ALPHAGAN

Main information

  • Trade name:
  • ALPHAGAN Eye Drops Solution 0.2 %w/v
  • Dosage:
  • 0.2 %w/v
  • Pharmaceutical form:
  • Eye Drops Solution
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ALPHAGAN Eye Drops Solution 0.2 %w/v
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1659/048/001
  • Authorization date:
  • 26-08-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Alphagan0.2%w/v(2mg/ml)EyeDrops,Solution

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Onemlofsolutioncontains2.0mgbrimonidinetartrate,equivalentto1.3mgofbrimonidine.

Excipient(s):containsbenzalkoniumchloride.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Eyedrops,solution

ProductimportedfromtheUK:

Clear,greenish-yellowtolightgreenish-yellowsolution.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Reductionofelevatedintraocularpressure(IOP)inpatientswithopenangleglaucomaorocularhypertension.

Asmonotherapyinpatientsinwhomtopicalbeta-blockertherapyiscontraindicated.

AsadjunctivetherapytootherintraocularpressureloweringmedicationswhenthetargetIOPisnotachievedwith

asingleagent(seeSection5.1).

4.2Posologyandmethodofadministration

Recommendeddosageinadults(includingtheelderly)

TherecommendeddoseisonedropofAlphaganintheaffectedeye(s)twicedaily,approximately12hoursapart.No

dosageadjustmentisrequiredfortheuseinelderlypatients.

Aswithanyeyedrops,toreducepossiblesystemicabsorption,itisrecommendedthatthelachrymalsacbecompressed

atthemedialcanthus(punctalocclusion)foroneminute.Thisshouldbeperformedimmediatelyfollowingthe

instillationofeachdrop.

Ifmorethanonetopicalophthalmicdrugistobeused,thedifferentdrugsshouldbeinstilled5-15minutesapart.

Useinrenalandhepaticimpairment

Alphaganhasnotbeenstudiedinpatientswithhepaticorrenalimpairment(seesection4.4).

Useinpaediatricsubjects

Noclinicalstudieshavebeenperformedinadolescents(12to17years).

Alphaganisnotrecommendedforuseinchildrenbelow12yearsandiscontraindicatedinneonatesandinfants(less

than2yearsofage)(seesections4.3,4.4and4.9).Itisknownthatsevereadversereactionscanoccurinneonates.The

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4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients.

Neonatesandinfants(seesection4.8).

Patientsreceivingmonoamineoxidase(MAO)inhibitortherapyandpatientsonantidepressantswhichaffect

noradrenergictransmission(e.g.tricyclicantidepressantsandmianserin).

4.4Specialwarningsandprecautionsforuse

Childrenof2yearsofageandabove,especiallythoseinthe2-7agerangeand/orweighing 20Kg,shouldbetreated

withcautionandcloselymonitoredduetothehighincidenceandseverityofsomnolence(seesection4.8).

Cautionshouldbeexercisedintreatingpatientswithsevereorunstableanduncontrolledcardiovasculardisease.

Some(12.7%)patientsinclinicaltrialsexperiencedanocularallergictypereactionwithAlphagan(seesection4.8for

details).Ifallergicreactionsareobserved,treatmentwithAlphaganshouldbediscontinued.

DelayedocularhypersensitivityreactionshavebeenreportedwithAlphagan0.2%,withsomereportedtobeassociated

withanincreaseinIOP.

Alphaganshouldbeusedwithcautioninpatientswithdepression,cerebralorcoronaryinsufficiency,Raynaud's

phenomenon,orthostatichypotensionorthromboangiitisobliterans.

Alphaganhasnotbeenstudiedinpatientswithhepaticorrenalimpairment;cautionshouldbeusedintreatingsuch

patients.

ThepreservativeinAlphagan,benzalkoniumchloride,maycauseeyeirritation.Avoidcontactwithsoftcontactlenses.

Removecontactlensespriortoapplicationandwaitatleast15minutesbeforereinsertion.Knowntodiscoloursoft

contactlenses.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Alphaganiscontraindicatedinpatientsreceivingmonoamineoxidase(MAO)inhibitortherapyandpatientson

antidepressantswhichaffectnoradrenagictransmission(e.g.tricyclicantidepressantsandmiaserin),(seesection4.3).

