COSOPT PRESERVATIVE-FREE

Main information

  • Trade name:
  • COSOPT PRESERVATIVE-FREE
  • Dosage:
  • 20/5 Mg/Ml
  • Pharmaceutical form:
  • Eye Drops Solution
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • COSOPT PRESERVATIVE-FREE
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1286/006/002
  • Authorization date:
  • 01-09-2006
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

COSOPTPreservative-Free20mg/ml+5mg/ml,eyedrops,solution,single-dosecontainer

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachmlcontains22.26mgofdorzolamidehydrochloridecorrespondingto20mgdorzolamideand6.83mgoftimolol

maleatecorrespondingto5mgtimolol.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Eyedrops,solution,singledosecontainer

Clear,colourlesstonearlycolourless,slightlyviscoussolution.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Indicatedinthetreatmentofelevatedintraocularpressure(IOP)inpatientswithopen-angleglaucomaor

pseudoexfoliativeglaucomawhentopicalbeta-blockermonotherapyisnotsufficient.

4.2Posologyandmethodofadministration

ThedoseisonedropofCOSOPTPreservative-Freeinthe(conjunctivalsacofthe)affectedeye(s)twotimes

daily.

Ifanothertopicalophthalmicagentisbeingused,COSOPTPreservative-Freeandtheotheragentshouldbe

administeredatleasttenminutesapart.

COSOPTPreservative-Freeisasterilesolutionthatdoesnotcontainapreservative.Thesolutionfromone

individualsingledosecontaineristobeusedimmediatelyafteropeningforadministrationtotheaffectedeye

(s).Sincesterilitycannotbemaintainedaftertheindividualsingledosecontainerisopened,anyremaining

contentsmustbediscardedimmediatelyafteradministration.

Patientsshouldbeinstructedtoavoidallowingthetipofthecontainertocomeintocontactwiththeeyeor

surroundingstructures.

Patientsshouldalsobeinstructedthatocularsolutions,ifhandledimproperly,canbecomecontaminatedby

commonbacteriaknowntocauseocularinfections.Seriousdamagetotheeyeandsubsequentlossofvision

mayresultfromusingcontaminatedsolutions.

UsageInstructions

Openthesachetwhichcontains15individualsingledosecontainers.Therearethreestripsof5singledose

containerseachinthesachet.

Firstwashyourhandsthenbreakoffonesingledosecontainerfromthestripandtwistopenthetop.

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Instillonedropintheaffectedeye(s)asdirectedbyyourphysician.Eachsingledosecontainercontainsenough

solutionforbotheyes.

Afterinstillation,discardtheusedsingledosecontainerevenifthereissolutionremaining.

Storetheremainingsingledosecontainersinthesachet;theremainingsingledosecontainersmustbeused

within15daysafteropeningofthesachet.

PediatricUse

Efficacyinpaediatricpatientshasnotbeenestablished.

Safetyinpaediatricpatientsbelowtheageof2yearshasnotbeenestablished.(Forinformationregardingsafetyin

paediatricpatients2and<6yearsofage,seesection5.1)

4.3Contraindications

COSOPTPreservative-Freeiscontraindicatedinpatientswith:

reactiveairwaydisease,includingbronchialasthmaorahistoryofbronchialasthma,orseverechronic

obstructivepulmonarydisease

sinusbradycardia,secondorthirddegreeatrioventricularblock,overtcardiacfailure,cardiogenicshock

severerenalimpairment(CrCl<30ml/min)orhyperchloremicacidosis

hypersensitivitytooneorbothactivesubstancesortoanyoftheexcipients.

Theabovearebasedonthecomponentsandarenotuniquetothecombination.

4.4Specialwarningsandprecautionsforuse

Cardiovascular/RespiratoryReactions

Aswithothertopically-appliedophthalmicagents,thismedicinalproductmaybeabsorbedsystemically.The

timololcomponentisabeta-blocker.Therefore,thesametypesofadversereactionsfoundwithsystemic

administrationofbeta-blockersmayoccurwithtopicaladministration,includingworseningofPrinzmetal

angina,worseningofsevereperipheralandcentralcirculatorydisorders,andhypotension.

