Levodopa/Carbidopa/Entacapone Accord 100 mg/25 mg/200 mg Filmdragerad tablett

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

21-10-2020

Produktens egenskaper Produktens egenskaper (SPC)

29-03-2019

Aktiva substanser:
entakapon; karbidopa (monohydrat); levodopa
Tillgänglig från:
Accord Healthcare B.V. ,
ATC-kod:
N04BA03
INN (International namn):
entacapone; carbidopa (monohydrate); levodopa
Dos:
100 mg/25 mg/200 mg
Läkemedelsform:
Filmdragerad tablett
Sammansättning:
karbidopa (monohydrat) 27 mg Aktiv substans; entakapon 200 mg Aktiv substans; levodopa 100 mg Aktiv substans
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Burk, 30 tabletter; Burk, 130 tabletter; Burk, 100 tabletter
Bemyndigande status:
Godkänd
Godkännandenummer:
51882
Tillstånd datum:
2016-03-31

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

21-10-2020

Produktens egenskaper Produktens egenskaper - engelska

21-10-2020

Läs hela dokumentet

Bipacksedel: Information till användaren

Levodopa/Carbidopa/Entacapone Accord 50 mg/12,5 mg/200 mg filmdragerade tabletter

Levodopa/Carbidopa/Entacapone Accord 75 mg/18,75 mg/200 mg filmdragerade tabletter

Levodopa/Carbidopa/Entacapone Accord 100 mg/25 mg/200 mg filmdragerade tabletter

Levodopa/Carbidopa/Entacapone Accord 125 mg/31,25 mg/200 mg filmdragerade tabletter

Levodopa/Carbidopa/Entacapone Accord 150 mg/37,5 mg/200 mg filmdragerade tabletter

Levodopa/Carbidopa/Entacapone Accord 200 mg/50 mg/200 mg filmdragerade tabletter

levodopa/karbidopa/entakapon

Läs noga igenom denna bipacksedel innan du börjar ta detta läkemedel. Den innehåller

information som är viktig för dig.

Spara denna information, du kan behöva läsa den igen.

Om du har ytterligare frågor vänd dig till läkare eller apotekspersonal.

Detta läkemedel har ordinerats enbart åt dig. Ge det inte till andra. Det kan skada dem, även om

de uppvisar sjukdomstecken som liknar dina.

Om du får biverkningar, tala med läkare eller apotekspersonal. Detta gäller även eventuella

biverkningar som inte nämns i denna information. Se avsnitt 4.

I denna bipacksedel finns information om följande

Vad Levodopa/Carbidopa/Entacapone Accord är och vad det används för

Vad du behöver veta innan du tar Levodopa/Carbidopa/Entacapone Accord

Hur du tar Levodopa/Carbidopa/Entacapone Accord

Eventuella biverkningar

Hur Levodopa/Carbidopa/Entacapone Accord ska förvaras

Förpackningens innehåll och övriga upplysningar

1.

Vad Levodopa/Carbidopa/Entacapone Accord är och vad det används för

Levodopa/Carbidopa/Entacapone Accord innehåller tre aktiva substanser (levodopa, karbidopa och

entakapon) i en filmdragerad tablett. Levodopa/Carbidopa/Entacapone Accord används för behandling

av Parkinsons sjukdom.

Parkinsons sjukdom beror på låga nivåer av ämnet dopamin i hjärnan. Levodopa ökar mängden

dopamin och lindrar därför symtomen av Parkinsons sjukdom. Karbidopa och entakapon förbättrar

den effekt levodopa har på Parkinsons sjukdom.

Levodopa/karbidopa/entakapon som finns i Levodopa/Carbidopa/Entacapone Accord kan också vara

godkänd för att behandla andra sjukdomar som inte nämns i denna produktinformation. Fråga läkare,

apotek eller annan hälsovårdspersonal om du har ytterligare frågor och följ alltid deras instruktion.

2.

Vad du behöver veta innan du tar Levodopa/Carbidopa/Entacapone Accord

Ta inte Levodopa/Carbidopa/Entacapone

Accord om du

är allergisk mot levodopa, karbidopa eller entakapon eller något annat innehållsämne i detta

läkemedel (anges i avsnitt 6)

har trångvinkelglaukom (en ögonsjukdom)

har tumör i binjuren

tar vissa läkemedel för behandling av depression (kombinationer av selektiva MAO-A- och

MAO-B-hämmare, eller icke-selektiva MAO-hämmare)

tidigare haft neuroleptiskt malignt syndrom (NMS – detta är en sällsynt reaktion mot läkemedel

som används för att behandla allvarlig psykisk sjukdom)

tidigare haft icke-traumatisk rabdomyolys (en sällsynt muskelsjukdom)

har en allvarlig leversjukdom.

Varningar och försiktighet

Tala med läkare eller apotekspersonal innan du tar Levodopa/Carbidopa/Entacapone Accord om du

har eller har haft:

en hjärtattack eller någon annan hjärtsjukdom inklusive arytmier, eller blodkärlssjukdom

astma eller annan lungsjukdom

leverproblem, din dos kan då behöva justeras

njursjukdom eller hormonrelaterad sjukdom

magsår eller krampanfall

om du upplever långvarig diarré, kontakta läkare då detta kan vara ett tecken på

tjocktarmsinflammation

någon form av allvarlig psykisk sjukdom, till exempel psykos

kroniskt vidvinkelglaukom. Din dos kan då behöva justeras och ditt ögontryck kan behöva

kontrolleras.

Rådfråga din läkare om du tar:

antipsykotika (läkemedel för behandling av psykos)

läkemedel som kan orsaka lågt blodtryck när du reser dig från en stol eller säng. Du bör vara

medveten om att Levodopa/Carbidopa/Entacapone Accord kan förvärra denna effekt.

Rådfråga din läkare om du under behandlingen med Levodopa/Carbidopa/Entacapone Accord:

upplever att dina muskler blir mycket stela eller rycker kraftigt, eller om du lider av skakningar,

upphetsning, förvirring, feber, snabb puls eller kraftiga blodtryckssvängningar. Om något av detta

händer,

kontakta genast läkare

känner dig deprimerad, har självmordstankar eller märker att ditt beteende förändras

plötsligt faller i sömn, eller känner dig mycket sömnig. Om det händer ska du inte köra bil eller

använda maskiner (se även avsnittet ”Körförmåga och användning av maskiner”).

får ofrivilliga rörelser eller om de förvärrats efter start av behandling med

Levodopa/Carbidopa/Entacapone Accord. Om detta händer kan läkaren behöva ändra din

dosering av läkemedel mot Parkinsons sjukdom.

får diarré: din vikt kan behöva övervakas för att undvika en eventuell kraftig viktminskning

upplever aptitlöshet som förvärras över tid, orkeslöshet (svaghet, utmattning) och viktminskning

inom en kort tidsperiod. Om detta händer bör en allmän läkarundersökning inklusive

leverfunktionstest övervägas.

känner att du vill sluta använda Levodopa/Carbidopa/Entacapone Accord, se avsnittet ”Om du

slutar ta Levodopa/Carbidopa/Entacapone Accord”.

Tala om för din läkare om du eller din familj/vårdgivare märker att du utvecklar beroendelika symtom

som leder till ett begär efter större doser av Levodopa/Carbidopa/Entacapone Accord och andra

läkemedel som används för att behandla Parkinsons sjukdom.

