Duloxetin Distriquimica 60 mg Enterokapsel, hård

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

08-12-2020

Produktens egenskaper Produktens egenskaper (SPC)

08-05-2020

Aktiva substanser:
duloxetinhydroklorid
Tillgänglig från:
Ebb Medical AB
ATC-kod:
N06AX21
INN (International namn):
duloxetine hydrochloride
Dos:
60 mg
Läkemedelsform:
Enterokapsel, hård
Sammansättning:
duloxetinhydroklorid 67,356 mg Aktiv substans; sockersfärer Hjälpämne; sackaros Hjälpämne; natriumlaurilsulfat Hjälpämne
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Burk, 112 (4 x 28) kapslar; Burk, 28 kapslar
Bemyndigande status:
Avregistrerad
Godkännandenummer:
59241
Tillstånd datum:
2019-07-31

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08-12-2020

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08-12-2020

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18-06-2015

Läs hela dokumentet

Bipacksedel: Information till användaren

Dulmis 30 mg hårda enterokapslar

Dulmis 60 mg hårda enterokapslar

duloxetin

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 finner du information om följande

Vad Dulmis är och vad det används för

Vad du behöver veta innan du tar Dulmis

Hur du tar Dulmis

Eventuella biverkningar

Hur Dulmis ska förvaras

Förpackningens innehåll och övriga upplysningar

1.

Vad Dulmis är och vad det används för

Dulmis innehåller den aktiva substansen duloxetin. Dulmis ökar mängden serotonin och noradrenalin i

nervsystemet.

Dulmis används hos vuxna för behandling av:

depression

generaliserat ångestsyndrom (ständig känsla av ångest eller oro)

smärtsam diabetesneuropati (beskrivs vanligen som brännande, stickande, svidande, huggande

eller molande smärta eller som en elektrisk chock. Smärta kan framkallas av beröring, värme,

kyla eller tryck men det berörda området kan även vara helt utan känsel).

Hos de flesta med depression eller ångest börjar Dulmis verka inom två veckor efter att behandlingen

påbörjats, men det kan ta 2-4 veckor innan du känner dig bättre. Tala med din läkare om du inte börjar

känna dig bättre efter denna tid. Din läkare kan fortsätta att ge dig Dulmis även när du känner dig

bättre för att förhindra återfall i depression eller ångest.

För de flesta som har smärtsam diabetesneuropati kan det ta några veckor innan man känner sig bättre.

Tala med din läkare om du inte känner dig bättre efter 2 månader.

Duloxetin som finns i Dulmis kan också vara godkänd för att behandla andra sjukdomar som inte

nämns i denna bipacksedel. Fråga läkare, apotekspersonal eller annan hälsovårdspersonal om du

har ytterligare frågor och följ alltid deras instruktion.

2.

Vad du behöver veta innan du tar Dulmis

Ta inte Dulmis om du:

är allergisk mot duloxetin eller något annat innehållsämne i detta läkemedel (anges i avsnitt 6)

har leversjukdom

har svår njursjukdom

tar eller under de senaste 14 dagarna tagit ett läkemedel, som tillhör gruppen

monoaminoxidashämmare (MAO-hämmare), se ”Andra läkemedel och Dulmis”)

tar fluvoxamin som vanligen används för att behandla depression, ciprofloxacin eller enoxacin

som används för att behandla vissa infektioner

tar andra läkemedel som innehåller duloxetin (se ”Andra läkemedel och Dulmis”).

Tala med din läkare om du har högt blodtryck eller hjärtsjukdom. Din läkare kommer att tala om för

dig om du ska ta Dulmis.

Varningar och försiktighet

Om du lider av något av följande, kanske Dulmis inte passar för dig. Tala med din läkare innan du

börjar ta Dulmis om du:

tar andra läkemedel mot depression (se ”Andra läkemedel och Dulmis”)

tar johannesört, ett naturläkemedel (Hypericum perforatum)

har njursjukdom

har haft kramper (anfall)

har haft mani

har bipolär sjukdom

har ögonproblem, som t ex en viss typ av glaukom (förhöjt tryck i ögat)

tidigare har haft blödningsstörningar (tendens att få blåmärken), särskilt om du är gravid (se

”Graviditet och amning”)

är i riskzonen för låga natriumvärden (till exempel om du tar vattendrivande läkemedel, särskilt

om du är äldre)

samtidigt behandlas med annat läkemedel som kan orsaka leverskada

tar andra läkemedel som innehåller duloxetin (se ”Andra läkemedel och Dulmis”)

Dulmis kan orsaka en känsla av rastlöshet och svårighet att sitta eller stå still. Om detta inträffar ska

du tala om det för din läkare.

Läkemedel såsom Dulmis (s.k. SNRI-preparat) kan orsaka symtom på sexuell dysfunktion (se avsnitt

4). I vissa fall har dessa symtom kvarstått efter avbruten behandling.

Om du börjar må sämre och har tankar på att skada dig själv

Du som är deprimerad och/eller lider av oro/ångest kan ibland ha tankar på att skada dig själv eller

begå självmord. Dessa symtom kan förvärras när man börjar använda läkemedel mot depression,

eftersom det tar tid innan läkemedel av den här typen har effekt, vanligtvis cirka 2 veckor, ibland

längre tid.

Dessa tankar kan vara vanliga om du:

tidigare har haft tankar på att skada dig själv eller begå självmord

är yngre än 25 år. Studier har visat att unga vuxna (yngre än 25 år) med psykisk sjukdom som

behandlas med antidepressiva läkemedel har en ökad risk för självmordstankar och tankar på att

skada sig själv.

Kontakta snarast läkare eller uppsök närmaste sjukhus om du har tankar på att skada dig själv

eller begå självmord.

Det kan vara till hjälp att berätta för en släkting eller nära vän att du är deprimerad och/eller lider av

oro/ångest. Be dem gärna läsa igenom denna bipacksedel. Du kan också be dem att berätta för dig om

de tycker att du verkar må sämre eller om de tycker att ditt beteende förändras.

Barn och ungdomar under 18 år

Dulmis ska normalt inte användas vid behandling av barn och ungdomar under 18 år. Risken för

biverkningar som självmordsförsök, självmordstankar och fientlighet (främst aggression, trots och

ilska) är större hos patienter under 18 år när de tar läkemedel av denna typ. Trots detta kan Dulmis

skrivas ut av läkare till patienter under 18 år om läkaren anser att detta är lämpligt. Om du är under 18

år och vill diskutera varför du fått detta läkemedel, ska du vända dig till din läkare igen. Du ska också

informera din läkare om du upptäcker något av ovan angivna symtom eller om de förvärras. Dessutom

har de långsiktiga effekterna på tillväxt, mognad och utveckling av intellekt och beteende ännu inte

fastställts för denna åldersgrupp.

Andra läkemedel och Dulmis

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

läkemedel, även receptfria sådana.

Den aktiva beståndsdelen i Dulmis, duloxetin, används i andra läkemedel för andra sjukdomstillstånd:

smärtsam diabetesneuropati, depression, ångest och urinläckage.

Användning av fler än ett av dessa läkemedel samtidigt ska undvikas. Ta kontakt med din läkare om

du redan tar andra läkemedel som innehåller duloxetin.

Din läkare ska avgöra om du kan ta Dulmis tillsammans med andra läkemedel.

Kontrollera med din

läkare innan du börjar eller slutar att ta några läkemedel, även receptfria läkemedel och

naturmedel.

Tala om för din läkare om du tar något av följande:

Monoaminoxidashämmare (MAO-hämmare):

Dulmis ska inte tas om du tar eller under de senaste 14

dagarna intagit ett annat läkemedel mot depressionen som kallas MAO-hämmare. Exempel på MAO-

hämmare är moklobemid (ett antidepressivt läkemedel) och linezolid (ett antibiotika). Många

receptbelagda läkemedel, inklusive Dulmis, kan, om de tas tillsammans med en MAO-hämmare,

orsaka allvarliga eller till och med livshotande biverkningar. Innan du kan ta Dulmis måste minst 14

dagar ha förflutit sedan behandling med en MAO-hämmare avslutats. Likaså måste minst 5 dagar ha

förflutit efter avslutad behandling med Dulmis innan du kan börja ta en MAO-hämmare.

Läkemedel som kan ge upphov till dåsighet:

Sådana läkemedel inkluderar receptbelagda läkemedel

som bensodiazepiner, starka smärtstillande medel, läkemedel mot psykos, fenobarbital och

antihistaminer.

Läkemedel som ökar halten av serotonin:

Triptaner, tramadol, tryptofan, SSRI-läkemedel (t ex

paroxetin och fluoxetin), SNRI-läkemedel (t ex venlafaxin), tricykliska antidepressiva (t ex

klomipramin, amitriptylin), petidin, johannesört och MAO-hämmare (t ex moklobemid och linezolid).

