Zonisamide Accord 25 mg Kapsel, hård

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

05-05-2021

Produktens egenskaper Produktens egenskaper (SPC)

05-05-2021

Aktiva substanser:
zonisamid
Tillgänglig från:
Accord Healthcare B.V.
ATC-kod:
N03AX15
INN (International namn):
zonisamide
Dos:
25 mg
Läkemedelsform:
Kapsel, hård
Sammansättning:
natriumlaurilsulfat Hjälpämne; propylenglykol Hjälpämne; zonisamid 25 mg Aktiv substans
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Blister, 14 kapslar; Blister, 28 kapslar; Blister, 56 kapslar
Bemyndigande status:
Godkänd
Godkännandenummer:
52873
Tillstånd datum:
2016-04-14

Dokument på andra språk

Produktens egenskaper Produktens egenskaper - engelska

03-09-2021

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25-08-2021

Läs hela dokumentet

Bipacksedel: Information till användaren

Zonisamide Accord 25 mg hård kapsel

Zonisamide Accord 50 mg hård kapsel

Zonisamide Accord 100 mg hård kapsel

zonisamid

Läs noga igenom denna bipacksedel innan du börjar använda 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 Zonisamide Accord är och vad det används för

Vad du behöver veta innan du använder Zonisamide Accord

Hur du använder Zonisamide Accord

Eventuella biverkningar

Hur Zonisamide Accord ska förvaras

Förpackningens innehåll och övriga upplysningar

1.

Vad Zonisamide Accord är och vad det används för

Zonisamide Accord innehåller den aktiva substansen zonisamid och används som ett antiepileptikum.

Zonisamide Accord används vid behandling av epilepsianfall som påverkar en del av hjärnan (partiellt

anfall), med eller utan efterföljande anfall som påverkar hela hjärnan (sekundär generalisering).

Zonisamide Accord kan användas:

Enskilt för att behandla anfall hos vuxna

Med andra antiepileptiska läkemedel för att behandla vuxna, ungdomar och barn i åldern 6 år

eller äldre.

Zonisamid som finns i Zonisamide Accord 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 använder Zonisamide Accord

Använd inte Zonisamide Accord:

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

avsnitt 6).

om du är allergisk mot andra läkemedel i gruppen sulfonamider. Dessa är till exempel:

antibiotika av sulfonamidtyp, tiaziddiuretika och antidiabetika i klassen sulfonylurea.

Varningar och försiktighet

Zonisamide Accord tillhör en grupp läkemedel (sulfonamider) som kan ge upphov till allvarliga

allergiska reaktioner, svåra hudutslag och blodrubbningar, som i mycket sällsynta fall kan ha dödlig

utgång (se avsnitt 4 Eventuella biverkningar).

Svåra hudutslag, inklusive fall av Stevens-Johnsons syndrom, förekommer i samband med

behandling med Zonisamide Accord.

Tala med läkare eller apotekspersonal innan du tar Zonisamide Accord

om du är yngre än 12 år, eftersom du kan löpa en större risk för minskad svettning, värmeslag,

pneumoni och leverproblem. Om du är yngre än 6 år rekommenderas inte Zonisamide Accord

för dig

om du är äldre, eftersom dosen Zonisamide Accord du tar kanske måste justeras, och det kan

vara mer sannolikt att du får en allergisk reaktion, allvarligt hudutslag, svullnad i fötter och

ben samt klåda när du tar Zonisamide Accord (se avsnitt 4 Eventuella biverkningar)

om du har leverproblem, eftersom dosen Zonisamide Accord du tar kanske måste justeras

har ögonbesvär såsom glaukom.

om du har njurproblem, eftersom dosen Zonisamide Accord du tar kanske måste justeras

om du tidigare har haft njursten eftersom du då löper större risk att få fler njurstenar.

Minska

risken för njursten genom att dricka tillräckligt med vatten

om du bor eller semestrar på en plats där vädret är varmt. Zonisamide Accord kan göra att du

svettas mindre, vilket kan leda till att din kroppstemperatur stiger.

Minska risken genom att

dricka tillräckligt med vatten och hålla dig sval

om du är underviktig eller har gått ned mycket i vikt, eftersom din vikt kan minska ytterligare

när du tar Zonisamide Accord. Tala om detta för din läkare eftersom vikten eventuellt måste

följas upp

är gravid eller skulle kunna bli gravid (se avsnittet "Graviditet, amning och fertilitet" för

vidare information).

Tala med din läkare innan du börjar ta Zonisamide Accord, om något av ovanstående gäller dig.

Användning av Zonisamide Accord kan orsaka höga nivåer av ammoniak i blodet, vilket kan leda till

förändrad hjärnfunktion, särskilt om du tar andra läkemedel som kan öka ammoniaknivåerna (till

exempel valproat) eller om du har en ärftlig sjukdom som orsakar ansamling av för mycket ammoniak

i kroppen (ureacykelrubbning) eller leverproblem. Informera din läkare omedelbart om du känner dig

ovanligt sömning eller förvirrad.

Barn och ungdomar

Tala med din läkare om nedanstående risker:

Förebyggande av överhettning och uttorkning hos barn

Zonisamide Accord kan göra att ditt barn svettas mindre och blir överhettat och om ditt barn inte

behandlas kan det leda till hjärnskador och dödsfall. Barn är mest utsatta, särskilt i varmt väder.

När ditt barn tar Zonisamide Accord ska ditt barn

hållas svalt, särskilt i varmt väder

- undvika kraftig ansträngning, särskilt i varmt väder

- dricka mycket kallt vatten

- inte ta dessa läkemedel:

karbanhydrashämmare (såsom topiramat och acetazolamid) och antikolinerga medel (såsom

klomipramin, hydroxyzin, difenhydramin, haloperidol, imipramin och oxybutynin).

Om ditt barns hud känns mycket varm med liten eller ingen svettning, om barnet blir förvirrat, får

muskelkramper eller om ditt barns hjärta börjar slå snabbt eller om andningen blir snabb:

Ta med ditt barn till en sval, skuggig plats.

Badda barnets hud med svalt (inte kallt) vatten.

Ge ditt barn kallt vatten att dricka.

Uppsök läkare snabbt.

Kroppsvikt: Du ska väga ditt barn varje månad och kontakta läkare snarast möjligt om ditt barn

inte går upp tillräckligt i vikt. Zonisamide Accord rekommenderas inte för barn som är

underviktiga eller har dålig aptit, och det bör användas med försiktighet till barn som väger

mindre än 20 kg.

Ökad surhetsgrad i blodet och njurstenar: Minska dessa risker genom att se till att ditt barn

dricker tillräckligt mycket vatten och inte tar några andra läkemedel som skulle kunna ge

upphov till njurstenar (se Andra läkemedel och Zonisamide Accord). Läkaren kontrollerar ditt

barns nivåer av blodbikarbonat och njurarna (se även avsnitt 4).

Ge inte detta läkemedel till barn under 6 år eftersom det för denna åldersgrupp är okänt om den

möjliga nyttan är större än riskerna.

Andra läkemedel och Zonisamide Accord

Tala om för läkare eller apotekspersonal om du använder, nyligen har använt eller kan tänkas använda

andra läkemedel.

Zonisamide Accord ska användas med försiktighet till vuxna när det tas tillsammans med

läkemedel som kan orsaka njursten såsom topiramat eller acetazolamid. Denna kombination

rekommenderas inte till barn.

Zonisamide Accord kan möjligtvis öka halten av läkemedel som digoxin och kinidin i blodet

och dosen av dessa läkemedel kan därför behöva sänkas.

Andra läkemedel som fenytoin, karbamazepin, fenobarbiton och rifampicin kan minska halten

Zonisamide Accord i blodet, och dosen Zonisamide Accord kan behöva justeras.

Zonisamide Accord med mat och dryck

Zonisamid Actavis kan tas med eller utan föda.

Graviditet, amning och fertilitet

Om du är kvinna i fertil ålder måste du använda en adekvat preventivmetod under behandling med

Zonisamide Accord och i en månad efter avslutad behandling med Zonisamide Accord.

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

innan du använder detta läkemedel. Avsluta inte behandlingen utan att diskutera detta med läkaren.