Berätta för din läkare om du eller din familj/omhändertagare upptäcker att du utvecklar drifter eller

begär att bete dig på sätt som är ovanliga för dig, eller du inte kan motstå impulsen, driften eller

frestelsen att bedriva viss aktivitet som kan skada dig själv eller andra. Detta beteende kallas

impulskontrollstörning och kan inkludera tvångsmässigt spelande, överdrivet matintag eller

spenderande, en onormalt hög sexualdrift eller en upptagenhet med ökning i sexuella tankar eller

känslor.

Din läkare kan behöva se över din behandling.

Din läkare kan behöva ta regelbundna prover på dig under långtidsbehandling med

Levodopa/Carbidopa/Entacapone Accord.

Om du behöver opereras ska du tala om för din läkare att du tar Levodopa/Carbidopa/Entacapone

Accord.

Levodopa/Carbidopa/Entacapone Accord rekommenderas inte för behandling av extrapyramidala

symtom (till exempel ofrivilliga rörelser, skakningar, muskelstelhet och muskelsammandragningar)

orsakade av andra mediciner.

Barn och ungdomar

Erfarenhet av behandling av patienter under 18 år med Levodopa/Carbidopa/Entacapone Accord är

begränsad. Levodopa/Carbidopa/Entacapone Accord rekommenderas därför inte för behandling av

barn.

Andra läkemedel och Levodopa/Carbidopa/Entacapone Accord

Tala om för läkare eller apotekspersonal om du tar, nyligen har tagit eller kan tänkas ta andra

läkemedel.

Ta inte Levodopa/Carbidopa/Entacapone Accord om du tar vissa läkemedel för behandling av

depression (kombinationer av selektiva MAO-A- och MAO-B-hämmare, eller icke-selektiva MAO-

hämmare).

Levodopa/Carbidopa/Entacapone Accord kan förstärka effekten och biverkningarna av vissa

läkemedel. Dessa inkluderar:

läkemedel för behandling av depression såsom moklobemid, amitriptylin, desipramin, maprotilin,

venlafaxin och paroxetin

rimiterol och isoprenalin, som används för att behandla sjukdomar i luftvägarna

adrenalin, som används vid svåra allergiska reaktioner

noradrenalin, dopamin och dobutamin, som används för att behandla hjärtsjukdomar och lågt

blodtryck

alfa-metyldopa, som används för att behandla högt blodtryck

apomorfin, som används för att behandla Parkinsons sjukdom

Vissa läkemedel kan försvaga effekten av Levodopa/Carbidopa/Entacapone Accord. Dessa är:

dopaminantagonister som används för att behandla mental sjukdom, illamående och kräkningar

fenytoin som används för att förhindra krampryckningar

papaverin som används för muskelavslappning

Levodopa/Carbidopa/Entacapone Accord kan försämra upptaget av järn. Ta därför inte

Levodopa/Carbidopa/Entacapone Accord och järntillskott samtidigt, utan med minst 2–3 timmars

mellanrum.

Levodopa/Carbidopa/Entacapone Accord med mat och dryck

Levodopa/Carbidopa/Entacapone Accord kan tas med eller utan mat. Hos vissa patienter kan

Levodopa/Carbidopa/Entacapone Accord upptas sämre om det tas samtidigt med eller kort efter att

man ätit proteinrik föda (som kött, fisk, mjölkprodukter, frö och nötter). Kontakta läkare om du tror att

detta gäller dig.

Graviditet, amning och fertilitet

Om du är gravid eller ammar, tror att du kan vara gravid eller planerar att skaffa barn, rådfråga läkare

eller apotekspersonal innan du använder detta läkemedel.

Du bör inte amma när du behandlas med Levodopa/Carbidopa/Entacapone Accord.

Körförmåga och användning av maskiner

Levodopa/Carbidopa/Entacapone Accord kan sänka ditt blodtryck, vilket kan orsaka att du känner dig

virrig eller yr. Var därför särskilt försiktig om du kör bil eller använder verktyg eller maskiner.

Om du känner dig mycket dåsig eller om du ibland plötsligt somnar, vänta tills du känner dig fullt

vaken innan du kör bil eller gör något annat som kräver att du är uppmärksam. Annars kan du utsätta

dig själv eller andra för skada eller död.

Du är själv ansvarig för att bedöma om du är i kondition att framföra motorfordon eller utföra arbeten

som kräver skärpt uppmärksamhet. En av faktorerna som kan påverka din förmåga i dessa avseenden

är användning av läkemedel på grund av deras effekter och/eller biverkningar. Beskrivning av dessa

effekter och biverkningar finns i andra avsnitt. Läs därför all information i denna bipacksedel för

vägledning. Diskutera med din läkare eller apotekspersonal om du är osäker.

3.

Hur du tar Levodopa/Carbidopa/Entacapone Accord

Använd alltid detta läkemedel enligt läkarens eller apotekspersonalens anvisningar. Rådfråga läkare

eller apotekspersonal om du är osäker.

För vuxna och äldre personer:

Din läkare informerar dig om exakt hur många tabletter Levodopa/Carbidopa/Entacapone Accord

du ska ta varje dag.

Det är inte meningen att tabletterna ska delas eller brytas i småbitar.

Du ska bara ta en tablett i taget.

Beroende på hur du svarar på behandlingen kan läkaren föreslå en höjning eller sänkning av

dosen.

Om du tar Levodopa/Carbidopa/Entacapone Accord 50 mg/12,5 mg/200 mg,

75 mg/18,75 mg/200 mg, 100 mg/25 mg/200 mg, 125 mg/31,25 mg/200 mg eller

150 mg/37,5 mg/200 mg filmdragerade tabletter, ta inte mer än 10 tabletter per dag.

Om du tar Levodopa/Carbidopa/Entacapone Accord 200 mg/50 mg/200 mg filmdragerade

tabletter, ta inte mer än 7 tabletter av den här styrkan dagligen.

Om du upplever att effekten av Levodopa/Carbidopa/Entacapone Accord är för stark eller för svag

eller om du upplever eventuella biverkningar, vänd dig till läkare eller apotekspersonal.

Om du har tagit för stor mängd av Levodopa/Carbidopa/Entacapone Accord

Om du fått i dig för stor mängd läkemedel eller om t.ex. ett barn fått i sig läkemedlet av misstag

kontakta läkare, sjukhus eller Giftinformationscentralen (tel. 112) för bedömning av risken samt

rådgivning.

Om du av misstag har tagit fler tabletter Levodopa/Carbidopa/Entacapone Accord än du ska kontakta

genast läkare eller apotekspersonal. I händelse av en överdosering kan du känna dig förvirrad eller

upprörd, din hjärtfrekvens kan vara långsammare eller snabbare än normalt eller kan huden, tungan,

ögonen eller urinen få färgförändringar.

Om du har glömt att ta Levodopa/Carbidopa/Entacapone Accord

Ta inte dubbel dos för att kompensera för glömd tablett.

Om det är mer än 1 timme till nästa dos:

Ta en tablett så snart du kommer ihåg och ta nästa tablett vid ordinarie tidpunkt.

Om det är mindre än 1 timme till nästa dos:

Ta en tablett så snart du kommer ihåg, vänta 1 timme och ta sedan ytterligare en tablett. Efter det kan

du fortsätta som vanligt.

Se alltid till att det är minst en timme mellan Levodopa/Carbidopa/Entacapone Accord-doserna för att

undvika eventuella biverkningar.