Becauseofthetimololmaleatecomponent,cardiacfailureshouldbeadequatelycontrolledbeforebeginning

therapywithCOSOPTPreservative-Free.Inpatientswithahistoryofseverecardiacdisease,signsofcardiac

failureshouldbewatchedforandpulseratesshouldbechecked.

Respiratoryreactionsandcardiacreactions,includingdeathduetobronchospasminpatientswithasthmaand

rarelydeathinassociationwithcardiacfailure,havebeenreportedfollowingadministrationoftimololmaleate.

HepaticImpairment

COSOPTPreservative-Freehasnotbeenstudiedinpatientswithhepaticimpairmentandshouldthereforebe

usedwithcautioninsuchpatients.

ImmunologyandHypersensitivity

Aswithothertopically-appliedophthalmicagents,COSOPTPreservative-Freemaybeabsorbedsystemically.

Dorzolamidecontainsasulfonamidogroup,whichalsooccursinsulfonamides.Therefore,thesametypesof

adversereactionsfoundwithsystemicadministrationofsulfonamidesmayoccurwithtopicaladministration,

includingseverereactionssuchasStevens-Johnsonsyndromeandtoxicepidermalnecrolysis.Ifsignsofserious

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Localocularadverseeffects,similartothoseobservedwithdorzolamidehydrochlorideeyedrops,havebeen

seenwithCOSOPTPreservative-Free.Ifsuchreactionsoccur,discontinuationofCOSOPTPreservative-Free

shouldbeconsidered.

Whiletakingbeta-blockers,patientswithahistoryofatopyorahistoryofsevereanaphylacticreactiontoa

varietyofallergensmaybemorereactivetoaccidental,diagnostic,ortherapeuticrepeatedchallengewithsuch

allergens.Suchpatientsmaybeunresponsivetotheusualdosesofepinephrineusedtotreatanaphylactic

reactions.

ConcomitantTherapy

Thefollowingconcomitantmedicationisnotrecommended:

dorzolamideandoralcarbonicanhydraseinhibitors

topicalbeta-adrenergicblockingagents

WithdrawalofTherapy

Aswithsystemicbeta-blockers,ifdiscontinuationofophthalmictimololisneededinpatientswithcoronary

heartdisease,therapyshouldbewithdrawngradually.

AdditionalEffectsofBeta-Blockade

Therapywithbeta-blockersmaymaskcertainsymptomsofhypoglycemiainpatientswithdiabetesmellitusor

hypoglycemia.

Therapywithbeta-blockersmaymaskcertainsymptomsofhyperthyroidism.Abruptwithdrawalofbeta-

blockertherapymayprecipitateaworseningofsymptoms.

Therapywithbeta-blockersmayaggravatesymptomsofmyastheniagravis.

AdditionalEffectsofCarbonicAnhydraseInhibition

Therapywithoralcarbonicanhydraseinhibitorshasbeenassociatedwithurolithiasisasaresultofacid-base

disturbances,especiallyinpatientswithapriorhistoryofrenalcalculi.Althoughnoacid-basedisturbances

havebeenobservedwithCOSOPT(preservedformulation),urolithiasishasbeenreportedinfrequently.

BecauseCOSOPTPreservative-Freecontainsatopicalcarbonicanhydraseinhibitorthatisabsorbed

systemically,patientswithapriorhistoryofrenalcalculimaybeatincreasedriskofurolithiasiswhileusing

COSOPTPreservative-Free.

Other

Themanagementofpatientswithacuteangle-closureglaucomarequirestherapeuticinterventionsinadditionto

ocularhypotensiveagents.COSOPTPreservative-Freehasnotbeenstudiedinpatientswithacuteangle-closure

glaucoma.