Du får ta Zonisamide Accord medan du är gravid endast om din läkare säger att du kan. Forskning har

visat en ökad risk för medfödda missbildningar hos barn till kvinnor som behandlas med läkemedel

mot epilepsi. En studie visade att spädbarn som föds till mödrar som använder zonisamid under

graviditet var mindre än vad som förväntades för deras ålder vid födseln, jämfört med barn som föddes

till mödrar som behandlats med lamotrigin som monoterapi. Se till att du är fullt informerad om

riskerna och fördelarna med att använda zonisamid för epilepsi under graviditet.

Du får inte amma medan du tar Zonisamide Accord och under den första månaden efter att du har

slutat att ta Zonisamide Accord.

Det finns inga kliniska data om effekterna av zonisamid på fertilitet hos människa. Studier på djur har

visat förändringar i fertilitetsparametrarna.

Körförmåga och användning av maskiner

Zonisamide Accord kan påverka din koncentrations- och reaktionsförmåga och kan göra att du känner

dig sömnig, särskilt i början av behandlingen och när din dos har ökats. Var särskilt försiktig när du

kör bil eller använder maskiner, om Zonisamide Accord påverkar dig på detta sätt.

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

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

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

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

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

3.

Hur du använder Zonisamide Accord

Använd alltid detta läkemedel enligt läkarens anvisningar. Rådfråga läkare eller apotekspersonal om

du är osäker.

Rekommenderad dos för vuxna

När du tar enbart Zonisamide Accord:

Startdosen är 100 mg som tas en gång dagligen.

Denna kan höjas med upp till 100 mg i intervaller på två veckor.

Rekommenderad dos är 300 mg en gång dagligen.

När du tar Zonisamide Accord med andra antiepileptiska läkemedel:

Startdosen är 50 mg dagligen uppdelad i två lika stora doser om 25 mg.

Dosen kan ökas med upp till 100 mg i intervall om en till två veckor.

Rekommenderad daglig dos är mellan 300 mg och 500 mg.

En del patienter får effekt av lägre doser. Dosen kan ökas långsammare om du får biverkningar,

om du är äldre eller om du har problem med njurarna eller levern.

Användning för barn och ungdomar

Användning till barn (6 till 11 år) och ungdomar (12 till 17 år) som väger minst 20 kg:

Startdosen är 1 mg per kg kroppsvikt som tas en gång om dagen.

- Denna dos kan ökas med 1 mg per kg kroppsvikt med intervall på en till två veckor.

Rekommenderad daglig dos är 6 till 8 mg per kg för ett barn med en kroppsvikt på upp till 55 kg

eller 300 till 500 mg för ett barn med en kroppsvikt på mer än 55 kg (beroende på vilken dos

som är lägst) som tas en gång om dagen.

Exempel: Ett barn som väger 25 kg ska ta 25 mg en gång om dagen under den första veckan, och

sedan öka den dagliga dosen med 25 mg vid starten av varje vecka tills en daglig dos mellan 150 och

200 mg har uppnåtts.

Om du upplever att effekten av Zonisamide Accord är för stark eller för svag, vänd dig till din läkare

eller apotekspersonal.

Zonisamide Accord kapslar måste sväljas hela med vatten.

Tugga inte kapslarna.

Zonisamide Accord kan tas en eller två gånger om dagen enligt läkarens ordination.

Om du tar Zonisamide Accord två gånger om dagen ska du ta halva dagsdosen på morgonen

och halva dagsdosen på kvällen.

Om du har använt för stor mängd av Zonisamide Accord

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

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

samt rådgivning. Ta med dig läkemedelsförpackningen.

Du kan bli sömnig eller förlora medvetandet. Du kan också må illa, ha magsmärtor, muskelspasmer,

ofrivilliga ögonrörelser, känna dig svag, ha långsam hjärtrytm, nedsatt andning eller nedsatt

njurfunktion. Kör inte bil.

Om du har glömt att använda Zonisamide Accord

Om du glömmer att ta en dos Zonisamide Accord, ska du helt enkelt ta nästa dos som vanligt.

Ta inte dubbel dos för att kompensera för glömd dos.

Om du slutar att använda Zonisamide Accord

Zonisamide Accord är avsett för långtidsbehandling. Minska inte dosen eller sluta att ta läkemedlet,

om inte din läkare råder dig att göra det.

Om din läkare råder dig att avsluta behandlingen med Zonisamide Accord, kommer din dos att

minskas gradvis för att minska risken för att du drabbas av fler anfall.

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.

Zonisamide Accord tillhör en grupp läkemedel (sulfonamider) som kan ge upphov till allvarliga,

allergiska reaktioner, svåra hudutslag och blodrubbningar som i mycket sällsynta fall kan ha dödlig

utgång.

Kontakta genast din läkare om du upplever följande symtom:

svårighet att andas, svullnad av ansikte, läppar eller tunga eller svåra hudutslag eftersom det kan

tyda på att du har fått en allvarlig, allergisk reaktion.

tecken på överhettning – hög kroppstemperatur men liten eller ingen svettning, snabba hjärtslag

och snabb andning, muskelkramper och förvirring.

tankar på att skada dig själv eller begå självmord. Ett litet antal personer som behandlas med

läkemedel mot epilepsi, som t.ex. Zonisamide Accord, har haft tankar på att skada sig själva

eller begå självmord.

muskelvärk eller känsla av svaghet eftersom dessa symtom kan vara tecken på onormal

muskelnedbrytning som kan leda till njurproblem.

plötslig värk i rygg eller mage, värk när du kissar eller blod i urinen eftersom dessa symtom kan

tyda på njursten

utvecklar synbesvär såsom ögonsmärta eller dimsyn medan du använder Zonisamide Accord.

Kontakta din läkare snarast möjligt om du:

får oförklarliga hudutslag eftersom dessa kan utvecklas till allvarligare utslag eller hudfjällning.

känner dig ovanligt trött eller febrig, har ont i halsen, svullna körtlar eller har märkt att du lätt

får blåmärken, eftersom dessa symtom kan betyda att du har en blodrubbning.

har tecken på en ökad surhetsgrad i blodet – får huvudvärk, blir dåsig, andfådd eller förlorar

aptiten. Detta måste eventuellt kontrolleras eller behandlas av läkare.

Din läkare kan bestämma att du bör sluta använda Zonisamide Accord.

De vanligaste biverkningarna av Zonisamide Accord är lindriga. De uppstår under den första månaden

av behandlingen och avtar vanligen under fortsatt behandling. Hos barn i åldern 6 till 17 år var

biverkningarna förenliga med de som beskrivs nedan med följande undantag: lunginflammation,

uttorkning, minskad svettning (vanligt) och onormala leverenzymer (mindre vanligt).

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

rastlöshet, irritabilitet, förvirring, depression

dålig muskelkoordination, yrsel, dåligt minne, sömnighet, dubbelseende

minskad aptit, minskad halt bikarbonat i blodet (ett ämne som förebygger försurning av blodet).

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

sömnsvårigheter, främmande eller ovanliga tankar, ångestkänslor eller känslosamhet

långsam tankegång, nedsatt koncentrationsförmåga, talsvårigheter, onormala hudförnimmelser

(stickningar och domningar), darrningar, ofrivilliga ögonrörelser

njursten

hudutslag, klåda, allergiska reaktioner, feber, trötthet, influensaliknande symtom, håravfall

ekkymos (ett litet blåmärke orsakat av blod från ett läckande blodkärl i huden)

viktminskning, illamående, matsmältningsbesvär, magsmärtor, diarré (lös avföring),

förstoppning

svullnad i fötter och ben.

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

vrede, aggression, självmordstankar, självmordsförsök

kräkningar

inflammation i gallblåsa, gallsten

sten i urinvägarna

lunginfektion/-inflammation, urinvägsinfektion

låg kaliumhalt i blodet, kramper/anfall.