Om du slutar att ta Levodopa/Carbidopa/Entacapone Accord

Sluta inte ta Levodopa/Carbidopa/Entacapone Accord annat än på uppmaning av din läkare. I ett

sådant fall kan din läkare behöva ändra din övriga antiparkisonmedicinering, speciellt levodopa, för att

behålla tillräcklig symtomkontroll. Om du plötsligt slutar ta Levodopa/Carbidopa/Entacapone Accord

och andra antiparkisonmedel kan det leda till oönskade biverkningar.

Om du har ytterligare frågor om detta läkemedel kontakta läkare eller apotekspersonal.

4.

Eventuella biverkningar

Liksom alla läkemedel kan detta läkemedel orsaka biverkningar, men alla användare behöver inte få

dem. Många biverkningar kan mildras genom att justera dosen.

Om du vid behandling med Levodopa/Carbidopa/Entacapone Accord upplever följande symtom,

kontakta genast läkare

dina muskler blir mycket stela eller rycker kraftigt, du lider av skakningar, upphetsning,

förvirring, feber, snabb puls eller kraftiga blodtryckssvängningar. Dessa kan vara symtom på

malignt neuroleptikasyndrom (NMS, en sällsynt svår reaktion på läkemedel som används för att

behandla sjukdomar i det centrala nervsystemet) eller rabdomyolys (en sällsynt svår

muskelsjukdom).

Allergisk reaktion, symtomen kan innefatta nässelfeber, klåda, hudutslag, svullnad av ansikte,

läppar, tunga eller svalg. Detta kan orsaka svårigheter att andas eller att svälja.

Mycket vanliga (kan förekomma hos fler än 1 av 10 personer):

ofrivilliga rörelser (dyskinesier)

illamående

rödbrun missfärgning av urinen (ofarlig)

muskelsmärta

diarré

Vanliga (kan förekomma hos upp till 1 av 10 personer):

tomhets- eller svimningskänsla p.g.a. lågt blodtryck, högt blodtryck

förvärrade symtom på Parkinsons sjukdom, yrsel, dåsighet

kräkningar, buksmärta och obehagskänslor, halsbränna, muntorrhet, förstoppning

sömnsvårigheter, hallucinationer, förvirring, onormala drömmar (inklusive mardrömmar), trötthet

mentala förändringar – inklusive minnesstörningar, oro och depression (eventuellt med

självmordstankar)

hjärt- eller artärsjukdom (t.ex. bröstsmärtor), oregelbunden hjärtfrekvens eller rytm

ökad tendens att falla

andfåddhet

ökad svettning, utslag

muskelkramper, svullnad av benen

dimsyn

blodbrist

minskad aptit, viktminskning

huvudvärk, ledsmärta

urinvägsinfektion

Mindre vanliga (kan förekomma hos upp till 1 av 100 personer):

hjärtattack

tarmblödning

förändring i blodets cellbild som kan leda till blödning, onormala leverfunktionsvärden

krampanfall

upprördhetskänslor

psykotiska symtom

kolit (inflammation i tjocktarmen)

missfärgning av annat än urin (t.ex. hud, naglar, hår, svett)

svårigheter att svälja

oförmåga att urinera

Följande biverkningar har också rapporterats:

hepatit (inflammation i levern)

klåda

Har rapporterats (förekommer hos ett okänt antal användare):

Begär efter högre doser av Levodopa/Carbidopa/Entacapone Accord som är större än det som krävs

för att kontrollera motoriska system, känt som dopaminergt dysregleringssyndrom. Vissa patienter

upplever svåra onormala ofrivilliga rörelser (dyskinesier), humörsvägningar eller andra biverkningar

efter att ha tagit större doser av Levodopa/Carbidopa/Entacapone Accord.

Du kan uppleva följande biverkningar:

Oförmåga att stå emot impulsen att utföra en handling som kan vara skadlig, vilket kan inkludera:

stark impuls att spela extremt mycket trots allvarliga personliga konsekvenser eller familjära

konsekvenser

förändrat eller ökat sexuellt intresse och beteende som berör dig eller andra betydligt, t.ex. en

ökad sexlust

okontrollerad överdriven shopping eller spenderande

hetsätning (äta stora mängder mat under en kort period) eller tvångsmässigt matintag (äta

mer mat än normalt och mer än vad som behövs för att tillfredsställa din hunger).

Berätta för din läkare om du upplever något av dessa symtom; man kommer diskutera hur man ska

hantera eller reducera dessa symtom.

Rapportering av biverkningar

Om du får biverkningar, tala med läkare eller sjuksköterska. Detta gäller även eventuella biverkningar

som inte nämns i denna information. Du kan också rapportera biverkningar direkt via

Läkemedelsverket

Box 26

751 03 Uppsala

Webbplats: www.lakemedelsverket.se

Genom att rapportera biverkningar kan du bidra till att öka informationen om läkemedels säkerhet.

5.

Hur Levodopa/Carbidopa/Entacapone Accord ska förvaras

Öppnad HDPE-burk ska användas inom 6 månader.

Förvara detta läkemedel utom syn

-

och räckhåll för barn.

Används före utgångsdatum som anges på burken och kartongen efter EXP. Utgångsdatumet är den

sista dagen i angiven månad.

Inga särskilda förvaringsanvisningar.

Läkemedel ska inte kastas i avloppet eller bland hushållsavfall. Fråga apotekspersonalen hur man

kastar läkemedel som inte längre används. Dessa åtgärder är till för att skydda miljön.

6.

Förpackningens innehåll och övriga upplysningar

Innehållsdeklaration

De aktiva substanserna i Levodopa/Carbidopa/Entacapone Accord är levodopa, karbidopa och

entakapon.

Varje Levodopa/Carbidopa/Entacapone Accord 50 mg/12,5 mg/200 mg filmdragerad tablett

innehåller 50 mg levodopa, 12,5 mg karbidopa och 200 mg entakapon.

Varje Levodopa/Carbidopa/Entacapone Accord 75 mg/18,75 mg/200 mg filmdragerad tablett

innehåller 75 mg levodopa, 18,75 mg karbidopa och 200 mg entakapon.

Varje Levodopa/Carbidopa/Entacapone Accord 100 mg/25 mg/200 mg filmdragerad tablett

innehåller 100 mg levodopa, 25 mg karbidopa och 200 mg entakapon.

Varje Levodopa/Carbidopa/Entacapone Accord 125 mg/31,25 mg/200 mg filmdragerad tablett

innehåller 125 mg levodopa, 31,25 mg karbidopa och 200 mg entakapon.

Varje Levodopa/Carbidopa/Entacapone Accord 150 mg/37,5 mg/200 mg filmdragerad tablett

innehåller 150 mg levodopa, 37,5 mg karbidopa och 200 mg entakapon.

Varje Levodopa/Carbidopa/Entacapone Accord 200 mg/50 mg/200 mg filmdragerad tablett

innehåller 200 mg levodopa, 50 mg karbidopa och 200 mg entakapon.

Övriga innehållsämnen i tablettkärnan är mikrokristallin cellulosa, krospovidon (typ B), povidon

K 30, magnesiumstearat och natriumcitrat.

Filmdrageringen innehåller hypromellos, makrogol 6000, titandioxid (E171), polysorbat 80, röd

järnoxid (E172) och gul järnoxid (E172) (50 mg/12,5 mg/200 mg, 100 mg/25 mg/200 mg och

150 mg/37,5 mg/200 mg).

Läkemedlets utseende och förpackningsstorlekar

Levodopa/Carbidopa/Entacapone Accord 50 mg/12,5 mg/200 mg filmdragerade tabletter: Ljusbruna

till gråröda, runda, bikonvexa filmdragerade tabletter, cirka 11,3 mm i diameter,märkta med ”50” på

ena sidan och ingen märkning på andra sidan.