Cornealoedemaandirreversiblecornealdecompensationhavebeenreportedinpatientswithpre-existing

chroniccornealdefectsand/orahistoryofintraocularsurgerywhileusingdorzolamide.Topicaldorzolamide

shouldbeusedwithcautioninsuchpatients.

Choroidaldetachmentconcomitantwithocularhypotonyhavebeenreportedafterfiltrationprocedureswith

administrationofaqueoussuppressanttherapies.

Aswiththeuseofotherantiglaucomadrugs,diminishedresponsivenesstoophthalmictimololmaleateafter

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However,inclinicalstudiesinwhich164patientshavebeenfollowedforatleastthreeyears,nosignificant

differenceinmeanintraocularpressurehasbeenobservedafterinitialstabilization.

ContactLensUse

COSOPTPreservative-Freehasnotbeenstudiedinpatientswearingcontactlenses.

PaediatricUse

Seesection5.1.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

SpecificdruginteractionstudieshavenotbeenperformedwithCOSOPTPreservative-Free.

Inaclinicalstudy,COSOPTPreservative-Freewasusedconcomitantlywiththefollowingsystemic

medicationswithoutevidenceofadverseinteractions:ACE-inhibitors,calciumchannelblockers,diuretics,non-

steroidalanti-inflammatorydrugsincludingaspirin,andhormones(e.g.,estrogen,insulin,thyroxine).

However,thepotentialexistsforadditiveeffectsandproductionofhypotensionand/ormarkedbradycardia

whentimololmaleateophthalmicsolutionisadministeredtogetherwithoralcalciumchannelblockers,

catecholamine-depletingdrugsorbeta-adrenergicblockingagents,antiarrhythmics(includingamiodarone),

digitalisglycosides,parasympathomimetics,narcotics,andmonoamineoxidase(MAO)inhibitors.

Potentiatedsystemicbeta-blockade(e.g.,decreasedheartrate,depression)hasbeenreportedduringcombined

treatmentwithCYP2D6inhibitors(e.g.quinidine,SSRIs)andtimolol.

AlthoughCOSOPT(preservedformulation)alonehaslittleornoeffectonpupilsize,mydriasisresultingfrom

concomitantuseofophthalmictimololmaleateandepinephrine(adrenaline)hasbeenreportedoccasionally.

Beta-blockersmayincreasethehypoglycemiceffectofantidiabeticagents.

Oralbeta-adrenergicblockingagentsmayexacerbatethereboundhypertensionwhichcanfollowthewithdrawalof

clonidine.

4.6Fertility,pregnancyandlactation

UseDuringPregnancy

COSOPTPreservative-Freeshouldnotbeusedduringpregnancy.

Dorzolamide

Noadequateclinicaldatainexposedpregnanciesareavailable.Inrabbits,dorzolamideproducedteratogeniceffectat

maternotoxicdoses(seeSection5.3).

Timolol

Wellcontrolledepidemiologicalstudieswithsystemicbeta-blockersshowednoevidenceofteratogeniceffects,

butsomepharmacologicaleffectssuchasbradycardiawereobservedinfoetusesorneonates.IfCOSOPT

Preservative-Freeisadministereduntildelivery,theneonateshouldbecarefullymonitoredduringthefirstdays

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UseDuringLactation

Itisnotknownwhetherdorzolamideisexcretedinhumanmilk.Inlactatingratsreceivingdorzolamide,

decreasesinthebodyweightgainofoffspringwereobserved.Timololdoesappearinhumanmilk.If

treatmentwithCOSOPTPreservative-Freeisrequired,thenlactationisnotrecommended.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.Possiblesideeffectssuchas

blurredvisionmayaffectsomepatients’abilitytodriveand/oroperatemachinery.

4.8Undesirableeffects

InaclinicalstudynoadverseexperiencesspecifictoCOSOPTPreservative-Freehavebeenobserved;adverse

reactionshavebeenlimitedtothosethatwerereportedpreviouslywithCOSOPT(preservedformulation),

dorzolamidehydrochlorideand/ortimololmaleate.