Mycket sällsynta (kan förekomma hos upp till 1 av 10 000 användare):

hallucinationer, minnesförlust, koma, malignt neuroleptiskt syndrom (oförmåga att röra sig,

svettning, feber, inkontinens), förlängda eller upprepade epilepsianfall

andningsbesvär, andfåddhet, lunginflammation

inflammation i bukspottkörteln (svår smärta i mage eller rygg)

leverproblem, njursvikt, förhöjt kreatinin i blodet (en avfallsprodukt som vanligen förs bort av

njurarna)

svåra hudutslag eller hudfjällning (samtidigt som du kan känna dig dålig eller få feber)

onormal muskelnedbrytning (du kan ha muskelvärk eller musklerna känns svaga) som kan leda

till njurproblem

svullna körtlar, blodrubbningar (nedsatt antal blodkroppar som kan leda till infektion och få dig

att se blek ut, känna dig trött och febrig eller göra att du lättare får blåmärken)

nedsatt svettning, värmeslag.

glaukom, som innebär blockering av vätskeflödet i ögat vilket orsakar ökat tryck i ögat.

Ögonsmärta, dimsyn eller försämrad syn kan uppträda och vara tecken på glaukom.

Rapportering av biverkningar

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

eventuella biverkningar som inte nämns i denna information. Genom att rapportera biverkningar kan

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

direkt via:

Läkemedelsverket

Box 26

751 03 Uppsala

www.lakemedelsverket.se

5.

Hur Zonisamide Accord ska förvaras

Förvara detta läkemedel utom syn- och räckhåll för barn.

Används före utgångsdatum som anges på kartongen och blistret efter ”Utg.dat.”. Utgångsdatumet är

den sista dagen i angiven månad.

Inga särskilda förvaringsanvisningar.

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

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

6.

Förpackningens innehåll och övriga upplysningar

Innehållsdeklaration

Den aktiva substansen är zonisamid. Zonisamide Accord 25 mg hårda kapslar innehåller 25 mg

zonisamid. Zonisamide Accord 50 mg hårda kapslar innehåller 50 mg zonisamid. Zonisamide

Accord 100 mg hårda kapslar innehåller 100 mg zonisamid.

Övriga innehållsämnen är:

Kapselns innehåll: mikrokristallin cellulosa, magnesiumstearat.

Kapselns skal: gelatin, titandioxid (E171), natriumlaurilsulfat, renat vatten, svart järnoxid

(E172) (50 mg hårda kapslar)

Tryckbläck: shellack, svart järnoxid (E172) och kaliumhydroxid.

Läkemedlets utseende och förpackningsstorlekar

Zonisamide Accord 25 mg hård kapsel

Vitt till benvitt granulärt pulver i hårda kapslar med vit till benvit kapselkropp och lock. Locket har

märkningen ”A730” i svart bläck.

Zonisamide Accord 50 mg hård kapsel

Vitt till benvitt granulärt pulver i hårda kapslar, storlek 3 (15,9 mm x 5,82 mm), med vit till benvit

kapselkropp och grått lock. Locket har märkningen ”A735” i svart.

Zonisamide Accord 100 mg hård kapsel

Vitt till benvitt granulärt pulver i hårda kapslar, storlek 1 (19,4 mm x 6,91 mm), med vit till benvit

kapselkropp och lock. Locket har märkningen ”A740” i svart bläck.

Zonisamide Accord kapslar är förpackade i blister som levereras i kartonger som innehåller:

25 mg: 14, 28 eller 56 hårda kapslar

50 mg: 14, 28 eller 56 hårda kapslar

100 mg: 28, 56, 98 eller 196 hårda kapslar

Eventuellt kommer inte alla förpackningsstorlekar att marknadsföras.

Innehavare av godkännande för försäljning och tillverkare

Innehavare av godkännande för försäljning:

Accord Healthcare B.V.

Winthontlaan 200

3526 KV Utrecht

Nederländerna

Tillverkare:

Balkanpharma-Dupnitsa AD, 3, Samokovsko shosse Str., 2600 Dupnitsa, Bulgarien

Denna bipacksedel ändrades senast 2021-05-05

Läs hela dokumentet

SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Zonisamide Accord 25 mg hard capsules.

Zonisamide Accord 50 mg hard capsules.

Zonisamide Accord 100 mg hard capsules.

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains 25 mg of zonisamide.

Each hard capsule contains 50 mg of zonisamide.

Each hard capsule contains 100 mg of zonisamide.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Hard capsules.

/…/ 25 mg hard capsules

White to off-white granular powder in hard capsules, size 4 (14.3 mm x 5.31 mm), with a white to

off-white capsule body and a white to off-white capsule cap. The cap is imprinted with “A730” in

black ink.

/…/ 50 mg hard capsules

White to off-white granular powder in hard capsules, size 3 (15.9 mm x 5.82 mm), with a white to

off-white capsule body and a grey capsule cap. The cap is imprinted with “A735” in black ink.

/…/ 100 mg hard capsules

White to off-white granular powder in hard capsules, size 1 (19.4 mm x 6.91 mm), with a white to

off-white capsule body and a white to off-white capsule cap. The cap is imprinted with “A740” in

black ink.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

/.../ is indicated as:

monotherapy in the treatment of partial seizures, with or without secondary generalisation, in

adults with newly diagnosed epilepsy (see section 5.1).

adjunctive therapy in the treatment of partial seizures, with or without secondary generalisation,

in adults, adolescents, and children aged 6 years and above.

4.2

Posology and method of administration

Posology

Adults

Dosage escalation and maintenance

/.../ may be taken as monotherapy or added to existing therapy in adults. The dose should be titrated

on the basis of clinical effect. Recommended escalation and maintenance doses are given in Table 1.

Some patients, especially those not taking CYP3A4-inducing agents, may respond to lower doses.

Withdrawal

When /.../ treatment is to be discontinued, it should be withdrawn gradually (see section 4.4). In

clinical studies of adult patients, dose reductions of 100 mg at weekly intervals have been used with

concurrent adjustment of other antiepileptic medicine doses (where necessary).

Table 1.

Adults – recommended dosage escalation and maintenance regimen

Treatment

Regimen

Titration Phase

Usual Maintenance

Dose

Week 1 + 2

Week 3 + 4

Week 5 + 6

Monotherapy

Newly diagnosed

adult patients

100 mg/day

(once a day)

200 mg /day

(once a day)

300 mg / day

(once a day)

300 mg per day

(once a day).

If a higher dose is

required: increase at

two-weekly intervals in

increments of 100 mg

up to a maximum of

500 mg.

Week 1

Week 2

Week 3 to 5

Adjunctive

therapy

- with CYP3A4-

inducing agents

(see section 4.5)

50 mg/day

(in two

divided doses)

100 mg /day

(in two divided

doses)

Increase at

weekly intervals

in increments of

100 mg

300 to 500 mg per day

(once a day or

two divided doses).

Week 1 + 2

Week 3 + 4

Week 5 to 10

- without

CYP3A4-inducing

agents; or with

renal or hepatic

impairment

50 mg/day

(in two

divided doses)

100 mg / day

(in two divided

doses)

Increase at

two-weekly

intervals

in increments of

up to 100 mg

300 to 500 mg per day

(once a day or

two divided doses).

Some patients may

respond to lower doses.

Paediatric population,

Dosage escalation and maintenance

/.../ must be added to existing therapy for paediatric patients aged 6 years and above. The dose should

be titrated on the basis of clinical effect. Recommended escalation and maintenance doses are given in

Table 2. Some patients, especially those not taking CYP3A4-inducing agents, may respond to lower

doses.

Physicians should draw the attention of paediatric patients and their parents/carers to the Patient Alert

Box (in the package leaflet) on preventing heatstroke (see section 4.4).

Table 2.

Paediatric population (aged 6 years and above) – recommended dosage escalation and

maintenance regimen

Treatment

Regimen

Titration Phase

Usual Maintenance Dose

Week 1

Weeks 2 to 8

Patients of weight

20 to 55 kg

a

Patients of

weight > 55 kg

Adjunctive

therapy

- with CYP3A4-

inducing agents

(see section 4.5)

1 mg/kg/day

(once a day)

Increase at

weekly intervals

in increments of

1 mg/kg

6 to 8 mg/kg/day

(once a day)

300 - 500 mg/day

(once a day)

Week 1 + 2

Weeks ≥ 3

- without

CYP3A4-inducing

agents

1 mg/kg/day

(once a day)

Increase at

two-weekly

intervals

increments of

1 mg/kg

6 to 8 mg/kg/day

(once a day)

300 - 500 mg/day

(once a day)

Note:

To ensure a therapeutic dose is maintained the weight of a child should be monitored and

the dose reviewed as weight changes occur up to a weight of 55 kg. The dose regime is

6-8mg/kg/day up to a maximum dose of 500 mg/day.

