproductandotherhandlingoftheproduct).

Thedoseisdeterminedbytheseverityandtypeofinfectionandtheage,weightandrenalfunctionofthepatient.

Shouldclinicalorbacteriologicalresponsebeslowthedosemaybeincreasedasindicatedbythepatient’scondition.

Serumlevelestimationsarerecommendedespeciallyinrenalimpairment,neonatesandcysticfibrosispatients.Levels

of10–15mg/l(approximately125-200units/ml)colistimethatesodiumshouldbeadequateformostinfections.

Aminimumof5daystreatmentisgenerallyrecommended.Forthetreatmentofrespiratoryexacerbationsincystic

fibrosispatients,treatmentshouldbecontinuedforupto12days.

Childrenandadults(includingtheelderly):

Upto60kg:50,000units/kg/daytoamaximumof75,000units/kg/day.Thetotaldailydoseshouldbedividedinto

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Over60kg:1-2millionunitsthreetimesaday.Themaximumdoseis6millionunitsin24hours.

Anomalousdistributioninpatientswithcysticfibrosismayrequirehigherdosesinordertomaintaintherapeuticserum

levels.

Renalimpairment:Inmoderatetosevererenalimpairment,excretionofcolistimethatesodiumisdelayed.Therefore,

thedoseanddoseintervalshouldbeadjustedinordertopreventaccumulation.Thetablebelowisaguidetodose

regimenmodificationsinpatientsof60kgbodyweightorgreater.Itisemphasisedthatfurtheradjustmentsmayhaveto

bemadebasedonbloodlevelsandevidenceoftoxicity.

SUGGESTEDDOSAGEADJUSTMENTINRENALIMPAIRMENT

AEROSOLINHALATION

ForlocaltreatmentoflowerrespiratorytractinfectionsColomycinpowderisdissolvedin2-4mlofwaterforinjections

or0.9%sodiumchlorideintravenousinfusionforuseinanebuliserattachedtoanair/oxygensupply(seesection6.6,

Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfromsuchaproductandother

handlingoftheproduct).

Insmall,uncontrolledclinicaltrials,dosesoffrom500,000unitstwicedailyupto2millionunitsthreetimesdaily

havebeenfoundtobesafeandeffectiveinpatientswithcysticfibrosis.

Thefollowingrecommendeddosesareforguidanceonlyandshouldbeadjustedaccordingtoclinicalresponse:

Children<2years: 500,000-1millionunitstwicedaily

Children>2yearsandadults: 1-2millionunitstwicedaily

4.3Contraindications

Hypersensitivitytocolistimethatesodium(colistin)ortopolymyxinB.

Patientswithmyastheniagravis.

4.4Specialwarningsandprecautionsforuse

Usewithextremecautioninpatientswithporphyria.

Nephrotoxicityorneurotoxicitymayoccuriftherecommendedparenteraldoseisexceeded.

Usewithcautioninrenalimpairment(seesection4.2,Posologyandmethodofadministration).Itisadvisableto

assessbaselinerenalfunctionandtomonitorduringtreatment.Serumcolistimethatesodiumconcentrationsshouldbe

monitored.

Bronchospasmmayoccuroninhalationofantibiotics.Thismaybepreventedortreatedwithappropriateuseofbeta

Grade Creatinineclearance(ml/min) Over60kgbodyweight

Mild 20-50 1-2millionunitsevery8hr

Moderate 10-20 1millionunitsevery12-18hr

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Concomitantuseofcolistimethatesodiumwithothermedicinalproductsofneurotoxicand/ornephrotoxicpotential

shouldbeavoided.Theseincludetheaminoglycosideantibioticssuchasgentamicin,amikacin,netilmicinand

tobramycin.Theremaybeanincreasedriskofnephrotoxicityifgivenconcomitantlywithcephalosporinantibiotics.

Neuromuscularblockingdrugsandethershouldbeusedwithextremecautioninpatientsreceivingcolistimethate

sodium.