Dessa läkemedel ökar risken för biverkningar. Kontakta din läkare om du får något ovanligt symtom

när du tar något av dessa läkemedel tillsammans med Dulmis.

Orala antikoagulantia eller trombycytaggregationshämmande medel:

Blodförtunnande medel eller

medel som förhindrar blodet från att bilda klumpar. Dessa medel kan öka risken för blödningar.

Dulmis med mat, dryck och alkohol

Dulmis kan tas oberoende av måltid. Du bör vara försiktig med alkohol under behandling med Dulmis.

Graviditet och amning

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.

Tala om för din läkare om du blir gravid eller planerar att bli gravid under behandlingen med

Dulmis. Du ska endast använda Dulmis efter att ha rådfrågat din läkare angående behandlingens

möjliga fördelar och eventuella risker för fostret.

Tala om för din barnmorska eller läkare att du använder Dulmis. När liknande läkemedel (SSRI)

används under graviditet kan risken öka för ett allvarligt tillstånd kallat persistent pulmonell

hypertension hos den nyfödde (PPHN). Detta tillstånd gör att barnet andas snabbare och ser

blåfärgat ut. Symtomen uppkommer vanligtvis inom 24 timmar från det att barnet är fött. Om

detta drabbar ditt barn, kontakta barnmorska eller läkare omedelbart.

Om du tar Dulmis i slutet av graviditeten, kan ditt barn drabbas av vissa symtom efter födseln.

Dessa symtom uppträder vanligen vid förlossningen eller inom några dagar efter att ditt barn har

fötts. Symtomen kan vara slappa muskler, skakningar, darrningar, matningssvårigheter,

andningsproblem och krampanfall. Om ditt nyfödda barn har något av dessa symtom, eller om

du är bekymrad för ditt barns hälsa, bör du kontakta din läkare eller barnmorska för råd.

Om du tar Dulmis i slutet av din graviditet finns en ökad risk för svår vaginal blödning kort efter

förlossning, särskilt om du tidigare haft blödningsstörningar. Din läkare eller barnmorska bör

informeras om att du tar duloxetin så att de kan ge dig råd.

Tillgängliga data från användning av Dulmis under de första tre månaderna av graviditeten visar

inte någon allmän ökad risk för fosterskador hos barnet. Om Dulmis tas under andra halvan av

graviditeten kan en ökad risk finnas för att barnet föds tidigt (6 extra för tidigt födda barn per

100 kvinnor som tar Cymbalta under andra hälften av graviditeten), mestadels mellan vecka 35

och 36 av graviditeten.

Tala om för din läkare om du ammar. Användning av Dulmis under amning rekommenderas ej.

Rådgör med din läkare eller apotekspersonal.

Körförmåga och användning av maskiner

Dulmis kan göra att du känner dig sömnig eller yr. Kör inte bil och använd inte verktyg eller maskiner

förrän du vet hur Dulmis påverkar dig.

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 läkare eller apotekspersonal om du är osäker.

Dulmis innehåller sackaros

Dulmis innehåller

sackaros

. Om du inte tål vissa sockerarter ska du kontakta din läkare innan du tar

detta läkemedel.

Dulmis innehåller natrium

Detta läkemedel innehåller mindre än 1 mmol (23 mg) natrium per kapsel, d.v.s. är näst intill

“natriumfritt”.

3.

Hur du tar Dulmis

Ta alltid detta läkemedel enligt läkarens anvisningar. Rådfråga läkare eller apotekspersonal om du är

osäker.

Dulmis intas genom munnen. Svälj kapseln hel tillsammans med vatten.

För depression och smärtsam diabetesneuropati:

Rekommenderad dos

är Dulmis 60 mg en gång dagligen, men din läkare förskriver den dos som är

lämplig för dig.

För generaliserat ångestsyndrom:

Den rekommenderade startdosen är Dulmis 30 mg en gång dagligen, och de flesta patienter går sedan

över till 60 mg en gång dagligen, men din läkare förskriver den dos som är lämplig för dig. Dosen kan

behöva justeras upp till 120 mg, beroende på hur du svarar på Dulmis.

Det är lättare att komma ihåg att ta Dulmis om man tar det vid samma tid varje dag.

Fråga din läkare hur länge du ska ta Dulmis. Sluta inte att ta Dulmis, eller ändra dos, utan att först ha

diskuterat detta med din läkare. För att du ska känna dig bättre är det viktigt att behandla din sjukdom

på rätt sätt. Om den inte behandlas, kan den kvarstå och bli allvarligare och svårare att behandla.

Om du har tagit för stor mängd Dulmis:

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.

Symtom på överdos är sömnighet, koma, serotonergt syndrom (en sällsynt reaktion som kan orsaka

kraftiga lyckokänslor, dåsighet, klumpighet, rastlöshet, berusningskänsla, feber, svettning eller stela

muskler), krampanfall, kräkningar och snabba hjärtslag.

Om du har glömt att ta Dulmis

Om du har glömt en dos, ta den så snart du kommer ihåg. Om det emellertid är dags för din nästa dos,

hoppa över den glömda dosen och ta endast en dos som vanligt. Ta inte dubbla doser för att

kompensera den dos du glömt. Ta inte fler Dulmis per dag än din läkare föreskrivit.

Om du slutar att ta Dulmis

SLUTA INTE att ta Dulmis, även om du känner dig bättre, utan att först tala med din läkare. Om din

läkare anser att du inte längre behöver Dulmis, kommer han/hon att minska dosen under minst två

veckor, innan behandlingen avslutas helt.

Vissa patienter, som abrupt slutar att ta Dulmis, kan få symtom såsom:

yrsel, stickningar och domningar eller förnimmelser av elektriska stötar (speciellt i huvudet),

sömnstörningar (livliga drömmar, mardrömmar, sömnlöshet), trötthet, sömnighet, känsla av

rastlöshet eller oro, ångest, illamående/kräkningar (känna sig sjuk), skakningar, huvudvärk,

muskelsmärta, irritationskänsla, diarré, kraftiga svettningar eller svindel.

Dessa besvär är vanligtvis lätta och försvinner inom några dagar. Rådfråga din läkare om reaktionerna

är besvärande.

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

4.

Eventuella biverkningar

Liksom alla läkemedel kan detta läkemedel orsaka biverkningar. Dessa är vanligtvis lätta till måttliga

och försvinner oftast efter några veckor.

Mycket vanliga biverkningar (kan förekomma hos fler än 1 av 10 användare)

huvudvärk, sömnighet

illamående, muntorrhet

Vanliga biverkningar (kan förekomma hos upp till 1 av 10 användare)

aptitlöshet

sömnsvårigheter, upprördhetskänslor, mindre sexlust, ångest, svårigheter att få eller utebliven

orgasm, konstiga drömmar

yrsel, känna sig trög, darrningar, domningar, som inkluderar domningar eller stickningar i huden

dimsyn

tinnitus (förnimmelse av ljud i örat utan yttre ljudkälla)

hjärtklappning

förhöjt blodtryck, blodvallning

gäspningar

förstoppning, diarré, ont i magen, illamående och kräkningar, halsbränna eller

matsmältningsbesvär, väderspänning

ökad svettning, (kliande) utslag

muskelsmärta, muskelspasm

smärtsam urinering, täta blåstömningar

erektionsproblem, ejakulationsstörningar

fallolyckor (mest hos äldre), trötthet

viktminskning

Barn och ungdomar under 18 år som behandlades med detta läkemedel mot depression fick viss

viktminskning när de påbörjade behandlingen. Vikten ökade dock efter 6 månaders behandling så att

den motsvarade andra barn och ungdomar i samma ålder och av samma kön.

Mindre vanliga biverkningar (kan förekomma hos upp till 1 av 10 användare)

svalginflammation som orsakar hes röst

självmordstankar, sömnsvårigheter, tandgnisslan, känna sig desorienterad, bristande motivation

plötsliga ofrivilliga ryckningar eller ryckningar i musklerna, en känsla av rastlöshet och

svårighet att sitta eller stå still, känna sig nervös, koncentrationssvårigheter, smakförändringar,

svårigheter att kontrollera rörelser t.ex. brist på koordination eller ofrivilliga rörelser i

musklerna, restless legs (domnande och stickande känsla i benen), dålig sömn

stora pupiller (det mörka fältet i mitten av ögat), synstörningar

svindel och ont i öronen

snabba eller oregelbundna hjärtslag

svimning och yrsel när man reser sig upp, kalla fingrar och/eller tår

känna sig tjock i halsen, näsblödning

blodiga kräkningar eller svart tjärartad avföring, mag-tarminflammation, rapningar, svårigheter

att svälja

inflammation i levern som kan orsaka smärta i buken och gulfärgning av hud och ögonvitor

nattsvettningar, nässelfeber, kallsvettning, känslighet för solljus, ökad benägenhet att få

blåmärken

muskelspänning, muskelryckningar

svårighet eller oförmåga att kasta vatten, svårighet att börja kissa, behov att tömma blåsan under

natten, behov att tömma blåsan oftare än vanligt, minskat urinflöde

onormal vaginalblödning, onormala menstruationer, inkluderande kraftig, smärtsam,

oregelbunden eller förlängd menstruation, ovanligt korta eller uteblivna menstruationer, smärta i

testiklarna eller pungen

bröstsmärta, känna sig kall, törst, skakningar, känna sig varm, onormal gång

viktökning

Dulmis kan orsaka effekter som du inte märker, såsom ökning av leverenzymer eller halten av

kalium, kreatinfosfokinas, socker eller kolesterol i blodet.