The safety and efficacy of /.../ in children aged below 6 years or those below 20 kg have not yet been

established.

There are limited data from clinical studies in patients with a body weight of less than 20 kg.

Therefore children aged 6 years and above and with a body weight less than 20 kg should be

treated with caution.

It is not always possible to precisely achieve the calculated dose with the commercially available

capsule strengths of /…/. In these cases it is therefore recommended that zonisamide total dose

should be rounded up or down to the nearest available dose that can be achieved with commercially

available capsule strengths of zonisamide.

Withdrawal

When /.../ treatment is to be discontinued, it should be withdrawn gradually (see section 4.4). In

clinical studies of paediatric patients, down-titration was completed by dose reductions at weekly

intervals in increments of about 2 mg/kg (i.e. in accordance with the schedule in Tablet 3).

Table 3.

Paediatric population (aged 6 years and above) – recommended down-titration

schedule

Weight

Decrease at weekly intervals in increments of:

20 – 28 kg

25 to 50 mg / day*

29 – 41 kg

50 to 75 mg / day*

42 – 55 kg

100 mg / day*

>55 kg

100 mg / day*

Note:

All doses are once daily.

Elderly

Caution should be exercised at initiation of treatment in elderly patients as there is limited information

on the use of /.../ in these patients. Prescribers should also take account of the safety profile of /.../ (see

section 4.8).

Patients with renal impairment

Caution must be exercised in treating patients with renal impairment, as there is limited information on

use in such patients and a slower titration of /.../ might be required. Since zonisamide and its

metabolites are excreted renally, it should be discontinued in patients who develop acute renal failure

or where a clinically significant sustained increase in serum creatinine is observed.

In subjects with renal impairment, renal clearance of single doses of zonisamide was positively

correlated with creatinine clearance. The plasma AUC of zonisamide was increased by 35 % in

subjects with creatinine clearance < 20 ml/min.

Patients with hepatic impairment

Use in patients with hepatic impairment has not been studied. Therefore use in patients with severe

hepatic impairment is not recommended. Caution must be exercised in treating patients with mild to

moderate hepatic impairment, and a slower titration of /.../ may be required.

Method of administration

/.../ hard capsules are for oral use.

/.../ may be taken with or without food (see section 5.2).

4.3

Contraindications

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

sulphonamides.

4.4

Special warnings and precautions for use

Unexplained rash

Serious rashes occur in association with /.../ therapy, including cases of Stevens-Johnson

syndrome.

Consideration must be given to discontinuing /.../ in patients who develop an otherwise unexplained

rash. All patients who develop a rash while taking /.../ must be closely supervised, with additional

levels of caution applied to those patients receiving concomitant antiepileptic agents that may

independently induce skin rashes.

Withdrawal seizures

In accordance with current clinical practice, discontinuation of /.../ in patients with epilepsy must be

accomplished by gradual dose reduction, to reduce the possibility of seizures on withdrawal. There are

insufficient data for the withdrawal of concomitant antiepileptic medicines once seizure control with

zonisamide has been achieved in the add-on situation, in order to reach monotherapy with /.../.

Therefore, withdrawal of concomitant anti-epileptic medicinal products must be undertaken with

caution.

Sulphonamide reactions

/.../ is a benzisoxazole derivative, which contains a sulphonamide group. Serious immune based

adverse reactions that are associated with medicinal products containing a sulphonamide group include

rash, allergic reaction and major haematological disturbances, including aplastic anaemia, which very

rarely can be fatal.

Cases of agranulocytosis, thrombocytopenia, leukopenia, aplastic anaemia, pancytopenia and

leucocytosis have been reported. There is inadequate information to assess the relationship, if any,

between dose and duration of treatment and these events.

Acute myopia and secondary angle closure glaucoma

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

reported in adult and paediatric patients receiving zonisamide. Symptoms include acute onset of

decreased visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, anterior

chamber shallowing, and ocular hyperaemia (redness) and increased intraocular pressure. This

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

and iris, with secondary angle closure glaucoma. Symptoms may occur within hours to weeks of

initiating therapy. Treatment includes discontinuation of zonisamide, as rapidly as possible in the

judgment of the treating physician, and appropriate measures to reduce intraocular pressure.

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

including permanent vision loss. Caution should be used when treating patients with history of eye

disorders with zonisamide.

Suicide ideation and behaviour

Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in

several indications. A meta-analysis of randomised placebo-controlled trials of anti-epileptic

medicinal products has also 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 /.../.

Therefore patients should be monitored for signs of suicidal ideation and behaviours 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.

Kidney stones

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.

Nephrolithiasis may lead to chronic kidney damage. Risk factors for nephrolithiasis include prior stone

formation, a family history of nephrolithiasis and hypercalciuria. None of these risk factors can

reliably predict stone formation during zonisamide treatment. In addition, patients taking other

medications associated with nephrolithiasis may be at increased risk. Increasing fluid intake and urine

output may help reduce the risk of stone formation, particularly in those with predisposing risk factors.

Metabolic acidosis

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

normal reference range in the absence of chronic respiratory alkalosis) is associated with /.../

treatment. This metabolic acidosis is caused by renal bicarbonate loss due to the inhibitory effect of

zonisamide on carbonic anhydrase. Such electrolyte imbalance has been observed with the use of /.../

in placebo-controlled clinical trials and in the post-marketing period. Generally, zonisamide- induced

metabolic acidosis occurs early in treatment although cases can occur at any time during treatment.

The amounts by which bicarbonate is decreased are usually small – moderate (average decrease of

approximately 3.5 mEq/l at daily doses of 300 mg in adults); rarely patients can experience more

severe decreases. Conditions or therapies that predispose to acidosis (such as renal disease, severe

respiratory disorders, status epilepticus, diarrhoea, surgery, ketogenic diet, or medicinal products) may

be additive to the bicarbonate lowering effects of zonisamide.

Metabolic acidosis has the potential to lead to hyperammonaemia, which has been reported with or

without encephalopathy during zonisamide treatment. The risk for hyperammonaemia may be

increased in patients concomitantly taking other medications that can cause hyperammonaemia (e.g.

valproate), or who have an underlying urea cycle disorder or reduced hepatic mitochondrial activity. In

patients who develop unexplained lethargy or changes in mental status during treatment with

zonisamide, it is recommended to consider hyperammonaemic encephalopathy and to measure

ammonia levels.

The risk of zonisamide induced metabolic acidosis appears to be more frequent and severe in younger

patients. Appropriate evaluation and monitoring of serum bicarbonate levels should be carried out in

patients taking zonisamide who have underlying conditions which might increase the risk of acidosis,

in patients who are at an increased risk of adverse consequences of metabolic acidosis and in patients

with symptoms suggestive of metabolic acidosis. If metabolic acidosis develops and persists,

consideration should be given to reducing the dose or discontinuing /.../ (by gradual discontinuation or

reduction of a therapeutic dose) as osteopenia may develop. If the decision is made to continue

patients on /.../ in the face of persistent acidosis, alkali treatment should be considered.

/.../ should be used with caution in adult patients being treated concomitantly with carbonic anhydrase

inhibitors such as topiramate or acetazolamide, as there are insufficient data to rule out a

pharmacodynamic interaction (see section 4.4 Paediatric population and 4.5).

Heat stroke

Cases of decreased sweating and elevated body temperature have been reported mainly in paediatric

patients (see section 4.4 Paediatric population for full warning). Caution should be used in adults when

/.../ is prescribed with other medicinal products that predispose patients to heat related disorders; these

include carbonic anhydrase inhibitors and medicinal products with anticholinergic activity (see ection

4.4 Paediatric population)

Pancreatitis

In patients taking /.../ who develop the clinical signs and symptoms of pancreatitis, it is recommended

that pancreatic lipase and amylase levels are monitored. If pancreatitis is evident, in the absence of

another obvious cause, it is recommended that discontinuation of /.../ be considered and appropriate

treatment initiated.

