Topimax 15 mg Kapsel, hård

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

03-02-2021

Produktens egenskaper Produktens egenskaper (SPC)

22-11-2019

Aktiva substanser:
topiramat
Tillgänglig från:
2care4 ApS,
ATC-kod:
N03AX11
INN (International namn):
topiramate
Dos:
15 mg
Läkemedelsform:
Kapsel, hård
Sammansättning:
sockersfärer Hjälpämne; propylenglykol Hjälpämne; topiramat 15 mg Aktiv substans
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Burk, 60 (3 x 20) kapslar
Bemyndigande status:
Godkänd
Godkännandenummer:
56187
Tillstånd datum:
2017-11-22

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Bipacksedel: Information till användaren

Topimax 15 mg kapslar, hårda

topiramat

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 Topimax är och vad det används för

Vad du behöver veta innan du tar Topimax

Hur du tar Topimax

Eventuella biverkningar

Hur Topimax ska förvaras

Förpackningens innehåll och övriga upplysningar

1.

Vad Topimax är och vad det används för

Topimax tillhör en grupp av läkemedel som kallas antiepileptiska läkemedel. Det används:

ensamt för behandling av epileptiska anfall hos vuxna och barn över 6 års ålder

tillsammans med andra läkemedel för behandling av epileptiska anfall hos vuxna och barn 2 år

eller äldre

för att förebygga migränhuvudvärk hos vuxna.

Topiramat som finns i Topimax kan också vara godkänd för att behandla andra sjukdomar som inte

nämns i denna produktinformation. Fråga läkare, apoteks- eller annan hälso- och sjukvårdspersonal om

du har ytterligare frågor och följ alltid deras instruktion.

2.

Vad du behöver veta innan du tar Topimax

Ta inte Topimax:

om du är allergisk mot topiramat eller något annat innehållsämne i detta läkemedel (anges i

avsnitt 6)

förebyggande mot migrän: om du är gravid eller om du är en kvinna i fertil ålder såvida du inte

använder någon effektiv preventivmetod (se avsnitt ”Graviditet och amning” för ytterligare

information). Tala med din läkare om vilken preventivmetod som är bäst att använda medan du

tar Topimax.

Om du är osäker på om ovanstående gäller dig, tala med läkare eller apotekspersonal innan du

använder Topimax.

Varningar och försiktighet

Tala med läkare eller apotekspersonal innan du tar Topimax om du:

har njurproblem, särskilt njursten, eller får njurdialys

har haft avvikelser i blod eller kroppsvätskor (metabolisk acidos)

har leverproblem

har ögonproblem, särskilt glaukom

har tillväxtproblem

står på fettrik diet (ketogen diet)

tar Topimax för att behandla epilepsi och du är gravid eller en kvinna i fertil ålder (se avsnitt

”Graviditet och amning” för ytterligare information).

Om du är osäker på om något av ovanstående gäller dig, tala med läkare eller apotekspersonal innan du

använder Topimax.

Det är viktigt att du inte slutar att ta din medicin utan att först rådfråga din läkare.

Du ska också tala med din läkare innan du tar någon medicin innehållande topiramat, som ges till dig

som alternativ till Topimax.

Du kan gå ned i vikt om du använder Topimax, så din vikt bör kontrolleras regelbundet när du

använder denna medicin. Om du går ned för mycket vikt eller om ett barn som använder denna

medicin inte ökar tillräckligt i vikt, ska du rådfråga din läkare.

Ett litet antal personer som har behandlas med läkemedel mot epilepsi, såsom Topimax, har också haft

tankar på att skada sig själva eller begå självmord. Om du någon gång får dessa tankar, kontakta

omedelbart din läkare.

Topimax kan orsaka allvarliga hudreaktioner. Tala omedelbart om för läkare om du får hudutslag

och/eller blåsor (se även avsnitt 4 ”Eventuella biverkningar”).

Topimax kan i sällsynta fall orsaka höga halter av ammoniak i blodet (påvisas i blodprover). Detta kan

leda till förändrad hjärnfunktion, i synnerhet om du även tar ett läkemedel som heter valproinsyra eller

natriumvalproat. Eftersom detta kan vara ett allvarligt tillstånd ska du omedelbart tala om för läkare

om du får följande symtom (se även avsnitt 4 ”Eventuella biverkningar”):

- har svårigheter att tänka, komma ihåg information eller lösa problem

är mindre alert eller uppmärksam

känner dig mycket sömnig med låg energi.

Vid högre doser av Topimax kan risken öka för att utveckla dessa symtom.

Andra läkemedel och Topimax

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

läkemedel. Topimax och vissa andra läkemedel kan påverka varandra. Ibland behöver dosen av några

av dina läkemedel eller Topimax justeras.

Du ska särskilt informera läkare eller apotekspersonal om du tar:

andra läkemedel som ger försämrad eller nedsatt tankeförmåga, koncentration eller

muskelkoordination (t.ex. läkemedel med dämpande effekt på centrala nervsystemet såsom

muskelavslappnande och lugnande medel)

p-piller. Topimax kan göra dina p-piller mindre effektiva. Tala med din läkare om vilken

preventivmetod som är bäst att använda medan du tar Topimax.

Tala om för din läkare om dina menstruationsblödningar förändras under tiden du tar p-piller och

Topimax.

För lista över alla läkemedel som du tar. Visa denna lista för läkare och apotekspersonal innan du

börjar med ett nytt läkemedel.

Andra läkemedel som du bör diskutera med din läkare eller apotekspersonal innefattar övriga

läkemedel mot epilepsi, risperidon, litium, hydroklortiazid, metformin, pioglitazon, glibenklamid,

amitriptylin, propranolol, diltiazem, venlafaxin, flunarazin, Johannesört (

Hypericum perforatum

) (ett

(traditionellt) växtbaserat läkemedel som används för att behandla depression), blodförtunnande

warfarin.

Om du inte är säker på om något av ovanstående gäller dig, tala med läkare eller apotekspersonal innan

du använder Topimax.

Topimax med mat och dryck

Du kan ta Topimax med eller utan mat. Drick mycket vätska under dagen för att motverka njurstenar

när du tar Topimax. Du bör undvika att dricka alkohol under tiden du tar Topimax.

Graviditet och amning

Förebyggande av migrän:

Topimax kan skada ett ofött barn. Du får inte använda Topimax om du är gravid. Du får inte använda

Topimax förebyggande mot migrän om du är en kvinna i fertil ålder om du inte använder en effektiv

preventivmetod. Tala med din läkare om vilken preventivmetod som är bäst och om Topimax är

lämpligt för dig. Ett graviditetstest ska göras innan behandlingen med Topimax påbörjas.

Behandling av epilepsi:

Om du är en kvinna i fertil ålder ska du tala med din läkare om andra behandlingsalternativ istället för

Topimax. Om beslutet är att använda Topimax ska du använda en effektiv preventivmetod. Tala med

din läkare om vilken preventivmetod som är bäst när du tar Topimax. Ett graviditetstest ska göras

innan behandlingen med Topimax påbörjas.

Tala med din läkare om du planerar att bli gravid.

Som för andra läkemedel mot epilepsi finns det risk för att det ofödda barnet skadas om Topimax

används under graviditet. Se till att du helt förstår riskerna och fördelarna med att använda Topimax

mot epilepsi under graviditet.

Om du tar Topimax under graviditeten löper barnet en högre risk för medfödda missbildningar, i

synnerhet läpp- och gomspalt. Nyfödda pojkar kan också få en missbildad penis (hypospadi).

Dessa missbildningar kan utvecklas tidigt under graviditeten, redan innan du vet om att du är

gravid.

Om du tar Topimax under graviditeten kan ditt barn vara mindre än förväntat vid födseln. Tala

med läkaren om du har några frågor om den här risken under graviditeten.

För ditt tillstånd kan det finnas andra läkemedelsbehandlingar som har en lägre risk för

missbildningar.

Tala genast om för din läkare om du blir gravid medan du tar Topimax. Du och läkaren avgör

om du ska fortsätta ta Topimax under graviditeten.

Amning

Den aktiva substansen i Topimax (topiramat) utsöndras i bröstmjölk hos människa. Påverkan hos

ammade spädbarn till behandlade mödrar har observerats och omfattar diarré, sömnighet, irritation och

dålig viktökning. Därför kommer din läkare att diskutera med dig om du ska avstå från amning eller

avstå från behandling med Topimax. Läkaren kommer att ta hänsyn till läkemedlets betydelse för

modern och risken för barnet.

Mödrar som ammar under tiden de tar Topimax måste informera läkaren så snart som möjligt om

barnet drabbas av något ovanligt.

Körförmåga och användning av maskiner

Yrsel, trötthet och synproblem kan förekomma under behandling med Topimax. Kör inte och använd

inte några verktyg eller maskiner utan att tala med din läkare först.

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.

Topimax innehåller sackaros

Om du inte tål vissa sockerarter bör du kontakta din läkare innan du tar detta läkemedel.