Sällsynta biverkningar (kan förekomma hos upp till 1 av 1000 användare)

allvarliga allergiska reaktioner som orsakar andningssvårigheter eller yrsel, med svullen tunga

eller svullna läppar, allergiska reaktioner

nedsatt sköldkörtelfunktion, vilket kan orsaka trötthet eller viktuppgång

uttorkning, lågt natriumvärde i blodet (drabbar mest äldre); symtomen kan vara att känna sig yr,

svag, förvirrad, sömnig eller mycket trött, illamående eller kräkningar, mer allvarliga symtom är

svimning, krampanfall eller fall, otillräcklig utsöndring av antidiuretiskt hormon (SIADH)

självmordsbeteende, mani (överaktivitet, tankeflykt och nedsatt behov av sömn), känsla av

aggression och vrede

”serotonergt syndrom” (en sällsynt reaktion som kan ge lyckokänsla, dåsighet, klumpighet,

rastlöshet, känsla av berusning, feber, svettningar eller stela muskler), krampattacker

ökat tryck i ögat (glaukom)

hosta, pipande andning och andfåddhet som kan åtföljas av hög kroppstemperatur.

inflammation i munnen, ljust rött blod i avföringen, dålig andedräkt, inflammation i tjocktarmen

(orsakar diarré)

leverproblem, gulfärgning av hud och ögonvitor (gulsot)

Stevens-Johnson syndrom (svår sjukdom med blåsor i huden, munnen, ögonen och

könsorganen), svåra allergiska reaktioner som orsakar svullnad av ansiktet och halsen

(angioödem).

kramp i käkmusklerna

avvikande lukt på urinen

klimakteriesymtom, onormal produktion av bröstmjölk hos män och kvinnor.

svår vaginal blödning kort efter förlossning (postpartumblödning).

Mycket sällsynta biverkningar (kan påverka upp till 1 användare av 10 000)

Inflammation i hudens blodkärl (kutan vaskulit)

Rapportering av biverkningar

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

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

detaljer nedan). Genom att rapportera biverkningar kan du bidra till att öka informationen om

läkemedels säkerhet.

Läkemedelsverket

Box 26

751 03 Uppsala

www.lakemedelsverket.se

5.

Hur Dulmis ska förvaras

Förvara detta läkemedel utom syn- och räckhåll för barn.

Används före utgångsdatum som anges på kartongen efter Utg.dat. Utgångsdatumet är den sista dagen

i angiven månad.

30 mg:

Blister Alu/Alu:

Inga särskilda temperaturanvisningar. Förvaras i originalförpackningen. Ljuskänsligt.

Blister PVC/PVDC-Alu:

Förvaras vid högst 30°C.

Burken:

Inga särskilda temperaturanvisningar. Tillslut burken väl. Ljuskänsligt och fuktkänsligt.

60mg:

Blister Alu/Alu:

Inga särskilda förvaringsanvisningar.

Blister PVD-PVDC/Alu:

Förvaras vid högst 30° C.

Burken

: 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

Den aktiva substansen är duloxetin. Varje kapsel innehåller 30 eller 60 mg duloxetin (som

hydroklorid).

Övriga innehållsämnen är:

Kapselinnehåll:

Hypromellos, metakrylsyra-etylakrylatpolymer, natriumlaurylsulfat, polysorbat

80, sackaros, sockersfärer (majsstärkelse och sackaros), talk, titandioxid, trietylcitrat.

Kapselhölje:

Gelatin, titandioxid (E171), indigokarmin (E132), märkningsbläck (svart järnoxid

(E172), kaliumhydroxid och shellack). 60 mg kapseln innehåller även gul järnoxid (E172).

Läkemedlets utseende och förpackningsstorlekar

Dulmis är en hård, magsaftresistent kapsel. Varje kapsel av Dulmis innehåller korn av

duloxetinhydroklorid med ett hölje som står emot den sura magsaften.

Dulmis finns i 2 styrkor: 30 mg och 60 mg.

30 mg-kapseln märkt E respektive 127 är blå och vit (med en storlek av ca 15 mm).

60 mg-kapseln märkt E respektive 129 är blå och grön (med en storlek av ca 19 mm).

Dulmis 30 mg tillhandahålls i blisterförpackningar innehållande 7, 10, 14, 20, 28, 30, 50, 56, 60, 84,

98 och 504 hårda enterokapslar; och burken

med 28 och

500 hårda enterokapslar.

Dulmis 60 mg tillhandahålls i blisterförpackningar innehållande 7, 10, 14, 20, 28, 30, 50, 56, 60, 84,

98 och 504 hårda enterokapslar; och burk

med 28 och

500 hårda enterokapslar.

Eventuellt kommer inte alla förpackningsstorlekar att marknadsföras.

Innehavare av godkännande för försäljning och tillverkare:

Innehavare av godkännande för försäljning:

TOWA Pharmaceutical Europe, S.L., C/ de Sant Martí,

75-97, 08107 Martorelles, Barcelona Spanien

Tillverkare:

TOWA Pharmaceutical Europe, S.L., C/ de Sant Martí, 75-97, 08107 Martorelles,

Barcelona, Spanien.

Detta läkemedel är godkänt inom Europeiska ekonomiska samarbetsområdet under namnen:

Frankrike:

Duloxétine Mylan Pharma 30 mg gélule gastro-résistante

Duloxétine Mylan Pharma 60 mg gélule gastro-résistante

Tyskland:

Dulmis 30 mg magensaftresistente Hartkapseln

Dulmis 60 mg magensaftresistente Hartkapseln

Island:

Duloxetin W&H 30 mg hörð sýruþolin hylki

Duloxetin W&H 60 mg hörð sýruþolin hylki

Spanien

Dulmis 30 mg cápsulas duras gastrorresistentes EFG

Dulmis 60 mg cápsulas duras gastrorresistentes EFG

Denna bipacksedel ändrades senast

2020-12-08

Läs hela dokumentet

SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Dulmis 30 mg gastro-resistant capsules, hard

Dulmis 60 mg gastro-resistant capsules, hard

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Dulmis 30 mg

Each capsule contains 30 mg of duloxetine (as hydrochloride).

Excipient(s) with known effect:

Each capsule contains approximately 63.7 mg sucrose.

Dulmis 60 mg

Each capsule contains 60 mg of duloxetine (as hydrochloride).

Excipient(s) with known effect:

Each capsule contains approximately 127.4 mg sucrose.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Gastro-resistant capsule, hard.

Dulmis 30 mg

Opaque blue cap and opaque white body capsules printed (cap E/body 127) of 15 mm approximately.

Dulmis 60 mg

Opaque blue cap and opaque green body capsules printed (cap E/body 129) of 19 mm approximately.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Treatment of major depressive disorder.

Treatment of diabetic peripheral neuropathic pain.

Treatment of generalised anxiety disorder.

Dulmis is indicated in adults.

For further information see section 5.1.

4.2

Posology and method of administration

Posology

Major depressive disorder

The starting and recommended maintenance dose is 60 mg once daily with or without food. Dosages

above 60 mg once daily, up to a maximum dose of 120 mg per day have been evaluated from a safety

perspective in clinical trials. However, there is no clinical evidence suggesting that patients not

responding to the initial recommended dose may benefit from dose up-titrations.

Therapeutic response is usually seen after 2-4 weeks of treatment.

After consolidation of the antidepressive response, it is recommended to continue treatment for several

months, in order to avoid relapse. In patients responding to duloxetine, and with a history of repeated

episodes of major depression, further long-term treatment at a dose of 60 to 120 mg/day could be

considered.

Generalised anxiety disorder

The recommended starting dose in patients with generalised anxiety disorder is 30 mg once daily with

or without food. In patients with insufficient response the dose should be increased to 60 mg, which is

the usual maintenance dose in most patients.

In patients with co-morbid major depressive disorder, the starting and maintenance dose is 60 mg once

daily (please see also dosing recommendation above).