AlthoughspecificdruginteractionsstudieshavenotbeenconductedwithAlphagan,thepossibilityofanadditiveor

potentiatingeffectwithCNSdepressants(alcohol,barbiturates,opiates,sedatives,oranaesthetics)shouldbe

considered.

NodataonthelevelofcirculatingcatecholaminesafterAlphaganadministrationareavailable.Caution,however,is

advisedinpatientstakingmedicationswhichcanaffectthemetabolismanduptakeofcirculatingaminese.g.

chlorpromazine,methylphenidate,reserpine.

AftertheapplicationofAlphagan,clinicallyinsignificantdecreasesinbloodpressurewerenotedinsomepatients.

Cautionisadvisedwhenusingdrugssuchasantihypertensivesand/orcardiacglycosidesconcomitantlywithAlphagan.

Cautionisadvisedwheninitiating(orchangingthedoseof)aconcomitantsystemicagent(irrespectiveof

pharmaceuticalform)whichmayinteractwith-adrenergicagonistsorinterferewiththeiractivityi.e.agonistsor

antagonistsoftheadrenergicreceptore.g.(isoprenaline,prazosin).

4.6Fertility,pregnancyandlactation

Thesafetyofuseduringhumanpregnancyhasnotbeenestablished.Inanimalstudies,brimonidinetartratedidnot

causeanyteratogeniceffects.Inrabbits,brimonidinetartrate,atplasmalevelshigherthanareachievedduringtherapy

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Alphaganshouldbeusedduringpregnancyonlyifthepotentialbenefittothemotheroutweighsthepotentialrisktothe

foetus.

Itisnotknownifbrimonidineisexcretedinhumanmilk.Thecompoundisexcretedinthemilkofthelactatingrat.

Alphaganshouldnotbeusedbywomennursinginfants.

4.7Effectsonabilitytodriveandusemachines

Alphaganmaycausefatigueand/ordrowsiness,whichmayimpairtheabilitytodriveoroperatemachinery.Alphagan

maycauseblurredand/orabnormalvision,whichmayimpairtheabilitytodriveortousemachinery,especiallyat

nightorinreducedlighting.Thepatientshouldwaituntilthesesymptomshaveclearedbeforedrivingorusing

machinery.

4.8Undesirableeffects

ThemostcommonlyreportedADRsareoraldryness,ocularhyperaemiaandburning/stinging,alloccurringin22to

25%ofpatients.Theyareusuallytransientandnotcommonlyofaseverityrequiringdiscontinuationoftreatment.

Symptomsofocularallergicreactionsoccurredin12.7%ofsubjects(causingwithdrawalin11.5%ofsubjects)in

clinicaltrialswiththeonsetbetween3and9monthsinthemajorityofpatients.

Withineachfrequencygrouping,undesirableeffectsarepresentedinorderofdecreasingseriousness.Thefollowing

terminologieshavebeenusedinordertoclassifytheoccurrenceofundesirableeffects: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).

Cardiacdisorders

Uncommon:palpitations/arrhythmias(includingbradycardiaandtachycardia)

Nervoussystemdisorders

Verycommon:headache,drowsiness

Common:dizziness,abnormaltaste

Veryrare:syncope

Eyedisorders

Verycommon:

ocularirritation(hyperaemia,burningandstinging,pruritus,foreignbodysensation,conjunctivalfollicles)

blurredvision

allergicblepharitis,allergicblepharoconjunctivitis,allergicconjunctivitis,ocularallergicreaction,andfollicular

conjunctivitis

Common:

localirritation(eyelidhyperaemiaandoedema,blepharitis,conjunctivaloedemaanddischarge,ocularpainand

tearing)

photophobia

cornealerosionandstaining

oculardryness

conjunctivalblanching

abnormalvision

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Veryrare:

iritis

miosis

Respiratory,thoracicandmediastinaldisorders

Common:upperrespiratorysymptoms

Uncommon:nasaldryness

Rare:dyspnoea

Gastrointestinaldisorders

Verycommon:oraldryness

Common:gastrointestinalsymptoms

Vasculardisorders

Veryrare:hypertension,hypotension

Generaldisordersandadministrationsiteconditions

Verycommon:fatigue

Common:asthenia

Immunesystemdisorders

Uncommon:systemicallergicreactions

Psychiatricdisorders

Uncommon:depression

Veryrare:insomnia

Thefollowingadversereactionshavebeenidentifiedduringpost-marketinguseofAlphaganinclinicalpractice.

