COSOPT

Main information

  • Trade name:
  • COSOPT Eye Drops Solution 20mg/ ml + Mg/ Ml
  • Dosage:
  • 20mg/ ml + Mg/ Ml
  • Pharmaceutical form:
  • Eye Drops Solution
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • COSOPT Eye Drops Solution 20mg/ml + Mg/Ml
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1659/049/001
  • Authorization date:
  • 19-08-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Cosopt20mg/ml+5mg/ml,eyedropssolution.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachmlcontains22.26mgofdorzolamidehydrochloridecorrespondingto20mgdorzolamideand6.83mgoftimolol

maleatecorrespondingto5mgtimolol.

Excipients:Benzalkoniumchloride0.075mg/ml

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Eyedrops,solution.

ProductimportedfromtheUK:

Clear,colourlesstonearlycolourless,slightlyviscoussolution.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Indicatedinthetreatmentofelevatedintraocularpressure(IOP)inpatientswithopen-angleglaucomaor

pseudoexfoliativeglaucomawhentopicalbeta-blockermonotherapyisnotsufficient.

4.2Posologyandmethodofadministration

ThedoseisonedropofCOSOPTinthe(conjunctivalsacofthe)affectedeye(s)twotimesdaily.

Ifanothertopicalophthalmicagentisbeingused,COSOPTandtheotheragentshouldbeadministeredatleast

tenminutesapart.

Patientsshouldbeinstructedtowashtheirhandsbeforeuseandavoidallowingthetipofthecontainertocome

intocontactwiththeeyeorsurroundingstructures.

Patientsshouldalsobeinstructedthatocularsolutions,ifhandledimproperly,canbecomecontaminatedby

commonbacteriaknowntocauseocularinfections.Seriousdamagetotheeyeandsubsequentlossofvision

mayresultfromusingcontaminatedsolutions.

PatientsshouldbeinformedofthecorrecthandlingoftheOCUMETERPLUSbottles.

UsageInstructions

Beforeusingthemedicationforthefirsttime,besuretheSafetyStriponthefrontofthebottleisunbroken.A

gapbetweenthebottleandthecapisnormalforanunopenedbottle.

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Toopenthebottle,unscrewthecapbyturningasindicatedbythearrowsonthetopofthecap.Donotpullthe

capdirectlyupandawayfromthebottle.Pullingthecapdirectlyupwillpreventyourdispenserfromoperating

properly.

Tiltyourheadbackandpullyourlowereyeliddownslightlytoformapocketbetweenyoureyelidandyoureye.

Invertthebottle,andpresslightlywiththethumborindexfingeroverthe“FingerPushArea”untilasingledrop

isdispensedintotheeyeasdirectedbyyourdoctor.DONOTTOUCHYOUREYEOREYELIDWITHTHE

DROPPERTIP.

Ifdropdispensingisdifficultafteropeningforthefirsttime,replacethecaponthebottleandtighten(Donot

overtighten)andthenremovebyturningthecapintheoppositedirectionsasindicatedbythearrowsonthetopof

thecap.

Repeatsteps4&5withtheothereyeifinstructedtodosobyyourdoctor.

Replacethecapbyturninguntilitisfirmlytouchingthebottle.Thearrowontheleftsideofthecapmustbe

alignedwiththearrowontheleftsideofthebottlelabelforproperclosure.Donotovertightenoryoumay

damagethebottleandcap.

Thedispensertipisdesignedtoprovideasingledrop;therefore,doNOTenlargetheholeofthedispensertip.

Afteryouhaveusedalldoses,therewillbesomeCOSOPTleftinthebottle.Youshouldnotbeconcernedsince

anextraamountofCOSOPThasbeenaddedandyouwillgetthefullamountofCOSOPTthatyourdoctor

prescribed.Donotattempttoremovetheexcessmedicinefromthebottle.

PaediatricUse

Efficacyinpaediatricpatientshasnotbeenestablished.

Safetyinpaediatricpatientsbelowtheageof2yearshasnotbeenestablished.(Forinformationregarding

safetyinpaediatricpatients ≥2and<6yearsofage,seesection5.1)

4.3Contraindications

COSOPTiscontraindicatedinpatientswith:

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

therapywithCOSOPT.Inpatientswithahistoryofseverecardiacdisease,signsofcardiacfailureshouldbe

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Respiratoryreactionsandcardiacreactions,includingdeathduetobronchospasminpatientswithasthmaand

rarelydeathinassociationwithcardiacfailure,havebeenreportedfollowingadministrationoftimololmaleate.