Rhabdomyolysis

In patients taking /.../, in whom severe muscle pain and/or weakness develop either in the presence or

absence of a fever, it is recommended that markers of muscle damage be assessed, including serum

creatine phosphokinase and aldolase levels. If elevated, in the absence of another obvious cause such

as trauma or grand mal seizures, it is recommended that /.../ discontinuation be considered and

appropriate treatment initiated.

Women of child-bearing potential

Women of child-bearing potential must use effective contraception during treatment with /.../ and for

one month after discontinuation (see section 4.6). /…/ must not be used in women of childbearing

potential not using effective contraception unless clearly necessary and only if the potential benefit is

considered to justify the risk to the foetus. Specialist advice should be given to women who are of

childbearing potential regarding the possible effects of /…/ on the foetus and these risks should be

discussed with the patient in relation to the benefits before starting treatment. Women planning a

pregnancy should meet with their specialists to reassess treatment with /…/ and to consider other

therapeutic options. Physicians treating patients with /.../ should ensure that patients are fully informed

about the need to use appropriate effective contraception, and should use clinical judgement when

assessing whether oral contraceptives (OCs), or the doses of the OC components, are adequate based

on the individual patient’s clinical situation.

Body weight

/.../ may cause weight loss. A dietary supplement or increased food intake may be considered if the

patient is losing weight or is underweight whilst on this medication. If substantial undesirable weight

loss occurs, discontinuation of /.../ should be considered. Weight loss is potentially more serious in

children (see section 4.4. Paediatric population).

Paediatric population

The warnings and precautions mentioned above are also applicable to adolescent and paediatric

patients. The warnings and precautions mentioned below are more relevant to paediatric and

adolescent patients.

Heat stroke and dehydration

Preventing overheating and dehydration in children

/.../ can cause children to sweat less and overheat and if the child is not treated this can lead to brain

damage and death. Children are most at risk especially in hot weather.

When a child is taking /.../:

The child should stay cool especially in hot weather

The child must avoid heavy exercise especially when the weather is hot

The child must drink plenty of cold water

The child must not take any of these medicines:

Carbonic anhydrase inhibitors (like topiramate and acetazolamide), and anticholinergic agents (like

clomipramine, hydroxyzine, diphenhydramine, haloperidol, imipramine and oxybutynin).

IF ANY OF THE FOLLOWING OCCUR, THE CHILD NEEDS URGENT MEDICAL

ATTENTION:

The skin feels very hot with little or no sweating, or the child becomes confused or has muscle cramps,

or the child’s heartbeat or breathing become rapid.

Take the child to a cool, shaded place

Keep the child's skin cool with water

Give the child cold water to drink

Cases of decreased sweating and elevated body temperature have been reported mainly in paediatric

patients. Heat stroke requiring hospital treatment was diagnosed in some cases. Heat stroke requiring

hospital treatment and leading to death has been reported. Most reports occurred during periods of

warm weather. Physicians should discuss with patients and their carers the potential seriousness of

heatstroke, situations in which it might arise, as well as action to take in the event of any signs or

symptoms. Patients or their carers must be warned to take care to maintain hydration and avoid

exposure to excessive temperatures and strenuous physical exercise depending on the condition of the

patient. Prescribers should draw the attention of paediatric patients and their parent/carers to the

advice in the Packaging Leaflet on preventingheatstroke and overheating in children as provided. In

the event of signs or symptoms of dehydration, oligohydrosis, or elevated body temperature,

discontinuation of /.../ should be considered.

/.../ should not be used as co-medication in paediatric patients with other medicinal products that

predispose patients to heat related disorders; these include carbonic anhydrase inhibitors and medicinal

products with anticholinergic activity.

Body weight

Weight loss leading to deterioration of general condition and failure to take anti-epilepsy medication

has been related to a fatal outcome (see section 4.8). /.../ is not recommended for paediatric patients

who are underweight (definition in accordance with the WHO age adjusted BMI categories) or have a

decreased appetite.

The incidence of decreased body weight is consistent across age groups (see section 4.8); however,

given the potential seriousness of weight loss in children, weight should be monitored in this

population. A dietary supplement or increased food intake should be considered if the patient is failing

to gain weight in accordance with growth charts, otherwise /.../ should be discontinued.

There are limited data from clinical studies in patients with a body weight of less than 20 kg.

Therefore children aged 6 years and above with a body weight of less than 20 kg should be treated

with caution. The long term effect of weight loss in the paediatric population on growth and

development is unknown.

Metabolic acidosis

The risk of zonisamide induced metabolic acidosis appears to be more frequent and severe in

paediatric and adolescent patients. Appropriate evaluation and monitoring of serum bicarbonate levels

should be carried out in this population (see section 4.4 - Metabolic acidosis for full warning; and 4.8

for incidence of low bicarbonate). The long term effect of low bicarbonate levels on growth and

development is unknown.

/.../ should not be used as co-medication in paediatric patients with other carbonic anhydrase inhibitors

such as topiramate and acetazolamide (see section 4.5).

Kidney stones

Kidney stones have occurred in paediatric patients (see section 4.4.). 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. Nephrolithiasis may lead

to chronic kidney damage. Risk factors for nephrolithiasis include prior stone formation, a family

history of nephrolithiasis and hypercalciuria. None of these risk factors can reliably predict stone

formation during zonisamide treatment. Increasing fluid intake and urine output may help reduce the

risk of stone formation, particularly in those with predisposing risk factors. Renal ultrasound should be

performed at the discretion of the physician. In the event kidney stones are detected, /.../ should be

discontinued.

Hepatic dysfunction

Increased levels of hepatobiliary parameters such as alanine aminotransferase (ALT), aspartate

aminotransferase (AST), gamma-glutamyltransferase (GGT) and bilirubin have occurred in paediatric

and adolescent patients, without any consistent pattern in the observations of values above the upper

limit of normal. Nevertheless, if a hepatic event is suspected, liver function should be evaluated and

discontinuation of /.../ should be considered.

Cognition

Cognitive impairment in patients affected by epilepsy has been associated with the underlying

pathology and/or the administration of anti-epileptic treatment. In a zonisamide placebo-controlled

study conducted in paediatric and adolescent patients, the proportion of patients with impaired

cognition was numerically greater in the zonisamide group compared with the placebo group.

4.5

Interaction with other medicinal products and other forms of interaction

Effect of /.../ on cytochrome P450 enzymes

In vitro studies using human liver microsomes show no or little (<25 %) inhibition of cytochrome

P450 isozymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 or 3A4 at zonisamide levels approximately

two- fold or greater than clinically relevant unbound serum concentrations. Therefore, /.../ is not

expected to affect the pharmacokinetics of other medicinal products via cytochrome P450-mediated

mechanisms, as demonstrated for carbamazepine, phenytoin, ethinylestradiol and desipramine in vivo.

Potential for /.../ to affect other medicinal products

Anti-epileptic medicinal products

In epileptic patients, steady-state dosing with zonisamide resulted in no clinically relevant

pharmacokinetic effects on carbamazepine, lamotrigine, phenytoin, or sodium valproate.

Oral contraceptives

In clinical studies in healthy subjects, steady-state dosing with zonisamide did not affect serum

concentrations of ethinylestradiol or norethisterone in a combined oral contraceptive.

Carbonic anhydrase inhibitors

/.../ should be used with caution in adult patients treated concomitantly with carbonic anhydrase

inhibitors such as topiramate and acetazolamide, as there are insufficient data to rule out a possible

pharmacodynamic interaction (see section 4.4).

/.../ should not be used as co-medication in paediatric patients with other carbonic anhydrase inhibitors

such as topiramate and acetazolamide (see section 4.4).

P-gp substrate

An in vitro study shows that zonisamide is a weak inhibitor of P-gp (MDR1) with an IC

267 µmol/l and there is the theoretical potential for zonisamide to affect the pharmacokinetics of

substances which are P-gp substrates. Caution is advised when starting or stopping zonisamide

treatment or changing the zonisamide dose in patients who are also receiving medicinal products

which are P-gp substrates (e.g. digoxin, quinidine).

