Arnalevocap 75 mg/18,75 mg/200 mg Filmdragerad tablett

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Produktens egenskaper Produktens egenskaper (SPC)

19-02-2015

Aktiva substanser:
entakapon; karbidopa (monohydrat); levodopa
Tillgänglig från:
Actavis Group PTC ehf.
ATC-kod:
N04BA03
INN (International namn):
entacapone; carbidopa (monohydrate); levodopa
Dos:
75 mg/18,75 mg/200 mg
Läkemedelsform:
Filmdragerad tablett
Sammansättning:
karbidopa (monohydrat) 20,25 mg Aktiv substans; levodopa 75 mg Aktiv substans; sojalecitin Hjälpämne; entakapon 200 mg Aktiv substans
Klass:
Apotek
Receptbelagda typ:
Receptbelagt
Terapiområde:
dekarboxylashämmare och COMT-hämmare
Bemyndigande status:
Avregistrerad
Godkännandenummer:
50309
Tillstånd datum:
2015-02-19

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

06-08-2014

Produktens egenskaper Produktens egenskaper - engelska

06-08-2014

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

19-02-2015

Läs hela dokumentet

Produktinformationen förArnalevocap50 mg50 mg/12,5mg/200 mg,filmdragerad tablett,

75 mg/18,75mg/200mgfilmdrageradtablett,100 mg/25 mg/200mgfilmdrageradtablett,

125 mg/31,25mg/200mgfilmdrageradtablett,150 mg/37,5 mg/200mgfilmdrageradtablett,

175 mg/43,75mg/200filmdragerad tablett, 200 mg/50mg/200mgfilmdrageradtablett.

MTnr 50308, 50309, 50310,50311, 50312, 50313, 50314 gäller vid dettillfälledåläkemedlet

godkändes. Informationenkommerinteattuppdateraseftersomläkemedletintemarknadsförs

iSverige.Av sammaanledning finnsintenågonsvensk produktinformation.

Den engelskaproduktinformationen kommer dock attuppdaterasför deprodukterdär Sverige

ärreferensland.

Omläkemedelsnamnetiföljandeproduktinformationintestämmermed namnetpå

dokumentet,beror detpåattläkemedletiSverigeär godkäntunder ettannatnamn.

SUMMARYOFPRODUCTCHARACTERISTICS

1. NAME OFTHEMEDICINALPRODUCT

Arnalevocap50mg/12.5mg/200mgfilm-coatedtablets

Arnalevocap75mg/18.75mg/200mgfilm-coatedtablets

Arnalevocap100mg/25mg/200mgfilm-coatedtablets

Arnalevocap125mg/31.25mg/200mgfilm-coatedtablets

Arnalevocap150mg/37.5mg/200mgfilm-coatedtablets

Arnalevocap175mg/43.75mg/200mgfilm-coatedtablets

Arnalevocap200mg/50mg/200mgfilm-coatedtablets

2. QUALITATIVEANDQUANTITATIVECOMPOSITION

Each film-coated tabletcontains50mgof levodopa,12.5mgof carbidopa(asmonohydrate)

and200mgof entacapone.

Each film-coated tabletcontains75mgof levodopa,18.75mgof carbidopa(asmonohydrate)

and200mgof entacapone.

Each film-coated tabletcontains100mgof levodopa,25mgof carbidopa(as

monohydrate)and200mgof entacapone.

Each film-coated tabletcontains125mgof levodopa,31.25mgof carbidopa(as

monohydrate)and200mgof entacapone.

Each film-coated tabletcontains150mgof levodopa,37.5mgof carbidopa(as

monohydrate)and200mgof entacapone.

Each film-coated tabletcontains175mgof levodopa,43.75mgof carbidopa(as

monohydrate)and200mgof entacapone.

Eachfilm-coatedtabletcontains200mgoflevodopa,50mgofcarbidopa(asmonohydrate)and

200mgofentacapone.

Excipientwith known effect:

Each film-coated tabletcontains0.48mglecithin(soya)(E322).

Each film-coated tabletcontains0.54mglecithin(soya)(E322).

Each film-coated tabletcontains0.60mglecithin(soya)(E322).

Each film-coated tabletcontains0.66mglecithin(soya)(E322).

Each film-coated tabletcontains0.72mglecithin(soya)(E322).

Each film-coated tabletcontains0.78mglecithin(soya)(E322).

Each film-coated tabletcontains0.83mglecithin(soya)(E322).

For thefulllistof excipients, seesection 6.1.

3. PHARMACEUTICALFORM

Film-coated tablet

Arnalevocap50mg/12.5mg/200mg:Brownish red oval, biconvex film-coated tabletof 6.85

x 14.2mmwith “50”markedon onesideand “LEC”on theoppositeside.

Arnalevocap75mg/18.75mg/200mg:Brownishred, oval,biconvex film-coatedtabletof

7.04 x 14.7mmwith “75”marked on onesideand “LEC”on theoppositeside.

Arnalevocap100mg/25mg/200mg:Brownishred, oval,biconvex film-coatedof 7.23 x

15.3mmtabletwith“100”markedon onesideand“LEC”on theoppositeside.

Arnalevocap125mg/31.25mg/200mg:Brownishred, oval,biconvex film-coatedtabletof

7.5 x 15.8mmwith “125”marked on onesideand “LEC”on theoppositeside.