Levodopa/Carbidopa/Entacapone Accord 75 mg/18,75 mg/200 mg filmdragerade tabletter: Ljusbruna

till ljusrosa, ovala filmdragerade tabletter (längd: cirka 15,2 mm, bredd: cirka 7,2 mm), märkta med

”75” på ena sidan och ingen märkning på andra sidan.

Levodopa/Carbidopa/Entacapone Accord 100 mg/25 mg/200 mg filmdragerade tabletter: Ljusbruna

till gråröda, ovala filmdragerade tabletter (längd: cirka 16,7 mm, bredd: cirka 7,7 mm), märkta med

”100” på ena sidan och ingen märkning på andra sidan.

Levodopa/Carbidopa/Entacapone Accord 125 mg/31,25 mg/200 mg filmdragerade tabletter: Ljusbruna

till ljusrosa, avlånga/ellipsformade filmdragerade tabletter (längd: cirka 15,2 mm, bredd: cirka

9,7 mm), märkta med ”125” på ena sidan och ingen märkning på andra sidan.

Levodopa/Carbidopa/Entacapone Accord 150 mg/37,5 mg/200 mg filmdragerade tabletter: Ljusbruna

till gråröda, avlånga/ellipsformade filmdragerade tabletter (längd: cirka 16,2 mm, bredd: cirka

10,2 mm), märkta med ”150” på ena sidan och ingen märkning på andra sidan.

Levodopa/Carbidopa/Entacapone Accord 200 mg/50 mg/200 mg filmdragerade tabletter: Mörkt

brunröda, ovala filmdragerade tabletter (längd: cirka 19,15 mm, bredd: cirka 9,05 mm), märkta med

”200” på ena sidan och ingen märkning på andra sidan.

Levodopa/Carbidopa/Entacapone Accord finns i tre olika förpackningsstorlekar (30, 100 och

130 tabletter). Eventuellt kommer inte alla förpackningsstorlekar att marknadsföras.

Innehavare av godkännande för försäljning och tillverkare

Innehavare av godkännande för försäljning

Accord Healthcare B.V.

Winthontlaan 200

3526 KV Utrecht

Nederländerna

Tillverkare

Accord Healthcare Ltd

Sage House, 319 Pinner Road, North Harrow,

Middlesex, HA1 4HF,

Storbritannien

Wessling Hungary Kft.,

Fóti út 56., Budapest 1047,

Ungern

Pharmacare Premium Ltd

HHF 003, Hal Far Industrial Estate,

Birzebbugia, BBG 3000,

Malta

Denna bipacksedel ändrades senast:

2020-10-19

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SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Levodopa/Carbidopa/Entacapone Accord 50 mg/12.5 mg/200 mg film-coated tablets

Levodopa/Carbidopa/Entacapone Accord 75 mg/18.75 mg/200 mg film-coated tablets

Levodopa/Carbidopa/Entacapone Accord 100 mg/25 mg/200 mg film-coated tablets

Levodopa/Carbidopa/Entacapone Accord 125 mg/31.25 mg/200 mg film-coated tablets

Levodopa/Carbidopa/Entacapone Accord 150 mg/37.5 mg/200 mg film-coated tablets

Levodopa/Carbidopa/Entacapone Accord 200 mg/50 mg/200 mg film-coated tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 50 mg of levodopa, 12.5 mg of carbidopa and 200 mg of entacapone.

Each film-coated tablet contains 75 mg of levodopa, 18.75 mg of carbidopa and 200 mg of

entacapone.

Each film-coated tablet contains 100 mg of levodopa, 25 mg of carbidopa and 200 mg of entacapone.

Each film-coated tablet contains 125 mg of levodopa, 31.25 mg of carbidopa and 200 mg of

entacapone.

Each film-coated tablet contains 150 mg of levodopa, 37.5 mg of carbidopa and 200 mg of

entacapone.

Each film-coated tablet contains 200 mg of levodopa, 50 mg of carbidopa and 200 mg of entacapone.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Film-coated tablet

50 mg/12.5 mg/200 mg: Light brown to grayish red colored, round, approximately 11.3 mm in

diameter, biconvex, film-coated tablets with debossed “50” on one side and plain on other side.

75 mg/18.75 mg/200 mg: Light brown to light pink colored, oval shaped, approximately 15.2 mm in

length and 7.2 mm in width, film-coated tablets with debossed “75” on one side and plain on other

side.

100 mg/25 mg/200 mg: Light brown to grayish red colored, oval shaped, approximately 16.7 mm in

length and 7.7 mm in width, film-coated tablets with debossed “100” on one side and plain on other

side.

125 mg/31.25 mg/200 mg: Light brown to light pink colored, elongated-ellipse shaped, approximately

15.2 mm in length and 9.7 mm in width, film-coated tablets with debossed “125” on one side and plain

on other side.

150 mg/37.5 mg/200 mg: Light brown to grayish red colored, elongated-ellipse shaped, approximately

16.2 mm in length and 10.2 mm in width, film-coated tablets with debossed “150” on one side and

plain on other side.

200 mg/50 mg/200 mg: Dark brownish red colored, oval shaped, approximately 19.15 mm in length

and 9.05 mm in width, film-coated tablets with debossed "200" on one side and plain on other side.

4.

CLINICAL PARTICULARS

4.1.

Therapeutic indications

<Invented Name> is indicated for the treatment of adult patients with Parkinson’s disease and end-of-

dose motor fluctuations not stabilised on levodopa/dopa decarboxylase (DDC) inhibitor treatment.

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4.2.

Posology and method of administration

Posology

The optimum daily dose must be determined by careful titration of levodopa in each patient. The daily

dose should be preferably optimised using one of the six available tablet strengths

(50 mg/12.5 mg/200 mg, 75 mg/18.75 mg/200 mg, 100 mg/25 mg/200 mg, 125 mg/31.25 mg/200 mg,

150 mg/37.5 mg/200 mg or 200 mg/50 mg/200 mg levodopa/carbidopa/entacapone).

Patients should be instructed to take only one <Invented name> tablet per dose administration. Patients

receiving less than 70-100 mg carbidopa a day are more likely to experience nausea and vomiting.

While the experience with total daily dose greater than 200 mg carbidopa is limited, the maximum

recommended daily dose of entacapone is 2,000 mg and therefore the maximum dose is 10 tablets per

day for the <Invented name> strengths of 50 mg/12.5 mg/200 mg, 75 mg/18.75 mg/200 mg,

100 mg/25 mg/200 mg, 125 mg/31.25 mg/200 mg and 150 mg/37.5 mg/200 mg. Ten tablets of

<Invented name> 150 mg/37.5 mg/200 mg equals 375 mg of carbidopa a day. According to this daily

carbidopa dose, the maximum recommended daily <Invented name> 200 mg/50 mg/200 mg dose is

7 tablets per day.

Usually <Invented name> is to be used in patients who are currently treated with corresponding doses

of standard release levodopa/DDC inhibitor and entacapone.

How to transfer patients taking levodopa/DDC inhibitor (carbidopa or benserazide) preparations and

entacapone tablets to <Invented name>

a. Patients who are currently treated with entacapone and with standard release levodopa/carbidopa in

doses equal to <Invented name> tablet strengths can be directly transferred to corresponding

<Invented name> tablets.