HepaticImpairment

COSOPThasnotbeenstudiedinpatientswithhepaticimpairmentandshouldthereforebeusedwithcautionin

suchpatients.

ImmunologyandHypersensitivity

Aswithothertopically-appliedophthalmicagents,thismedicinalproductmaybeabsorbedsystemically.

Dorzolamidecontainsasulfonamidogroup,whichalsooccursinsulfonamides.Therefore,thesametypesof

adversereactionsfoundwithsystemicadministrationofsulfonamidesmayoccurwithtopicaladministration,

includingseverereactionssuchasStevens-Johnsonsyndromeandtoxicepidermalnecrolysis.Ifsignsofserious

reactionsorhypersensitivityoccur,discontinueuseofthispreparation.

Localocularadverseeffects,similartothoseobservedwithdorzolamidehydrochlorideeyedrops,havebeen

seenwithCOSOPT.Ifsuchreactionsoccur,discontinuationofCOSOPTshouldbeconsidered.

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,urolithiasishasbeenreportedinfrequently.BecauseCOSOPTcontainsa

topicalcarbonicanhydraseinhibitorthatisabsorbedsystemically,patientswithapriorhistoryofrenalcalculi

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Other

Themanagementofpatientswithacuteangle-closureglaucomarequirestherapeuticinterventionsinadditionto

ocularhypotensiveagents.COSOPThasnotbeenstudiedinpatientswithacuteangle-closureglaucoma.

Cornealoedemaandirreversiblecornealdecompensationhavebeenreportedinpatientswithpre-existing

chroniccornealdefectsand/orahistoryofintraocularsurgerywhileusingdorzolamide.Topicaldorzolamide

shouldbeusedwithcautioninsuchpatients.

Choroidaldetachmentconcomitantwithocularhypotonyhavebeenreportedafterfiltrationprocedureswith

administrationofaqueoussuppressanttherapies.

Aswiththeuseofotherantiglaucomadrugs,diminishedresponsivenesstoophthalmictimololmaleateafter

prolongedtherapyhasbeenreportedinsomepatients.However,inclinicalstudiesinwhich164patientshave

beenfollowedforatleastthreeyears,nosignificantdifferenceinmeanintraocularpressurehasbeenobserved

afterinitialstabilization.

ContactLensUse

COSOPTcontainsthepreservativebenzalkoniumchloride,whichmaycauseeyeirritation.Removecontact

lensespriortoapplicationandwaitatleast15minutesbeforereinsertion.Benzalkoniumchlorideisknownto

discoloursoftcontactlenses.

PaediatricUse

Seesection5.1.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

SpecificdruginteractionstudieshavenotbeenperformedwithCOSOPT.

Inclinicalstudies,COSOPTwasusedconcomitantlywiththefollowingsystemicmedicationswithoutevidence

ofadverseinteractions:ACE-inhibitors,calciumchannelblockers,diuretics,non-steroidalanti-inflammatory

drugsincludingaspirin,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.

AlthoughCOSOPTalonehaslittleornoeffectonpupilsize,mydriasisresultingfromconcomitantuseof

ophthalmictimololmaleateandepinephrine(adrenaline)hasbeenreportedoccasionally.

Beta-blockersmayincreasethehypoglycemiceffectofantidiabeticagents.

Oralbeta-adrenergicblockingagentsmayexacerbatethereboundhypertensionwhichcanfollowthe

withdrawalofclonidine.

4.6Fertility,pregnancyandlactation

UseDuringPregnancy

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Dorzolamide

Noadequateclinicaldatainexposedpregnanciesareavailable.Inrabbits,dorzolamideproducedteratogeniceffectat

maternotoxicdoses(seeSection5.3).

Timolol

Wellcontrolledepidemiologicalstudieswithsystemicbeta-blockersshowednoevidenceofteratogeniceffects,

butsomepharmacologicaleffectssuchasbradycardiawereobservedinfoetusesorneonates.IfCOSOPTis

administereduntildelivery,theneonateshouldbecarefullymonitoredduringthefirstdaysoflife.