Duringclinicalstudies,1035patientsweretreatedwithCOSOPT(preservedformulation).Approximately2.4%

ofallpatientsdiscontinuedtherapywithCOSOPT(preservedformulation)becauseoflocalocularadverse

reactions;approximately1.2%ofallpatientsdiscontinuedbecauseoflocaladversereactionssuggestiveof

allergyorhypersensitivity(suchaslidinflammationandconjunctivitis).

COSOPTPreservative-FreehasbeenshowntohaveasimilarsafetyprofiletoCOSOPT(preservative

containingformulation)inarepeatdosedouble-masked,comparativestudy.

ThefollowingadversereactionshavebeenreportedwithCOSOPToroneofitscomponentseitherduring

clinicaltrialsorduringpost-marketingexperience:

[VeryCommon:(1/10),Common:(1/100,<1/10),Uncommon:(1/1000,<1/100),andRare:(1/10,000,

<1/1000)]

Musculoskeletalandconnectivetissuedisorders:

Timololmaleateeyedrops,solution:

Rare:systemiclupuserythematosus

Nervoussystemdisorders:

Dorzolamidehydrochlorideeyedrops,solution:

Common:headache*

Rare:dizziness*,paresthesia*

Timololmaleateeyedrops,solution:

Common:headache*

Uncommon:dizziness*,depression*

Rare:insomnia*,nightmares*,memoryloss,paresthesia*,increaseinsignsandsymptomsofmyasthenia

gravis,decreasedlibido*,cerebrovascularaccident*

Eyedisorders:

COSOPT:

VeryCommon:burningandstinging

Common:conjunctivalinjection,blurredvision,cornealerosion,ocularitching,tearing

Dorzolamidehydrochlorideeyedrops,solution:

Common:eyelidinflammation*,eyelidirritation*

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Rare:irritationincludingredness*,pain*,eyelidcrusting*,transientmyopia(whichresolvedupon

discontinuationoftherapy),cornealoedema*,ocularhypotony*,choroidaldetachment(followingfiltration

surgery)*

Timololmaleateeyedrops,solution:

Common:signsandsymptomsofocularirritationincludingblepharitis*,keratitis*,decreasedcorneal

sensitivity,anddryeyes*

Uncommon:visualdisturbancesincludingrefractivechanges(duetowithdrawalofmiotictherapyinsome

cases)*

Rare:ptosis,diplopia,choroidaldetachment(followingfiltrationsurgery)*

Earandlabyrinthdisorders:

Timololmaleateeyedrops,solution:

Rare:tinnitus*

Cardiacandvasculardisorders:

Timololmaleateeyedrops,solution:

Uncommon:bradycardia*,syncope*

Rare:hypotension*,chestpain*,palpitation*,edema*,arrhythmia*,congestiveheartfailure*,heartblock*,

cardiacarrest*,cerebralischemia,claudication,Raynaud’sphenomenon*,coldhandsandfeet*

Respiratory,thoracic,andmediastinaldisorders:

COSOPT:

Common:sinusitis

Rare:shortnessofbreath,respiratoryfailure,rhinitis

Dorzolamidehydrochlorideeyedrops,solution:

Rare:epistaxis*

Timololmaleateeyedrops,solution:

Uncommon:dyspnea*

Rare:bronchospasm(predominantlyinpatientswithpre-existingbronchospasticdisease)*,cough*

Gastrointestinaldisorders:

COSOPT:

VeryCommon:tasteperversion

Dorzolamidehydrochlorideeyedrops,solution:

Common:nausea*

Rare:throatirritation,drymouth*

Timololmaleateeyedrops,solution:

Uncommon:nausea*,dyspepsia*

Rare:diarrhea,drymouth*

Skinandsubcutaneoustissuedisorders:

COSOPT:

Rare:contactdermatitis,Stevens-Johnsonsyndrome,toxicepidermalnecrolysis

Dorzolamidehydrochlorideeyedrops,solution:

Rare:rash*

Timololmaleateeyedrops,solution:

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Renalandurinarydisorders:

COSOPT:

Uncommon:urolithiasis

Reproductivesystemandbreastdisorders:

Timololmaleateeyedrops,solution:

Rare:Peyronie’sdisease*

Generaldisordersandadministrationsitedisorders:

COSOPT:

Rare:signsandsymptomsofsystemicallergicreactions,includingangioedema,urticaria,pruritus,rash,

anaphylaxis,rarelybronchospasm

Dorzolamidehydrochlorideeyedrops,solution:

Common:asthenia/fatigue*

Timololmaleateeyedrops,solution:

Uncommon:asthenia/fatigue*

*TheseadversereactionswerealsoobservedwithCOSOPT(preservedformulation)duringpost-marketing

experience.

LaboratoryFindings

COSOPT(preservedformulation)wasnotassociatedwithclinicallymeaningfulelectrolytedisturbancesinclinical

studies.

4.9Overdose

NodataareavailableinhumansinregardtooverdosebyaccidentalordeliberateingestionofCOSOPT

(preservedformulation)orCOSOPTPreservative-Free.

Symptoms

Therehavebeenreportsofinadvertentoverdoseswithtimololmaleateophthalmicsolutionresultinginsystemic

effectssimilartothoseseenwithsystemicbeta-adrenergicblockingagentssuchasdizziness,headache,

shortnessofbreath,bradycardia,bronchospasm,andcardiacarrest.Themostcommonsignsandsymptomsto

beexpectedwithoverdosesofdorzolamideareelectrolyteimbalance,developmentofanacidoticstate,and

possiblycentralnervoussystemeffects.

Onlylimitedinformationisavailablewithregardtohumanoverdosebyaccidentalordeliberateingestionof

dorzolamidehydrochloride.Withoralingestion,somnolencehasbeenreported.Withtopicalapplicationthe

followinghavebeenreported:nausea,dizziness,headache,fatigue,abnormaldreams,anddysphagia.

Treatment

Treatmentshouldbesymptomaticandsupportive.Serumelectrolytelevels(particularlypotassium)andbloodpH

levelsshouldbemonitored.Studieshaveshownthattimololdoesnotdialyzereadily.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Antiglaucomapreparationsandmiotics,Betablockingagents,Timolol,combinations,

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MechanismofAction

COSOPTPreservative-Freeiscomprisedoftwocomponents:dorzolamidehydrochlorideandtimololmaleate.

Eachofthesetwocomponentsdecreaseselevatedintraocularpressurebyreducingaqueoushumorsecretion,

butdoessobyadifferentmechanismofaction.

DorzolamidehydrochlorideisapotentinhibitorofhumancarbonicanhydraseII.Inhibitionofcarbonic

anhydraseintheciliaryprocessesoftheeyedecreasesaqueoushumorsecretion,presumablybyslowingthe

formationofbicarbonateionswithsubsequentreductioninsodiumandfluidtransport.Timololmaleateisa

nonselectivebeta-adrenergicreceptorblockingagent.Theprecisemechanismofactionoftimololmaleatein

loweringintraocularpressureisnotclearlyestablishedatthistime,althoughafluoresceinstudyandtonography

studiesindicatethatthepredominantactionmayberelatedtoreducedaqueousformation.However,insome

studiesaslightincreaseinoutflowfacilitywasalsoobserved.Thecombinedeffectofthesetwoagentsresults

inadditionalintraocularpressurereduction(IOP)comparedtoeithercomponentadministeredalone.