For example, a patient taking one tablet of 50 mg/12.5 mg of levodopa/carbidopa with one tablet of

entacapone 200 mg four times daily can take one 50 mg/12.5 mg/200 mg <Invented name> tablet four

times daily in place of their usual levodopa/carbidopa and entacapone doses.

b. When initiating <Invented name> therapy for patients currently treated with entacapone and

levodopa/carbidopa in doses not equal to <Invented name> 50 mg/12.5 mg/200 mg (or

75 mg/18.75 mg/200 mg, 100 mg/25 mg/200 mg, 125 mg/31.25 mg/200 mg, 150 mg/37.5 mg/200 mg

or 200 mg/50 mg/200 mg) tablets, <Invented name> dosing should be carefully titrated for optimal

clinical response. At the initiation, <Invented name> should be adjusted to correspond as closely as

possible to the total daily dose of levodopa currently used.

c. When initiating <Invented name> in patients currently treated with entacapone and

levodopa/benserazide in a standard release formulation, the dosing of levodopa/benserazide should be

discontinued in the previous night, and <Invented name> should be started in the next morning. The

starting dose of <Invented name> should provide either the same amount of levodopa or slightly

(5-10 %) more.

How to transfer patients not currently treated with entacapone to <Invented name>

Initiation of <Invented name> may be considered at corresponding doses to current treatment in some

patients with Parkinson's disease and end-of-dose motor fluctuations, who are not stabilised on their

current standard release levodopa/DDC inhibitor treatment. However, a direct switch from

levodopa/DDC inhibitor to <Invented name> is not recommended for patients who have dyskinesias

or whose daily levodopa dose is above 800 mg. In such patients it is advisable to introduce entacapone

treatment as a separate treatment (entacapone tablets) and adjust the levodopa dose if necessary,

before switching to <Invented name>.

Entacapone enhances the effects of levodopa. It may therefore be necessary, particularly in patients

with dyskinesia, to reduce levodopa dose by 10-30 % within the first days to first weeks after initiating

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<Invented name> treatment. The daily dose of levodopa can be reduced by extending the dosing

intervals and/or by reducing the amount of levodopa per dose, according to the clinical condition of

the patient.

Dose adjustment during the course of the treatment

When more levodopa is required, an increase in the frequency of doses and/or the use of an alternative

strength of <Invented name> should be considered, within the dose recommendations.

When less levodopa is required, the total daily dose of <Invented name> should be reduced either by

decreasing the frequency of administration by extending the time between doses, or by decreasing the

strength of <Invented name> at an administration.

If other levodopa products are used concomitantly with a <Invented name> tablet, the maximum dose

recommendations should be followed.

Discontinuation of <Invented name> therapy:

If <Invented name> treatment

(levodopa/carbidopa/entacapone) is discontinued and the patient is transferred to levodopa/DDC

inhibitor therapy without entacapone, it is necessary to adjust the dosing of other antiparkinsonian

treatments, especially levodopa, to achieve a sufficient level of control of the parkinsonian symptoms.

Paediatric population:

The safety and efficacy of levodopa/carbidopa/entacapone in children aged

below 18 years have not been established. No data are available.

Elderly patients:

No dose adjustment of <Invented name> is required for elderly patients.

Patients with hepatic impairment:

It is advised that <Invented name> should be administered

cautiously to patients with mild to moderate hepatic impairment. Dose reduction may be needed (see

section 5.2). For severe hepatic impairment see section 4.3.

Patients with renal impairment:

Renal impairment does not affect the pharmacokinetics of

entacapone. No particular studies are reported on the pharmacokinetics of levodopa and carbidopa in

patients with renal insufficiency, therefore <Invented name> therapy should be administered

cautiously to patients in severe renal impairment including those receiving dialysis therapy (see

section 5.2).

Method of administration

Each tablet is to be taken orally either with or without food (see section 5.2). One tablet

contains one

treatment dose and the tablet may only be administered as whole tablets.

4.3.

Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Severe hepatic impairment.

Narrow-angle glaucoma.

Pheochromocytoma.

Coadministration of <Invented name> with non-selective monoamine oxidase (MAO-A and

MAO-B) inhibitors (e.g. phenelzine, tranylcypromine).

Coadministration with a selective MAO-A inhibitor and a selective MAO-B inhibitor (see

section 4.5).

A previous history of Neuroleptic Malignant Syndrome (NMS) and/or non-traumatic

rhabdomyolysis.

4.4.

Special warnings and precautions for use

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<Invented name> is not recommended for the treatment of drug-induced extrapyramidal

reactions.

<Invented name> therapy should be administered cautiously to patients with ischemic heart

disease, severe cardiovascular or pulmonary disease, bronchial asthma, renal or endocrine

disease, history of peptic ulcer disease or history of convulsions.

In patients with a history of myocardial infarction who have residual atrial nodal or ventricular

arrhythmias; cardiac function should be monitored with particular care during the period of

initial dose adjustments.

All patients treated with <Invented name> should be monitored carefully for the development of

mental changes, depression with suicidal tendencies, and other serious antisocial behaviour.

Patients with past or current psychosis should be treated with caution.

Concomitant administration of antipsychotics with dopamine receptor-blocking properties,

particularly D

receptor antagonists should be carried out with caution, and the patient carefully

observed for loss of antiparkinsonian effect or worsening of parkinsonian symptoms.

Patients with chronic wide-angle glaucoma may be treated with <Invented name> with caution,

provided the intra-ocular pressure is well controlled and the patient is monitored carefully for

changes in intra-ocular pressure.

<Invented name> may induce orthostatic hypotension. Therefore <Invented name> should be

given cautiously to patients who are taking other medicinal products which may cause

orthostatic hypotension.

Entacapone in association with levodopa has been associated with somnolence and episodes of

sudden sleep onset in patients with Parkinson’s disease and caution should therefore be

exercised when driving or operating machines (see section 4.7).

In clinical studies, dopaminergic adverse reactions, e.g. dyskinesia, were more common in

patients who received entacapone and dopamine agonists (such as bromocriptine), selegiline or

amantadine compared to those who received placebo with this combination. The doses of other

antiparkinsonian medicinal products may need to be adjusted when <Invented name> treatment

is substituted for a patient currently not treated with entacapone.

Rhabdomyolysis secondary to severe dyskinesias or neuroleptic malignant syndrome (NMS)

has been observed rarely in patients with Parkinson’s disease. Therefore, any abrupt dose

reduction or withdrawal of levodopa should be carefully observed, particularly in patients who

are also receiving neuroleptics. NMS, including rhabdomyolysis and hyperthermia, is

characterised by motor symptoms (rigidity, myoclonus, tremor), mental status changes (e.g.,

agitation, confusion, coma), hyperthermia, autonomic dysfunction (tachycardia, labile blood

pressure) and elevated serum creatine phosphokinase. In individual cases, only some of these

symptoms and/or findings may be evident. The early diagnosis is important for the appropriate

management of NMS. A syndrome resembling the neuroleptic malignant syndrome including

muscular rigidity, elevated body temperature, mental changes and increased serum creatine

phosphokinase has been reported with the abrupt withdrawal of antiparkinsonian agents. Neither

NMS nor rhabdomyolysis have been reported in association with entacapone treatment from

controlled trials in which entacapone was discontinued abruptly. Since the introduction of

entacapone into the market, isolated cases of NMS have been reported, especially following

abrupt reduction or discontinuation of entacapone and other concomitant dopaminergic

medicinal products. When considered necessary, the replacement of <Invented name> with

levodopa and DDC inhibitor without entacapone or other dopaminergic treatment should

proceed slowly and an increase in levodopa dose may be necessary.