Potential medicinal product interactions affecting /.../

In clinical studies co-administration of lamotrigine had no apparent effect on zonisamide

pharmacokinetics. The combination of /.../ with other medicinal products that may lead to urolithiasis

may enhance the risk of developing kidney stones; therefore the concomitant administration of such

medicinal products should be avoided.

Zonisamide is metabolised partly by CYP3A4 (reductive cleavage), and also by N-acetyl-transferases

and conjugation with glucuronic acid; therefore, substances that can induce or inhibit these enzymes

may affect the pharmacokinetics of zonisamide:

Enzyme induction: Exposure to zonisamide is lower in epileptic patients receiving

CYP3A4-inducing agents such as phenytoin, carbamazepine, and phenobarbitone. These effects

are unlikely to be of clinical significance when /.../ is added to existing therapy; however,

changes in zonisamide concentrations may occur if concomitant CYP3A4-inducing anti-

epileptic or other medicinal products are withdrawn, dose adjusted or introduced, an adjustment

of the /.../ dose may be required. Rifampicin is a potent CYP3A4 inducer. If co-administration is

necessary, the patient should be closely monitored and the dose of /.../ and other CYP3A4

substrates adjusted as needed.

CYP3A4 inhibition: Based upon clinical data, known specific and non-specific CYP3A4

inhibitors appear to have no clinically relevant effect on zonisamide pharmacokinetic exposure

parameters. Steady-state dosing of either ketoconazole (400 mg/day) or cimetidine

(1200 mg/day) had no clinically relevant effects on the single-dose pharmacokinetics of

zonisamide given to healthy subjects. Therefore, modification of /.../ dosing should not be

necessary when co-administered with known CYP3A4 inhibitors.

Paediatric population

Interaction studies have only been performed in adults.

4.6

Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential must use effective contraception during treatment with /.../, and for

one month after discontinuation.

/…/ must not be used in women of childbearing potential not using effective contraception unless

clearly necessary and only if the potential benefit is considered to justify the risk to the foetus.

Specialist medical advice should be given to women treated with zonisamide who are of childbearing

potential. Women planning a pregnancy should meet with their specialists to reassess treatment with

zonisamide and to consider other therapeutic options.

As with all antiepileptic medicines, sudden discontinuation of zonisamide should be avoided as this

may lead to breakthrough seizures that could have serious consequences for the woman and the

unborn child. The risk of birth defect is increased by factor 2 to 3 in the offspring of mothers treated

with an antiepileptic medicinal product. The most frequently reported are cleft lip, cardiovascular

malformations and neural tube defect. Multiple antiepileptic medicinal product therapy may be

associated with a higher risk of congenital malformations than monotherapy.

Pregnancy

There are limited data from the use of /.../ in pregnant women. Studies in animals have shown

reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Data from a registry study suggest an increase in the proportion of babies born at a low birth

weight (LBW), pre-term or small for gestational age (SGA). These increases are from about 5% to

8% for LBW, from about 8% to 10% for pre-term birth and from about 7% to 12% for SGA, all

compared with mothers treated with lamotrigine monotherapy.

/.../ must not be used during pregnancy unless clearly necessary and only if the potential benefit is

considered to justify the risk to the foetus. If /…/is prescribed during pregnancy, patients should be

fully informed of the potential harm to the foetus and use of the minimal effective dose is advised

along with careful monitoring.

Breastfeeding

Zonisamide is excreted in human milk; the concentration in breast milk is similar to maternal plasma.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from /.../

therapy. Due to the long retention time of zonisamide in the body, breast-feeding must not be resumed

until one month after /.../ therapy is completed.

Fertility

There are no clinical data available on the effects of zonisamide on human fertility. Studies in animals

have shown changes in fertility parameters (see section 5.3).

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. However,

given that some patients may experience drowsiness or difficulty with concentration, particularly early

in treatment or after a dose increase, patients must be advised to exercise caution during activities

requiring a high degree of alertness, e.g., driving or operating machines.

4.8

Undesirable effects

Summary of the safety profile

Zonisamide has been administered to over 1,200 patients in clinical studies, more than 400 of whom

received zonisamide for at least 1 year. In addition there has been extensive post-marketing experience

with zonisamide in Japan since 1989 and in the USA since 2000.

It should be noted that /.../ is a benzisoxazole derivative, which contains a sulphonamide group.

Serious immune based adverse reactions that are associated with medicinal products containing a

sulphonamide group include rash, allergic reaction and major haematological disturbances including

aplastic anaemia, which very rarely can be fatal (see section 4.4).

The most common adverse reactions in controlled adjunctive-therapy studies were somnolence,

dizziness and anorexia. The most common adverse reactions in a randomised, controlled monotherapy

trial comparing zonisamide with carbamazepine prolonged release were decreased bicarbonate,

decreased appetite, and decreased weight. The incidence of markedly abnormally low serum

bicarbonate (a decrease to less than 17 mEq/l and by more than 5 mEq/l) was 3.8 %. The incidence of

marked decreases in weight of 20 % or more was 0.7 %.

Tabulated list of adverse reactions

Adverse reactions associated with zonisamide obtained from clinical studies and post-marketing

surveillance are tabulated below. The frequencies are arranged according to the following scheme:

very common ≥ 1/10

common

≥ 1/100 to < 1/10

uncommon

≥ 1/1,000 to < 1/100

rare

≥ 1/10,000 to < 1/1,000

very rare

< 1/10,000

not known

cannot be estimated from the available data

Table 4.

Adverse reactions associated with zonisamide obtained from adjunctive use clinical

studies and post-marketing surveillance

System Organ

Class

(MedDRA

terminology)

Very

Common

Common

Uncommon

Very Rare

Infections and

infestation

Pneumonia,

Urinary tract

infection

Blood and

lymphatic

system disorders

Ecchymosis

Agranulocytosis,

Aplastic anaemia,

Leucocytosis,

Leucopoenia,

Lymphadenopathy,

Pancytopenia,

Thrombocytopenia

Immune system

disorders

Hypersensitivity

Drug-induced

hypersensitivity syndrome,

Drug rash with eosinophilia

and systemic symptoms

Metabolism and

nutrition

disorders

Anorexia

Hypokalaemia

Metabolic acidosis,

Renal tubular acidosis

Psychiatric

Disorders

Agitation,

Irritability,

Confusional

state,

Depression

Affect lability,

Anxiety,

Insomnia,

Psychotic

disorder

Anger,

Aggression,

Suicidal ideation,

Suicide attempt

Hallucination

Nervous system

disorders

Ataxia,

Dizziness,

Memory

impairment,

Somnolence

Bradyphrenia,

Disturbance in

attention,

Nystagmus,

Paraesthesia,

Speech disorder,

Tremor

Convulsion

Amnesia,

Coma,

Grand mal seizure,

Myasthenic syndrome,

Neuroleptic malignant

syndrome,

Status epilepticus

Eye disorders

Diplopia

Angle closure

glaucoma,

Eye pain,

Myopia,

Vision blurred,

Visual acuity reduced,

System Organ

Class

(MedDRA

terminology)

Very

Common

Common

Uncommon

Very Rare

Respiratory,

thoracic and

mediastinal

disorders

Dyspnoea,

Pneumonia aspiration,

Respiratory disorder,

Hypersensitivity-type

Pneumonitis

Gastrointestinal

disorders

Abdominal pain,

Constipation,

Diarrhoea,

Dyspepsia,

Nausea

Vomiting

Pancreatitis

Hepatobiliary

disorders

Cholecystitis,

Cholelithiasis

Hepatocellular damage

Skin and

subcutaneous

tissue disorders

Rash,

Pruritus,

Alopecia

Anhidrosis,

Erythema multiforme,

Stevens-Johnson syndrome,

Toxic epidermal necrolysis

Musculoskeletal

and connective

tissue disorders

Rhabdomyolysis

Renal and

urinary

disorders

Nephrolithiasis

Calculus urinary

Hydronephrosis,

Renal failure,

Urine abnormality

General

disorders and

administration

site conditions

Fatigue,

Influenza-like

illness,

Pyrexia,

Oedema

peripheral

Investigations

Decreased

bicarbonate

Weight decreased

Blood creatine

phosphokinase increased,

Blood creatinine increased,

Blood urea increased,

Liver function tests

abnormal

Injury,

poisoning and

procedural

complications

Heat stroke

In addition there have been isolated cases of Sudden Unexplained Death in Epilepsy Patients (SUDEP)

receiving zonisamide.