Arnalevocap150mg/37.5mg/200mg:Brownishred, oval,biconvex film-coatedtabletof

7.68 x 16.2mmwith “150”marked on onesideand “LEC”on theoppositeside.

Arnalevocap175mg/43.75mg/200mg:Brownishred, oval,biconvex film-coatedof 7.92 x

16.6mmtabletwith“175”markedon onesideand“LEC”on theoppositeside.

Arnalevocap200mg/50mg/200mg:Brownishred, oval,biconvex film-coatedtabletof 8.21

x 17.2mmwith “200”marked on onesideand “LEC”on theoppositeside.

4. CLINICALPARTICULARS

4.1 Therapeuticindications

Arnalevocap isindicated for thetreatmentof adultpatientswith Parkinson’sdiseaseand end-

of-dosemotorfluctuationsnotstabilisedon levodopa/dopadecarboxylase(DDC) inhibitor

treatment.

4.2 Posologyandmethodof administration

Posology

Theoptimumdailydosemustbedetermined bycarefultitration of levodopaineach patient.

Thedailydoseshouldbepreferablyoptimised using oneof theseven availabletablet

strengths(50mg/12.5mg/200mg, 75mg/18.75mg/200mg,100mg/25mg/200mg,

125mg/31.25mg/200mg,150mg/37.5mg/200mg, 175 mg/43.75mg/200 mgor

200mg/50mg/200mglevodopa/carbidopa/entacapone).

Patientsshould beinstructedto takeonlyoneArnalevocaptabletperdoseadministration.

Patientsreceivinglessthan 70-100mgcarbidopaadayaremorelikelyto experiencenausea

andvomiting.Whiletheexperiencewith totaldailydosegreaterthan 200 mg carbidopais

limited, themaximumrecommended dailydoseof entacaponeis2,000mgand thereforethe

maximumdoseis10 tabletsper dayfor theArnalevocap strengthsof 50mg/12.5mg/200mg,

75mg/18.75mg/200mg,100mg/25mg/200mg, 125mg/31.25mg/200mgand

150mg/37.5mg/200mg.TentabletsofArnalevocap 150mg/37.5mg/200mgequals375mg

of carbidopaaday.Accordingto thisdailycarbidopadose,themaximumrecommended daily

175 mg/43.75mg/200 mgdoseis8 tabletsper dayandArnalevocap 200mg/50mg/200mg

doseis7 tabletsperday.

UsuallyArnalevocapisto beused inpatientswho arecurrentlytreatedwith corresponding

dosesof standard releaselevodopa/DDC inhibitor and entacapone.

How to transferpatientstaking levodopa/DDC inhibitor(carbidopaorbenserazide)

preparationsand entacaponetabletstoArnalevocap

a.Patientswho arecurrentlytreatedwith entacaponeand with standardrelease

levodopa/carbidopain dosesequaltoArnalevocap tabletstrengthscan bedirectlytransferred

tocorrespondingArnalevocaptablets.

For example, apatienttaking onetabletof 50mg/12.5mgof levodopa/carbidopawith one

tabletof entacapone200mgfour timesdailycantakeone50mg/12.5mg/200mg

Arnalevocap tabletfour timesdailyin placeof theirusuallevodopa/carbidopaandentacapone

doses.

b.WheninitiatingArnalevocap therapyfor patientscurrentlytreatedwith entacaponeand

levodopa/carbidopain dosesnotequaltoArnalevocap 50mg/12.5mg/200mg(or

75mg/18.75mg/200mgor 100mg/25mg/200mgor 125mg/31.25mg/200mgor

150mg/37.5mg/200mgor 175mg/43.75mg/200mgor 200mg/50mg/200mg)tablets,

Arnalevocap dosing should becarefullytitratedfor optimalclinicalresponse.Attheinitiation,

Arnalevocap should beadjusted tocorrespond ascloselyaspossibleto thetotaldailydoseof

levodopacurrentlyused.

c.When initiatingArnalevocapin patientscurrentlytreatedwith entacaponeand

levodopa/benserazidein astandardreleaseformulation, thedosing of levodopa/benserazide

should bediscontinuedin thepreviousnight,andArnalevocap should bestarted inthenext

morning.Thestarting doseofArnalevocapshouldprovideeither thesameamountof

levodopaor slightly(5-10%) more.

How to transferpatientsnotcurrentlytreated withentacaponetoArnalevocap

Initiation ofArnalevocapmaybeconsidered atcorresponding dosesto currenttreatmentin

somepatientswith Parkinson'sdiseaseand end-of-dosemotorfluctuations, who arenot

stabilised on their currentstandardreleaselevodopa/DDC inhibitortreatment.However,a

directswitchfromlevodopa/DDC inhibitortoArnalevocapisnotrecommendedfor patients

who havedyskinesiasor whosedailylevodopadoseisabove800 mg.In suchpatientsitis

advisabletointroduceentacaponetreatmentasaseparatetreatment(entacaponetablets)and

adjustthelevodopadoseifnecessary,beforeswitching toArnalevocap.

Entacaponeenhancestheeffectsof levodopa.Itmaythereforebenecessary,particularlyin

patientswithdyskinesia, toreducelevodopadoseby10-30% withinthefirstdaysto first

weeksafterinitiatingArnalevocaptreatment.Thedailydoseof levodopacan bereduced by

extending thedosing intervalsand/orbyreducingtheamountof levodopaper dose, according

totheclinicalconditionof thepatient.