If general anaesthesia is required, therapy with <Invented name> may be continued for as long

as the patient is permitted to take fluids and medicinal products by mouth. If therapy has to be

stopped temporarily, <Invented name> may be restarted as soon as oral medicinal products can

be taken at the same daily dose as before.

Periodic evaluation of hepatic, haematopoietic, cardiovascular and renal function is

recommended during extended therapy with <Invented name>.

For patients experiencing diarrhoea, a follow-up of weight is recommended in order to avoid

potential excessive weight decrease. Prolonged or persistent diarrhoea appearing during use of

entacapone may be a sign of colitis. In the event of prolonged or persistent diarrhoea, the drug

should be discontinued and appropriate medical therapy and investigations considered.

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Patients should be regularly monitored for the development of impulse control disorders.

Patients and carers should be made aware that behavioural symptoms of impulse control

disorders including pathological gambling, increased libido, hypersexuality, compulsive

spending or buying, binge eating and compulsive eating can occur in patients treated with

dopamine agonists and/or other dopaminergic treatments containing levodopa including

<Invented name>. Review of treatment is recommended if such symptoms develop.

For patients who experience progressive anorexia, asthenia and weight decrease within a

relatively short period of time, a general medical evaluation including liver function should be

considered.

Levodopa/carbidopa may cause false positive result when a dipstick is used to test for urinary

ketone and this reaction is not altered by boiling the urine sample. The use of glucose oxidase

methods may give false negative results for glycosuria.

Dopamine Dysregulation Syndrome (DDS) is an addictive disorder resulting in excessive use

of the product seen in some patients treated with carbidopa/ levodopa. Before initiation of

treatment, patients and caregivers should be warned of the potential risk of developing DDS

(see also section 4.8).

4.5.

Interaction with other medicinal products and other forms of interaction

Other antiparkinsonian medicinal products:

To date there has been no indication of interactions that

would preclude concurrent use of standard antiparkinsonian medicinal products with <Invented name>

therapy. Entacapone in high doses may affect the absorption of carbidopa. However, no interaction

with carbidopa has been observed with the recommended treatment schedule (200 mg of entacapone

up to 10 times daily). Interactions between entacapone and selegiline have been investigated in

repeated dose studies in Parkinson's disease patients treated with levodopa/DDC inhibitor and no

interaction was observed. When used with <Invented name>, the daily dose of selegiline should not

exceed 10 mg.

Caution should be exercised when the following active substances are administered concomitantly

with levodopa therapy.

Antihypertensives:

Symptomatic postural hypotension may occur when levodopa is added to the

treatment of patients already receiving antihypertensives. Dose adjustment of the antihypertensive

agent may be required.

Antidepressants:

Rarely, reactions including hypertension and dyskinesia have been reported with the

concomitant use of tricyclic antidepressants and levodopa/carbidopa. Interactions between entacapone

and imipramine and between entacapone and moclobemide have been investigated in single dose

studies in healthy volunteers. No pharmacodynamic interactions were observed. A significant number

of Parkinson's disease patients have been treated with the combination of levodopa, carbidopa and

entacapone with several active substances including MAO-A inhibitors, tricyclic antidepressants,

noradrenaline reuptake inhibitors such as desipramine, maprotiline and venlafaxine and medicinal

products that are metabolised by COMT (e.g. catechol-structured compounds, paroxetine). No

pharmacodynamic interactions have been observed. However, caution should be exercised when these

medicinal products are used concomitantly with <Invented name> (see sections 4.3 and 4.4).

Other active substances:

Dopamine receptor antagonists (e.g. some antipsychotics and antiemetics),

phenytoin and papaverine may reduce the therapeutic effect of levodopa. Patients taking these

medicinal products with <Invented name> should be carefully observed for loss of therapeutic

response.

Due to entacapone's affinity to cytochrome P450 2C9

in vitro

(see section 5.2), <Invented name> may

potentially interfere with active substances whose metabolism is dependent on this isoenzyme, such as

S-warfarin. However, in an interaction study with healthy volunteers, entacapone did not change the

plasma levels of S-warfarin, while the AUC for R-warfarin increased on average by 18 %

11-26 %]. The INR values increased on average by 13 % [CI

6-19 %]. Thus, a control of INR

is recommended when <Invented name> is initiated for patients receiving warfarin.

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Other forms of interactions:

Since levodopa competes with certain amino acids, the absorption of

<Invented name> may be impaired in some patients on high protein diet.

Levodopa and entacapone may form chelates with iron in the gastrointestinal tract. Therefore,

<Invented name> and iron preparations should be taken at least 2-3 hours apart (see section 4.8).

In vitro data:

Entacapone binds to human albumin binding site II which also binds several other

medicinal products, including diazepam and ibuprofen. According to

in vitro

studies, significant

displacement is not anticipated at therapeutic concentrations of the medicinal products. Accordingly,

to date there has been no indication of such interactions.

4.6.

Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of the combination of levodopa/carbidopa/entacapone in

pregnant women. Studies in animals have shown reproductive toxicity of the separate compounds (see

section 5.3). The potential risk for humans is unknown. <Invented name> should not be used during

pregnancy unless the benefits for the mother outweigh the possible risks to the foetus.

Breast-feeding

Levodopa is excreted in human breast milk. There is evidence that breastfeeding is suppressed during

treatment with levodopa. Carbidopa and entacapone were excreted in milk in animals but is not known

whether they are excreted in human breast milk. The safety of levodopa, carbidopa or entacapone in

the infant is not known. Women should not breast-feed during treatment with <Invented name>.

Fertility

No adverse reactions on fertility were observed in preclinical studies with entacapone, carbidopa or

levodopa alone. Fertility studies in animals have not been conducted with the combination of

entacapone, levodopa and carbidopa.

4.7.

Effects on ability to drive and use machines

<Invented name> may have major influence on the ability to drive and use machines. Levodopa,

carbidopa and entacapone together may cause dizziness and symptomatic orthostatism. Therefore,

caution should be exercised when driving or using machines.

Patients being treated with <Invented name> and presenting with somnolence and/or sudden sleep

onset episodes must be instructed to refrain from driving or engaging in activities where impaired

alertness may put themselves or others at risk of serious injury or death (e.g. operating machines) until

such recurrent episodes have resolved (see section 4.4).

4.8.

Undesirable effects

a. Summary of the safety profile

The most frequently reported adverse reactions with levodopa/carbidopa/entacapone are dyskinesias

occurring in approximately 19 % of patients; gastrointestinal symptoms including nausea and

diarrhoea occurring in approximately 15 % and 12 % of patients, respectively; muscle,

musculoskeletal and connective tissue pain occurring in approximately 12 % of patients; and harmless

reddish-brown discolouration of urine (chromaturia) occurring in approximately 10 % of patients.

Serious events of gastrointestinal haemorrhage (uncommon) and angioedema (rare) have been

identified from the clinical trials with levodopa/carbidopa/entacapone or entacapone combined with

levodopa/DDC inhibitor. Serious hepatitis with mainly cholestatic features, rhabdomyolysis and

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neuroleptic malignant syndrome may occur with levodopa/carbidopa/entacapone although no cases

have been identified from the clinical trial data.

b. Tabulated list of adverse reactions

The following adverse reactions, listed in Table 1, have been accumulated both from a pooled data of

eleven double-blind clinical trials consisting of 3,230 patients (1,810 treated with

levodopa/carbidopa/entacapone or entacapone combined with levodopa/DDC inhibitor, and 1,420

treated with placebo combined with levodopa/DDC inhibitor or cabergoline combined with levodopa/

DDC inhibitor), and from the post-marketing data since the introduction of entacapone into the market

for the combination use of entacapone with levodopa/DDC inhibitor.