3.

Hur du tar Topimax

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

osäker.

Din läkare låter dig vanligtvis börja med en låg dos av Topimax och sakta öka dosen tills du har

hittat den bästa dosen för dig.

Topimax hårda kapslar kan sväljas hela eller öppnas och innehållet strös över en tesked med

mjuk mat av något slag. Exempel är äppelmos, kräm, glass, gröt, pudding eller yoghurt. Drick

vätska direkt efter, så att hela blandningen av mat och läkemedel med säkerhet sväljs ned.

Håll den hårda kapseln upprätt så att du kan läsa ordet ”TOP”.

Vrid försiktigt av den genomskinliga delen av kapseln. Det kan vara bra att göra detta över den

lilla portion mat som du ska strö kornen över.

Strö hela innehållet i kapseln över en sked med mjuk mat, och se till så att hela den ordinerade

dosen strös över maten.

Se till att hela blandningen av läkemedel och mat som finns i skeden sväljs omedelbart. Undvik

att tugga. Drick vätska omedelbart, så att hela blandningen med säkerhet sväljs ned.

Spara aldrig någon blandning av läkemedel och mat för senare användning.

Topimax kan tas före, under eller efter en måltid. Drick mycket vätska under dagen för att

förebygga att det bildas njurstenar när du tar Topimax.

Om du har tagit för stor mängd av Topimax

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

Uppsök omedelbart läkare. Ta läkemedelsförpackningen med dig.

Du kan känna dig sömnig, trött eller mindre alert, sakna koordination, få tal- och

koncentrationssvårigheter, få dubbelseende eller dimsyn, känna dig yr på grund av lågt

blodtryck, känna dig nedstämd eller upprörd eller få magsmärtor eller krampanfall.

Överdosering kan ske om du tar andra läkemedel tillsammans med Topimax.

Om du har glömt att ta Topimax

Om du glömmer att ta en dos, ta den så snart du kommer ihåg det. Om det snart är tid för nästa

dos, hoppa över den missade dosen och fortsätt som vanligt. Om du missar två eller flera doser,

kontakta din läkare.

Ta inte dubbel dos (två doser på samma gång) för att kompensera för glömd dos.

Om du slutar att ta Topimax

Sluta inte att ta detta läkemedel om inte läkaren har sagt att du ska göra det. Dina symtom kan komma

tillbaka. Om din läkare beslutar att avbryta behandlingen med detta läkemedel, kan dosen gradvis

minskas under några dagar.

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.

Tala om för din läkare eller uppsök omedelbart läkare om du får följande biverkningar:

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

Depression (ny eller försämrad).

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

Krampanfall.

Ångest, irritabilitet, humörförändringar, förvirring, desorientering.

Koncentrationsproblem, nedsatt tankeförmåga, minnesförlust, problem med minnet (ny, plötslig

förändring eller ökad allvarlighetsgrad).

Njursten, täta eller smärtsamma urineringar.

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

Ökad surhetsgrad i blodet (kan orsaka orolig andning inklusive andnöd, aptitlöshet, illamående,

kräkningar, överdriven trötthet och snabba eller ojämna hjärtslag).

Minskad eller förlorad förmåga att svettas (framför allt hos små barn som utsätts för höga

temperaturer).

Ha tankar på allvarlig självskada, försök att orsaka allvarlig självskada.

Förlust av en del av synfältet.

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

Glaukom som är en blockering av vätska i ögat och ger ökat tryck i ögat, smärta eller nedsatt

syn.

Ha svårigheter att tänka, komma ihåg information eller lösa problem, vara mindre alert eller

uppmärksam, känna sig väldigt sömnig med låg energi – dessa symtom kan vara ett tecken på

höga halter av ammoniak i blodet (hyperammonemi) som kan leda till förändrad hjärnfunktion

(hyperammonemisk encefalopati).

Allvarliga hudreaktioner såsom Stevens-Johnsons syndrom eller toxisk epidermal nekrolys –

dessa kan framträda som utslag med eller utan blåsor. Hudirritation, sår eller svullnad i mun,

hals, näsa, ögon och runt genitalierna. Hudutslagen kan utvecklas till allvarlig utbredd hudskada

(hudavlossning av de yttre hudlagren och ytliga slemhinnor) med livshotande följder.

Har rapporterats (förekommer hos ett okänt antal användare):

Ögoninflammation (uveit) med symtom såsom rodnad i ögat, smärta, känslighet för ljus, rinnande

ögon, små prickar i synfältet eller dimsyn.

Andra biverkningar inkluderar följande. Om de blir värre ska du kontakta läkare eller

apotekspersonal:

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

Täppt, rinnande näsa eller halsont.

Stickningar, smärta och/eller domningar i olika kroppsdelar.

Sömnighet, trötthet.

Yrsel.

Illamående, diarré.

Viktförlust.

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

Anemi (lågt blodvärde).

Allergiska reaktioner (som hudutslag, rodnad, klåda, ansiktssvullnad, nässelfeber).

Aptitlöshet, minskad aptit.

Aggression, upphetsning, ilska, onormalt beteende.

Svårigheter att somna eller att sova.

Problem med tal eller talsvårigheter, sluddrigt tal.

Klumpighet eller bristande koordination, känsla av ostadig gång.

Minskad förmåga att slutföra rutinuppgifter.

Minskad, förlust av, eller obefintligt smaksinne.

Ofrivilliga darrningar eller skakningar, snabba okontrollerade ögonrörelser.

Synstörningar som dubbelseende, dimsyn, försämrad synskärpa, svårighet att fokusera.

Känsla av yrsel (vertigo), ringningar i öronen, ont i öronen.

Andnöd.

Hosta.

Näsblod.

Feber, känsla att inte vara kry, svaghet.

Kräkningar, förstoppning, buksmärta eller obehag, matsmältningsbesvär, mag- eller

tarminfektion.

Muntorrhet.

Håravfall.

Klåda.

Ledsmärta eller svullnad, muskelkramper eller muskelryckningar, muskelvärk eller svaghet,

bröstsmärta.

Viktökning.

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

Minskat antal blodplättar (blodkroppar som hjälper till att stoppa blödning), minskat antal vita

blodkroppar som hjälper till att skydda dig mot infektion, minskat kalium i blodet.

Ökade leverenzymer, ökade eosinofiler (en typ av vita blodkroppar) i blodet.

Svullna körtlar i halsen, armhålan eller ljumsken.

Ökad aptit.

Förhöjt humör.

Att höra, se eller känna saker som inte finns, allvarlig psykisk störning (psykos).

Inte visa och/eller känna känslor, ovanlig misstänksamhet, panikattack.

Läs-, tal- och skrivsvårigheter.

Rastlöshet, överaktivitet.

Svårighet att tänka, minskad vakenhet eller uppmärksamhet.

Minskade eller långsamma kroppsrörelser, ofrivilliga onormala eller upprepade muskelrörelser.

Svimning.

Onormal eller nedsatt känsel.

Försämrat, förvrängt eller inget luktsinne.

Ovanlig känsla eller känsla som kan föregå migrän eller en viss typ av anfall.

Torra ögon, ljuskänslighet, ofrivilliga ögonlocksryckningar, rinnande ögon.

Nedsatt eller förlorad hörsel, förlorad hörsel på ena örat.

Långsam eller oregelbunden hjärtrytm, känsla att hjärtat slår i bröstet.

Lågt blodtryck vid stående (därför kan vissa personer som tar Topimax känna sig svaga, yra

eller kan svimma när de står upp eller plötslig sätter sig upp).

Rodnad, värmekänsla.

Pankreatit (inflammation i bukspottkörteln).

Gaser, halsbränna, mättnad eller uppsvälldhet.

Blödande tandkött, ökad salivutsöndring, dreglande, dålig andedräkt.

Intag av onormalt stora mängder vätska, ökad törst.

Missfärgad hud.

Muskelstelhet, smärta i sidan.

Blod i urinen, inkontinens (brist på kontroll) av urin, brådskande önskan att urinera, smärta i

sidan eller njursmärta.

Svårighet att få eller hålla erektion, sexuell dysfunktion.

Influensaliknande symtom

Kalla fingrar och tår.

Berusningskänsla.

Inlärningsproblem.

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

Onormalt förhöjt humör.

Medvetslöshet.

Blindhet på ett öga, tillfällig blindhet, nattblindhet.

Synsvaghet.

Svullnad i och runt ögonen.

Domningar, stickningar och färgförändringar (vit, blå och sedan röd) i fingrar och tår när man

utsätts för kyla.

Leverinflammation, leversvikt.

Onormal lukt i huden.

Obehag i armar eller ben.

Njursjukdom.

Har rapporterats (förekommer hos ett okänt antal användare):

Makulopati är en sjukdom i gula fläcken, den lilla fläcken på näthinnan där synen är skarpast.

Du ska uppsöka läkare om du märker en förändring eller försämring av synen.