Doses up to 120 mg per day have been shown to be efficacious and have been evaluated from a safety

perspective in clinical trials. In patients with insufficient response to 60 mg, escalation up to 90 mg or

120 mg may therefore be considered. Dose escalation should be based upon clinical response and

tolerability.

After consolidation of the response, it is recommended to continue treatment for several months, in

order to avoid relapse.

Diabetic peripheral neuropathic pain

The starting and recommended maintenance dose is 60 mg daily with or without food. Dosages above

60 mg once daily, up to a maximum dose of 120 mg per day administered in evenly divided doses,

have been evaluated from a safety perspective in clinical trials. The plasma concentration of

duloxetine displays large inter-individual variability (see section 5.2). Hence, some patients that

respond insufficiently to 60 mg may benefit from a higher dose.

Response to treatment should be evaluated after 2 months. In patients with inadequate initial response,

additional response after this time is unlikely.

The therapeutic benefit should be reassessed regularly (at least every three months) (see section 5.1).

Special populations

Elderly

No dosage adjustment is recommended for elderly patients solely on the basis of age. However, as

with any medicine, caution should be exercised when treating the elderly, especially with Dulmis 120

mg per day for major depressive disorder or generalised anxiety disorder, for which data are limited

(see sections 4.4 and 5.2).

Hepatic impairment

Dulmis must not be used in patients with liver disease resulting in hepatic impairment (see sections 4.3

and 5.2).

Renal impairment

No dosage adjustment is necessary for patients with mild or moderate renal dysfunction (creatinine

clearance 30 to 80 ml/min). Dulmis must not be used in patients with severe renal impairment

(creatinine clearance <30 ml/min; see section 4.3).

Paediatric population

Duloxetine should not be used in children and adolescents under the age of 18 years for the treatment

of major depressive disorder because of safety and efficacy concerns (see sections 4.4, 4.8 and 5.1).

The safety and efficacy of duloxetine for the treatment of generalised anxiety disorder in paediatric

patients aged 7-17 years have not been established. Current available data are described in sections

4.8, 5.1 and 5.2.

The safety and efficacy of duloxetine for the treatment of diabetic peripheral neuropathic pain has not

been studied. No data are available.

Discontinuation of treatment

Abrupt discontinuation should be avoided. When stopping treatment with Dulmis the dose should be

gradually reduced over a period of at least one to two weeks in order to reduce the risk of withdrawal

reactions (see sections 4.4 and 4.8). If intolerable symptoms occur following a decrease in the dose or

upon discontinuation of treatment, then resuming the previously prescribed dose may be considered.

Subsequently, the physician may continue decreasing the dose, but at a more gradual rate.

Method of administration

For oral use.

4.3

Contraindications

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

Concomitant use of Dulmis with nonselective, irreversible monoamine oxidase inhibitors (MAOIs) is

contraindicated (see section 4.5).

Liver disease resulting in hepatic impairment (see section 5.2).

Dulmis should not be used in combination with fluvoxamine, ciprofloxacin or enoxacin (i.e. potent

CYP1A2 inhibitors) since the combination results in elevated plasma concentrations of duloxetine (see

section 4.5).

Severe renal impairment (creatinine clearance <30 ml/min) (see section 4.4).

The initiation of treatment with Dulmis is contraindicated in patients with uncontrolled hypertension

that could expose patients to a potential risk of hypertensive crisis (see sections 4.4 and 4.8).

4.4

Special warnings and precautions for use

Mania and seizures

Dulmis should be used with caution in patients with a history of mania or a diagnosis of bipolar

disorder, and/or seizures.

Mydriasis

Mydriasis has been reported in association with duloxetine, therefore, caution should be used when

prescribing Dulmis to patients with increased intraocular pressure, or those at risk of acute narrow-

angle glaucoma.

Blood pressure and heart rate

Duloxetine has been associated with an increase in blood pressure and clinically significant

hypertension in some patients. This may be due to the noradrenergic effect of duloxetine. Cases of

hypertensive crisis have been reported with duloxetine, especially in patients with pre-existing

hypertension. Therefore, in patients with known hypertension and/or other cardiac disease, blood

pressure monitoring is recommended, especially during the first month of treatment. Duloxetine

should be used with caution in patients whose conditions could be compromised by an increased heart

rate or by an increase in blood pressure. Caution should also be exercised when duloxetine is used

with medicinal products that may impair its metabolism (see section 4.5). For patients who experience

a sustained increase in blood pressure while receiving duloxetine either dose reduction or gradual

discontinuation should be considered (see section 4.8). In patients with uncontrolled hypertension

duloxetine should not be initiated (see section 4.3).

Renal impairment

Increased plasma concentrations of duloxetine occur in patients with severe renal impairment on

haemodialysis (creatinine clearance <30 ml/min). For patients with severe renal impairment, see

section 4.3. See section 4.2 for information on patients with mild or moderate renal dysfunction.

Serotonin syndrome

As with other serotonergic agents, serotonin syndrome, a potentially life-threatening condition, may

occur with duloxetine treatment, particularly with concomitant use of other serotonergic agents

(including SSRIs, SNRIs tricyclic antidepressants or triptans), with agents that impair metabolism of

serotonin such as MAOIs, or with antipsychotics or other dopamine antagonists that may affect the

serotonergic neurotransmitter systems (see sections 4.3 and 4.5).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations,

coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular

aberrations (e.g. hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea,

vomiting, diarrhoea).

If concomitant treatment with duloxetine and other serotonergic agents that may affect the

serotonergic and/or dopaminergic neurotransmitter systems is clinically warranted, careful observation

of the patient is advised, particularly during treatment initiation and dose increases.

St John’s wort

Adverse reactions may be more common during concomitant use of Dulmis and herbal preparations

containing St John’s wort (Hypericum perforatum).

Suicide

Major Depressive Disorder and Generalised Anxiety Disorder:

Depression is associated with an

increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persists

until significant remission occurs. As improvement may not occur during the first few weeks or more

of treatment, patients should be closely monitored until such improvement occurs. It is general clinical

experience that the risk of suicide may increase in the early stages of recovery.

Other psychiatric conditions for which Dulmis is prescribed can also be associated with an increased

risk of suicide-related events. In addition, these conditions may be co-morbid with major depressive

disorder. The same precautions observed when treating patients with major depressive disorder should

therefore be observed when treating patients with other psychiatric disorders.

Patients with a history of suicide-related events or those exhibiting a significant degree of suicidal

thoughts prior to commencement of treatment are known to be at greater risk of suicidal thoughts or

suicidal behaviour, and should receive careful monitoring during treatment. A meta-analysis of

placebo-controlled clinical trials of antidepressant medicinal products in psychiatric disorders showed

an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than

25 years old.

Cases of suicidal thoughts and suicidal behaviours have been reported during duloxetine therapy or

early after treatment discontinuation (see section 4.8).

Close supervision of patients and in particular those at high risk should accompany medicinal product

therapy especially in early treatment and following dose changes. Patients (and caregivers of patients)

should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts

and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

Diabetic Peripheral Neuropathic Pain:

As with other medicinal products with similar

pharmacological action (antidepressants), isolated cases of suicidal ideation and suicidal behaviours

have been reported during duloxetine therapy or early after treatment discontinuation. Concerning risk

factors for suicidality in depression see above. Physicians should encourage patients to report any

distressing thoughts or feelings at any time.

Use in children and adolescents under 18 years of age

Dulmis should not be used in the treatment of children and adolescents under the age of 18 years.

Suicide-related behaviours (suicide attempts and suicidal thoughts), and hostility (predominantly

aggression, oppositional behaviour and anger), were more frequently observed in clinical trials among

children and adolescents treated with antidepressants compared to those treated with placebo. If, based

on clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored for

the appearance of suicidal symptoms (see section 5.1). In addition, long-term safety data in children

and adolescents concerning growth, maturation and cognitive and behavioural development are

lacking (see section 4.8).

Haemorrhage

There have been reports of bleeding abnormalities, such as ecchymoses, purpura and gastrointestinal

haemorrhage with selective serotonin reuptake inhibitors (SSRIs) and serotonin/noradrenaline

reuptake inhibitors (SNRIs), including duloxetine. Duloxetine may increase the risk of postpartum

haemorrhage (see section 4.6). Caution is advised in patients taking anticoagulants and/or medicinal

products known to affect platelet function (e.g. NSAIDs or acetylsalicylic acid (ASA)), and in patients

with known bleeding tendencies.

Hyponatraemia

Hyponatraemia has been reported when administering duloxetine, including cases with serum sodium

lower than110 mmol/l. Hyponatraemia may be due to a syndrome of inappropriate anti-diuretic

hormone secretion (SIADH). The majority of cases of hyponatraemia were reported in the elderly,

especially when coupled with a recent history of, or condition pre-disposing to, altered fluid balance.