Doseadjustmentduring thecourseofthetreatment

Whenmorelevodopaisrequired, an increaseinthefrequencyof dosesand/or theuseof an

alternativestrength ofArnalevocapshouldbeconsidered,within thedoserecommendations.

Whenlesslevodopaisrequired, thetotaldailydoseofArnalevocap should bereduced either

bydecreasing thefrequencyof administrationbyextendingthetimebetweendoses, or by

decreasing thestrength ofArnalevocapatanadministration.

If otherlevodopaproductsareused concomitantlywith aArnalevocaptablet, themaximum

doserecommendationsshould befollowed.

DiscontinuationofArnalevocaptherapy:IfArnalevocaptreatment

(levodopa/carbidopa/entacapone) isdiscontinuedand thepatientistransferredto

levodopa/DDC inhibitor therapywithoutentacapone, itisnecessarytoadjustthedosingof

otherantiparkinsoniantreatments, especiallylevodopa,to achieveasufficientlevelof control

of theparkinsoniansymptoms.

Paediatricpopulation:Thesafetyand efficacyofArnalevocapin children agedbelow18

yearshavenotbeenestablished.No dataareavailable.

Olderpeople:No doseadjustmentofArnalevocapisrequiredfor older patients.

Patientswith hepaticimpairment:ItisadvisedthatArnalevocapshould beadministered

cautiouslytopatientswith mild tomoderatehepaticimpairment.Dosereduction maybe

needed (seesection 5.2). For severehepaticimpairmentseesection4.3.

Patientswith renalimpairment:Renalimpairmentdoesnotaffectthepharmacokineticsof

entacapone.No particular studiesarereportedon thepharmacokineticsof levodopaand

carbidopainpatientswith renalinsufficiency,thereforeArnalevocaptherapyshouldbe

administered cautiouslytopatientsin severerenalimpairmentincludingthosereceiving

dialysistherapy(seesection5.2).

Methodof administration

Each tabletisto betaken orallyeither with or withoutfood (seesection 5.2). Onetablet

containsonetreatmentdoseandthetabletmayonlybeadministeredaswholetablets.

4.3 Contraindications

Hypersensitivityto theactivesubstance,soya,peanutor to anyof theexcipientslisted

in section6.1.

Severehepaticimpairment.

Narrow-angleglaucoma.

Pheochromocytoma.

CoadministrationofArnalevocap withnonselectivemonoamineoxidase(MAO-Aand

MAOB) inhibitors(e.g. phenelzine,tranylcypromine).

Coadministrationwith aselectiveMAOAinhibitorand aselectiveMAOB inhibitor (see

section4.5).

Aprevioushistoryof NeurolepticMalignantSyndrome(NMS) and/or non-traumatic

rhabdomyolysis.

4.4 Specialwarningsandprecautionsforuse

Arnalevocapisnotrecommendedfor thetreatmentof druginduced extrapyramidal

reactions

Arnalevocaptherapyshouldbeadministeredcautiouslyto patientswithischemicheart

disease, severecardiovascular or pulmonarydisease,bronchialasthma,renalor

endocrinedisease, historyof pepticulcerdiseaseor historyof convulsions.

In patientswith ahistoryof myocardialinfarction who haveresidualatrialnodalor

ventriculararrhythmias;cardiacfunction should bemonitoredwith particularcare

during theperiod of initialdoseadjustments.

AllpatientstreatedwithArnalevocap should bemonitoredcarefullyfor the

developmentof mentalchanges, depressionwith suicidaltendencies, andother serious

antisocialbehaviour.Patientswith pastor currentpsychosisshouldbetreated with

caution.

Concomitantadministrationof antipsychoticswithdopaminereceptor-blocking

properties,particularlyD

receptor antagonistsshould becarriedoutwith caution, and

thepatientcarefullyobserved for lossof antiparkinsonianeffector worseningof

parkinsoniansymptoms.

Patientswith chronicwide-angleglaucomamaybetreatedwithArnalevocap with

caution,providedtheintra-ocularpressureiswellcontrolledand thepatientis

monitored carefullyfor changesin intra-ocularpressure.

Arnalevocapmayinduceorthostatichypotension.ThereforeArnalevocapshouldbe

given cautiouslyto patientswho aretaking othermedicinalproductswhich maycause

orthostatichypotension.

Entacaponeinassociationwith levodopahasbeen associated withsomnolenceand

episodesof sudden sleep onsetin patientswith Parkinson’sdiseaseand caution should

thereforebeexercised when drivingor operatingmachines(seesection4.7).

In clinicalstudies, dopaminergicadversereactions, e.g. dyskinesia,weremorecommon

in patientswho received entacaponeand dopamineagonists(such asbromocriptine),

selegilineor amantadinecomparedto thosewho received placebo withthis

combination.Thedosesof other antiparkinsonianmedicinalproductsmayneed tobe

adjustedwhenArnalevocaptreatmentissubstitutedfor apatientcurrentlynottreated

with entacapone.