Barn

Biverkningarna hos barn liknar i allmänhet dem som setts hos vuxna, men följande biverkningar kan

vara vanligare hos barn än hos vuxna:

Koncentrationsproblem.

Ökad surhetsgrad i blodet.

Ha tankar på allvarligt självskadande.

Trötthet.

Minskad eller ökad aptit.

Aggression, onormalt beteende.

Svårigheter att somna eller att sova.

Känsla av ostadig gång.

Känsla av att inte må bra.

Minskat kalium i blodet.

Inte visa och/eller känna känslor.

Rinnande ögon.

Långsamma eller oregelbundna hjärtslag.

Andra biverkningar som kan uppträda hos barn är:

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

Yrsel.

Kräkningar.

Feber.

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

Ökade eosinofiler (en typ av vita blodkroppar) i blodet.

Överaktivitet.

Värmekänsla.

Inlärningsproblem.

Rapportering av biverkningar

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

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

Webbplats: www.lakemedelsverket.se

5.

Hur Topimax ska förvaras

Förvara detta läkemedel utom syn och räckhåll för barn.

Används före utgångsdatum som anges på burken/kartongen efter Utg.dat.. Utgångsdatumet är den

sista dagen i angiven månad.

Förvaras vid högst 25

C. Tillslut burken väl. Fuktkänsligt.

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 topiramat.

-

Varje Topimax hård kapsel innehåller 15 mg topiramat.

-

Övriga innehållsämnen är:

-

sockersfärer (majsstärkelse, sackaros), povidon, cellulosaacetat

-

kapsel: gelatin, titandioxid (E171)

-

tryckfärg: svart bläck (järnoxid svart (E172), shellack och propylenglykol).

Läkemedlets utseende och förpackningsstorlekar

15 mg kapslar: Små vita/benvita korn i hårda gelatinkapslar med vit ogenomskinlig

underdel märkt

’15 mg’ och genomskinlig

överdel märkt ’TOP’.

Ogenomskinlig plastburk av HDPE med förseglat lock innehållande 60 (3x20) kapslar med granulat.

Importör/Ompackare:

2care4 ApS, 6710 Esbjerg V, Danmark, Tel. 08 - 68 40 98 40

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1.

NAME OF THE MEDICINAL PRODUCT

Topimax 15 mg capsules, hard

Topimax 25 mg capsules, hard

Topimax 50 mg capsules, hard

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

One capsule contains 15 mg of topiramate.

One capsule contains 25 mg of topiramate.

One capsule contains 50 mg of topiramate.

Excipients with known effect:

Also includes sugar spheres containing not less than 62.5% and not more than 91.5% of sucrose:

One 15 mg capsule contains between 28.1 and 41.2 mg sucrose

One 25 mg capsule contains between 46.8 and 68.6 mg sucrose

One 50 mg capsule contains between 93.7 and 137.2 mg sucrose

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Hard capsule.

15 mg: Small white to off-white spheres in Size 2 hard gelatin capsules with white opaque body

marked '15 mg’ and clear cap marked 'TOP'.

25 mg: Small white to off-white spheres in Size 1 hard gelatin capsules with white opaque body

marked '25 mg’ and clear cap marked 'TOP'.

50 mg: Small white to off-white spheres in Size 0 hard gelatin capsules with white opaque body

marked '50 mg’ and clear cap marked 'TOP'.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Monotherapy in adults, adolescents and children over 6 years of age with partial seizures with or

without secondary generalised seizures, and primary generalised tonic-clonic seizures.

Adjunctive therapy in children aged 2 years and above, adolescents and adults with partial onset

seizures with or without secondary generalization or primary generalized tonic-clonic seizures and for

the treatment of seizures associated with Lennox-Gastaut syndrome.

Topiramate is indicated in adults for the prophylaxis of migraine headache after careful evaluation of

possible alternative treatment options. Topiramate is not intended for acute treatment.

4.2

Posology and method of administration

Posology

It is recommended that therapy be initiated at a low dose followed by titration to an effective dose.

Dose and titration rate should be guided by clinical response.

It is not necessary to monitor topiramate plasma concentrations to optimize therapy with Topimax. On

rare occasions, the addition of topiramate to phenytoin may require an adjustment of the dose of

phenytoin to achieve optimal clinical outcome. Addition or withdrawal of phenytoin and

carbamazepine to adjunctive therapy with Topimax may require adjustment of the dose of Topimax.

In patients with or without a history of seizures or epilepsy, antiepileptic drugs (AEDs) including

topiramate should be gradually withdrawn to minimize the potential for seizures or increased seizure

frequency. In clinical trials, daily dosages were decreased in weekly intervals by 50-100 mg in adults

with epilepsy and by 25-50 mg in adults receiving topiramate at doses up to 100 mg/day for migraine

prophylaxis. In paediatric clinical trials, topiramate was gradually withdrawn over a 2-8 week period.

Monotherapy epilepsy

General

When concomitant AEDs are withdrawn to achieve monotherapy with topiramate, consideration

should be given to the effects this may have on seizure control. Unless safety concerns require an

abrupt withdrawal of the concomitant AED, a gradual discontinuation at the rate of approximately

one-third of the concomitant AED dose every 2 weeks is recommended.

When enzyme inducing medicinal products are withdrawn, topiramate levels will increase. A decrease

in Topimax (topiramate) dosage may be required if clinically indicated.

Adults

Dose and titration should be guided by clinical response. Titration should begin at 25 mg nightly for

1 week. The dosage should then be increased at 1- or 2-week intervals by increments of 25 or

50 mg/day, administered in two divided doses. If the patient is unable to tolerate the titration regimen,

smaller increments or longer intervals between increments can be used.

The recommended initial target dose for topiramate monotherapy in adults is 100 mg/day to

200 mg/day in 2 divided doses. The maximum recommended daily dose is 500 mg/day in 2 divided

doses. Some patients with refractory forms of epilepsy have tolerated topiramate monotherapy at

doses of 1,000 mg/day. These dosing recommendations apply to all adults including the elderly in the

absence of underlying renal disease.

Paediatric population (children over 6 years of age)

Dose and titration rate in children should be guided by clinical outcome. Treatment of children over

6 years of age should begin at 0.5 to 1 mg/kg nightly for the first week. The dosage should then be

increased at 1 or 2 week intervals by increments of 0.5 to 1 mg/kg/day, administered in two divided

doses. If the child is unable to tolerate the titration regimen, smaller increments or longer intervals

between dose increments can be used.

The recommended initial target dose range for topiramate monotherapy in children over 6 years of age

is 100 mg/day depending on clinical response, (this is about 2.0 mg/kg/day in children 6-16 years).

Adjunctive therapy epilepsy (partial onset seizures with or without secondary generalization, primary

generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome)

Adults

Therapy should begin at 25-50 mg nightly for one week. Use of lower initial doses has been reported,

but has not been studied systematically. Subsequently, at weekly or bi-weekly intervals, the dose

should be increased by 25-50 mg/day and taken in two divided doses. Some patients may achieve

efficacy with once-a-day dosing.

In clinical trials as adjunctive therapy, 200 mg was the lowest effective dose. The usual daily dose is

200-400 mg in two divided doses.

These dosing recommendations apply to all adults, including the elderly, in the absence of underlying

renal disease (see section 4.4).

Paediatric population (children aged 2 years and above)

The recommended total daily dose of Topimax (topiramate) as adjunctive therapy is approximately 5

to 9 mg/kg/day in two divided doses. Titration should begin at 25 mg (or less, based on a range of 1 to

3 mg/kg/day) nightly for the first week. The dosage should then be increased at 1- or 2-week intervals

by increments of 1 to 3 mg/kg/day (administered in two divided doses), to achieve optimal clinical

response.

Daily doses up to 30 mg/kg/day have been studied and were generally well tolerated.

Migraine

Adults

The recommended total daily dose of topiramate for prophylaxis of migraine headache is 100 mg/day

administered in two divided doses. Titration should begin at 25 mg nightly for 1 week. The dosage

should then be increased in increments of 25 mg/day administered at 1-week intervals. If the patient is

unable to tolerate the titration regimen, longer intervals between dose adjustments can be used.

Some patients may experience a benefit at a total daily dose of 50 mg/day. Patients have received a

total daily dose up to 200 mg/day. This dose may be benefit in some patients, nevertheless, caution is

advised due to an increase incidence of side effects.

Paediatric population

Topimax (topiramate) is not recommended for treatment or prevention of migraine in children due to

insufficient data on safety and efficacy.

General dosing recommendations for Topimax in special patient populations

Renal impairment

In patients with impaired renal function (CL

≤ 70 mL/min) topiramate should be administered with

caution as the plasma and renal clearance of topiramate are decreased. Subjects with known renal

impairment may require a longer time to reach steady-state at each dose. Half of the usual starting and

maintenance dose is recommended (see section 5.2).