UseDuringLactation

Itisnotknownwhetherdorzolamideisexcretedinhumanmilk.Inlactatingratsreceivingdorzolamide,

decreasesinthebodyweightgainofoffspringwereobserved.Timololdoesappearinhumanmilk.If

treatmentwithCOSOPTisrequired,thenlactationisnotrecommended.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.Possiblesideeffects

suchasblurredvisionmayaffectsomepatients’abilitytodriveand/oroperatemachinery.

4.8Undesirableeffects

InclinicalstudiesnoadverseexperiencesspecifictoCOSOPThavebeenobserved;adversereactionshavebeen

limitedtothosethatwerereportedpreviouslywithdorzolamidehydrochlorideand/ortimololmaleate.

Duringclinicalstudies,1035patientsweretreatedwithCOSOPT.Approximately2.4%ofallpatients

discontinuedtherapywithCOSOPTbecauseoflocalocularadversereactions,approximately1.2%ofall

patientsdiscontinuedbecauseoflocaladversereactionssuggestiveofallergyorhypersensitivity(suchaslid

inflammationandconjunctivitis).

ThefollowingadversereactionshavebeenreportedwithCOSOPToroneofitscomponentseitherduring

clinicaltrialsorduringpost-marketingexperience:

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

to<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

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Eyedisorders:

COSOPT:

VeryCommon:burningandstinging

Common:conjunctivalinjection,blurredvision,cornealerosion,ocularitching,tearing

Dorzolamidehydrochlorideeyedrops,solution:

Common:eyelidinflammation*,eyelidirritation*

Uncommon:iridocyclitis*

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*

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Timololmaleateeyedrops,solution:

Uncommon:nausea*,dyspepsia*

Rare:diarrhea,drymouth*

Skinandsubcutaneoustissuedisorders:

COSOPT:

Rare:contactdermatitis,Stevens-Johnsonsyndrome,toxicepidermalnecrolysis

Dorzolamidehydrochlorideeyedrops,solution:

Rare:rash*

Timololmaleateeyedrops,solution:

Rare:alopecia*,psoriasiformrashorexacerbationofpsoriasis*

Renalandurinarydisorders:

COSOPT:

Uncommon:urolithiasis

Reproductivesystemandbreastdisorders:

Timololmaleateeyedrops,solution:

Rare:Peyronie’sdisease*

Generaldisordersandadministrationsiteconditions:

COSOPT:

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

anaphylaxis,rarelybronchospasm

Dorzolamidehydrochlorideeyedrops,solution:

Common:asthenia/fatigue*

Timololmaleateeyedrops,solution:

Uncommon:asthenia/fatigue*

*TheseadversereactionswerealsoobservedwithCOSOPTduringpost-marketingexperience.

LaboratoryFindings

COSOPTwasnotassociatedwithclinicallymeaningfulelectrolytedisturbancesinclinicalstudies.

4.9Overdose

NodataareavailableinhumansinregardtooverdosebyaccidentalordeliberateingestionofCOSOPT.

Symptoms

Therehavebeenreportsofinadvertentoverdoseswithtimololmaleateophthalmicsolutionresultingin

systemiceffectssimilartothoseseenwithsystemicbeta-adrenergicblockingagentssuchasdizziness,

headache,shortnessofbreath,bradycardia,bronchospasm,andcardiacarrest.Themostcommonsignsand

symptomstobeexpectedwithoverdosesofdorzolamideareelectrolyteimbalance,developmentofanacidotic

state,andpossiblycentralnervoussystemeffects.

Onlylimitedinformationisavailablewithregardtohumanoverdosebyaccidentalordeliberateingestionof

dorzolamidehydrochloride.Withoralingestion,somnolencehasbeenreported.Withtopicalapplicationthe

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Treatment

Treatmentshouldbesymptomaticandsupportive.Serumelectrolytelevels(particularlypotassium)andblood

pHlevelsshouldbemonitored.Studieshaveshownthattimololdoesnotdialyzereadily.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Antiglaucomapreparationsandmiotics,Betablockingagents,Timolol,

combinations,ATCcode:S01ED51

MechanismofAction

COSOPTiscomprisedoftwocomponents:dorzolamidehydrochlorideandtimololmaleate.Eachofthesetwo

componentsdecreaseselevatedintraocularpressurebyreducingaqueoushumorsecretion,butdoessobya

differentmechanismofaction.