Table 5

Adverse reactions in a randomised, controlled monotherapy trial comparing

zonisamide with carbamazepine prolonged release

System Organ Class

(MedDRA terminology†)

Very Common

Common

Uncommon

Infections and

infestation

Urinary tract infection,

Pneumonia

Blood and lymphatic

disorders

Leukopenia,

Thrombocytopenia

Metabolism and

nutrition disorders

Decreased appetite

Hypokalaemia

Psychiatric Disorders

Agitation,

Depression,

Insomnia,

Mood swings,

Anxiety

Confusional state,

Acute psychosis,

Aggression,

Suicidal ideation,

Hallucination

Nervous system

disorders

Ataxia,

Dizziness,

Memory impairment,

Somnolence,

Bradyphrenia,

Disturbance in attention,

Paraesthesia

Nystagmus,

Speech disorder,

Tremor,

Convulsion

Eye disorders

Diplopia

Respiratory, thoracic

and mediastinal

disorders

Respiratory disorder

Gastrointestinal

disorders

Constipation,

Diarrhoea,

Dyspepsia,

Nausea,

Vomiting

Abdominal pain

Hepatobiliary disorders

Cholecystitis acute

Skin and subcutaneous

tissue disorders

Rash

Pruritus,

Ecchymosis

General disorders and

administration site

conditions

Fatigue,

Pyrexia,

Irritability

Investigations

Decreased

bicarbonate

Weight decreased,

Blood creatinine

phosphokinase increased,

Alanine aminotransferase

increased,

Aspartate aminotransferase

increased

Urine analysis

abnormal

† MedDRA version 13.1

Additional information on special populations

Elderly

A pooled analysis of safety data on 95 elderly subjects has shown a relatively higher reporting

frequency of oedema peripheral and pruritus compared to the adult population.

Review of post-marketing data suggests that patients aged 65 years or older report a higher frequency

than the general population of the following events: Stevens-Johnson syndrome (SJS) and Drug

Induced Hypersensitivity syndrome (DIHS).

Paediatric population

The adverse event profile of zonisamide in paediatric patients aged 6 to 17 years in placebo-controlled

clinical studies was consistent with that of adults. Among 465 subjects in the paediatric safety

database (including a further 67 subjects from the extension phase of the controlled clinical trial) there

were 7 deaths (1.5 %; 14.6/1000 person-years): 2 cases of status epilepticus, of which one was related

to severe weight loss (10 % within 3 months) in an underweight subject and subsequent failure to take

medication; 1 case of head injury/haematoma, and 4 deaths in subjects with pre-existing functional

neurological deficits for various causes (2 cases of pneumonia-induced sepsis/organ failure, 1 SUDEP

and 1 head injury). A total of 70.4 % of paediatric subjects who received ZNS in the controlled study

or its open label extension had at least one treatment-emergent bicarbonate measurement below

22 mmol/L. The duration of low bicarbonate measurements was also long (median 188 days). A

pooled analysis of safety data on 420 paediatric subjects (183 subjects aged 6 to 11 years, and 237

subjects aged 12 to 16 years with a mean duration of exposure of approximately 12 months) has

shown a relatively higher reporting frequency of pneumonia, dehydration, decreased sweating,

abnormal liver function tests, otitis media, pharyngitis, sinusitis and upper respiratory tract infection,

cough, epistaxis and rhinitis, abdominal pain, vomiting, rash and eczema, and fever compared to the

adult population (particularly in subjects aged below 12 years) and, at a low incidence, amnesia,

creatinine increased, lymphadenopathy, and thrombocytopenia. The incidence of a decrease in body

weight of 10 % or more was 10.7 % (see section 4.4). In some cases of weight decrease there was a

delay in transition to the next Tanner stage and in bone maturation.

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

There have been cases of accidental and intentional overdose in adult and paediatric patients. In some

cases, the overdoses were asymptomatic, particularly where emesis or lavage was prompt. In other

cases, the overdose was followed by symptoms such as somnolence, nausea, gastritis, nystagmus,

myoclonus, coma, bradycardia, reduced renal function, hypotension and respiratory depression.

A very high plasma concentration of 100.1 μg/ml zonisamide was recorded approximately 31 hours

after a patient took an overdose of zonisamide and clonazepam; the patient became comatose and had

respiratory depression, but recovered consciousness five days later and had no sequelae.

Treatment

No specific antidotes for /.../ overdose are available. Following a suspected recent overdose, emptying

the stomach by gastric lavage or by induction of emesis may be indicated with the usual precautions to

protect the airway. General supportive care is indicated, including frequent monitoring of vital signs

and close observation. Zonisamide has a long elimination half-life so its effects may be persistent.

Although not formally studied for the treatment of overdose, haemodialysis reduced plasma

concentrations of zonisamide in a patient with reduced renal function, and may be considered as

treatment of overdose if clinically indicated.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Antiepileptics, other antiepileptics, ATC code: N03AX15

Zonisamide is a benzisoxazole derivative. It is an anti-epileptic medicine with weak carbonic

anhydrase activity

in-vitro

. It is chemically unrelated to other anti-epileptic agents.

Mechanism of action

The mechanism of action of zonisamide is not fully elucidated, but it appears to act on voltage-

sensitive sodium and calcium channels, thereby disrupting synchronised neuronal firing, reducing the

spread of seizure discharges and disrupting subsequent epileptic activity. Zonisamide also has a

modulatory effect on GABA-mediated neuronal inhibition.

Pharmacodynamic effects

The anticonvulsant activity of zonisamide has been evaluated in a variety of models, in several species

with induced or innate seizures, and zonisamide appears to act as a broad-spectrum anti-epileptic in

these models. Zonisamide prevents maximal electroshock seizures and restricts seizure spread,

including the propagation of seizures from cortex to sub-cortical structures and suppresses

epileptogenic focus activity. Unlike phenytoin and carbamazepine however, zonisamide acts

preferentially on seizures originating in the cortex.

Clinical efficacy and safety

Monotherapy in partial seizures, with or without secondary generalisation

Efficacy of zonisamide as monotherapy was established in a double-blind, parallel group, non-

inferiority comparison to carbamazepine prolonged release (PR) in 583 adult subjects with newly

diagnosed partial seizures with or without secondary generalised tonic-clonic seizures. Subjects were

randomised to carbamazepine and zonisamide received treatment for a duration of up to 24 months

depending on response. Subjects were titrated to the initial target dose of 600 mg carbamazepine or

300 mg of zonisamide. Subjects who experienced a seizure were titrated to the next target dose i.e.

800 mg carbamazepine or 400 mg of zonisamide. Subjects who experienced a further seizure were

titrated to the maximal target dose of 1200 mg carbamazepine or 500 mg zonisamide. Subjects who

were seizure-free for 26 weeks at a target dose level continued on this dose for another 26 weeks.

Main outcomes of this study are presented in this table:

Table 6

Efficacy results for Monotherapy Study 310

Zonisamide

Carbamazepine

n (ITT population)

Six months seizure freedom

Diff

PP-population*

79.4%

83.7%

-4.5%

-12.2% ; 3.1%

ITT-population

< 4 seizures during 3 month

baseline period

> 4 seizures during 3 month

baseline period

69.4%

71.7%

52.9%

74.7%

75.7%

68.9%

-6.1%

-4.0%

-15.9%

-13.6% ; 1.4%

-11.7% ; 3.7%

-37.5% ; 5.6%

Twelve months seizure freedom

PP-population

67.6%

74.7%

-7.9%

- 17.2% ; 1.5%

ITT-population

< 4 seizures during 3 month

baseline period

> 4 seizures during 3 month

baseline period

55.9%

57.4%

44.1%

62.3%

64.7%

48.9%

-7.7%

-7.2%

-4.8%

- 16.1% ; 0.7%

-15.7% ; 1.3%

-26.9% ; 17.4%

Seizure sub-type (6 month

seizure freedom-PP population)

All partial

Simple partial

Complex partial

All generalized Tonic-Clonic

Secondary Tonic-Clonic

Generalized Tonic-Clonic

76.4%

72.3%

76.9%

78.9%

77.4%

85.7%

86.0%

75.0%

93.0%

81.6%

80.0%

92.0%

-9.6%

-2.7%

-16.1%

2.8%

-2.6%

-6.3%

-19.2% ; 0.0%

-20.0% ; 14.7%

-26.3% ; -5.9%

-11.5% ; 6.0%

-12.4% ; 7.1%

-23.1% ; 10.5%

PP = Per Protocol Population; ITT = Intent To Treat Population

*Primary endpoint

Adjunctive therapy in the treatment of partial seizures, with or without secondary generalisation in

adults

In adults, efficacy has been demonstrated with zonisamide in 4 double-blind, placebo-controlled

studies of periods of up to 24 weeks with either once or twice daily dosing. These studies show that

the median reduction in partial seizure frequency is related to zonisamide dose with sustained efficacy

at doses of 300-500 mg per day.