Rhabdomyolysissecondaryto severedyskinesiasor neurolepticmalignantsyndrome

(NMS) hasbeen observed rarelyinpatientswith Parkinson'sdisease.Therefore,any

abruptdosereduction or withdrawalof levodopashould becarefullyobserved,

particularlyin patientswho arealso receiving neuroleptics.NMS, including

rhabdomyolysisandhyperthermia, ischaracterised bymotorsymptoms(rigidity,

myoclonus, tremor), mentalstatuschanges(e.g.agitation,confusion,coma),

hyperthermia,autonomicdysfunction(tachycardia,labileblood pressure) and elevated

serumcreatinephosphokinase.In individualcases,onlysomeof thesesymptomsand/or

findingsmaybeevident.Theearlydiagnosisisimportantfor theappropriate

managementof NMS.Asyndromeresemblingtheneurolepticmalignantsyndrome

including muscularrigidity,elevated bodytemperature, mentalchangesand increased

serumcreatinephosphokinasehasbeen reported with theabruptwithdrawalof

antiparkinsonianagents. NeitherNMSnor rhabdomyolysishavebeenreported in

associationwith entacaponetreatmentfromcontrolledtrialsin which entacaponewas

discontinuedabruptly.Sincetheintroductionof entacaponeinto themarket,isolated

casesof NMShavebeenreported,especiallyfollowing abruptreductionor

discontinuationof entacaponeand other concomitantdopaminergicmedicinalproducts.

When considered necessary,thereplacementofArnalevocapwith levodopaand DDC

inhibitor withoutentacaponeor otherdopaminergictreatmentshouldproceed slowly

and an increaseinlevodopadosemaybenecessary.

If generalanaesthesiaisrequired,therapywithArnalevocapmaybecontinuedfor as

long asthepatientispermittedto takefluidsandmedicinalproductsbymouth.If

therapyhasto bestopped temporarily,Arnalevocapmayberestartedassoon asoral

medicinalproductscanbetakenatthesamedailydoseasbefore.

Periodicevaluation of hepatic,haematopoietic,cardiovascular andrenalfunction is

recommended duringextendedtherapywithArnalevocap.

For patientsexperiencing diarrhoea, afollow-up of weightisrecommended inorder to

avoid potentialexcessiveweightdecrease. Prolongedor persistentdiarrhoeaappearing

during useof entacaponemaybeasign of colitis. In theeventof prolongedor persistent

diarrhoea,thedrug should bediscontinuedand appropriatemedicaltherapyand

investigationsconsidered.

Patientsshouldberegularlymonitored for thedevelopmentof impulsecontrol

disorders. Patientsand carersshould bemadeawarethatbehaviouralsymptomsof

impulsecontroldisordersincludingpathologicalgambling, increased libido,

hypersexuality,compulsivespendingor buying, bingeeatingand compulsiveeating can

occur inpatientstreated withdopamineagonistsand/orother dopaminergictreatments

containing levodopaincludingArnalevocap. Reviewof treatmentisrecommendedif

suchsymptomsdevelop.

For patientswho experienceprogressiveanorexia, astheniaandweightdecreasewithin

arelativelyshortperiodof time,ageneralmedicalevaluationincluding liverfunction

shouldbeconsidered.

Levodopa/carbidopamaycausefalsepositiveresultwhen adipstick isused to testfor

urinaryketone;and thisreactionisnotaltered byboiling theurinesample.Theuseof

glucoseoxidasemethodsmaygivefalsenegativeresultsfor glycosuria.

4.5 Interactionwithothermedicinalproductsandotherformsofinteraction

Otherantiparkinsonian medicinalproducts:To datetherehasbeenno indicationof

interactionsthatwould precludeconcurrentuseof standardantiparkinsonian medicinal

productswithArnalevocap therapy.Entacaponein highdosesmayaffecttheabsorptionof

carbidopa. However, no interaction withcarbidopahasbeen observed withtherecommended

treatmentschedule(200 mg of entacaponeup to 10 timesdaily).Interactionsbetween

entacaponeand selegilinehavebeeninvestigatedin repeated dosestudiesinParkinson's

diseasepatientstreated withlevodopa/DDC inhibitor andno interactionwasobserved.When

used withArnalevocap,thedailydoseof selegilineshould notexceed 10 mg.

Cautionshouldbeexercisedwhenthefollowingactivesubstancesareadministeredconcomitantly

withlevodopatherapy.

Antihypertensives:Symptomaticposturalhypotensionmayoccurwhenlevodopaisaddedtothe

treatmentofpatientsalreadyreceivingantihypertensives.Doseadjustmentoftheantihypertensive

agentmayberequired.

Antidepressants:Rarely,reactionsincludinghypertension anddyskinesiahavebeen reported

withtheconcomitantuseof tricyclicantidepressantsandlevodopa/carbidopa.Interactions

between entacaponeand imipramineand between entacaponeand moclobemidehavebeen

investigated in singledosestudiesin healthyvolunteers. No pharmacodynamicinteractions

wereobserved.Asignificantnumberof Parkinson'sdiseasepatientshavebeentreated with

thecombinationof levodopa,carbidopaand entacaponewithseveralactivesubstances

includingMAO-Ainhibitors,tricyclicantidepressants, noradrenalinereuptakeinhibitorssuch

asdesipramine,maprotilineand venlafaxineand medicinalproductsthataremetabolised by

COMT(e.g. catechol-structuredcompounds, paroxetine). No pharmacodynamicinteractions

havebeen observed. However, cautionshouldbeexercisedwhen thesemedicinalproductsare

used concomitantlywithArnalevocap (seesections4.3 and 4.4).

Otheractivesubstances:Dopaminereceptor antagonists(e.g. someantipsychoticsand

antiemetics),phenytoinand papaverinemayreducethetherapeuticeffectof levodopa.

Patientstaking thesemedicinalproductswithArnalevocapshouldbecarefullyobservedfor

lossof therapeuticresponse.