4.6Pregnancyandlactation

Therearenoadequatedatafromtheuseofcolistimethatesodiuminpregnantwomen.Singledosestudiesinhuman

pregnancyshowthatcolistimethatesodiumcrossestheplacentalbarrierandtheremaybeariskoffoetaltoxicityif

repeateddosesaregiventopregnantpatients.Animalstudiesareinsufficientwithrespecttotheeffectofcolistimethate

sodiumonreproductionanddevelopment(seesection5.3,Preclinicalsafetydata).Colistimethatesodiumshouldbe

usedinpregnancyonlyifthebenefittothemotheroutweighsthepotentialrisktothefoetus.

Colistimethatesodiumissecretedinbreastmilk.Colistimethatesodiumshouldbeadministeredtobreastfeeding

womenonlywhenclearlyneeded.

4.7Effectsonabilitytodriveandusemachines

Duringparenteraltreatmentwithcolistimethatesodiumneurotoxicitymayoccurwiththepossibilityofdizziness,

confusionorvisualdisturbance.Patientsshouldbewarnednottodriveoroperatemachineryiftheseeffectsoccur.

4.8Undesirableeffects

Systemictreatment

Thelikelihoodofadverseeventsmayberelatedtotheage,renalfunctionandconditionofthepatient.

Incysticfibrosispatientsneurologicaleventshavebeenreportedinupto27%ofpatients.Thesearegenerallymild

andresolveduringorshortlyaftertreatment.

Neurotoxicitymaybeassociatedwithoverdose,failuretoreducethedoseinpatientswithrenalinsufficiencyand

concomitantuseofeithercurariformagentsorotherdrugswithsimilarneurologicaleffects.Reducingthedosemay

alleviatesymptoms.Effectsmayincludeapnoea,transientsensorydisturbances(suchasfacialparaesthesiaand

vertigo)and,rarely,vasomotorinstability,slurredspeech,visualdisturbances,confusionorpsychosis.

Adverseeffectsonrenalfunctionhavebeenreported,usuallyfollowinguseofhigherthanrecommendeddosesin

patientswithnormalrenalfunction,orfailuretoreducethedosageinpatientswithrenalimpairmentorduring

concomitantuseofothernephrotoxicdrugs.Theeffectsareusuallyreversibleondiscontinuationoftherapy.

Incysticfibrosispatientstreatedwithintherecommendeddosagelimits,nephrotoxicityappearstoberare(lessthan

1%).Inseriouslyillhospitalisednon-CFpatients,signsofnephrotoxicityhavebeenreportedinapproximately20%of

patients.

Hypersensitivityreactionsincludingskinrashanddrugfeverhavebeenreported.Iftheseoccurtreatmentshouldbe

withdrawn.

Localirritationatthesiteofinjectionmayoccur.

Inhalationtreatment

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SorethroatormouthhasbeenreportedandmaybeduetoCandidaalbicansinfectionorhypersensitivity.Skinrash

mayalsoindicatehypersensitivity,ifthisoccurstreatmentshouldbewithdrawn.

4.9Overdose

Overdosecanresultinneuromuscularblockadethatcanleadtomuscularweakness,apnoeaandpossiblerespiratory

arrest.Overdosecanalsocauseacuterenalfailurecharacterisedbydecreasedurineoutputandincreasedserum

concentrationsofBUNandcreatinine.

Thereisnospecificantidote,managebysupportivetreatment.Measurestoincreasetherateofeliminationofcolistin

e.g.mannitoldiuresis,prolongedhaemodialysisorperitonealdialysismaybetried,buteffectivenessisunknown.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Antibacterialsforsystemicuse.

ATCCode:JOIXB01

Modeofaction

ColistimethatesodiumisacyclicpolypeptideantibioticderivedfromBacilluspolymyxavar.colistinusandbelongsto

thepolymyxingroup.Thepolymyxinantibioticsarecationicagentsthatworkbydamagingthecellmembrane.The

resultingphysiologicalaffectsarelethaltothebacterium.PolymyxinsareselectiveforGram-negativebacteriathat

haveahydrophobicoutermembrane.

Resistance

Resistantbacteriaarecharacterisedbymodificationofthephosphategroupsoflipopolysaccharidethatbecome

substitutedwithethanolamineoraminoarabinose.NaturallyresistantGram-negativebacteria,suchasProteus

mirabilisandBurkholderiacepacia,showcompletesubstitutionoftheirlipidphosphatebyethanolamineor

aminoarabinose.