In patients with end-stage renal failure, since topiramate is removed from plasma by haemodialysis, a

supplemental dose of Topimax equal to approximately one-half the daily dose should be administered

on haemodialysis days. The supplemental dose should be administered in divided doses at the

beginning and completion of the haemodialysis procedure. The supplemental dose may differ based

on the characteristics of the dialysis equipment being used (see section 5.2).

Hepatic impairment

In patients with moderate to severe hepatic impairment topiramate should be administered with

caution as the clearance of topiramate is decreased.

Elderly

No dose adjustment is required in the elderly population providing renal function is intact.

Method of administration

Topimax is available in film-coated tablets and a hard capsule formulation, for oral administration. It

is recommended that film-coated tablets not be broken. The hard capsule formulation is provided for

those patients who cannot swallow tablets, e.g. paediatric and the elderly.

Topimax hard capsules may be swallowed whole or may be administered by carefully opening the

capsule and sprinkling the entire contents on a small amount (teaspoon) of soft food. This medicinal

product/food mixture is to be swallowed immediately and not chewed. It must not be stored for future

use.

Topimax can be taken without regard to meals.

4.3

Contraindications

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

Migraine prophylaxis in pregnancy and in women of childbearing potential if not using a highly

effective method of contraception.

4.4

Special warnings and precautions for use

In situations where rapid withdrawal of topiramate is medically required, appropriate monitoring is

recommended (see section 4.2).

As with other AEDs, some patients may experience an increase in seizure frequency or the onset of

new types of seizures with topiramate. These phenomena may be the consequence of an overdose, a

decrease in plasma concentrations of concomitantly used AEDs, progress of the disease, or a

paradoxical effect.

Adequate hydration while using topiramate is very important. Hydration can reduce the risk of

nephrolithiasis (see below). Proper hydration prior to and during activities such as exercise or

exposure to warm temperatures may reduce the risk of heat-related adverse reactions (see section 4.8).

Women of childbearing potential

Topiramate may cause fetal harm and fetal growth restriction (small for gestational age and low birth

weight) when administered to a pregnant woman. The North American Antiepileptic Drug pregnancy

registry data for topiramate monotherapy showed an approximate 3-fold higher prevalence of major

congenital malformations (4.3%), compared with a reference group not taking AEDs (1.4%). In

addition, data from other studies indicate that, compared with monotherapy, there is an increased risk

of teratogenic effects associated with the use of AEDs in combination therapy.

Before the initiation of treatment with topiramate in a woman of childbearing potential, pregnancy

testing should be performed and a highly effective contraceptive method advised (see section 4.5).

The patient should be fully informed of the risks related to the use of topiramate during pregnancy

(see sections 4.3 and 4.6).

Oligohydrosis

Oligohydrosis (decreased sweating) has been reported in association with the use of topiramate.

Decreased sweating and hyperthermia (rise in body temperature) may occur especially in young

children exposed to high ambient temperature.

Mood disturbances/depression

An increased incidence of mood disturbances and depression has been observed during topiramate

treatment.

Suicide/suicide ideation

Suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents in

several indications. A meta-analysis of randomised placebo-controlled trials of AEDs has shown a

small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and

the available data do not exclude the possibility of an increased risk for topiramate.

In double blind clinical trials, suicide related events (SREs) (suicidal ideation, suicide attempts and

suicide) occurred at a frequency of 0.5% in topiramate treated patients (46 out of 8,652 patients

treated) and at a nearly 3-fold higher incidence than those treated with placebo (0.2%; 8 out of

4,045 patients treated).

Patients therefore should be monitored for signs of suicidal ideation and behaviour and appropriate

treatment should be considered. Patients (and caregivers of patients) should be advised to seek

medical advice should signs of suicidal ideation or behaviour emerge.

Serious skin reactions

Serious skin reactions (Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN))

have been reported in patients receiving topiramate (see section 4.8). It is recommended that patients

be informed about the signs of serious skin reactions. If SJS or TEN are suspected, use of Topimax

should be discontinued.

Nephrolithiasis

Some patients, especially those with a predisposition to nephrolithiasis, may be at increased risk for

renal stone formation and associated signs and symptoms such as renal colic, renal pain or flank pain.

Risk factors for nephrolithiasis include prior stone formation, a family history of nephrolithiasis and

hypercalciuria (see below – Metabolic acidosis). None of these risk factors can reliably predict stone

formation during topiramate treatment. In addition, patients taking other medicinal products

associated with nephrolithiasis may be at increased risk.

Decreased renal function

In patients with impaired renal function (CL

≤ 70 mL/min) topiramate should be administered with

caution as the plasma and renal clearance of topiramate are decreased. For specific posology

recommendations in patients with decreased renal function, see section 4.2.

Decreased hepatic function

In hepatically-impaired patients, topiramate should be administered with caution as the clearance of

topiramate may be decreased.

Acute myopia and secondary angle closure glaucoma

A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been

reported in patients receiving topiramate. Symptoms include acute onset of decreased visual acuity

and/or ocular pain. Ophthalmologic findings can include myopia, anterior chamber shallowing, ocular

hyperaemia (redness) and increased intraocular pressure. Mydriasis may or may not be present. This

syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens

and iris, with secondary angle closure glaucoma. Symptoms typically occur within 1 month of

initiating topiramate therapy. In contrast to primary narrow angle glaucoma, which is rare under

40 years of age, secondary angle closure glaucoma associated with topiramate has been reported in

paediatric patients as well as adults. Treatment includes discontinuation of topiramate, as rapidly as

possible in the judgment of the treating physician, and appropriate measures to reduce intraocular

pressure. These measures generally result in a decrease in intraocular pressure.

Elevated intraocular pressure of any aetiology, if left untreated, can lead to serious sequelae including

permanent vision loss.

A determination should be made whether patients with history of eye disorders should be treated with

topiramate.

Visual field defects

Visual field defects have been reported in patients receiving topiramate independent of elevated

intraocular pressure. In clinical trials, most of these events were reversible after topiramate

discontinuation. If visual field defects occur at any time during topiramate treatment, consideration

should be given to discontinuing the drug.

Metabolic acidosis

Hyperchloremic, non-anion gap, metabolic acidosis (i.e. decreased serum bicarbonate below the

normal reference range in the absence of respiratory alkalosis) is associated with topiramate

treatment. This decrease in serum bicarbonate is due to the inhibitory effect of topiramate on renal

carbonic anhydrase. Generally, the decrease in bicarbonate occurs early in treatment although it can

occur at any time during treatment. These decreases are usually mild to moderate (average decrease of

4 mmol/l at doses of 100 mg/day or above in adults and at approximately 6 mg/kg/day in paediatric

patients). Rarely, patients have experienced decreases to values below 10 mmol/l. Conditions or

therapies that predispose to acidosis (such as renal disease, severe respiratory disorders, status

epilepticus, diarrhoea, surgery, ketogenic diet, or certain medicinal products) may be additive to the

bicarbonate lowering effects of topiramate.

Chronic, untreated metabolic acidosis increases the risk of nephrolithiasis and nephrocalcinosis, and

may potentially lead to osteopenia (see above - Nephrolithiasis).

Chronic metabolic acidosis in paediatric patients can reduce growth rates. The effect of topiramate on

bone-related sequelae has not been systematically investigated in paediatric or adult populations.

Depending on underlying conditions, appropriate evaluation including serum bicarbonate levels is

recommended with topiramate therapy. If signs or symptoms are present (e.g. Kussmaul’s deep

breathing, dyspnoea, anorexia, nausea, vomiting, excessive tiredness, tachycardia or arrhythmia),

indicative of metabolic acidosis, measurement of serum bicarbonate is recommended. If metabolic

acidosis develops and persists, consideration should be given to reducing the dose or discontinuing

topiramate (using dose tapering).

Topiramate should be used with caution in patients with conditions or treatments that represent a risk

factor for the appearance of metabolic acidosis.

Impairment of cognitive function

Cognitive impairment in epilepsy is multifactorial and may be due to the underlying aetiology, due to

the epilepsy or due to the antiepileptic treatment. There have been reports in the literature of

impairment of cognitive function in adults on topiramate therapy which required reduction in dosage

or discontinuation of treatment. However, studies regarding cognitive outcomes in children treated

with topiramate are insufficient and its effect in this regard still needs to be elucidated.

Hyperammonemia and encephalopathy

Hyperammonemia with or without encephalopathy has been reported with topiramate treatment (see

section 4.8). The risk for hyperammonemia with topiramate appears dose-related. Hyperammonemia

has been reported more frequently when topiramate is used concomitantly with valproic acid (see

section 4.5).

In patients who develop unexplained lethargy, or changes in mental status associated with topiramate

monotherapy or adjunctive therapy, it is recommended to consider hyperammonemic encephalopathy

and measuring ammonia levels.

Nutritional supplementation

Some patients may experience weight loss whilst on treatment with topiramate. It is recommended

that patients on topiramate treatment should be monitored for weight loss. A dietary supplement or

increased food intake may be considered if the patient is losing weight while on topiramate.

Sucrose intolerance

This medicinal product contains sucrose. Patients with rare hereditary problems of fructose

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

medicine.