Duetoentacapone'saffinitytocytochromeP4502C9invitro(seesection 5.2),Arnalevocap

maypotentiallyinterferewithactivesubstanceswhosemetabolismisdependenton this

isoenzyme, such asS-warfarin. However, inan interaction studywith healthyvolunteers,

entacaponedid notchangetheplasmalevelsof S-warfarin,whiletheAUC for R-warfarin

increased on averageby18% [CI

11-26%].TheINR valuesincreased on averageby13%

6-19%].Thus, acontrolof INR isrecommended whenArnalevocap isinitiatedfor

patientsreceivingwarfarin.

Otherformsofinteractions:Sincelevodopacompeteswith certainamino acids, the

absorptionofArnalevocap maybeimpairedin somepatientson highproteindiet.

Levodopaand entacaponemayformchelateswithiron in thegastrointestinaltract.Therefore,

Arnalevocap andiron preparationsshould betaken atleast2-3 hoursapart(seesection4.8).

In vitro data:Entacaponebindstohuman albuminbinding siteII which also bindsseveral

othermedicinalproducts, including diazepamand ibuprofen.Accordingtoinvitrostudies,

significantdisplacementisnotanticipated attherapeuticconcentrationsof themedicinal

products.Accordingly,to datetherehasbeen no indication of such interactions.

4.6 Fertility, pregnancyandlactation

Pregnancy

Thereareno adequatedatafromtheuseof thecombination of

levodopa/carbidopa/entacaponeinpregnantwomen.Studiesinanimalshaveshown

reproductivetoxicityof theseparatecompounds(seesection 5.3).Thepotentialrisk for

humansisunknown.Arnalevocapshouldnotbeused during pregnancyunlessthebenefitsfor

themotheroutweigh thepossiblerisksto thefoetus.

Breastfeeding

Levodopaisexcreted inhuman breastmilk.Thereisevidencethatbreastfeeding issuppressed

duringtreatmentwith levodopa.Carbidopaand entacaponewereexcreted in milk inanimals

butisnotknown whether theyareexcretedin human breastmilk.Thesafetyof levodopa,

carbidopaor entacaponein theinfantisnotknown.Womenshould notbreast-feed during

treatmentwithArnalevocap.

Fertility

No adversereactionson fertilitywereobservedin preclinicalstudieswith entacapone,

carbidopaor levodopaalone. Fertilitystudiesin animalshavenotbeenconductedwith the

combination of entacapone,levodopaand carbidopa.

4.7 Effectsonabilityto driveandusemachines

Arnalevocapmayhavemajorinfluenceontheabilitytodriveandusemachines.Levodopa,carbidopa

andentacaponetogethermaycausedizzinessandsymptomaticorthostatism.Therefore,cautionshould

beexercisedwhendrivingorusingmachines.

Patientsbeingtreated withArnalevocapand presenting with somnolenceand/or sudden sleep

onsetepisodesmustbeinstructed torefrainfromdrivingor engaging inactivitieswhere

impairedalertnessmayputthemselvesor othersatrisk of seriousinjuryor death(e.g.

operating machines)untilsuch recurrentepisodeshaveresolved(seesection4.4).

4.8 Undesirableeffects

a. Summary of thesafetyprofile

Themostfrequentlyreported adversereactionswith levodopa/carbidopa/entacaponeare

dyskinesiasoccurring inapproximately19% of patients;gastrointestinalsymptomsincluding

nauseaand diarrhoeaoccurringin approximately15% and12% of patients, respectively;

muscle, musculoskeletaland connectivetissuepainoccurringin approximately12% of

patients;and harmlessreddish-brown discolourationof urine(chromaturia) occurring in

approximately10% of patients.Seriouseventsof gastrointestinalhaemorrhage(uncommon)

andangioedema(rare)havebeenidentifiedfromtheclinicaltrialswith

levodopa/carbidopa/entacaponeor entacaponecombined withlevodopa/DDC inhibitor.

Serioushepatitiswith mainlycholestaticfeatures, rhabdomyolysisand neurolepticmalignant

syndromemayoccurwith levodopa/carbidopa/entacaponealthough no caseshavebeen

identified fromtheclinicaltrialdata.

b.Tabulatedlist of adversereactions

Thefollowingadversereactions,listedinTable1,havebeenaccumulatedbothfromapooleddataof

elevendouble-blindclinicaltrialsconsistingof3230patients(1810treatedwith

levodopa/carbidopa/entacaponeorentacaponecombinedwithlevodopa/DDCinhibitor,and1420

treatedwithplacebocombinedwithlevodopa/DDCinhibitororcabergolinecombinedwithlevodopa/

DDCinhibitor),andfromthepost-marketingdatasincetheintroductionofentacaponeintothemarket

forthecombinationuseofentacaponewithlevodopa/DDCinhibitor.

Adversereactionsareranked under headingsof frequency,themostfrequentfirst, using the

followingconvention:Verycommon(≥1/10);common (≥1/100 to<1/10);uncommon

(≥1/1,000 to<1/100);rare(≥1/10,000to <1/1,000), veryrare(<1/10,000), notknown (cannot

beestimated fromtheavailabledata, sinceno valid estimatecanbederivedfromclinical

trialsor epidemiologicalstudies).