Becausetheyarereportedvoluntarilyfromapopulationofunknownsize,estimatesoffrequencycannotbemade:

Notknown:

Eyedisorders

iridocyclitis(anterioruveitis)

eyelidpruritus

Skinandsubcutaneoustissuedisorders

Skinreactionincludingerythema,faceoedema,pruritus,rashandvasodilatation

Incaseswherebrimonidinehasbeenusedaspartofthemedicaltreatmentofcongenitalglaucoma,symptomsof

brimonidineoverdosesuchaslossofconsciousness,lethargy,somnolence,hypotension,hypotonia,bradycardia,

hypothermia,cyanosis,pallor,respiratorydepressionandapnoeahavebeenreportedinneonatesandinfantsreceiving

brimonidine(seesection4.3).

Ina3-month,phase3studyinchildrenaged2-7yearswithglaucoma,inadequatelycontrolledbybeta-blockers,ahigh

prevalenceofsomnolence(55%)wasreportedwithAlphaganasadjunctivetreatment.In8%ofchildren,thiswas

severeandledtodiscontinuationoftreatmentin13%.Theincidenceofsomnolencedecreasedwithincreasingage,

beingleastinthe7-year-oldagegroup(25%),butwasmoreaffectedbyweight,occurringmorefrequentlyinthose

childrenweighing20kg(63%)comparedtothoseweighing>20kg(25%)(seesection4.4).

4.9Overdose

Ophthalmicoverdose(Adults):

Inthosecasesreceived,theeventsreportedhavegenerallybeenthosealreadylisted

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Systemicoverdoseresultingfromaccidentalingestion(Adults):

Thereisverylimitedinformationregardingaccidentalingestionofbrimonidineinadults.Theonlyadverseevent

reportedtodatewashypotension.Itwasreportedthatthehypotensiveepisodewasfollowedbyreboundhypertension.

Treatmentoforaloverdoseincludessupportiveandsymptomatictherapy;patient’sairwaysshouldbemaintained.

Oraloverdosesofotheralpha-2-agonistshavebeenreportedtocausesymptomssuchashypotension,asthenia,

vomiting,lethargy,sedation,bradycardia,arrhythmias,miosis,apnoea,hypotonia,hypothermia,respiratorydepression

andseizure.

Paediatricpopulation

ReportsofseriousadverseeffectsfollowinginadvertentingestionofAlphaganbypaediatricsubjectshavebeen

publishedorreportedtoAllergan.ThesubjectsexperiencedsymptomsofCNSdepression,typicallytemporarycomaor

lowlevelofconsciousness,lethargy,somnolence,hypotonia,bradycardia,hypothermia,pallor,respiratorydepression

andapnoea,andrequiredadmissiontointensivecarewithintubationifindicated.Allsubjectswerereportedtohave

madeafullrecovery,usuallywithin6-24hours.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Sympathomimeticsinglaucomatherapy,ATCcode=S01EA05.

Brimonidineisanalpha-2adrenergicreceptoragonistthatis1000-foldmoreselectiveforthealpha-2adrenoceptor

thanthealpha-1adrenoreceptor.

Thisselectivityresultsinnomydriasisandtheabsenceofvasoconstrictioninmicrovesselsassociatedwithhuman

retinalxenografts.

Topicaladministrationofbrimonidinetartratedecreasesintraocularpressure(IOP)inhumanswithminimaleffecton

cardiovascularorpulmonaryparameters.

Limiteddataareavailableforpatientswithbronchialasthmashowingnoadverseeffects.

Alphaganhasarapidonsetofaction,withpeakocularhypotensiveeffectseenattwohourspost-dosing.Intwo1year

studies,AlphaganloweredIOPbymeanvaluesofapproximately4-6mmHg.