4.5

Interaction with other medicinal products and other forms of interaction

Effects of Topimax on other antiepileptic medicinal products

The addition of Topimax to other AEDs (phenytoin, carbamazepine, valproic acid, phenobarbital,

primidone) has no effect on their steady-state plasma concentrations, except in the occasional patient,

where the addition of Topimax to phenytoin may result in an increase of plasma concentrations of

phenytoin. This is possibly due to inhibition of a specific enzyme polymorphic isoform (CYP2C19).

Consequently, any patient on phenytoin showing clinical signs or symptoms of toxicity should have

phenytoin levels monitored.

A pharmacokinetic interaction study of patients with epilepsy indicated the addition of topiramate to

lamotrigine had no effect on steady state plasma concentration of lamotrigine at topiramate doses of

100 to 400 mg/day. In addition, there was no change in steady state plasma concentration of

topiramate during or after removal of lamotrigine treatment (mean dose of 327 mg/day).

Topiramate inhibits the enzyme CYP 2C19 and may interfere with other substances metabolized via

this enzyme (e.g., diazepam, imipramin, moclobemide, proguanil, omeprazol).

Effects of other antiepileptic medicinal products on Topimax

Phenytoin and carbamazepine decrease the plasma concentration of topiramate. The addition or

withdrawal of phenytoin or carbamazepine to Topimax therapy may require an adjustment in dosage

of the latter. This should be done by titrating to clinical effect. The addition or withdrawal of valproic

acid does not produce clinically significant changes in plasma concentrations of Topimax and,

therefore, does not warrant dosage adjustment of Topimax. The results of these interactions are

summarized below:

AED Coadministered

AED Concentration

Topimax Concentration

Phenytoin

↔**

Carbamazepine (CBZ)

Valproic acid

Lamotrigine

Phenobarbital

Primidone

= No effect on plasma concentration (≤15% change)

= Plasma concentrations increase in individual patients

= Plasma concentrations decrease

= Not studied

= antiepileptic drug

Other medicinal product interactions

Digoxin

In a single-dose study, serum digoxin area under plasma concentration curve (AUC) decreased 12%

due to concomitant administration of Topimax. The clinical relevance of this observation has not been

established. When Topimax is added or withdrawn in patients on digoxin therapy, careful attention

should be given to the routine monitoring of serum digoxin.

Central nervous system depressants

Concomitant administration of Topimax and alcohol or other central nervous system (CNS)

depressant medicinal products has not been evaluated in clinical studies. It is recommended that

Topimax not be used concomitantly with alcohol or other CNS depressant medicinal products.

St John’s Wort (Hypericum perforatum)

A risk of decreased plasma concentrations resulting in a loss of efficacy could be observed with

co-administration of topiramate and St John’s Wort. There have been no clinical studies evaluating

this potential interaction.

Oral contraceptives

In a pharmacokinetic interaction study in healthy volunteers with a concomitantly administered

combination oral contraceptive product containing 1 mg norethindrone (NET) plus 35 µg ethinyl

estradiol (EE), Topimax given in the absence of other medications at doses of 50 to 200 mg/day was

not associated with statistically significant changes in mean exposure (AUC) to either component of

the oral contraceptive. In another study, exposure to EE was statistically significantly decreased at

doses of 200, 400, and 800 mg/day (18%, 21%, and 30%, respectively) when given as adjunctive

therapy in epilepsy patients taking valproic acid. In both studies, Topimax (50-200 mg/day in healthy

volunteers and 200-800 mg/day in epilepsy patients) did not significantly affect exposure to NET.

Although there was a dose-dependent decrease in EE exposure for doses between 200-800 mg/day (in

epilepsy patients), there was no significant dose-dependent change in EE exposure for doses of

50-200 mg/day (in healthy volunteers). The clinical significance of the changes observed is not

known. The possibility of decreased contraceptive efficacy and increased breakthrough bleeding

should be considered in patients taking combination oral contraceptive products with Topimax.

Patients taking estrogen containing contraceptives should be asked to report any change in their

bleeding patterns. Contraceptive efficacy can be decreased even in the absence of breakthrough

bleeding.

Lithium

In healthy volunteers, there was an observed reduction (18% for AUC) in systemic exposure for

lithium during concomitant administration with topiramate 200 mg/day. In patients with bipolar

disorder, the pharmacokinetics of lithium were unaffected during treatment with topiramate at doses

of 200 mg/day; however, there was an observed increase in systemic exposure (26% for AUC)

following topiramate doses of up to 600 mg/day. Lithium levels should be monitored when

co-administered with topiramate.

Risperidone

Drug-drug interaction studies conducted under single dose conditions in healthy volunteers and

multiple dose conditions in patients with bipolar disorder, yielded similar results. When administered

concomitantly with topiramate at escalating doses of 100, 250 and 400 mg/day there was a reduction

in risperidone (administered at doses ranging from 1 to 6 mg/day) systemic exposure (16% and 33%

for steady-state AUC at the 250 and 400 mg/day doses, respectively). However, differences in AUC

for the total active moiety between treatment with risperidone alone and combination treatment with

topiramate were not statistically significant.Minimal alterations in the pharmacokinetics of the total

active moiety (risperidone plus 9-hydroxyrisperidone) and no alterations for 9-hydroxyrisperidone

were observed. There were no significant changes in the systemic exposure of the risperidone total

active moiety or of topiramate. When topiramate was added to existing risperidone (1-6 mg/day)

treatment, adverse events were reported more frequently than prior to topiramate (250-400 mg/day)

introduction (90% and 54% respectively). The most frequently reported AE’s when topiramate was

added to risperidone treatment were: somnolence (27% and 12%), paraesthesia (22% and 0%) and

nausea (18% and 9% respectively).

Hydrochlorothiazide (HCTZ)

A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state

pharmacokinetics of HCTZ (25 mg every 24 h) and topiramate (96 mg every 12 h) when administered

alone and concomitantly. The results of this study indicate that topiramate C

increased by 27% and

AUC increased by 29% when HCTZ was added to topiramate. The clinical significance of this change

is unknown. The addition of HCTZ to topiramate therapy may require an adjustment of the topiramate

dose. The steady-state pharmacokinetics of HCTZ were not significantly influenced by the

concomitant administration of topiramate. Clinical laboratory results indicated decreases in serum

potassium after topiramate or HCTZ administration, which were greater when HCTZ and topiramate

were administered in combination.

Metformin

A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state

pharmacokinetics of metformin and topiramate in plasma when metformin was given alone and when

metformin and topiramate were given simultaneously. The results of this study indicated that

metformin mean C

and mean AUC

0-12h

increased by 18% and 25%, respectively, while mean CL/F

decreased 20% when metformin was co-administered with topiramate. Topiramate did not affect

metformin t

The clinical significance of the effect of topiramate on metformin pharmacokinetics is

unclear. Oral plasma clearance of topiramate appears to be reduced when administered with

metformin. The extent of change in the clearance is unknown. The clinical significance of the effect

of metformin on topiramate pharmacokinetics is unclear.

When Topimax is added or withdrawn in patients on metformin therapy, careful attention should be

given to the routine monitoring for adequate control of their diabetic disease state.

Pioglitazone

A drug-drug interaction study conducted in healthy volunteers evaluated the steady-state

pharmacokinetics of topiramate and pioglitazone when administered alone and concomitantly. A 15%

decrease in the AUC

of pioglitazone with no alteration in C

max,ss

was observed. This finding was not

statistically significant. In addition, a 13% and 16% decrease in C

max,ss

and AUC

respectively, of the

active hydroxy-metabolite was noted as well as a 60% decrease in C

max,ss

and AUC

of the active

keto-metabolite. The clinical significance of these findings is not known. When Topimax is added to

pioglitazone therapy or pioglitazone is added to Topimax therapy, careful attention should be given to

the routine monitoring of patients for adequate control of their diabetic disease state.

Glibenclamide

A drug-drug interaction study conducted in patients with type 2 diabetes evaluated the steady-state

pharmacokinetics of glibenclamide (5 mg/day) alone and concomitantly with topiramate

(150 mg/day). There was a 25% reduction in glibenclamide AUC

during topiramate administration.

Systemic exposure of the active metabolites, 4-

trans

-hydroxy-glyburide (M1) and 3-

cis

hydroxyglyburide (M2), were also reduced by 13% and 15%, respectively. The steady-state

pharmacokinetics of topiramate were unaffected by concomitant administration of glibenclamide.

When topiramate is added to glibenclamide therapy or glibenclamide is added to topiramate therapy,

careful attention should be given to the routine monitoring of patients for adequate control of their

diabetic disease state.

Other forms of interactions

Agents predisposing to nephrolithiasis

Topimax, when used concomitantly with other agents predisposing to nephrolithiasis, may increase

the risk of nephrolithiasis. While using Topimax, agents like these should be avoided since they may

create a physiological environment that increases the risk of renal stone formation.