Caution is required in patients at increased risk for hyponatraemia, such as elderly, cirrhotic, or

dehydrated patients or patients treated with diuretics.

Discontinuation of treatment

Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is

abrupt (see section 4.8). In clinical trials adverse events seen on abrupt treatment discontinuation

occurred in approximately 45% of patients treated with duloxetine and 23% of patients taking placebo.

The risk of withdrawal symptoms seen with SSRI’s and SNRI’s may be dependent on several factors

including the duration and dose of therapy and the rate of dose reduction. The most commonly

reported reactions are listed in section 4.8. Generally these symptoms are mild to moderate, however,

in some patients they may be severe in intensity. They usually occur within the first few days of

discontinuing treatment, but there have been very rare reports of such symptoms in patients who have

inadvertently missed a dose. Generally these symptoms are self-limiting and usually resolve within 2

weeks, though in some individuals they may be prolonged (2-3 months or more). It is therefore

advised that duloxetine should be gradually tapered when discontinuing treatment over a period of no

less than 2 weeks, according to the patient’s needs (see section 4.2).

Elderly

Data on the use of duloxetine 120mg in elderly patients with major depressive disorders and

generalised anxiety disorder are limited. Therefore, caution should be exercised when treating the

elderly with the maximum dosage (see sections 4.2 and 5.2).

Akathisia/psychomotor restlessness

The use of duloxetine has been associated with the development of akathisia, characterised by a

subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability

to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who

develop these symptoms, increasing the dose may be detrimental.

Medicinal products containing duloxetine

Duloxetine is used under different trademarks in several indications (treatment of diabetic neuropathic

pain, major depressive disorder, generalised anxiety disorder and stress urinary incontinence). The use

of more than one of these products concomitantly should be avoided.

Hepatitis/increased liver enzymes

Cases of liver injury, including severe elevations of liver enzymes (>10 times upper limit of normal),

hepatitis and jaundice have been reported with duloxetine (see section 4.8). Most of them occurred

during the first months of treatment. The pattern of liver damage was predominantly hepatocellular.

Duloxetine should be used with caution in patients treated with other medicinal products associated

with hepatic injury.

Sexual dysfunction

Serotonin norepinephrine reuptake inhibitors (SNRIs) may cause symptoms of sexual dysfunction (see

section 4.8). There have been reports of long-lasting sexual dysfunction where the symptoms have

continued despite discontinuation of SNRI.

Sucrose

Dulmis gastro-resistant capsules, hard contain sucrose. Patients with rare hereditary problems of

fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not

take this medicine.

Sodium

This medicine contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially

'sodium-free'.

4.5

Interaction with other medicinal products and other forms of interaction

Monoamine oxidase inhibitors (MAOIs):

Due to the risk of serotonin syndrome, duloxetine should not

be used in combination with non-selective irreversible monoamine oxidase inhibitors (MAOIs), or

within at least 14 days of discontinuing treatment with an MAOI. Based on the half-life of duloxetine,

at least 5 days should be allowed after stopping Dulmis before starting an MAOI (see section 4.3).

The concomitant use of Dulmis with selective, reversible MAOIs, like moclobemide, is not

recommended (see section 4.4). The antibiotic linezolid is a reversible non-selective MAOI and should

not be given to patients treated with Dulmis (see section 4.4).

Inhibitors of CYP1A2:

Because CYP1A2 is involved in duloxetine metabolism, concomitant use of

duloxetine with potent inhibitors of CYP1A2 is likely to result in higher concentrations of duloxetine.

Fluvoxamine (100 mg once daily), a potent inhibitor of CYP1A2, decreased the apparent plasma

clearance of duloxetine by about 77% and increased AUC

6-fold. Therefore Dulmis should not be

administered in combination with potent inhibitors of CYP1A2 like fluvoxamine (see section 4.3).

CNS medicinal products

: The risk of using duloxetine in combination with other CNS-active

medicinal products has not been systematically evaluated, except in the cases described in this section.

Consequently, caution is advised when Dulmis is taken in combination with other centrally acting

medicinal products or substances, including alcohol and sedative medicinal products (e.g.

benzodiazepines, morphinomimetics, antipsychotics, phenobarbital, sedative antihistamines).

Serotonergic agents:

In rare cases, serotonin syndrome has been reported in patients using

SSRIs/SNRIs concomitantly with serotonergic agents. Caution is advisable if Dulmis is used

concomitantly with serotonergic agents like SSRIs, SNRIs, tricyclic antidepressants like clomipramine

or amitriptyline, MAOIs like moclobemide or linezolid, St John’s wort (Hypericum perforatum) or

triptans, tramadol, pethidine and tryptophan (see section 4.4).

Effect of duloxetine on other medicinal products

Medicinal products metabolised by CYP1A2:

The pharmacokinetics of theophylline, a CYP1A2

substrate, were not significantly affected by co-administration with duloxetine (60 mg twice daily).

Medicinal products metabolised by CYP2D6:

Duloxetine is a moderate inhibitor of CYP2D6. When

duloxetine was administered at a dose of 60 mg twice daily with a single dose of desipramine, a

CYP2D6 substrate, the AUC of desipramine increased 3-fold. The co-administration of duloxetine (40

mg twice daily) increases steady state AUC of tolterodine (2 mg twice daily) by 71 %, but does not

affect the pharmacokinetics of its active 5-hydroxyl metabolite and no dosage adjustment is

recommended. Caution is advised if Dulmis is co-administered with medicinal products that are

predominantly metabolised by CYP2D6 (risperidone, tricyclic antidepressants [TCAs] such as

nortriptyline, amitriptyline, and imipramine) particularly if they have a narrow therapeutic index (such

as flecainide, propafenone and metoprolol).

Oral contraceptives and other steroidal agents:

Results of

in vitro

studies demonstrate that duloxetine

does not induce the catalytic activity of CYP3A. Specific

in vivo

drug interaction studies have not

been performed.

Anticoagulants and antiplatelet agents:

Caution should be exercised when duloxetine is combined

with oral anticoagulants or antiplatelet agents due to a potential increased risk of bleeding attributable

to a pharmacodynamic interaction. Furthermore, increases in INR values have been reported when

duloxetine was co-administered to patients treated with warfarin. However, concomitant

administration of duloxetine with warfarin under steady state conditions, in healthy volunteers, as part

of a clinical pharmacology study, did not result in a clinically significant change in INR from baseline

or in the pharmacokinetics of R- or S-warfarin.

Effects of other medicinal products on duloxetine

Antacids and H

2

antagonists:

Co-administration of duloxetine with aluminium- and magnesium-

containing antacids or duloxetine with famotidine had no significant effect on the rate or extent of

duloxetine absorption after administration of a 40 mg oral dose.

Inducers of CYP1A2:

Population pharmacokinetic analyses have shown that smokers have almost 50%

lower plasma concentrations of duloxetine compared with non-smokers.

4.6

Fertility, pregnancy and lactation

Fertility

In animal studies, duloxetine had no effect on male fertility, and effects in females were only evident

at doses that caused maternal toxicity.

Pregnancy

Studies in animals have shown reproductive toxicity at systemic exposure levels (AUC) of duloxetine

lower than the maximum clinical exposure (see section 5.3).

Two large observational studies do not suggest an overall increased risk of major congenital

malformation (one from the US including 2,500 exposed to duloxetine during the first trimester and

one from the EU including 1,500 exposed to duloxetine during the first trimester). The analysis on

specific malformations such as cardiac malformations shows inconclusive results.

In the EU study, maternal exposure to duloxetine during late pregnancy (at any time from 20 weeks

gestational age to delivery) was associated with an increased risk for preterm birth (less than 2-fold,

corresponding to approximately 6 additional premature births per 100 women treated with duloxetine

late in pregnancy). The majority occurred between 35 and 36 weeks of gestation. This association was

not seen in the US study.

The US observational data have provided evidence of an increased risk (less than 2-fold) of

postpartum haemorrhage following duloxetine exposure within the month prior to birth.

Epidemiological data have suggested that the use of SSRIs in pregnancy, particularly in late

pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN).

Although no studies have investigated the association of PPHN to SNRI treatment, this potential risk

cannot be ruled out with duloxetine taking into account the related mechanism of action (inhibition of

the re-uptake of serotonin).

As with other serotonergic medicinal products, discontinuation symptoms may occur in the neonate

after maternal duloxetine use near term. Discontinuation symptoms seen with duloxetine may include

hypotonia, tremor, jitteriness, feeding difficulty, respiratory distress and seizures. The majority of

cases have occurred either at birth or within a few days of birth.

Dulmis should be used in pregnancy only if the potential benefit justifies the potential risk to the

foetus. Women should be advised to notify their physician if they become pregnant, or intend to

become pregnant, during therapy.