Paediatric population

Adjunctive therapy in the treatment of partial seizures, with or without secondary generalisation, in

adolescent and paediatric patients (aged 6 years and above)

In paediatric patients (aged 6 years and above), efficacy has been demonstrated with zonisamide in a

double-blind, placebo-controlled study, which included 207 subjects and had a treatment duration of

up to 24 weeks. A 50 % or greater reduction from baseline in seizure frequency during the 12-week

stable dose period was seen in 50 % of the zonisamide-treated subjects and 31 % of the patients on

placebo.

Specific safety issues that were encountered in the paediatric studies were: decreased appetite and

weight loss, decreased bicarbonate levels, increased risk of kidney stones and dehydration. All these

effects and specifically weight loss may have deleterious implications for growth and development,

and may lead to general deterioration of health. Altogether, data on effects on long-term growth and

development are limited.

5.2

Pharmacokinetic properties

Absorption

Zonisamide is almost completely absorbed after oral administration, generally reaching peak serum or

plasma concentrations within 2 to 5 hours of dosing. The first-pass metabolism is believed to be

negligible. Absolute bioavailability is estimated to be approximately 100 %. Oral bioavailability is not

affected by food, although peak plasma and serum concentrations may be delayed.

Zonisamide AUC and C

values increased almost linearly after single dose over the dose range of

100-800 mg and after multiple doses over the dose range of 100-400 mg once daily. The increase at

steady state was slightly more than expected on the basis of dose, probably due to the saturable

binding of zonisamide to erythrocytes. Steady state was achieved within 13 days. Slightly greater than

expected accumulation occurs relative to single dosing.

Distribution

Zonisamide is 40-50 % bound to human plasma proteins, with in vitro studies showing that this is

unaffected by the presence of various antiepileptic medicinal products (i.e., phenytoin,

phenobarbitone, carbamazepine, and sodium valproate). The apparent volume of distribution is about

1.1-1.7 l/kg in adults indicating that zonisamide is extensively distributed to tissues.

Erythrocyte/plasma ratios are about 15 at low concentrations and about 3 at higher concentrations.

Biotransformation

Zonisamide is metabolised primarily through reductive cleavage of the benzisoxazole ring of the

parent drug by CYP3A4 to form 2-sulphamoylacetylphenol (SMAP) and also by N-acetylation. Parent

drug and SMAP can additionally be glucuronidated. The metabolites, which could not be detected in

plasma, are devoid of anticonvulsant activity. There is no evidence that zonisamide induces its own

metabolism.

Elimination

Apparent clearance of zonisamide at steady-state after oral administration is about 0.70 l/h and the

terminal elimination half-life is about 60 hours in the absence of CYP3A4 inducers. The elimination

half-life was independent of dose and not affected by repeat administration. Fluctuation in serum or

plasma concentrations over a dosing interval is low (< 30 %). The main route of excretion of

zonisamide metabolites and unchanged drug is via the urine. Renal clearance of unchanged

zonisamide is relatively low (approximately 3.5 ml/min); about 15-30 % of the dose is eliminated

unchanged.

Linearity / non-linearity

Zonisamide exposure increases with time until steady state is achieved by approximately 8 weeks.

When comparing the same dose level, subjects of higher total body weight appear to have lower

steady-state serum concentrations, but this effect appears to be relatively modest. Age (≥ 12 years) and

gender, after adjustment for body weight effects, have no apparent effect on zonisamide exposure in

epileptic patients during steady-state dosing. There is no need for dose adjustment with any of the

AEDs including CYP3A4 inducers.

Pharmacokinetic-pharmacodynamic relationship

Zonisamide lowers the 28-day average seizure frequency and the decrease is proportional (log-linear)

to zonisamide average concentration.

Special patient groups

In subjects with renal impairment

, renal clearance of single doses of zonisamide was positively

correlated with creatinine clearance. The plasma AUC of zonisamide was increased by 35 % in

subjects with creatinine clearance <20 ml/min (see also section 4.2.).

Patients with an impaired liver function

: The pharmacokinetics of zonisamide in patients with

impaired liver function have not been adequately studied.

Elderly

: No clinically significant differences were observed in the pharmacokinetics between young

(aged 21-40 years) and elderly (65-75 years).

Children and adolescents (5-18 years)

: Limited data indicate that pharmacokinetics in children and

adolescents dosed to steady state at 1, 7 or 12 mg/kg daily, in divided doses, are similar to those

observed in adults, after adjustment for bodyweight.

5.3

Preclinical safety data

Findings not observed in clinical studies, but seen in the dog at exposure levels similar to clinical use,

were liver changes (enlargement, dark-brown discolouration, mild hepatocyte enlargement with

concentric lamellar bodies in the cytoplasm and cytoplasmic vacuolation) associated with increased

metabolism.

Zonisamide was not genotoxic and has no carcinogenic potential.

Zonisamide caused developmental abnormalities in mice, rats, and dogs, and was embryolethal in

monkeys, when administered during the period of organogenesis at zonisamide dosage and maternal

plasma levels similar to or lower than therapeutic levels in humans.

In a repeated-dose oral toxicity study in juvenile rats, at exposure levels similar to those observed in

paediatric patients at the maximum recommended dose, decreases in body weight and changes in renal

histopathology and clinical pathology parameters and behavioural changes were observed. Changes in

renal histopathology and clinical pathology parameters were considered to be related to carbonic

anhydrase inhibition by zonisamide. The effects at this dose level were reversible during the recovery

period. At a higher dose level (2-3-fold systemic exposure compared to therapeutic exposure) renal

histopathological effects were more severe and only partially reversible. Most adverse effects

observed in the juvenile rats were similar to those seen in the repeated-dose toxicity studies of

zonisamide in adult rats, but renal tubular hyaline droplets and transitional hyperplasia were observed

in the juvenile study only. At this higher dose level, juvenile rats showed a decrease in growth,

learning, and developmental parameters. These effects were considered likely related to the decreased

body weight and exaggerated pharmacologic effects of zonisamide at the maximum tolerated dose.

In rats, decreased numbers of corpora lutea and implantation sites were observed at exposure levels

equivalent to the maximum therapeutic dose in humans; irregular oestrus cycles and a decreased

number of live foetuses were observed at exposure levels three times higher.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Capsule content

Microcrystalline cellulose

Magnesium Stearate

Capsule shell

/…/ 25 mg and 100 mg hard capsules

Titanium dioxide (E171)

Gelatin

Sodium laurilsulfate

Purified water

/…/ 50 mg hard capsules

Black iron oxide (E172)

Titanium dioxide (E171)

Gelatin

Sodium laurilsulfate

Purified water

Printing ink

Shellac

Black iron oxide (E172)

Potassium hydroxide

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

2 years

6.4

Special precautions for storage

This medicinal product does not require any special storage conditions

6.5

Nature and contents of container

25 mg and 50 mg

PVC/Aclar-aluminium blisters containing 14, 28 or 56 hard capsules.

100 mg

PVC/Aclar-aluminium blisters containing 28, 56, 98 or 196 hard capsules.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

No special requirements for disposal.

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

2021-08-25

<Detailed information on this medicinal product is available on the website of {name of

MS/Agency}>

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