Followingtopicaladministration,COSOPTPreservative-Freereduceselevatedintraocularpressure,whetheror

notassociatedwithglaucoma.Elevatedintraocularpressureisamajorriskfactorinthepathogenesisofoptic

nervedamageandglaucomatousvisualfieldloss.COSOPTPreservative-Freereducesintraocularpressure

withoutthecommonsideeffectsofmioticssuchasnightblindness,accommodativespasmandpupillary

constriction.

Pharmacodynamiceffects

ClinicalEffects

Clinicalstudiesofupto15monthsdurationwereconductedtocomparetheIOP-loweringeffectofCOSOPT

(preservedformulation)b.i.d.(dosedmorningandbedtime)toindividually-andconcomitantly-administered

0.5%timololand2.0%dorzolamideinpatientswithglaucomaorocularhypertensionforwhomconcomitant

therapywasconsideredappropriateinthetrials.Thisincludedbothuntreatedpatientsandpatientsinadequately

controlledwithtimololmonotherapy.Themajorityofpatientsweretreatedwithtopicalbeta-blocker

monotherapypriortostudyenrollment.Inananalysisofthecombinedstudies,theIOP-loweringeffectof

COSOPT(preservedformulation)b.i.d.wasgreaterthanthatofmonotherapywitheither2%dorzolamidet.i.d.

or0.5%timololb.i.d.TheIOP-loweringeffectofCOSOPT(preservedformulation)b.i.d.wasequivalentto

thatofconcomitanttherapywithdorzolamideb.i.d.andtimololb.i.d.TheIOP-loweringeffectofCOSOPT

(preservedformulation)b.i.d.wasdemonstratedwhenmeasuredatvarioustimepointsthroughoutthedayand

thiseffectwasmaintainedduringlong-termadministration.

Inanactive-treatment-controlled,parallel,double-maskedstudyin261patientswithelevatedintraocular

pressure22mmHginoneorbotheyes,COSOPTPreservative-FreehadanIOP-loweringeffectequivalentto

thatofCOSOPT(preservedformulation).ThesafetyprofileofCOSOPTPreservative-Freewassimilarto

COSOPT(preservedformulation).

Paediatricuse

A3monthcontrolledstudy,withtheprimaryobjectiveofdocumentingthesafetyof2%dorzolamide

hydrochlorideophthalmicsolutioninchildrenundertheageof6yearshasbeenconducted.Inthisstudy,30

patientsunder6andgreaterthanorequalto2yearsofagewhoseIOPwasnotadequatelycontrolledwith

monotherapybydorzolamideortimololreceivedCOSOPT(preservedformulation)inanopenlabelphase.

Efficacyinthosepatientshasnotbeenestablished.Inthissmallgroupofpatients,twicedailyadministrationof

COSOPT(preservedformulation)wasgenerallywelltoleratedwith19patientscompletingthetreatmentperiod

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5.2Pharmacokineticproperties

DorzolamideHydrochloride

Unlikeoralcarbonicanhydraseinhibitors,topicaladministrationofdorzolamidehydrochlorideallowsforthe

activesubstancetoexertitseffectsdirectlyintheeyeatsubstantiallylowerdosesandthereforewithless

systemicexposure.Inclinicaltrials,thisresultedinareductioninIOPwithouttheacid-basedisturbancesor

alterationsinelectrolytescharacteristicoforalcarbonicanhydraseinhibitors.

Whentopicallyapplied,dorzolamidereachesthesystemiccirculation.Toassessthepotentialforsystemic

carbonicanhydraseinhibitionfollowingtopicaladministration,activesubstanceandmetaboliteconcentrations

inredbloodcells(RBCs)andplasmaandcarbonicanhydraseinhibitioninRBCsweremeasured.Dorzolamide

accumulatesinRBCsduringchronicdosingasaresultofselectivebindingtoCA-IIwhileextremelylow

concentrationsoffreeactivesubstanceinplasmaaremaintained.TheparentactivesubstanceformsasingleN-

desethylmetabolitethatinhibitsCA-IIlesspotentlythantheparentactivesubstancebutalsoinhibitsaless

activeisoenzyme(CA-I).ThemetabolitealsoaccumulatesinRBCswhereitbindsprimarilytoCA-I.