DorzolamidehydrochlorideisapotentinhibitorofhumancarbonicanhydraseII.Inhibitionofcarbonic

anhydraseintheciliaryprocessesoftheeyedecreasesaqueoushumorsecretion,presumablybyslowingthe

formationofbicarbonateionswithsubsequentreductioninsodiumandfluidtransport.Timololmaleateisa

nonselectivebeta-adrenergicreceptorblockingagent.Theprecisemechanismofactionoftimololmaleatein

loweringintraocularpressureisnotclearlyestablishedatthistime,althoughafluoresceinstudyandtonography

studiesindicatethatthepredominantactionmayberelatedtoreducedaqueousformation.However,insome

studiesaslightincreaseinoutflowfacilitywasalsoobserved.Thecombinedeffectofthesetwoagentsresults

inadditionalintraocularpressurereduction(IOP)comparedtoeithercomponentadministeredalone.

Followingtopicaladministration,COSOPTreduceselevatedintraocularpressure,whetherornotassociated

withglaucoma.Elevatedintraocularpressureisamajorriskfactorinthepathogenesisofopticnervedamage

andglaucomatousvisualfieldloss.COSOPTreducesintraocularpressurewithoutthecommonsideeffectsof

mioticssuchasnightblindness,accommodativespasmandpupillaryconstriction.

Pharmacodynamiceffects

ClinicalEffects

Clinicalstudiesofupto15monthsdurationwereconductedtocomparetheIOP-loweringeffectofCOSOPT

b.i.d.(dosedmorningandbedtime)toindividually-andconcomitantly-administered0.5%timololand2.0%

dorzolamideinpatientswithglaucomaorocularhypertensionforwhomconcomitanttherapywasconsidered

appropriateinthetrials.Thisincludedbothuntreatedpatientsandpatientsinadequatelycontrolledwithtimolol

monotherapy.Themajorityofpatientsweretreatedwithtopicalbeta-blockermonotherapypriortostudy

enrollment.Inananalysisofthecombinedstudies,theIOP-loweringeffectofCOSOPTb.i.d.wasgreaterthan

thatofmonotherapywitheither2%dorzolamidet.i.d.or0.5%timololb.i.d.TheIOP-loweringeffectof

COSOPTb.i.d.wasequivalenttothatofconcomitanttherapywithdorzolamideb.i.d.andtimololb.i.d.The

IOP-loweringeffectofCOSOPTb.i.d.wasdemonstratedwhenmeasuredatvarioustimepointsthroughoutthe

dayandthiseffectwasmaintainedduringlong-termadministration.

Paediatricuse

A3monthcontrolledstudy,withtheprimaryobjectiveofdocumentingthesafetyof2%dorzolamide

hydrochlorideophthalmicsolutioninchildrenundertheageof6yearshasbeenconducted.Inthisstudy,30

patientsunder6andgreaterthanorequalto2yearsofagewhoseIOPwasnotadequatelycontrolledwith

monotherapybydorzolamideortimololreceivedCOSOPTinanopenlabelphase.Efficacyinthosepatients

hasnotbeenestablished.Inthissmallgroupofpatients,twicedailyadministrationofCOSOPTwasgenerally

welltoleratedwith19patientscompletingthetreatmentperiodand11patientsdiscontinuingforsurgery,a

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5.2Pharmacokineticproperties

DorzolamideHydrochloride

Unlikeoralcarbonicanhydraseinhibitors,topicaladministrationofdorzolamidehydrochlorideallowsforthe

activesubstancetoexertitseffectsdirectlyintheeyeatsubstantiallylowerdosesandthereforewithless

systemicexposure.Inclinicaltrials,thisresultedinareductioninIOPwithouttheacid-basedisturbancesor

alterationsinelectrolytescharacteristicoforalcarbonicanhydraseinhibitors.

Whentopicallyapplied,dorzolamidereachesthesystemiccirculation.Toassessthepotentialforsystemic

carbonicanhydraseinhibitionfollowingtopicaladministration,activesubstanceandmetaboliteconcentrations

inredbloodcells(RBCs)andplasmaandcarbonicanhydraseinhibitioninRBCsweremeasured.