Breast feeding

Duloxetine is very weakly excreted into human milk based on a study of 6 lactating patients, who did

not breast feed their children. The estimated daily infant dose on a mg/kg basis is approximately

0.14% of the maternal dose (see section 5.2). As the safety of duloxetine in infants is not known, the

use of Dulmis while breast-feeding is not recommended.

4.7

Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. Dulmis may

be associated with sedation and dizziness. Patients should be instructed that if they experience

sedation or dizziness they should avoid potentially hazardous tasks such as driving or operating

machinery.

4.8

Undesirable effects

a. Summary of the safety profile

The most commonly reported adverse reactions in patients treated with duloxetine were nausea,

headache, dry mouth, somnolence, and dizziness. However, the majority of common adverse reactions

were mild to moderate, they usually started early in therapy, and most tended to subside even as

therapy was continued.

b. Tabulated summary of adverse reactions

Table 1 gives the adverse reactions observed from spontaneous reporting and in placebo-controlled

clinical trials

Table 1: Adverse reactions

Frequency estimate: 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).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Very common

Common

Uncommon

Rare

Very Rare

Infections and infestations

Laryngitis

Immune system disorders

Anaphylactic

reaction

Hyper-sensitivity

disorder

Endocrine disorders

Very common

Common

Uncommon

Rare

Very Rare

Hypo-thyroidism

Metabolism and nutrition disorders

Decreased

appetite

Hyperglycaemia

(reported

especially in

diabetic patients)

Dehydration

Hyponatraemia

SIADH

Psychiatric disorders

Insomnia

Agitation

Libido decreased

Anxiety

Orgasm abnormal

Abnormal dreams

Suicidal

ideation

Sleep disorder

Bruxism

Disorientation

Apathy

Suicidal

behaviour

Mania

Hallucinations

Aggression and

anger

Nervous system disorders

Headache

Somnolence

Dizziness

Lethargy

Tremor

Paraesthesia

Myoclonus

Akathisia

Nervousness

Disturbance in

attention

Dysgeusia

Dyskinesia

Restless legs

syndrome

Poor quality sleep

Serotonin

syndrome

Convulsion

Psychomotor

restlessness

Extra-pyramidal

symptoms

Eye disorders

Blurred vision

Mydriasis

Visual impairment

Glaucoma

Ear and labyrinth disorders

Tinnitus

Vertigo

Ear pain

Cardiac disorders

Palpitations

Tachycardia

Supra-ventricular

arrhythmia,

mainly atrial

fibrillation

Vascular disorders

Blood pressure

increase

Flushing

Syncope

Hypertension

Orthostatic

hypotension

Peripheral

coldness

Hypertensive

crisis

Respiratory, thoracic and mediastinal disorders

Yawning

Throat tightness

Epistaxis

Interstitial lung

disease

Eosinophilic

pneumonia

Gastrointestinal disorders

Very common

Common

Uncommon

Rare

Very Rare

Nausea

Dry mouth

Constipation

Diarrhoea

Abdominal pain

Vomiting

Dyspepsia

Flatulence

Gastrointestinal

haemorrhage

Gastroenteritis

Eructation

Gastritis

Dysphagia

Stomatitis

Haematochezia

Breath odour

Microscopic

colitis

Hepato-biliary disorders

Hepatitis

Elevated liver

enzymes (ALT,

AST, alkaline

phosphatase)

Acute liver injury

Hepatic failure

Jaundice

Skin and subcutaneous tissue disorders

Sweating

increased

Rash

Night sweats

Urticaria

Dermatitis contact

Cold sweat

Photo-sensitivity

reactions

Increased

tendency to bruise

Stevens-Johnson

Syndrome

Angio-neurotic

oedema

Cutaneous

vasculitis

Musculoskeletal and connective tissue disorders

Musculo-skeletal

pain

Muscle spasm

Muscle tightness

Muscle twitching

Trismus

Renal and urinary disorders

Dysuria

Pollakiuria

Urinary retention

Urinary hesitation

Nocturia

Polyuria

Urine flow

decreased

Urine odour

abnormal

Reproductive system and breast disorders

Erectile

dysfunction

Ejaculation

disorder

Ejaculation

delayed

Gynaecological

haemorrhage

Menstrual

disorder

Sexual

dysfunction

Testicular pain

Menopausal

symptoms

Galactorrhoea

Hyperprolactinae

Postpartum

haemorrhage

General disorders and administration site conditions

Falls

Fatigue

Chest pain

Feeling abnormal

Feeling cold

Thirst

Chills

Malaise

Feeling hot

Gait disturbance

Investigations

Very common

Common

Uncommon

Rare

Very Rare

Weight decrease

Weight increase

Blood creatine

phosphokinase

increased

Blood potassium

increased

Blood cholesterol

increased

Cases of convulsion and cases of tinnitus have also been reported after treatment discontinuation.

Cases of orthostatic hypotension and syncope have been reported especially at the initiation of

treatment.

See section 4.4.

Cases of aggression and anger have been reported particularly early in treatment or after treatment

discontinuation.

Cases of suicidal ideation and suicidal behaviours have been reported during duloxetine therapy or

early after treatment discontinuation (see section 4.4).

Estimated frequency of post-marketing surveillance reported adverse reactions; not observed in

placebo-controlled clinical trials.

Not statistically significantly different from placebo.

Falls were more common in the elderly (

65 years old)

Estimated frequency based on all clinical trial data.

Estimated frequency based on placebo-controlled clinical trials

c. Description of selected adverse reactions

Discontinuation of duloxetine (particularly when abrupt) commonly leads to withdrawal symptoms.

Dizziness, sensory disturbances (including paraesthesia or electric shock-like sensations, particularly

in the head), sleep disturbances (including insomnia and intense dreams), fatigue, somnolence,

agitation or anxiety, nausea and/or vomiting, tremor, headache, myalgia, irritability, diarrhoea,

hyperhydrosis and vertigo are the most commonly reported reactions.

Generally, for SSRIs and SNRIs, these events are mild to moderate and self-limiting, however, in

some patients they may be severe and/or prolonged. It is therefore advised that when duloxetine

treatment is no longer required, gradual discontinuation by dose tapering should be carried out (see

sections 4.2 and 4.4).

In the 12 week acute phase of three clinical trials of duloxetine in patients with diabetic neuropathic

pain, small but statistically significant increases in fasting blood glucose were observed in duloxetine-

treated patients. HbA1c was stable in both duloxetine-treated and placebo-treated patients. In the

extension phase of these studies, which lasted up to 52 weeks, there was an increase in HbA1c in both

the duloxetine and routine care groups, but the mean increase was 0.3% greater in the duloxetine-

treated group. There was also a small increase in fasting blood glucose and in total cholesterol in

duloxetine-treated patients while those laboratory tests showed a slight decrease in the routine care

group.

The heart rate-corrected QT interval in duloxetine-treated patients did not differ from that seen in

placebo-treated patients. No clinically significant differences were observed for QT, PR, QRS, or

QTcB measurements between duloxetine-treated and placebo-treated patients.

d. Paediatric population

A total of 509 paediatric patients aged 7 to 17 years with major depressive disorder and 241 paediatric

patients aged 7 to 17 years with generalised anxiety disorder were treated with duloxetine in clinical

trials. In general, the adverse reaction profile of duloxetine in children and adolescents was similar to

that seen for adults.

A total of 467 paediatric patients initially randomized to duloxetine in clinical trials experienced a 0.1

kg mean decrease in weight at 10-weeks compared with a 0.9 kg mean increase in 353 placebo-treated

patients. Subsequently, over the four- to six-month extension period, patients on average trended

toward recovery to their expected baseline weight percentile based on population data from age- and

gender-matched peers.

In studies of up to 9 months an overall mean decrease of 1% in height percentile (decrease of 2% in

children (7-11 years) and increase of 0.3% in adolescents (12-17 years)) was observed in duloxetine-

treated paediatric patients (see section 4.4).

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

Cases of overdoses, alone or in combination with other medicinal products, with duloxetine doses of

5400 mg were reported. Some fatalities have occurred, primarily with mixed overdoses, but also with

duloxetine alone at a dose of approximately 1000 mg. Signs and symptoms of overdose (duloxetine

alone or in combination with other medicinal products) included somnolence, coma, serotonin

syndrome, seizures, vomiting and tachycardia.

No specific antidote is known for duloxetine but if serotonin syndrome ensues, specific treatment

(such as with cyproheptadine and/or temperature control) may be considered. A free airway should be

established. Monitoring of cardiac and vital signs is recommended, along with appropriate

symptomatic and supportive measures. Gastric lavage may be indicated if performed soon after

ingestion or in symptomatic patients. Activated charcoal may be useful in limiting absorption.