Crossresistance

CrossresistancebetweencolistimethatesodiumandpolymyxinBwouldbeexpected.Sincethemechanismofactionof

thepolymyxinsisdifferentfromthatofotherantibiotics,resistancetocolistinandpolymixinbytheabovemechanism

alonewouldnotbeexpectedtoresultinresistancetootherdrugclasses.

Breakpoints

ThesuggestedgeneralMICbreakpointtoidentifybacteriasusceptibletocolistimethatesodiumis<4mg/l.

BacteriaforwhichtheMICofcolistimethatesodiumis 8mg/lshouldbeconsideredresistant.

Susceptibility

Theprevalenceofacquiredresistancemayvarygeographicallyandwithtimeforselectedspeciesandlocalinformation

onresistanceisdesirable,particularlywhentreatingsevereinfections.Asnecessary,expertadviceshouldbesought

whenthelocalprevalenceofresistanceissuchthattheutilityoftheagentinatleastsometypesofinfectionsis

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*In-vitroresultsmaynotcorrelatewithclinicalresponsesinthecaseofAcinetobacterspp.

5.2Pharmacokineticproperties

Absorption

Absorptionfromthegastrointestinaltractdoesnotoccurtoanyappreciableextentinthenormalindividual.

Whengivenbynebulisation,variableabsorptionhasbeenreportedthatmaydependontheaerosolparticlesize,

nebulisersystemandlungstatus.Studiesinhealthyvolunteersandpatientswithvariousinfectionshavereported

serumlevelsfromniltopotentiallytherapeuticconcentrationsof4mg/lormore.Therefore,thepossibilityofsystemic

absorptionshouldalwaysbeborneinmindwhentreatingpatientsbyinhalation.

Distribution

Aftertheadministrationtopatientswithcysticfibrosisof7.5mg/kg/dayindivideddosesgivenas30-minintravenous

infusionstosteadystatetheCmaxwasdeterminedtobe23+6mg/landCminat8hwas4.5+4mg/l.Inanotherstudy

insimilarpatientsgiven2millionunitsevery8hoursfor12daystheCmaxwas12.9mg/l(5.7–29.6mg/l)andtheC

minwas2.76mg/l(1.0–6.2mg/l).Inhealthyvolunteersgivenabolusinjectionof150mg(2millionunitsapprox.)

peakserumlevelsof18mg/lwereobserved10minutesafterinjection.

Proteinbindingislow.Polymyxinspersistintheliver,kidney,brain,heartandmuscle.Onestudyincysticfibrosis

patientsgivesthesteady-statevolumeofdistributionas0.09L/kg.

Biotransformation

Colistimethatesodiumisconvertedtothebaseinvivo.As80%ofthedosecanberecoveredunchangedintheurine,

andthereisnobiliaryexcretion,itcanbeassumedthattheremainingdrugisinactivatedinthetissues.Themechanism

isunknown.

Elimination

Themainrouteofeliminationafterparenteraladministrationisbyrenalexcretionwith40%ofaparenteraldose

recoveredintheurinewithin8hoursandaround80%in24hours.Becausecolistimethatesodiumislargelyexcreted

intheurine,dosereductionisrequiredinrenalimpairmenttopreventaccumulation.Refertothetableinsection4.2.,

Posologyandadministration.

Afterintravenousadministrationtohealthyadultstheeliminationhalf-lifeisaround1.5hrs.Inastudyincystic

fibrosispatientsgivenasingle30-minuteintravenousinfusiontheeliminationhalf-lifewas3.4+1.4hrs.

Theeliminationofcolistimethatesodiumfollowinginhalationhasnotbeenstudied.Astudyincysticfibrosispatients

Commonlysusceptiblespecies

Acinetobacterspecies*

Citrobacterspecies

Escherichiacoli

Haemophilusinfluenzae

Pseudomonasaeruginosa

Speciesforwhichacquiredresistancemaybeaproblem

Enterobacterspecies

Klebsiellaspecies

Inherentlyresistantorganisms

Brucellaspecies

Burkholderiacepaciaandrelatedspecies.