Valproic acid

Concomitant administration of topiramate and valproic acid has been associated with

hyperammonemia with or without encephalopathy in patients who have tolerated either medicinal

product alone. In most cases, symptoms and signs abated with discontinuation of either medicinal

product (see section 4.4 and section 4.8). This adverse reaction is not due to a pharmacokinetic

interaction.

Hypothermia, defined as an unintentional drop in body core temperature to <35°C, has been reported

in association with concomitant use of topiramate and valproic acid (VPA) both in conjunction with

hyperammonemia and in the absence of hyperammonemia. This adverse event in patients using

concomitant topiramate and valproate can occur after starting topiramate treatment or after increasing

the daily dose of topiramate.

Warfarin

Decreased Prothrombin Time/International Normalized Ratio (PT/INR) has been reported in patients

treated with topiramate in combination with warfarin. Therefore, INR should be carefully monitored

in patients concomitantly treated with topiramate and warfarin.

Additional pharmacokinetic drug interaction studies

Clinical studies have been conducted to assess the potential pharmacokinetic drug interaction between

topiramate and other agents. The changes in C

or AUC as a result of the interactions are

summarized below. The second column (concomitant drug concentration) describes what happens to

the concentration of the concomitant drug listed in the first column when topiramate is added. The

third column (topiramate concentration) describes how the coadministration of a drug listed in the

first column modifies the concentration of topiramate.

Summary of Results from Additional Clinical Pharmacokinetic Drug Interaction Studies

Concomitant Drug

Concomitant Drug

Concentration

a

Topiramate Concentration

a

Amitriptyline

↔ 20% increase in C

AUC of nortriptyline metabolite

Dihydroergotamine (Oral

and Subcutaneous)

Haloperidol

↔ 31% increase in AUC of the

reduced metabolite

Propranolol

↔ 17% increase in C

4-OH propranolol (TPM 50 mg

q12h)

9% and 16% increase in C

9% and17% increase in AUC

(40 and 80 mg propranolol

q12h respectively)

Sumatriptan (Oral and

Subcutaneous)

Pizotifen

Diltiazem

25% decrease in AUC of

diltiazem and 18% decrease in

DEA, and ↔ for DEM*

20% increase in AUC

Venlafaxine

Flunarizine

16% increase in AUC

(TPM 50 mg q12h)

= % values are the changes in treatment mean C

or AUC with respect to monotherapy

= No effect on C

and AUC (≤15% change) of the parent compound

= Not studied

*DEA =

des acetyl diltiazem, DEM = N-demethyl diltiazem

= Flunarizine AUC increased 14% in subjects taking flunarizine alone. Increase in exposure may be attributed

to accumulation during achievement of steady state.

4.6

Fertility, pregnancy and lactation

Pregnancy

Risk related to epilepsy and AEDs in general

Specialist advice should be given to women who are of childbearing potential. The need for treatment

with AEDs should be reviewed when a woman is planning to become pregnant. In women being

treated for epilepsy, sudden discontinuation of AED therapy should be avoided as this may lead to

breakthrough seizures that could have serious consequences for the woman and the unborn child.

Monotherapy should be preferred whenever possible because therapy with multiple AEDs could be

associated with a higher risk of congenital malformations than monotherapy, depending on the

associated antiepileptics.

Risk related to topiramate

Topiramate was teratogenic in mice, rats and rabbits (see section 5.3). In rats, topiramate crosses the

placental barrier.

In humans, topiramate crosses the placenta and similar concentrations have been reported in the

umbilical cord and maternal blood.

Clinical data from pregnancy registries indicate that infants exposed to topiramate monotherapy have:

An increased risk of congenital malformations (particularly cleft lip/palate, hypospadias, and

anomalies involving various body systems) following exposure during the first trimester. The

North American Antiepileptic Drug pregnancy registry data for topiramate monotherapy

showed an approximate 3-fold higher prevalence of major congenital malformations (4.3%),

compared with a reference group not taking AEDs (1.4%). In addition, data from other studies

indicate that, compared with monotherapy, there is an increased risk of teratogenic effects

associated with the use of AEDs in combination therapy. The risk has been reported to be dose

dependent; effects were observed in all doses. In women treated with topiramate who have had

a child with a congenital malformation, there appears to be an increased risk of malformations

in subsequent pregnancies when exposed to topiramate.

A higher prevalence of low birth weight (<2500 grams) compared with a reference group.

An increased prevalence of being small for gestational age (SGA; defined as birth weight below

the 10

percentile corrected for their gestational age, stratified by sex). The long term

consequences of the SGA findings could not be determined.

Indication epilepsy

It is recommended to consider alternative therapeutic options in women of childbearing potential. If

topirmate is used in women of childbearing potential, it is recommended that highly effective

contraception be used (see section 4.5), and that the woman is fully informed of the known risks of

uncontrolled epilepsy to the pregnancy and the potential risks of the medicinal product to the foetus.

If a woman plans a pregnancy, a preconceptional visit is recommended in order to reassess the

treatment, and to consider other therapeutic options. In case of administration during the first

trimester, careful prenatal monitoring should be performed.

Indication migraine prophylaxis

Topiramate is contraindicated in pregnancy and in women of childbearing potential if a highly

effective method of contraception is not used (see sections 4.3 and 4.5).

Breast-feeding

Animal studies have shown excretion of topiramate in milk. The excretion of topiramate in human

milk has not been evaluated in controlled studies. Limited observations in patients suggest an

extensive excretion of topiramate into human milk. Effects that have been observed in breastfed

newborns/infants of treated mothers, include diarrhea, drowsiness, irritability and inadequate weight

gain. Therefore, a decision must be made whether to suspend breast-feeding or to discontinue/ abstain

from topiramate therapy taking into account the benefit of breast-feeding for the child and the benefit

of topiramate therapy for the women (see section 4.4).

Fertility

Animal studies did not reveal impairment of fertility by topiramate (see section 5.3). The effect of

topiramate on human fertility has not been established.

4.7

Effects on ability to drive and use machines

Topimax has minor or moderate influence on the ability to drive and use machines. Topiramate acts

on the central nervous system and may produce drowsiness, dizziness or other related symptoms. It

may also cause visual disturbances and/or blurred vision. These adverse reactions could potentially be

dangerous in patients driving a vehicle or operating machinery, particularly until such time as the

individual patient's experience with the medicinal products established.

4.8

Undesirable effects

The safety of topiramate was evaluated from a clinical trial database consisting of 4,111 patients

(3,182 on topiramate and 929 on placebo) who participated in 20 double-blind trials and

2,847 patients who participated in 34 open-label trials, respectively, for topiramate as adjunctive

treatment of primary generalized tonic-clonic seizures, partial onset seizures, seizures associated with

Lennox-Gastaut syndrome, monotherapy for newly or recently diagnosed epilepsy or migraine

prophylaxis. The majority of adverse reactions were mild to moderate in severity. Adverse reactions

identified in clinical trials, and during post-marketing experience (as indicated by “*”) are listed by

their incidence in clinical trials in Table 1. Assigned frequencies are as follows:

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

Not known

cannot be estimated from the available data

The most common adverse reactions (those with an incidence of >5% and greater than that observed

in placebo in at least 1 indication in double-blind controlled studies with topiramate) include:

anorexia, decreased appetite, bradyphrenia, depression, expressive language disorder, insomnia,

coordination abnormal, disturbance in attention, dizziness, dysarthria, dysgeusia, hypoesthesia,

lethargy, memory impairment, nystagmus, paresthesia, somnolence, tremor, diplopia, vision blurred,

diarrhoea, nausea, fatigue, irritability, and weight decreased.