Table1.Adversereactions

Bloodandlymphaticsystemdisorders

Common: Anaemia

Uncommon: Thrombocytopenia

Metabolismand nutritiondisorders

Common: Weightdecreased*,decreasedappetite*

Psychiatricdisorders

Common: Depression,hallucination, confusionalstate*,abnormaldreams*, anxiety,

insomnia

Uncommon: Psychosis, agitation*

Notknown: Suicidalbehaviour

Nervoussystemdisorders

Verycommon:Dyskinesia*

Common: Parkinsonismaggravated (e.g.bradykinesia)*,tremor,on and off

phenomenon,

dystonia, mentalimpairment(e.g. memoryimpairment, dementia),

somnolence,

dizziness*, headache

Notknown: Neurolepticmalignantsyndrome*

Eyedisorders

Common: Blurred vision

Cardiacdisorders

Common: Ischemicheartdiseaseeventsother thanmyocardialinfarction (e.g. angina

pectoris)**,irregularheartrhythm

Uncommon: Myocardialinfarction**

Vasculardisorders:

Common: Orthostatichypotension,hypertension

Uncommon: Gastrointestinalhaemorrhage

Respiratory, thoracicand mediastinaldisorders

Common: Dyspnoea

Gastrointestinaldisorders

Verycommon:Diarrhoea*,nausea*

Common: Constipation*, vomiting*, dyspepsia,abdominalpainand discomfort*,dry

mouth*

Uncommon: Colitis*, dysphagia

Hepatobiliarydisorders

Uncommon: Hepaticfunctiontestabnormal*

Notknown: Hepatitiswithmainlycholestaticfeatures(seesection4.4)*

Skinand subcutaneoustissuedisorders

Common: Rash*, hyperhidrosis

Uncommon: Discolourationsother thanurine(e.g.skin,nail,hair, sweat)*

Rare: Angioedema

Notknown: Urticaria*

Musculoskeletaland connectivetissuedisorders

Verycommon:Muscle,musculoskeletaland connectivetissuepain*

Common: Musclespasms,arthralgia

Notknown: Rhabdomyolysis*

Renaland urinarydisorders

Verycommon:Chromaturia*

Common: Urinarytractinfection

Uncommon: Urinaryretention

Generaldisordersand administrationsiteconditions

Common: Chestpain,peripheraloedema, fall, gaitdisturbance, asthenia, fatigue

Uncommon: Malaise

*Adversereactionsthataremainlyattributabletoentacaponeor aremorefrequent(bythe

frequencydifferenceof atleast1% in theclinicaltrialdata)with entacaponethan

levodopa/DDC inhibitor alone.Seesection c.

**Theincidenceratesof myocardialinfarction andother ischemicheartdiseaseevents

(0.43% and1.54%, respectively)arederivedfroman analysisof 13 double-blindstudies

involving 2082 patientswithend-of-dosemotorfluctuationsreceivingentacapone.

c.Descriptionofselectedadversereactions

Adversereactionsthataremainlyattributabletoentacaponeor aremorefrequentwith

entacaponethan levodopa/DDC inhibitor aloneareindicated withan asterisk inTable1,

section 4.8b. Someof theseadversereactionsrelateto theincreaseddopaminergicactivity

(e.g.dyskinesia, nauseaandvomiting) and occurmostcommonlyatthebeginning of the

treatment. Reductionof levodopadosedecreasestheseverityandfrequencyof these

dopaminergicreactions. Fewadversereactionsareknown tobedirectlyattributableto the

activesubstanceentacaponeincludingdiarrhoeaand reddish-brown discolourationof urine.

Entacaponemayin somecasescausealso discolouration of e.g.skin,nail,hair and sweat.

Otheradversereactionswith anasterisk inTable1, section4.8b aremarked based on either

their morefrequentoccurring (bythefrequencydifferenceof atleast1%) intheclinicaltrial

datawith entacaponethanlevodopa/DDCI aloneor theindividualcasesafetyreportsreceived

after theintroduction of entacaponeintothemarket.

Convulsionshaveoccurredrarelywithlevodopa/carbidopa;however acausalrelationshipto

levodopa/carbidopatherapyhasnotbeen established.

Impulsecontroldisorders:Pathologicalgambling,increasedlibido,hypersexuality,compulsive

spendingorbuying,bingeeatingandcompulsiveeatingcanoccurinpatientstreatedwithdopamine

agonistsand/orotherdopaminergictreatmentscontaininglevodopaincluding Arnalevocap (see

section4.4).

Entacaponein association withlevodopahasbeenassociatedwith isolated casesof excessive

daytimesomnolenceand sudden sleeponsetepisodes.

Reporting of suspectedadversereactions

Reporting suspectedadversereactionsafterauthorisation of themedicinalproductis

important.Itallowscontinuedmonitoringof thebenefit/risk balanceof themedicinalproduct.

Healthcareprofessionalsareaskedto reportanysuspected adversereactionsvia[To be

completed nationally].

4.9 Overdose

In isolated casesof overdosethereported highestdailydosesof levodopaand entacapone

havebeen atleast10,000 mgand 40,000 mg,respectively.Theacutesymptomsandsignsin

thesecasesof overdoseincluded agitation, confusionalstate,coma,bradycardia,ventricular

tachycardia, Cheyne-Stokesrespiration,discolourationsof skin, tongueand conjunctiva,and

chromaturia.Managementof acuteoverdosewithArnalevocaptherapyissimilarto acute

overdosewithlevodopa.Pyridoxine, however,isnoteffectiveinreversing theactionsof

levodopa/carbidopa/entacapone.Hospitalisationisadvised andgeneralsupportivemeasures

should beemployedwith immediategastriclavageandrepeateddosesof charcoalover time.