Duloxetine has a large volume of distribution and forced diuresis, haemoperfusion, and exchange

perfusion are unlikely to be beneficial.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Other antidepressants. ATC code: N06AX21.

Mechanism of action

Duloxetine is a combined serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor. It weakly

inhibits dopamine reuptake with no significant affinity for histaminergic, dopaminergic, cholinergic

and adrenergic receptors. Duloxetine dose-dependently increases extracellular levels of serotonin and

noradrenaline in various brain areas of animals.

Pharmacodynamic effects

Duloxetine normalised pain thresholds in several preclinical models of neuropathic and inflammatory

pain and attenuated pain behaviour in a model of persistent pain. The pain inhibitory action of

duloxetine is believed to be a result of potentiation of descending inhibitory pain pathways within the

central nervous system.

Clinical efficacy and safety

Major Depressive Disorder:

Duloxetine was studied in a clinical programme involving 3,158 patients

(1,285 patient-years of exposure) meeting DSM-IV criteria for major depression. The efficacy of

duloxetine at the recommended dose of 60 mg once a day was demonstrated in three out of three

randomised, double-blind, placebo-controlled, fixed dose acute studies in adult outpatients with major

depressive disorder. Overall, duloxetine’s efficacy has been demonstrated at daily doses between 60

and 120 mg in a total of five out of seven randomised, double-blind, placebo-controlled, fixed dose

acute studies in adult outpatients with major depressive disorder.

Duloxetine demonstrated statistical superiority over placebo as measured by improvement in the 17-

item Hamilton Depression Rating Scale (HAM-D) total score (including both the emotional and

somatic symptoms of depression). Response and remission rates were also statistically significantly

higher with duloxetine compared with placebo. Only a small proportion of patients included in pivotal

clinical trials had severe depression (baseline HAM-D>25).

In a relapse prevention study, patients responding to 12-weeks of acute treatment with open-label

duloxetine 60 mg once daily were randomised to either duloxetine 60 mg once daily or placebo for a

further 6-months. Duloxetine 60 mg once daily demonstrated a statistically significant superiority

compared to placebo (p=0.004) on the primary outcome measure, the prevention of depressive relapse,

as measured by time to relapse. The incidence of relapse during the 6-months double-blind follow-up

period was 17% and 29% for duloxetine and placebo, respectively.

During 52 weeks of placebo-controlled double blind treatment, duloxetine-treated patients with

recurrent MDD had a significantly longer symptom free period (p<0.001) compared with patients

randomised to placebo. All patients had previously responded to duloxetine during open-label

duloxetine treatment (28 to 34 weeks) at a dose of 60 to 120 mg/day. During the 52-week placebo-

controlled double blind treatment phase 14.4% of the duloxetine-treated patients and 33.1% of the

placebo-treated patients experience a return of their depressive symptoms (p<0.001).

The effect of duloxetine 60 mg once a day in elderly depressed patients (≥65 years) was specifically

examined in a study that showed a statistically significant difference in the reduction of the HAMD17

score for duloxetine-treated patients compared to placebo. Tolerability of duloxetine 60 mg once daily

in elderly patients was comparable to that seen in the younger adults. However, data on elderly

patients exposed to the maximum dose (120mg per day) are limited and thus, caution is recommended

when treating this population.

Generalised Anxiety Disorder:

Duloxetine demonstrated statistically significant superiority over

placebo in five out of five studies including four randomised, double-blind, placebo-controlled acute

studies and a relapse prevention study in adult patients with generalised anxiety disorder.

Duloxetine demonstrated statistically significant superiority over placebo as measured by

improvement in the Hamilton Anxiety Scale (HAM-A) total score and by the Sheehan Disability Scale

(SDS) global functional impairment score. Response and remission rates were also higher with

duloxetine compared to placebo. Duloxetine showed comparable efficacy results to venlafaxine in

terms of improvements on the HAM-A total score.

In a relapse prevention study, patients responding to 6 months of acute treatment with open-label

duloxetine were randomised to either duloxetine or placebo for a further 6-months. Duloxetine 60 mg

to 120 mg once daily demonstrated statistically significant superiority compared to placebo (p<0.001)

on the prevention of relapse, as measured by time to relapse. The incidence of relapse during the 6-

months double-blind follow-up period was 14% for duloxetine and 42% for placebo.

The efficacy of duloxetine 30-120 mg (flexible dosing) once a day in elderly patients (>65 years) with

generalised anxiety disorder was evaluated in a study that demonstrated statistically significant

improvement in the HAM-A total score for duloxetine treated patients compared to placebo treated

patients. The efficacy and safety of duloxetine 30-120 mg once daily in elderly patients with

generalised anxiety disorder was similar to that seen in studies of younger adult patients. However,

data on elderly patients exposed to the maximum dose (120 mg per day) are limited and, thus, caution

is recommended when using this dose with the elderly population.

Diabetic Peripheral Neuropathic Pain:

The efficacy of duloxetine as a treatment for diabetic

neuropathic pain was established in 2 randomised, 12-week, double-blind, placebo-controlled, fixed

dose studies in adults (22 to 88 years) having diabetic neuropathic pain for at least 6 months. Patients

meeting diagnostic criteria for major depressive disorder were excluded from these trials. The primary

outcome measure was the weekly mean of 24-hour average pain, which was collected in a daily diary

by patients on an 11-point Likert scale.

In both studies, duloxetine 60 mg once daily and 60 mg twice daily significantly reduced pain

compared with placebo. The effect in some patients was apparent in the first week of treatment. The

difference in mean improvement between the two active treatment arms was not significant. At least

30% reported pain reduction was recorded in approximately 65% of duloxetine treated patients versus

40% for placebo. The corresponding figures for at least 50% pain reduction were 50% and 26%

respectively. Clinical response rates (50% or greater improvement in pain) were analysed according to

whether or not the patient experienced somnolence during treatment. For patients not experiencing

somnolence, clinical response was observed in 47% of patients receiving duloxetine and 27% of

patients on placebo. Clinical response rates in patients experiencing somnolence were 60% on

duloxetine and 30% on placebo. Patients not demonstrating a pain reduction of 30% within 60 days of

treatment were unlikely to reach this level during further treatment.

In an open label long-term uncontrolled study, the pain reduction in patients responding to 8-weeks of

acute treatment of duloxetine 60 mg once daily was maintained for a further 6-months as measured by

change on the Brief Pain Inventory (BPI) 24-hour average pain item.

Paediatric population

Duloxetine has not been studied in patients under the age of 7. Two randomized, double-blind, parallel

clinical trials were performed in 800 paediatric patients aged 7 to 17 years with major depressive

disorder (see section 4.2). These two studies included a 10 week placebo and active (fluoxetine)

controlled acute phase followed by six months period of active controlled extension treatment. Neither

duloxetine (30-120 mg) nor the active control arm (fluoxetine 20-40 mg) statistically separated from

placebo on change from baseline to endpoint in the Children´s Depression Rating Scale-Revised

(CDRS-R) total score. Discontinuation due to adverse events was higher in patients taking duloxetine

compared with those treated with fluoxetine, mostly due to nausea. During the 10-week acute

treatment period, suicidal behaviours were reported (duloxetine 0/333 [0%], fluoxetine 2/225 [0.9%],

placebo 1/220 [0.5%]). Over the entire 36-week course of the study, 6 out of 333 patients initially

randomized to duloxetine and 3 out of 225 patients initially randomized to fluoxetine experienced

suicidal behaviour (exposure adjusted incidence 0.039 events per patient year for duloxetine, and

0.026 for fluoxetine). In addition, one patient who transitioned from placebo to duloxetine experienced

a suicidal behaviour while taking duloxetine.

A randomised, double-blind, placebo-controlled study was performed in 272 patients aged 7-17 years

with generalised anxiety disorder. The study included a 10 week placebo-controlled acute phase,

followed by an 18 week extension treatment period. A flexible dose regimen was used in this study, to

allow for slow dose escalation from 30 mg once daily to higher doses (maximum 120 mg once daily).

Treatment with duloxetine showed a statistically significantly greater improvement in GAD

symptoms, as measured by PARS severity score for GAD (mean difference between duloxetine and

placebo of 2.7 points [95% CI 1.3-4.0]), after 10 weeks of treatment. The maintenance of the effect

has not been evaluated. There was no statistically significant difference in discontinuation due to

adverse events between duloxetine and placebo groups during the 10 week acute treatment phase. Two

patients who transitioned from placebo to duloxetine after the acute phase experienced suicidal

behaviours while taking duloxetine during the extension phase. A conclusion on the overall

benefit/risk in this age group has not been established (see also sections 4.2 and 4.8).

The European Medicines Agency has waived the obligation to submit the results of studies with the

reference medicinal product containing duloxetine in all subsets of the paediatric population in the

treatment of major depressive disorder, diabetic neuropathic pain and generalised anxiety disorder. See

section 4.2 for information on paediatric use.