Table 1: Topiramate Adverse Reactions

System Organ

Class

Very common

Common

Uncommon

Rare

Not known

Infections and

infestations

nasopharyngitis*

Blood and

lymphatic system

disorders

anaemia

leucopenia,

thrombocytopenia

lymphadenopathy,

eosinophilia

neutropenia*

Immune system

disorders

hypersensitivity

allergic

oedema*

Metabolism and

nutrition disorders

anorexia,

decreased appetite

metabolic acidosis,

hypokalaemia,

increased appetite,

polydipsia

acidosis

hyperchloraemic,

hyperammonemia*,

hyperammonemic

encephalopathy*

Table 1: Topiramate Adverse Reactions

System Organ

Class

Very common

Common

Uncommon

Rare

Not known

Psychiatric

disorders

depression

bradyphrenia,

insomnia,

expressive

language disorder,

anxiety,

confusional state,

disorientation,

aggression, mood

altered, agitation,

mood swings,

depressed mood,

anger, abnormal

behaviour

suicidal ideation,

suicide attempt,

hallucination,

psychotic disorder,

hallucination

auditory,

hallucination

visual, apathy, lack

of spontaneous

speech, sleep

disorder, affect

lability, libido

decreased,

restlessness, crying,

dysphemia,

euphoric mood,

paranoia,

perseveration,

panic attack,

tearfulness, reading

disorder, initial

insomnia, flat

affect, thinking

abnormal, loss of

libido, listless,

middle insomnia,

distractibility, early

morning

awakening, panic

reaction, elevated

mood

mania, panic

disorder, feeling of

despair*,

hypomania

Table 1: Topiramate Adverse Reactions

System Organ

Class

Very common

Common

Uncommon

Rare

Not known

Nervous system

disorders

paraesthesia,

somnolence,

dizziness

disturbance in

attention, memory

impairment,

amnesia, cognitive

disorder, mental

impairment,

psychomotor skills

impaired,

convulsion,

coordination

abnormal, tremor,

lethargy,

hypoaesthesia,

nystagmus,

dysgeusia, balance

disorder,

dysarthria,

intention tremor,

sedation

depressed level of

consciousness,

grand mal

convulsion, visual

field defect,

complex partial

seizures, speech

disorder,

psychomotor

hyperactivity,

syncope, sensory

disturbance,

drooling,

hypersomnia,

aphasia, repetitive

speech,

hypokinesia,

dyskinesia,

dizziness postural,

poor quality sleep,

burning sensation,

sensory loss,

parosmia,

cerebellar

syndrome,

dysaesthesia,

hypogeusia, stupor,

clumsiness, aura,

ageusia,

dysgraphia,

dysphasia,

neuropathy

peripheral,

presyncope,

dystonia,

formication

apraxia, circadian

rhythm sleep

disorder,

hyperaesthesia,

hyposmia, anosmia,

essential tremor,

akinesia,

unresponsive to

stimuli

Eye disorders

vision blurred,

diplopia, visual

disturbance

visual acuity

reduced, scotoma,

myopia*, abnormal

sensation in eye*,

dry eye,

photophobia,

blepharospasm,

lacrimation

increased,

photopsia,

mydriasis,

presbyopia

blindness unilateral,

blindness transient,

glaucoma,

accommodation

disorder, altered

visual depth

perception,

scintillating

scotoma, eyelid

oedema*, night

blindness,

amblyopia

angle closure

glaucoma*,

maculopathy

*, eye

movement

disorder*,

conjunctival

oedema*,

uveitis

Ear and labyrinth

disorders

vertigo, tinnitus,

ear pain

deafness, deafness

unilateral, deafness

neurosensory, ear

discomfort, hearing

impaired

Cardiac disorders

bradycardia, sinus

bradycardia,

palpitations

Table 1: Topiramate Adverse Reactions

System Organ

Class

Very common

Common

Uncommon

Rare

Not known

Vascular disorders

hypotension,

orthostatic

hypotension,

flushing, hot flush

Raynaud's

phenomenon

Respiratory,

thoracic and

mediastinal

disorders

dyspnoea,

epistaxis, nasal

congestion,

rhinorrhoea,

cough*

dyspnoea

exertional,

paranasal sinus

hypersecretion,

dysphonia

Gastrointestinal

disorders

nausea, diarrhoea vomiting,

constipation,

abdominal pain

upper, dyspepsia,

abdominal pain,

dry mouth,

stomach

discomfort,

paraesthesia oral,

gastritis,

abdominal

discomfort

pancreatitis,

flatulence,

gastrooesophageal

reflux disease,

abdominal pain

lower,

hypoaesthesia oral,

gingival bleeding,

abdominal

distension,

epigastric

discomfort,

abdominal

tenderness, salivary

hypersecretion, oral

pain, breath odour,

glossodynia

Hepatobiliary

disorders

hepatitis, hepatic

failure

Skin and

subcutaneous

tissue disorders

alopecia, rash,

pruritus

anhidrosis,

hypoaesthesia

facial, urticaria,

erythema, pruritus

generalised, rash

macular, skin

discolouration,

dermatitis allergic,

swelling face

Stevens-Johnson

syndrome*

erythema

multiforme*, skin

odour abnormal,

periorbital oedema*,

urticaria localised

toxic

epidermal

necrolysis*

Musculoskeletal

and connective

tissue disorders

arthralgia, muscle

spasms, myalgia,

muscle twitching,

muscular

weakness,

musculoskeletal

chest pain

joint swelling*,

musculoskeletal

stiffness, flank

pain, muscle

fatigue

limb discomfort*

Renal and urinary

disorders

nephrolithiasis,

pollakiuria,

dysuria,

nephrocalcinosis*

calculus urinary,

urinary

incontinence,

haematuria,

incontinence,

micturition

urgency, renal

colic, renal pain

calculus ureteric,

renal tubular

acidosis*

Reproductive

system and breast

disorders

erectile

dysfunction, sexual

dysfunction

Table 1: Topiramate Adverse Reactions

System Organ

Class

Very common

Common

Uncommon

Rare

Not known

General disorders

and administration

site conditions

fatigue

pyrexia, asthenia,

irritability, gait

disturbance,

feeling abnormal,

malaise

hyperthermia,

thirst, influenza like

illness*,

sluggishness,

peripheral coldness,

feeling drunk,

feeling jittery

face oedema

Investigations

weight decreased weight increased* crystal urine

present, tandem

gait test abnormal,

white blood cell

count decreased,

Increase in liver

enzymes

blood bicarbonate

decreased

Social

circumstances

learning disability

identified as an adverse reaction from postmarketing spontaneous reports. Its frequency was calculated based on the incidence in

clinical trials, or was calculated if the event did not occur in clinical trials.

Congenital malformations and fetal growth restrictions (see section 4.4 and section 4.6).

Paediatric population

Adverse reactions reported more frequently (

2-fold) in children than in adults in double-blind

controlled studies include:

Decreased appetite

Increased appetite

Hyperchloraemic acidosis

Hypokalaemia

Abnormal behaviour

Aggression

Apathy

Initial insomnia

Suicidal ideation

Disturbance in attention

Lethargy

Circadian rhythm sleep disorder

Poor quality sleep

Lacrimation increased

Sinus bradycardia

Feeling abnormal

Gait disturbance.

Adverse reactions that were reported in children but not in adults in double-blind controlled studies

include:

Eosinophilia

Psychomotor hyperactivity

Vertigo

Vomiting

Hyperthermia

Pyrexia

Learning disability.

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

Signs and symptoms

Overdoses of topiramate have been reported. Signs and symptoms included convulsions, drowsiness,

speech disturbances, blurred vision, diplopia, impaired mentation, lethargy, abnormal coordination,

stupor, hypotension, abdominal pain, agitation, dizziness and depression. The clinical consequences

were not severe in most cases, but deaths have been reported after overdoses with multiple medicinal

products including topiramate.

Topiramate overdose can result in severe metabolic acidosis (see section 4.4).

Treatment

In the event of overdose, topiramate should be discontinued and general supportive treatment given

until clinical toxicity has been diminished or resolved. The patient should be well hydrated.

Haemodialysis has been shown to be an effective means of removing topiramate from the body. Other

measures may also be taken at the physician’s discretion.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: antiepileptics, other antiepileptics, ATC code: N03AX11.

Topiramate is classified as a sulfamate-substituted monosaccharide. The precise mechanism by which

topiramate exerts its antiseizure and migraine prophylaxis effects are unknown. Electrophysiological

and biochemical studies on cultured neurons have identified three properties that may contribute to

the antiepileptic efficacy of topiramate.

Action potentials elicited repetitively by a sustained depolarization of the neurons were blocked by

topiramate in a time-dependent manner, suggestive of a state-dependent sodium channel blocking

action. Topiramate increased the frequency at which γ-aminobutyrate (GABA) activated GABA

receptors, and enhanced the ability of GABA to induce a flux of chloride ions into neurons,

suggesting that topiramate potentiates the activity of this inhibitory neurotransmitter.

This effect was not blocked by flumazenil, a benzodiazepine antagonist, nor did topiramate increase

the duration of the channel open time, differentiating topiramate from barbiturates that modulate

GABA

receptors.

Because the antiepileptic profile of topiramate differs markedly from that of the benzodiazepines, it

may modulate a benzodiazepine-insensitive subtype of GABA

receptor. Topiramate antagonized the

ability of kainate to activate the kainate/AMPA (α -amino-3-hydroxy-5-methylisoxazole-4-propionic

acid) subtype of excitatory amino acid (glutamate) receptor, but had no apparent effect on the activity

of N-methyl-D-aspartate (NMDA) at the NMDA receptor subtype. These effects of topiramate were

concentration-dependent over a range of 1 µM to 200 µM, with minimum activity observed at 1 µM

to 10 µM.

In addition, topiramate inhibits some isoenzymes of carbonic anhydrase. This pharmacologic effect is

much weaker than that of acetazolamide, a known carbonic anhydrase inhibitor, and is not thought to

be a major component of topiramate's antiepileptic activity.

In animal studies, topiramate exhibits anticonvulsant activity in rat and mouse maximal electroshock

seizure (MES) tests and is effective in rodent models of epilepsy, which include tonic and

absence-like seizures in the spontaneous epileptic rat (SER) and tonic and clonic seizures induced in

rats by kindling of the amygdala or by global ischemia. Topiramate is only weakly effective in

blocking clonic seizures induced by the GABA

receptor antagonist, pentylenetetrazole.