DorzolamideaccumulatesinRBCsduringchronicdosingasaresultofselectivebindingtoCA-IIwhile

extremelylowconcentrationsoffreeactivesubstanceinplasmaaremaintained.Theparentactivesubstance

formsasingleN-desethylmetabolitethatinhibitsCA-IIlesspotentlythantheparentactivesubstancebutalso

inhibitsalessactiveisoenzyme(CA-I).ThemetabolitealsoaccumulatesinRBCswhereitbindsprimarilyto

CA-I.Dorzolamidebindsmoderatelytoplasmaproteins(approximately33%).Dorzolamideisprimarily

excretedunchangedintheurine;themetaboliteisalsoexcretedinurine.Afterdosingends,dorzolamide

washesoutofRBCsnonlinearly,resultinginarapiddeclineofactivesubstanceconcentrationinitially,

followedbyaslowereliminationphasewithahalf-lifeofaboutfourmonths.

Whendorzolamidewasgivenorallytosimulatethemaximumsystemicexposureafterlongtermtopicalocular

administration,steadystatewasreachedwithin13weeks.Atsteadystate,therewasvirtuallynofreeactive

substanceormetaboliteinplasma;CAinhibitioninRBCswaslessthanthatanticipatedtobenecessaryfora

pharmacologicaleffectonrenalfunctionorrespiration.Similarpharmacokineticresultswereobservedafter

chronic,topicaladministrationofdorzolamidehydrochloride.However,someelderlypatientswithrenal

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

differencesincarbonicanhydraseinhibitionandnoclinicallysignificantsystemicsideeffectsweredirectly

attributabletothisfinding.

TimololMaleate

Inastudyofplasmaactivesubstanceconcentrationinsixsubjects,thesystemicexposuretotimololwas

determinedfollowingtwicedailytopicaladministrationoftimololmaleateophthalmicsolution0.5%.The

meanpeakplasmaconcentrationfollowingmorningdosingwas0.46ng/mlandfollowingafternoondosingwas

0.35ng/ml.

5.3Preclinicalsafetydata

Theocularandsystemicsafetyprofileoftheindividualcomponentsiswellestablished.

Dorzolamide

Inrabbitsgivenmaternotoxicdosesofdorzolamideassociatedwithmetabolicacidosis,malformationsofthe

vertebralbodieswereobserved.

Timolol

Animalstudieshavenotshownteratogeniceffect.

Furthermore,noadverseoculareffectswereseeninanimalstreatedtopicallywithdorzolamidehydrochloride

andtimololmaleateophthalmicsolutionorwithconcomitantly-administereddorzolamidehydrochlorideand

timololmaleate.Invitroandinvivostudieswitheachofthecomponentsdidnotrevealamutagenicpotential.

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Benzalkoniumchloride

Hydroxyethylcellulose

Mannitol(E421)

Sodiumcitrate(E331)

Sodiumhydroxide(E524)forpHadjustment

Waterforinjections

6.2Incompatibilities

Notapplicable.

6.3Shelflife

Theshelf-lifeexpirydateofthisproductshallbethedateshownonthecontainerandouterpackageoftheproducton

themarketinthecountryoforigin.

COSOPTshouldbeusednolongerthan28daysafterfirstopeningthecontainer.

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialtemperaturestorageconditions.Keepthebottleintheoutercarton,

inordertoprotectfromlight.

6.5Natureandcontentsofcontainer

TheOCUMETERPlusOphthalmicDispenserconsistsofatranslucent,high-densitypolyethylenecontainerwitha

sealeddroppertip,aflexibleflutedsideareawhichisdepressedtodispensethedrops,anda2-piececapassembly.The

2-piececapmechanismpuncturesthesealeddroppertipuponinitialuse,thenlockstogethertoprovideasinglecap

duringtheusageperiod.Tamperevidenceisprovidedbyasafetystriponthecontainerlabel.TheOCUMETERPlus

OphthalmicDispensercontains5mlofsolution.

Inpacksof1x5ml(single5-mlcontainer)inanover-labelledoutercarton.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

IPSHealthcareLimited

SterlingHouse

501MiddletonRoad

Chadderton

Oldham

Lancashire

OL99LY

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8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1659/49/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:19thAugust2011

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