Thismayhastentheeliminationof entacaponeinparticular bydecreasing its

absorption/reabsorption fromtheGI tract.Theadequacyof therespiratory,circulatoryand

renalsystemsshould becarefullymonitoredand appropriatesupportivemeasuresemployed.

ECGmonitoringshouldbestartedand thepatientcarefullymonitoredfor thepossible

developmentof arrhythmias. If required, appropriateanti-arrhythmictherapyshouldbegiven.

Thepossibilitythatthepatienthastakenother activesubstancesin addition to

levodopa/carbidopa/entacaponeshould betakeninto consideration.Thevalueof dialysisin

thetreatmentof overdoseisnotknown.

5. PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:anti-parkinsondrugs,dopaanddopaderivatives,ATCcode:N04BA03

Accordingto thecurrentunderstanding, thesymptomsof Parkinson’sdiseasearerelatedto

depletionof dopaminein thecorpusstriatum. Dopaminedoesnotcrosstheblood-brain

barrier.Levodopa, theprecursor of dopamine, crossesthebloodbrain barrier and relievesthe

symptomsof thedisease.Aslevodopaisextensivelymetabolised intheperiphery,onlya

smallportionof agivendosereachesthecentralnervoussystemwhen levodopais

administered withoutmetabolicenzymeinhibitors.

Carbidopaand benserazideareperipheralDDC inhibitorswhich reducetheperipheral

metabolismof levodopato dopamine, andthus, morelevodopaisavailableto thebrain.When

decarboxylation of levodopaisreducedwith theco-administration of aDDC inhibitor, a

lowerdoseof levodopacanbeused and theincidenceof adversereactionssuch asnauseais

reduced.

With inhibition of thedecarboxylasebyaDDC inhibitor,catechol-O-methyltransferase

(COMT) becomesthemajor peripheralmetabolicpathwaycatalyzing theconversion of

levodopato 3-O-methyldopa(3-OMD), apotentiallyharmfulmetaboliteof levodopa.

Entacaponeisareversible, specificandmainlyperipherallyactingCOMTinhibitordesigned

for concomitantadministrationwith levodopa.Entacaponeslowstheclearanceof levodopa

fromthebloodstreamresulting inan increasedareaunder thecurve(AUC) inthe

pharmacokineticprofileof levodopa.Consequentlytheclinicalresponseto each doseof

levodopaisenhanced and prolonged.

Theevidenceof thetherapeuticeffectsoflevodopa/carbidopa/entacaponeisbased on two

phaseIII double-blindstudies, in which376 Parkinson’sdiseasepatientswithend-of-dose

motorfluctuationsreceivedeitherentacaponeor placebowith eachlevodopa/DDC inhibitor

dose. DailyONtimewithand withoutentacaponewasrecordedin home-diariesbypatients.

In thefirststudy,entacaponeincreased themean dailyONtimeby1 h 20 min(CI 95% 45

min,1 h 56 min)frombaseline.Thiscorrespondedto an 8.3% increaseintheproportionof

dailyONtime.Correspondingly,thedecreasein dailyOFFtimewas24% intheentacapone

group and0% in theplacebogroup. In thesecond study,themeanproportionof dailyON

timeincreasedby4.5% (CI95% 0.93%, 7.97%) frombaseline.Thisistranslatedto amean

increaseof 35 minin thedailyONtime. Correspondingly,thedailyOFFtimedecreased by

18% on entacaponeand by5% on placebo. Becausetheeffectsof

levodopa/carbidopa/entacaponetabletsareequivalentwith entacapone200 mgtablet

administered concomitantlywiththecommerciallyavailablestandardrelease

carbidopa/levodopapreparationsin corresponding dosestheseresultsareapplicableto

describetheeffectsof levodopa/carbidopa/entacaponeaswell.

5.2 Pharmacokineticproperties

Generalcharacteristicsoftheactivesubstances

Absorption/distribution:Therearesubstantialinter-andintra-individualvariationsintheabsorptionof

levodopa,carbidopaandentacapone.Bothlevodopaandentacaponearerapidlyabsorbedand

eliminated.Carbidopaisabsorbedandeliminatedslightlyslowercomparedwithlevodopa.When

givenseparatelywithoutthetwootheractivesubstances,thebioavailabilityforlevodopais15-33%,

forcarbidopa40-70%andforentacapone35%aftera200mgoraldose.Mealsrichinlargeneutral

aminoacidsmaydelayandreducetheabsorptionoflevodopa.Fooddoesnotsignificantlyaffectthe

absorptionofentacapone.Thedistributionvolumeofbothlevodopa(Vd0.36-1.6l/kg)andentacapone

(Vdss0.27l/kg)ismoderatelysmallwhilenodataforcarbidopaareavailable.

Levodopaisbound to plasmaprotein onlyto aminorextentof about10-30% and carbidopais

bound approximately36%, whileentacaponeisextensivelybound to plasmaproteins(about

98%) –mainlyto serumalbumin.Attherapeuticconcentrations, entacaponedoesnotdisplace

otherextensivelybound activesubstances(e.g. warfarin,salicylicacid, phenylbutazone,or

diazepam),nor isitdisplacedto anysignificantextentbyanyof thesesubstancesat

therapeuticor higherconcentrations.