A single study has been performed in paediatric patients with juvenile primary fibromyalgia syndrome

(JPFS) in which the duloxetine-treated group did not separate from placebo group for the primary

efficacy measure. Therefore, there is no evidence of efficacy in this paediatric patient population. The

randomised, double-blind, placebo-controlled, parallel study of duloxetine was conducted in 184

adolescents aged 13 to 18 years (mean age 15.53 years) with JPFS. The study included a 13-week

double-blind period where patients were randomised to duloxetine 30 mg/60 mg, or placebo daily.

Duloxetine did not show efficacy in reducing pain as measured by primary outcome measure of Brief

Pain Inventory (BPI) average pain score endpoint: least squares (LS) mean change from baseline in

BPI average pain score at 13 weeks was -0.97 in the placebo group, compared with -1.62 in the

duloxetine 30/60 mg group (p = 0.052). The safety results from this study were consistent with the

known safety profile of duloxetine.

5.2

Pharmacokinetic properties

Duloxetine is administered as a single enantiomer. Duloxetine is extensively metabolised by oxidative

enzymes (CYP1A2 and the polymorphic CYP2D6), followed by conjugation. The pharmacokinetics

of duloxetine demonstrate large intersubject variability (generally 50-60%), partly due to gender, age,

smoking status and CYP2D6 metaboliser status.

Absorption:

Duloxetine is well absorbed after oral administration with a C

occurring 6 hours post

dose. The absolute oral bioavailability of duloxetine ranged from 32% to 80% (mean of 50%). Food

delays the time to reach the peak concentration from 6 to 10 hours and it marginally decreases the

extent of absorption (approximately 11 %). These changes do not have any clinical significance.

Distribution:

Duloxetine is approximately 96% bound to human plasma proteins. Duloxetine binds to

both albumin and alpha-l acid glycoprotein. Protein binding is not affected by renal or hepatic

impairment.

Biotransformation:

Duloxetine is extensively metabolised and the metabolites are excreted principally

in urine. Both cytochromes P450-2D6 and 1A2 catalyse the formation of the two major metabolites

glucuronide conjugate of 4-hydroxy duloxetine and sulphate conjugate of 5-hydroxy 6-methoxy

duloxetine. Based upon

in vitro

studies, the circulating metabolites of duloxetine are considered

pharmacologically inactive. The pharmacokinetics of duloxetine in patients who are poor metabolisers

with respect to CYP2D6 has not been specifically investigated. Limited data suggest that the plasma

levels of duloxetine are higher in these patients.

Elimination:

The elimination half-life of duloxetine ranges from 8 to 17 hours (mean of 12 hours).

After an intravenous dose the plasma clearance of duloxetine ranges from 22 l/hr to 46 l/hr (mean of

36 l/hr). After an oral dose the apparent plasma clearance of duloxetine ranges from 33 to 261 l/hr

(mean 101 l/hr).

Special populations

Gender:

Pharmacokinetic differences have been identified between males and females (apparent

plasma clearance is approximately 50% lower in females). Based upon the overlap in the range of

clearance, gender-based pharmacokinetic differences do not justify the recommendation for using a

lower dose for female patients.

Age:

Pharmacokinetic differences have been identified between younger and elderly females (≥65

years) (AUC increases by about 25% and half-life is about 25% longer in the elderly), although the

magnitude of these changes is not sufficient to justify adjustments to the dose. As a general

recommendation, caution should be exercised when treating the elderly (see sections 4.2 and 4.4).

Renal impairment:

End stage renal disease (ESRD) patients receiving dialysis had 2-fold higher

duloxetine C

and AUC values compared with healthy subjects. Pharmacokinetic data on duloxetine

is limited in patients with mild or moderate renal impairment.

Hepatic impairment:

Moderate liver disease (Child Pugh Class B) affected the pharmacokinetics of

duloxetine. Compared with healthy subjects, the apparent plasma clearance of duloxetine was 79%

lower, the apparent terminal half-life was 2.3 times longer, and the AUC was 3.7 times higher in

patients with moderate liver disease. The pharmacokinetics of duloxetine and its metabolites have not

been studied in patients with mild or severe hepatic insufficiency.

Breast-feeding mothers:

The disposition of duloxetine was studied in 6 lactating women who were at

least 12-weeks postpartum. Duloxetine is detected in breast milk, and steady-state concentrations in

breast milk are about one-fourth those in plasma. The amount of duloxetine in breast milk is

approximately 7 μg/day while on 40 mg twice daily dosing. Lactation did not influence duloxetine

pharmacokinetics.

Paediatric population:

Pharmacokinetics of duloxetine in paediatric patients aged 7 to 17 years with

major depressive disorder following oral administration of 20 to 120 mg once daily dosing regimen

was characterized using population modelling analyses based on data from 3 studies. The model-

predicted duloxetine steady state plasma concentrations in paediatric patients were mostly within the

concentration range observed in adult patients.

5.3

Preclinical safety data

Duloxetine was not genotoxic in a standard battery of tests and was not carcinogenic in rats.

Multinucleated cells were seen in the liver in the absence of other histopathological changes in the rat

carcinogenicity study. The underlying mechanism and the clinical relevance are unknown. Female

mice receiving duloxetine for 2 years had an increased incidence of hepatocellular adenomas and

carcinomas at the high dose only (144 mg/kg/day), but these were considered to be secondary to

hepatic microsomal enzyme induction. The relevance of this mouse data to humans is unknown.

Female rats receiving duloxetine (45 mg/kg/day) before and during mating and early pregnancy had a

decrease in maternal food consumption and body weight, oestrous cycle disruption, decreased live

birth indices and progeny survival, and progeny growth retardation at systemic exposure levels

estimated to be at the most at maximum clinical exposure (AUC). In an embryotoxicity study in the

rabbit, a higher incidence of cardiovascular and skeletal malformations was observed at systemic

exposure levels below the maximum clinical exposure (AUC). No malformations were observed in

another study testing a higher dose of a different salt of duloxetine. In prenatal/postnatal toxicity

studies in the rat, duloxetine induced adverse behavioural effects in the offspring at exposures below

maximum clinical exposure (AUC).

Studies in juvenile rats reveal transient effects on neurobehaviour, as well as significantly decreased

body weight and food consumption; hepatic enzyme induction; and hepatocellular vacuolation at 45

mg/kg/day. The general toxicity profile of duloxetine in juvenile rats was similar to that in adult rats.

The no-adverse effect level was determined to be 20 mg/kg/day.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Capsule content:

Hypromellose

Talc

Titanium dioxide

Methacrylic acid-ethyl acrylate copolymer

Sodium lauryl sulphate

Polysorbate 80

Triethyl citrate

Sugar spheres (maize starch and sucrose)

Sucrose

Capsule shell:

Dulmis 30 mg

Gelatin

Titanium dioxide (E171)

Indigo carmine (E132)

Printing ink (black iron oxide (E-172), potassium hydroxide and shellac)

Dulmis 60 mg

Gelatin

Titanium dioxide (E171)

Indigo carmine (E132)

Yellow iron oxide (E172)

Printing ink (black iron oxide (E-172), potassium hydroxide and shellac)

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

Blister Alu/Alu:

18 months

Blister PVC/PVDC-Alu:

30 months

Bottle: 2 years

6.4

Special precautions for storage

Dulmis 30 mg

Blister Alu/Alu:

This medicinal product does not require any special temperature storage conditions.

Store in the original package in order to protect from light.

Blister PVC/PVDC-Alu:

Store below 30ºC. Store in the original package in order to protect from light.

Bottle:

This medicinal product does not require any special temperature storage conditions. Keep the

bottle tightly closed in order to protect from light.

Dulmis 60 mg

Blister Alu/Alu:

This medicinal product does not require any special storage conditions.

Blister PVC/PVDC-Alu:

Store below 30ºC.

Bottle:

This medicinal product does not require any special storage conditions.

6.5

Nature and contents of container

- Aluminium / Aluminium blister foil.

- PVC/PVDC – Aluminium blister foil.

- White opaque polyethylene (PE) bottle, containing desiccant sachets, and a polypropylene (PP) cap

with a tamper evident ring closure.

Dulmis 30 mg gastro-resistant capsules, hard

Blister packs of 7, 10, 14, 20, 28, 30, 50, 56, 60, 84, 98 and 504 hard gastro-resistant capsules; and

bottle pack of 28 and 500 hard gastro-resistant capsules.

Dulmis 60 mg gastro-resistant capsules, hard

Blister packs of 7, 10, 14, 20, 28, 30, 50, 56, 60, 84, 98 and 504 hard gastro-resistant capsules; and

bottle pack of 28 and 500 hard gastro-resistant capsules.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

No special 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

2020-11-05

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