Adverse reactions are ranked under headings of frequency, the most frequent first, using the following

convention: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare

(≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available

data, since no valid estimate can be derived from clinical trials or epidemiological studies).

Table 1. Adverse reactions

Blood and lymphatic system disorders

Common:

Anaemia

Uncommon:

Thrombocytopenia

Metabolism and nutrition disorders

Common:

Weight decreased*, decreased appetite*

Psychiatric disorders

Common:

Depression, hallucination, confusional state*, abnormal dreams*, anxiety, insomnia

Uncommon:

Psychosis, agitation*

Not known:

Suicidal behaviour, Dopamine dysregulation syndrome

Nervous system disorders

Very common:

Dyskinesia*

Common:

Parkinsonism aggravated (e.g. bradykinesia)*, tremor, on and off phenomenon,

dystonia, mental impairment (e.g. memory impairment, dementia), somnolence,

dizziness*, headache

Not known:

Neuroleptic malignant syndrome*

Eye disorders

Common:

Blurred vision

Cardiac disorders

Common:

Ischemic heart disease events other than myocardial infarction (e.g. angina

pectoris)**, irregular heart rhythm

Uncommon:

Myocardial infarction**

Vascular disorders

Common:

Orthostatic hypotension, hypertension

Uncommon:

Gastrointestinal haemorrhage

Respiratory, thoracic and mediastinal disorders

Common:

Dyspnoea

Gastrointestinal disorders

Very common:

Diarrhoea*, nausea*

Common:

Constipation*, vomiting*, dyspepsia, abdominal pain and discomfort*, dry mouth*

Uncommon:

Colitis*, dysphagia

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Hepatobiliary disorders

Uncommon:

Hepatic function test abnormal*

Not known:

Hepatitis with mainly cholestatic features (see section 4.4)*

Skin and subcutaneous tissue disorders

Common:

Rash*, hyperhidrosis

Uncommon:

Discolourations other than urine (e.g. skin, nail, hair, sweat)*

Rare:

Angioedema

Not known:

Urticaria*

Musculoskeletal and connective tissue disorders

Very common:

Muscle, musculoskeletal and connective tissue pain*

Common:

Muscle spasms, arthralgia

Not known:

Rhabdomyolysis*

Renal and urinary disorders

Very common:

Chromaturia*

Common:

Urinary tract infection

Uncommon:

Urinary retention

General disorders and administration site conditions

Common:

Chest pain, peripheral oedema, fall, gait disturbance, asthenia, fatigue

Uncommon:

Malaise

* Adverse reactions that are mainly attributable to entacapone or are more frequent (by the frequency

difference of at least 1 % in the clinical trial data) with entacapone than levodopa/DDC inhibitor

alone. See section c.

** The incidence rates of myocardial infarction and other ischemic heart disease events (0.43 % and

1.54 %, respectively) are derived from an analysis of 13 double-blind studies involving 2,082 patients

with end-of-dose motor fluctuations receiving entacapone.

c. Description of selected adverse reactions

Adverse reactions that are mainly attributable to entacapone or are more frequent with entacapone than

levodopa/DDC inhibitor alone are indicated with an asterisk in Table 1, section 4.8b. Some of these

adverse reactions relate to the increased dopaminergic activity (e.g. dyskinesia, nausea and vomiting)

and occur most commonly at the beginning of the treatment. Reduction of levodopa dose decreases the

severity and frequency of these dopaminergic reactions. Few adverse reactions are known to be

directly attributable to the active substance entacapone including diarrhoea and reddish-brown

discolouration of urine. Entacapone may in some cases cause also discolouration of e.g. skin, nail, hair

and sweat. Other adverse reactions with an asterisk in Table 1, section 4.8b are marked based on either

their more frequent occurring (by the frequency difference of at least 1 %) in the clinical trial data with

entacapone than levodopa/DDCI alone or the individual case safety reports received after the

introduction of entacapone into the market.

Dopamine Dysregulation Syndrome (DDS) is an addictive disorder seen in some patients treated

with carbidopa/levodopa. Affected patients show a compulsive pattern of dopaminergic drug

misuse above doses adequate to control motor symptoms, which may in some cases result in

severe dyskinesias (see also section 4.4).

Convulsions have occurred rarely with levodopa/carbidopa; however a causal relationship to

levodopa/carbidopa therapy has not been established.

Impulse control disorders:

Pathological gambling, increased libido, hypersexuality, compulsive

spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine

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agonists and/or other dopaminergic treatments containing levodopa including <Invented name> (see

section 4.4).

Entacapone in association with levodopa has been associated with isolated cases of excessive daytime

somnolence and sudden sleep onset episodes.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It

allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare

professionals are asked to report any suspected adverse reactions via the national reporting system

listed in Appendix V.

4.9.

Overdose

The post-marketing data includes isolated cases of overdose in which the reported highest daily doses

of levodopa and entacapone have been at least 10,000 mg and 40,000 mg, respectively. The acute

symptoms and signs in these cases of overdose included agitation, confusional state, coma,

bradycardia, ventricular tachycardia, Cheyne-Stokes respiration, discolourations of skin, tongue and

conjunctiva, and chromaturia. Management of acute overdose with <Invented name> therapy is similar

to acute overdose with levodopa. Pyridoxine, however, is not effective in reversing the actions of

<Invented name>. Hospitalisation is advised and general supportive measures should be employed

with immediate gastric lavage and repeated doses of charcoal over time. This may hasten the

elimination of entacapone in particular by decreasing its absorption/reabsorption from the GI tract.

The adequacy of the respiratory, circulatory and renal systems should be carefully monitored and

appropriate supportive measures employed. ECG monitoring should be started and the patient

carefully monitored for the possible development of arrhythmias. If required, appropriate anti-

arrhythmic therapy should be given. The possibility that the patient has taken other active substances

in addition to <Invented name> should be taken into consideration. The value of dialysis in the

treatment of overdose is not known.

5.

PHARMACOLOGICAL PROPERTIES

5.1.

Pharmacodynamic properties

Pharmacotherapeutic group:

anti-parkinson drugs, dopa and dopa derivatives, ATC code:

N04BA03

According to the current understanding, the symptoms of Parkinson’s disease are related to depletion

of dopamine in the corpus striatum. Dopamine does not cross the blood-brain barrier. Levodopa, the

precursor of dopamine, crosses the blood brain barrier and relieves the symptoms of the disease. As

levodopa is extensively metabolised in the periphery, only a small portion of a given dose reaches the

central nervous system when levodopa is administered without metabolic enzyme inhibitors.

Carbidopa and benserazide are peripheral DDC inhibitors which reduce the peripheral metabolism of

levodopa to dopamine, and thus, more levodopa is available to the brain. When decarboxylation of

levodopa is reduced with the co-administration of a DDC inhibitor, a lower dose of levodopa can be

used and the incidence of adverse reactions such as nausea is reduced.