Biotransformationand elimination:Levodopaisextensivelymetabolisedto various

metabolites:decarboxylationbydopadecarboxylase(DDC) and O-methylationbycatechol-

O-methyltransferase(COMT)being themostimportantpathways.

Carbidopaismetabolized totwo mainmetaboliteswhich areexcretedin theurineas

glucuronidesand unconjugatedcompounds. Unchanged carbidopaaccountsfor 30% of the

totalurinaryexcretion.

Entacaponeisalmostcompletelymetabolized priorto excretion viaurine(10 to 20%) and

bile/faeces(80 to90%).Themainmetabolicpathwayisglucuronidation of entacaponeand its

activemetabolite,

thecis-isomer,which accountsfor about5% of plasmatotalamount.

Totalclearancefor levodopaisin therangeof 0.55-1.38 l/kg/h and for entacaponeisin the

rangeof 0.70 l/kg/h.Theelimination-half lifeis(t1/2)is0.6-1.3 hoursfor levodopa, 2-3 hours

for carbidopaand0.4-0.7 hoursfor entacapone,eachgiven separately.

Duetoshortelimination half-lives, no trueaccumulation of levodopaor entacaponeoccurson

repeatedadministration.

Datafrominvitrostudiesusing humanlivermicrosomalpreparationsindicatethatentacapone

inhibitscytochromeP450 2C9 (IC50 ~ 4 μM). Entacaponeshowedlittleor no inhibition of

othertypesof P450 isoenzymes(CYP1A2, CYP2A6, CYP2D6, CYP2E1,CYP3Aand

CYP2C19);seesection 4.5.

Characteristicsinpatients

Olderpeople :When givenwithoutcarbidopaand entacapone, theabsorptionof levodopais

greater andelimination isslower in oldersubjectsthan in young subjects. However,after

combination of carbidopawithlevodopa, theabsorptionof levodopaissimilarbetween the

olderand theyoung,buttheAUC isstill1.5 foldgreaterin theolder peopleduetodecreased

DDC activityandlower clearancebyaging.Thereareno significantdifferencesin theAUC

of carbidopaor entacaponebetweenyounger(45–64 years) and oldersubjects(65–75 years).

Gender:Bioavailabilityof levodopaissignificantlyhigherin women thanin men.In the

pharmacokineticstudieswithlevodopa/carbidopa/entacaponethebioavailabilityof levodopa

ishigherin womenthanin menprimarilydueto thedifferenceinbodyweight,whilethereis

no genderdifferencewith carbidopaandentacapone.

Hepaticimpairment:Themetabolismof entacaponeisslowed inpatientswith mild to

moderatehepaticimpairment(Child-Pugh ClassAand B) leadingto an increased plasma

concentration of entacaponeboth intheabsorptionand elimination phases(seesections4.2

and4.3). No particularstudieson thepharmacokineticsof carbidopaand levodopainpatients

withhepaticimpairmentarereported,however,itisadvised thatArnalevocap should be

administered cautiouslytopatientswith mild or moderatehepaticimpairment.

Renalimpairment :Renalimpairmentdoesnotaffectthepharmacokineticsof entacapone. No

particular studiesarereportedon thepharmacokineticsof levodopaandcarbidopain patients

withrenalimpairment.However,alonger dosing intervalofArnalevocap maybeconsidered

for patientswho arereceiving dialysistherapy(seesection 4.2).

5.3 Preclinicalsafetydata

Preclinicaldataof levodopa, carbidopaand entacapone,testedaloneor in combination,

revealedno specialhazard for humansbased on conventionalstudiesof safetypharmacology,

repeateddosetoxicity,genotoxicity,andcarcinogenicpotential. In repeateddosetoxicity

studieswith entacapone, anaemiamostlikelydueto ironchelating propertiesof entacapone

wasobserved. Regardingreproduction toxicityof entacapone, decreased foetalweightand a

slightlydelayed bonedevelopmentwerenoticedin rabbitstreated atsystemicexposurelevels

inthetherapeuticrange.Both levodopaand combinationsof carbidopaand levodopahave

causedvisceraland skeletalmalformationsinrabbits.

6. PHARMACEUTICALPARTICULARS

6.1 List ofexcipients

Tabletcore:

Croscarmellosesodium

Hydroxypropylcellulose

Trehalosedihydrate

Cellulose, powdered

Sodiumsulfate,anhydrous

Cellulose, microcrystalline

Magnesiumstearate

Filmcoat:

Polyvinylalcohol-part.hydrolyzed

Talc

Titaniumdioxide(E171)

Macrogol

Iron oxidered (E172)

Lecithin (soya) (E322)

Iron oxideyellow(E172)

6.2 Incompatibilities

Notapplicable.

6.3 Shelflife

2 years.

6.4 Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5 Natureandcontentsofcontainer

HDPEtabletcontainersealed withfoilandclosed with PPscrewcap.

Packsizes:

10, 30, 100, 130, and175 film-coatedtablets.

Notallpacksizesmaybemarketed.

6.6 Specialprecautionsfordisposal

Anyunused productor wastematerialshouldbedisposed of in accordancewith local

requirements.

7. MARKETINGAUTHORISATIONHOLDER

<To becompletednationally>

8. MARKETINGAUTHORISATIONNUMBER(S)

<To becompletednationally>

9. DATE OFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

<To becompletednationally>

10. DATE OFREVISIONOFTHETEXT

6August2014

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