Neisseriaspecies

Proteusspecies

Providenciaspecies

Serratiaspecies

Anaerobes

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Colistimethatesodiumkineticsappeartobesimilarinchildrenandadults,includingtheelderly,providedrenal

functionisnormal.Limiteddataareavailableonuseinneonateswhichsuggestkineticsaresimilartochildrenand

adultsbutthepossibilityofhigherpeakserumlevelsandprolongedhalf-lifeinthesepatientsshouldbeconsideredand

serumlevelsmonitored.

5.3Preclinicalsafetydata

Dataonpotentialgenotoxicityarelimitedandcarcinogenicitydataforcolistimethatesodiumarelacking.

Colistimethatesodiumhasbeenshowntoinducechromosomalaberrationsinhumanlymphocytes,invitro.Thiseffect

mayberelatedtoareductioninmitoticindex,whichwasalsoobserved.

Reproductivetoxicitystudiesinratsandmicedonotindicateteratogenicproperties.However,colistimethatesodium

givenintramuscularlyduringorganogenesistorabbitsat4.15and9.3mg/kgresultedintalipesvarusin2.6and2.9%of

foetusesrespectively.Thesedosesare0.5and1.2timesthemaximumdailyhumandose.Inaddition,increased

resorptionoccurredat9.3mg/kg.

Therearenootherpreclinicalsafetydataofrelevancetotheprescriberwhichareadditionaltosafetydataderivedfrom

patientexposureandalreadyincludedinothersectionsoftheSPC.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

None.

6.2Incompatibilities

Mixedinfusions,injectionsandnebulisersolutionsinvolvingcolistimethatesodiumshouldbeavoided.

6.3ShelfLife

Beforeopening:3years

Reconstitutedsolutions:

Solutionsforinfusionorinjection:

Chemicalandphysicalin-usestabilityfor28daysat4 o

Chasbeendemonstrated.

Fromamicrobiologicalpointofview,solutionsshouldbeusedimmediately.Ifnotusedimmediatelyin-usestorage

timesandconditionspriortousearetheresponsibilityoftheuser.Theywouldnormallybenolongerthan24hoursat

2to8 °

C,unlessreconstitutedanddilutedundercontrolledandvalidatedasepticconditions.

Solutionsfornebulisation:

Solutionsfornebulisationhavesimilarin-usestabilityandshouldbetreatedasabove.Patientsself-treatingwith

nebulisedantibioticshouldbeadvisedtousesolutionsimmediatelyafterpreparation.Ifthisisnotpossible,solutions

shouldnotbestoredforlongerthan24hrsinarefrigerator.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.Keepthevialsintheoutercarton.

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6.5Natureandcontentsofcontainer

TypeIglassvialswithablue‘flip-off’capsuppliedincartonsoftenvials.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Parenteraladministration

Thenormaladultdoseof2millionunitsshouldbedissolvedin10-50mlof0.9%sodiumchlorideintravenousinfusion

orwaterforinjectionstoformaclearsolution.Thesolutionisforsingleuseonlyandanyremainingsolutionshould

bediscarded.

Inhalation

Therequiredamountofpowderisdissolvedpreferablyin2-4ml0.9%sodiumchloridesolutionandpouredintothe

nebuliser.Alternatively,waterforinjectionsmaybeused.Thesolutionwillbeslightlyhazyandmayfrothifshaken.

Usuallyjetorultrasonicnebulisersarepreferredforantibioticdelivery.Theseshouldproducethemajorityoftheir

outputintherespirableparticlediameterrangeof0.5-5.0micronswhenusedwithasuitablecompressor.The

instructionsofthemanufacturersshouldbefollowedfortheoperationandcareofthenebuliserandcompressor.

Theoutputfromthenebulisermaybeventedtotheopenairorafiltermaybefitted.Nebulisationshouldtakeplacein

awellventilatedroom.

Thesolutionisforsingleuseonlyandanyremainingsolutionshouldbediscarded.

7MARKETINGAUTHORISATIONHOLDER

ForestLaboratoriesUKLimited

BourneRoad

Bexley

KentDA51NX

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA0100/001/007

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation: 07June2005

Dateoflastrenewal: 07November2006

10DATEOFREVISIONOFTHETEXT

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