With inhibition of the decarboxylase by a DDC inhibitor, catechol-

O

-methyltransferase (COMT)

becomes the major peripheral metabolic pathway catalyzing the conversion of levodopa to 3-O-

methyldopa (3-OMD), a potentially harmful metabolite of levodopa. Entacapone is a reversible,

specific and mainly peripherally acting COMT inhibitor designed for concomitant administration with

levodopa. Entacapone slows the clearance of levodopa from the bloodstream resulting in an increased

area under the curve (AUC) in the pharmacokinetic profile of levodopa. Consequently the clinical

response to each dose of levodopa is enhanced and prolonged.

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The evidence of the therapeutic effects of levodopa/carbidopa/entacapone is based on two phase III

double-blind studies, in which 376 Parkinson’s disease patients with end-of-dose motor fluctuations

received either entacapone or placebo with each levodopa/DDC inhibitor dose. Daily ON time with

and without entacapone was recorded in home-diaries by patients. In the first study, entacapone

increased the mean daily ON time by 1 h 20 min (CI

45 min, 1 h 56 min) from baseline. This

corresponded to an 8.3 % increase in the proportion of daily ON time. Correspondingly, the decrease

in daily OFF time was 24 % in the entacapone group and 0 % in the placebo group. In the second

study, the mean proportion of daily ON time increased by 4.5 % (CI

0.93 %, 7.97 %) from baseline.

This is translated to a mean increase of 35 min in the daily ON time. Correspondingly, the daily OFF

time decreased by 18 % on entacapone and by 5 % on placebo. Because the effects of

levodopa/carbidopa/entacapone tablets are equivalent with entacapone 200 mg tablet administered

concomitantly with the commercially available standard release carbidopa/levodopa preparations in

corresponding doses these results are applicable to describe the effects of

levodopa/carbidopa/entacapone as well.

5.2.

Pharmacokinetic properties

General characteristics of the active substances

Absorption/distribution

There are substantial inter- and intra-individual variations in the absorption of levodopa, carbidopa and

entacapone. Both levodopa and entacapone are rapidly absorbed and eliminated. Carbidopa is

absorbed and eliminated slightly slower compared with levodopa. When given separately without the

two other active substances, the bioavailability for levodopa is 15-33 %, for carbidopa 40-70 % and

for entacapone 35 % after a 200 mg oral dose. Meals rich in large neutral amino acids may delay and

reduce the absorption of levodopa. Food does not significantly affect the absorption of entacapone.

The distribution volume of both levodopa (Vd 0.36-1.6 L/kg) and entacapone (Vd

0.27 L/kg) is

moderately small while no data for carbidopa are available.

Levodopa is bound to plasma protein only to a minor extent of about 10-30 % and carbidopa is bound

approximately 36 %, while entacapone is extensively bound to plasma proteins (about 98 %) - mainly

to serum albumin. At therapeutic concentrations, entacapone does not displace other extensively

bound active substances (e.g. warfarin, salicylic acid, phenylbutazone, or diazepam), nor is it

displaced to any significant extent by any of these substances at therapeutic or higher concentrations.

Biotransformation and elimination

Levodopa is extensively metabolised to various metabolites: decarboxylation by dopa decarboxylase

(DDC) and O-methylation by catechol-

O

-methyltransferase (COMT) being the most important

pathways.

Carbidopa is metabolized to two main metabolites which are excreted in the urine as glucuronides and

unconjugated compounds. Unchanged carbidopa accounts for 30% of the total urinary excretion.

Entacapone is almost completely metabolized prior to excretion via urine (10 to 20 %) and bile/faeces

(80 to 90 %). The main metabolic pathway is glucuronidation of entacapone and its active metabolite,

the cis-isomer, which accounts for about 5% of plasma total amount.

Total clearance for levodopa is in the range of 0.55-1.38 L/kg/h and for entacapone is in the range of

0.70 L/kg/h. The elimination-half life is (t

) is 0.6-1.3 hours for levodopa, 2-3 hours for carbidopa

and 0.4-0.7 hours for entacapone, each given separately.

Due to short elimination half-lives, no true accumulation of levodopa or entacapone occurs on

repeated administration.

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Data from in vitro studies using human liver microsomal preparations indicate that entacapone inhibits

cytochrome P450 2C9 (IC50 ~ 4 μM). Entacapone showed little or no inhibition of other types of

P450 isoenzymes (CYP1A2, CYP2A6, CYP2D6, CYP2E1, CYP3A and CYP2C19); see section 4.5.

Characteristics in patients

Elderly:

When given without carbidopa and entacapone, the absorption of levodopa is greater and

elimination is slower in elderly than in young subjects. However, after combination of carbidopa with

levodopa, the absorption of levodopa is similar between the elderly and the young, but the AUC is still

1.5 fold greater in the elderly due to decreased DDC activity and lower clearance by aging. There are

no significant differences in the AUC of carbidopa or entacapone between younger (45-64 years) and

elderly subjects (65-75 years).

Gender:

Bioavailability of levodopa is significantly higher in women than in men. In the

pharmacokinetic studies with levodopa/carbidopa/entacapone the bioavailability of levodopa is higher

in women than in men, primarily due to the difference in body weight, while there is no gender

difference with carbidopa and entacapone.

Hepatic impairment:

The metabolism of entacapone is slowed in patients with mild to moderate

hepatic impairment (Child-Pugh Class A and B) leading to an increased plasma concentration of

entacapone both in the absorption and elimination phases (see sections 4.2 and 4.3). No particular

studies on the pharmacokinetics of carbidopa and levodopa in patients with hepatic impairment are

reported, however, it is advised that <Invented name> should be administered cautiously to patients

with mild or moderate hepatic impairment.

Renal impairment:

Renal impairment does not affect the pharmacokinetics of entacapone. No

particular studies are reported on the pharmacokinetics of levodopa and carbidopa in patients with

renal impairment. However, a longer dosing interval of <Invented name> may be considered for

patients who are receiving dialysis therapy (see section 4.2).

5.3.

Preclinical safety data

Preclinical data of levodopa, carbidopa and entacapone, tested alone or in combination, revealed no

special hazard for humans based on conventional studies of safety pharmacology, repeated dose

toxicity, genotoxicity, and carcinogenic potential. In repeated dose toxicity studies with entacapone,

anaemia most likely due to iron chelating properties of entacapone was observed. Regarding

reproduction toxicity of entacapone, decreased foetal weight and a slightly delayed bone development

were noticed in rabbits treated at systemic exposure levels in the therapeutic range. Both levodopa and

combinations of carbidopa and levodopa have caused visceral and skeletal malformations in rabbits.

6.

PHARMACEUTICAL PARTICULARS

6.1.

List of excipients

Core tablet

Microcrystalline cellulose

Crospovidone (Type B)

Povidone K-30

Magnesium stearate

Sodium citrate

Film-coating

Hypromellose

Macrogol 6000

Titanium dioxide (E171)

Polysorbate 80

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Iron oxide red (E172)

Iron oxide yellow (E172) (for 50 mg/12.5 mg/200 mg, 100 mg/25 mg/200 mg and

150 mg/37.5 mg/200 mg)

6.2.

Incompatibilities

Not applicable

6.3.

Shelf life

3 years

In-use shelf life after first opening:

6 months

6.4.

Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5.

Nature and contents of container

HDPE bottle with a child resistant PP-closure and a silica gel canister.

Pack sizes:

30, 100 and 130 tablets.

Not all pack sizes may be marketed.

6.6.

Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local

requirements.

7.

MARKETING AUTHORISATION HOLDER

<To be completed nationally>

8.

MARKETING AUTHORISATION NUMBER(S)

<To be completed nationally>

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

<To be completed nationally>

10.

DATE OF REVISION OF THE TEXT

<To be completed nationally>

9 October 2020

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