Fluorophotometricstudiesinanimalsandhumanssuggestthatbrimonidinetartratehasadualmechanismofaction.It

isthoughtthatAlphaganmaylowerIOPbyreducingaqueoushumourformationandenhancinguveoscleraloutflow.

ClinicaltrialsshowthatAlphaganiseffectiveincombinationwithtopicalbeta-blockers.Shortertermstudiesalso

suggestthatAlphaganhasaclinicallyrelevantadditiveeffectincombinationwithtravoprost(6weeks)andlatanoprost

(3months).

5.2Pharmacokineticproperties

Generalcharacteristics

Afterocularadministrationofa0.2%solutiontwicedailyfor10days,plasmaconcentrationswerelow(meanCmax

was0.06ng/ml).Therewasaslightaccumulationinthebloodaftermultiple(2timesdailyfor10days)instillations.

Theareaundertheplasmaconcentration-timecurveover12hoursatsteadystate(AUC )was0.31ng·hr/ml,as

comparedto0.23ng·hr/mlafterthefirstdose.Themeanapparenthalf-lifeinthesystemiccirculationwas

approximately3hoursinhumansaftertopicaldosing.

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Brimonidinebindsreversiblytomelanininoculartissues,invitroandinvivo.Following2weeksofocular

instillation,theconcentrationsofbrimonidineiniris,ciliarybodyandchoroid-retinawere3-to17-foldhigherthan

thoseafterasingledose.Accumulationdoesnotoccurintheabsenceofmelanin.

Thesignificanceofmelaninbindinginhumansisunclear.However,nosignificantocularadversereactionwasfound

duringbiomicroscopicexaminationofeyesinpatientstreatedwithAlphaganforuptooneyear,norwassignificant

oculartoxicityfoundduringaoneyearocularsafetystudyinmonkeysgivenapproximatelyfourtimesthe

recommendeddoseofbrimonidinetartrate.

Followingoraladministrationtoman,brimonidineiswellabsorbedandrapidlyeliminated.Themajorpartofthedose

(around75%ofthedose)wasexcretedasmetabolitesinurinewithinfivedays;nounchangeddrugwasdetectedin

urine.Invitrostudies,usinganimalandhumanliver,indicatethatthemetabolismismediatedlargelybyaldehyde

oxidaseandcytochromeP450.Hence,thesystemiceliminationseemstobeprimarilyhepaticmetabolism.

Kineticsprofile:

NogreatdeviationfromdoseproportionalityforplasmaCmaxandAUCwasobservedfollowingasingletopicaldose

of0.08%,0.2%and0.5%.

Characteristicsinpatients

Characteristicsinelderlypatients:

TheC ,AUC,andapparenthalf-lifeofbrimonidinearesimilarintheelderly(subjects65yearsorolder)aftera

singledosecomparedwithyoungadults,indicatingthatitssystemicabsorptionandeliminationarenotaffectedbyage.

Basedondatafroma3monthclinicalstudy,whichincludedelderlypatients,systemicexposuretobrimonidinewas

verylow.

5.3Preclinicalsafetydata

Non-clinicaldatarevealnospecialhazardforhumansbasedonconventionalstudiesofsafetypharmacology,repeated

dosetoxicity,genotoxicity,carcinogenicpotential,toxicitytoreproduction.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

BenzalkoniumChloride

Poly(vinylalcohol)

Sodiumchloride

Sodiumcitrate

Citricacidmonohydrate

Purifiedwater

Hydrochloricacid(forpH-adjustment)or

Sodiumhydroxide(forpH-adjustment)

6.2Incompatibilities

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6.3Shelflife

Theshelf-lifeexpirydateofthisproductshallbethedateshownonthebottleandouterpackageoftheproductonthe

marketinthecountryoforigin.

Afterfirstopening:usewithin28days.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.

6.5Natureandcontentsofcontainer

Whitelowdensitypolyethylenedropperbottleswitha35microlitretip.Thecapiseitheraconventionalpolystyrene

screwcaporaComplianceCap(C-Cap).

5mlbottleinpacksizeof1,inanover-labelledoutercarton

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

IPSHealthcareLimited

SterlingHouse

501MiddletonRoad

Chadderton

Oldham

LancashireOL99LY

UnitedKingdom

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1659/048/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:26 th

August2011

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