Dorzolamidebindsmoderatelytoplasmaproteins(approximately33%).Dorzolamideisprimarilyexcreted

unchangedintheurine;themetaboliteisalsoexcretedinurine.Afterdosingends,dorzolamidewashesoutof

RBCsnonlinearly,resultinginarapiddeclineofactivesubstanceconcentrationinitially,followedbyaslower

eliminationphasewithahalf-lifeofaboutfourmonths.

Whendorzolamidewasgivenorallytosimulatethemaximumsystemicexposureafterlongtermtopicalocular

administration,steadystatewasreachedwithin13weeks.Atsteadystate,therewasvirtuallynofreeactive

substanceormetaboliteinplasma;CAinhibitioninRBCswaslessthanthatanticipatedtobenecessaryfora

pharmacologicaleffectonrenalfunctionorrespiration.Similarpharmacokineticresultswereobservedafter

chronic,topicaladministrationofdorzolamidehydrochloride.However,someelderlypatientswithrenal

impairment(estimatedCrCl30-60ml/min)hadhighermetaboliteconcentrationsinRBCs,butnomeaningful

differencesincarbonicanhydraseinhibitionandnoclinicallysignificantsystemicsideeffectsweredirectly

attributabletothisfinding.

TimololMaleate

Inastudyofplasmaactivesubstanceconcentrationinsixsubjects,thesystemicexposuretotimololwasdetermined

followingtwicedailytopicaladministrationoftimololmaleateophthalmicsolution0.5%.Themeanpeakplasma

concentrationfollowingmorningdosingwas0.46ng/mlandfollowingafternoondosingwas0.35ng/ml.

5.3Preclinicalsafetydata

Theocularandsystemicsafetyprofileoftheindividualcomponentsiswellestablished.

Dorzolamide

Inrabbitsgivenmaternotoxicdosesofdorzolamideassociatedwithmetabolicacidosis,malformationsofthe

vertebralbodieswereobserved.

Timolol

Animalstudieshavenotshownteratogeniceffect.

Furthermore,noadverseoculareffectswereseeninanimalstreatedtopicallywithdorzolamidehydrochloride

andtimololmaleateophthalmicsolutionorwithconcomitantly-administereddorzolamidehydrochlorideand

timololmaleate.Invitroandinvivostudieswitheachofthecomponentsdidnotrevealamutagenicpotential.

Therefore,nosignificantriskforhumansafetyisexpectedwiththerapeuticdosesofCOSOPTPreservative-

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Hydroxyethylcellulose

Mannitol(E421)

Sodiumcitrate(E331)

Sodiumhydroxide(E524)forpHadjustment

Waterforinjections.

6.2Incompatibilities

Notapplicable.

6.3Shelflife

2years.

Afterfirstopeningofthesachet:15days.Discardanyunusedsingledosecontainersafterthattime.

Discardtheopenedsingledosecontainerimmediatelyafterfirstuse.

6.4Specialprecautionsforstorage

Donotstoreabove30°C.

Donotfreeze.

Storeintheoriginalpackageinordertoprotectfromlight.

6.5Natureandcontentsofcontainer

COSOPTPreservative-Freeisavailablein0.2mllowdensitypolyethylenesingledosecontainersinanaluminum

sachetcontaining15single-dosecontainers.

Packsizes:

30x0.2ml(2sachetswith15singledosecontainers)

60x0.2ml(4sachetswith15singledosecontainers)

120x0.2ml(8sachetswith15singledosecontainers)

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

MerckSharp&DohmeIreland(HumanHealth)Limited

PelhamHouse,

SouthCountyBusinessPark

Leopardstown

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8MARKETINGAUTHORISATIONNUMBER

PA1286/6/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:1 st

September2006

Dateoflastrenewal:6 th

March2008

10DATEOFREVISIONOFTHETEXT

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