Studies in mice receiving concomitant administration of topiramate and carbamazepine or

phenobarbital showed synergistic anticonvulsant activity, while combination with phenytoin showed

additive anticonvulsant activity. In well-controlled add-on trials, no correlation has been demonstrated

between trough plasma concentrations of topiramate and its clinical efficacy. No evidence of

tolerance has been demonstrated in man.

Absence seizures

Two small one arm studies were carried out with children aged 4-11 years old (CAPSS-326 and

TOPAMAT-ABS-001). One included 5 children and the other included 12 children before it was

terminated early due to lack of therapeutic response. The doses used in these studies were up to

approximately 12 mg/kg in study TOPAMAT-ABS-001 and a maximum of the lesser of 9 mg/kg/day

or 400 mg/day in study CAPSS-326. These studies do not provide sufficient evidence to reach

conclusion regarding efficacy or safety in the paediatric population.

5.2

Pharmacokinetic properties

The film-coated tablet and hard capsule formulations are bioequivalent.

The pharmacokinetic profile of topiramate compared to other AEDs shows a long plasma half-life,

linear pharmacokinetics, predominantly renal clearance, absence of significant protein binding, and

lack of clinically relevant active metabolites.

Topiramate is not a potent inducer of drug metabolizing enzymes, can be administered without regard

to meals, and routine monitoring of plasma topiramate concentrations is not necessary. In clinical

studies, there was no consistent relationship between plasma concentrations and efficacy or adverse

events.

Absorption

Topiramate is rapidly and well absorbed. Following oral administration of 100 mg topiramate to

healthy subjects, a mean peak plasma concentration (C

) of 1.5 µg/ml was achieved within 2 to

3 hours (T

Based on the recovery of radioactivity from the urine the mean extent of absorption of a 100 mg oral

dose of

C-topiramate was at least 81%. There was no clinically significant effect of food on the

bioavailability of topiramate.

Distribution

Generally, 13 to 17% of topiramate is bound to plasma protein. A low capacity binding site for

topiramate in/on erythrocytes that is saturable above plasma concentrations of 4 µg/ml has been

observed. The volume of distribution varied inversely with the dose. The mean apparent volume of

distribution was 0.80 to 0.55 l/kg for a single dose range of 100 to 1200 mg. An effect of gender on

the volume of distribution was detected, with values for females circa 50% of those for males. This

was attributed to the higher percent body fat in female patients and is of no clinical consequence.

Biotransformation

Topiramate is not extensively metabolized (~20%) in healthy volunteers. It is metabolized up to 50%

in patients receiving concomitant antiepileptic therapy with known inducers of drug metabolizing

enzymes. Six metabolites, formed through hydroxylation, hydrolysis and glucuronidation, have been

isolated, characterized and identified from plasma, urine and faeces of humans. Each metabolite

represents less than 3% of the total radioactivity excreted following administration of

C-topiramate.

Two metabolites, which retained most of the structure of topiramate, were tested and found to have

little or no anticonvulsant activity.

Elimination

In humans, the major route of elimination of unchanged topiramate and its metabolites is via the

kidney (at least 81% of the dose). Approximately 66% of a dose of

C-topiramate was excreted

unchanged in the urine within four days. Following twice a day dosing with 50 mg and 100 mg of

topiramate the mean renal clearance was approximately 18 ml/min and 17 ml/min, respectively. There

is evidence of renal tubular reabsorption of topiramate. This is supported by studies in rats where

topiramate was co-administered with probenecid, and a significant increase in renal clearance of

topiramate was observed. Overall, plasma clearance is approximately 20 to 30 ml/min in humans

following oral administration.

Linearity/non-linearity

Topiramate exhibits low intersubject variability in plasma concentrations and, therefore, has

predictable pharmacokinetics. The pharmacokinetics of topiramate are linear with plasma clearance

remaining constant and area under the plasma concentration curve increasing in a dose-proportional

manner over a 100 to 400 mg single oral dose range in healthy subjects. Patients with normal renal

function may take 4 to 8 days to reach steady-state plasma concentrations. The mean C

following

multiple, twice a day oral doses of 100 mg to healthy subjects was 6.76 µg/ml. Following

administration of multiple doses of 50 mg and 100 mg of topiramate twice a day, the mean plasma

elimination half-life was approximately 21 hours.

Use with other AEDs

Concomitant multiple-dose administration of topiramate, 100 to 400 mg twice a day, with phenytoin

or carbamazepine shows dose proportional increases in plasma concentrations of topiramate.

Renal impairment

The plasma and renal clearance of topiramate are decreased in patients with moderate and severe

impaired renal function (CL

≤ 70 ml/min). As a result, higher steady-state topiramate plasma

concentrations are expected for a given dose in renal-impaired patients as compared to those with

normal renal function. In addition, patients with renal impairment will require a longer time to reach

steady-state at each dose. In patients with moderate and severe renal impairment, half of the usual

starting and maintenance dose is recommended.

Topiramate is effectively removed from plasma by haemodialysis. A prolonged period of

hemodialysis may cause topiramate concentration to fall below levels that are required to maintain an

anti-seizure effect. To avoid rapid drops in topiramate plasma concentration during hemodialysis, a

supplemental dose of topiramate may be required. The actual adjustment should take into account 1)

the duration of dialysis period, 2) the clearance rate of the dialysis system being used, and 3) the

effective renal clearance of topiramate in the patient being dialyzed.

Hepatic impairment

Plasma clearance of topiramate decreased a mean of 26% in patients with moderate to severe hepatic

impairment. Therefore, topiramate should be administered with caution in patients with hepatic

impairment.

Elderly population

Plasma clearance of topiramate is unchanged in elderly subjects in the absence of underlying renal

disease.

Paediatric population (pharmacokinetics, up to 12 years of age)

The pharmacokinetics of topiramate in children, as in adults receiving add-on therapy, are linear, with

clearance independent of dose and steady-state plasma concentrations increasing in proportion to

dose. Children, however, have a higher clearance and a shorter elimination half-life. Consequently,

the plasma concentrations of topiramate for the same mg/kg dose may be lower in children compared

to adults. As in adults, hepatic enzyme inducing AEDs decrease the steady-state plasma

concentrations.

5.3

Preclinical safety data

In nonclinical studies of fertility, despite maternal and paternal toxicity as low as 8 mg/kg/day, no

effects on fertility were observed, in male or female rats with doses up to 100 mg/kg/day.

In preclinical studies, topiramate has been shown to have teratogenic effects in the species studied

(mice, rats and rabbits). In mice, fetal weights and skeletal ossification were reduced at

500 mg/kg/day in conjunction with maternal toxicity. Overall numbers of fetal malformations in mice

were increased for all drug-treated groups (20, 100 and 500 mg/kg/day).

In rats, dosage-related maternal and embryo/fetal toxicity (reduced fetal weights and/or skeletal

ossification) were observed down to 20 mg/kg/day with teratogenic effects (limb and digit defects) at

400 mg/kg/day and above. In rabbits, dosage-related maternal toxicity was noted down to

10 mg/kg/day with embryo/fetal toxicity (increased lethality) down to 35 mg/kg/day, and teratogenic

effects (rib and vertebral malformations) at 120 mg/kg/day.

The teratogenic effects seen in rats and rabbits were similar to those seen with carbonic anhydrase

inhibitors, which have not been associated with malformations in humans. Effects on growth were

also indicated by lower weights at birth and during lactation for pups from female rats treated with 20

or 100 mg/kg/day during gestation and lactation. In rats, topiramate crosses the placental barrier.

In juvenile rats, daily oral administration of topiramate at doses up to 300 mg/kg/day during the

period of development corresponding to infancy, childhood, and adolescence resulted in toxicities

similar to those in adult animals (decreased food consumption with decreased body weight gain,

centrolobullar hepatocellular hypertrophy). There were no relevant effects on long bone (tibia) growth

or bone (femur) mineral density, preweaning and reproductive development, neurological

development (including assessments on memory and learning), mating and fertility or hysterotomy

parameters.

In a battery of

in vitro

in vivo

mutagenicity assays, topiramate did not show genotoxic potential.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Sugar spheres (maize starch, sucrose), Povidone, Cellulose acetate

Capsule

Gelatine, Titanium dioxide (E171)

Printing ink

Black ink (iron oxide black (E172), shellac and propylene glycol).

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

2 years.

6.4

Special precautions for storage

Do not store above 25°C. Keep the bottle tightly closed to protect the capsules from moisture.

6.5

Nature and contents of container

Opaque plastic bottle of HDPE with tamper-evident closure containing 20, 28, 60 or 100 capsules

with granules.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal and other handling

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

Date of first authorisation: 30 June 2000

Date of last renewal: 30 June 2010

10.

DATE OF REVISION OF THE TEXT

2020-11-05

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