Fluconazol Krka 200 mg Kapsel, hård

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

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Bipacksedel Bipacksedel (PIL)

24-08-2021

Produktens egenskaper Produktens egenskaper (SPC)

20-06-2017

Aktiva substanser:
flukonazol
Tillgänglig från:
Orifarm AB
ATC-kod:
J02AC01
INN (International namn):
fluconazole
Dos:
200 mg
Läkemedelsform:
Kapsel, hård
Sammansättning:
laktosmonohydrat Hjälpämne; flukonazol 200 mg Aktiv substans; azorubin Hjälpämne; natriumlaurilsulfat Hjälpämne
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Blister, 28 kapslar
Bemyndigande status:
Avregistrerad
Godkännandenummer:
58288
Tillstånd datum:
2019-01-30

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Bipacksedel Bipacksedel - engelska

05-06-2020

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22-06-2021

Läs hela dokumentet

Bipacksedel: Information till användaren

Fluconazol Krka 50 mg hårda kapslar

Fluconazol Krka 100 mg hårda kapslar

Fluconazol Krka 150 mg hårda kapslar

Fluconazol Krka 200 mg hårda kapslar

flukonazol

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, apotekspersonal eller sjuksköterska.

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, apotekspersonal eller sjuksköterska. Detta gäller även

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

I denna bipacksedel finns information om följande:

Vad Fluconazol Krka är och vad det används för

Vad du behöver veta innan du tar Fluconazol Krka

Hur du tar Fluconazol Krka

Eventuella biverkningar

Hur Fluconazol Krka ska förvaras

Förpackningens innehåll och övriga upplysningar

1.

Vad Fluconazol Krka är och vad det används för

Fluconazol Krka tillhör en grupp läkemedel som används mot svampinfektioner. Den aktiva

substansen är flukonazol.

Fluconazol Krka används för att behandla infektioner som orsakas av svamp, och kan också användas

för att förebygga att man får en svampinfektion. Den vanligaste orsaken till svampinfektioner är en

jästsvamp vid namn

Candida

Vuxna

Du kan få denna medicin av läkare för behandling av följande svampinfektioner:

hjärnhinneinflammation orsakad av kryptokocker – svampinfektion i hjärnan

koccidioidomykoser - en lungsjukdom

infektioner orsakade av

Candida

och som finns i blodbanan, inre organ (t.ex. hjärta, lungor)

eller urinvägarna

svampinfektioner i munnen som påverkar slemhinnan i mun, svalg och kan ge inflammation i

munslemhinnan vid användning av tandprotes

svampinfektion i slida eller på penis (genital svampinfektion)

hudinfektioner – t.ex. fotsvamp, ringorm, ljumsksvamp, nagelinfektion

Du kan också få Fluconazol Krka för att:

förebygga att hjärnhinneinflammation orsakad av kryptokocker återkommer

förebygga att svampinfektion i munnen återkommer

förebygga återkommande svampinfektion i slidan

förebygga infektioner orsakade av

Candida

(om du har försvagat immunförsvar)

Barn och ungdomar (0 till 17 år)

Du kan få denna medicin av din läkare för att behandla dessa typer av svampinfektioner:

svampinfektion i munnen – infektion som påverkar slemhinnan i mun och svalg

infektioner orsakade av

Candida

och som finns i blodbanan, inre organ (t.ex. hjärta, lungor)

eller urinvägarna

hjärnhinneinflammation orsakad av kryptokocker – svampinfektion i hjärnan

Du kan också få Fluconazol Krka för att:

förebygga infektioner orsakade av

Candida

(om du har försvagat immunförsvar)

förebygga att hjärnhinneinflammation orsakad av kryptokocker återkommer

Flukonazol som finns i Fluconazol Krka kan också vara godkänd för att behandla andra sjukdomar

som inte nämns i denna bipacksedel. Fråga läkare, apotek eller annan hälso- och sjukvårdspersonal om

du har ytterligare frågor och följ alltid deras instruktion.

2.

Vad du behöver veta innan du tar Fluconazol Krka

Ta inte Fluconazol Krka om du:

är allergisk mot flukonazol, andra läkemedel du har tagit för att behandla en svampinfektion,

eller något annat innehållsämne i detta läkemedel (anges i avsnitt 6). Symtomen kan vara

klåda, hudrodnad eller svårigheter att andas.

tar astemizol eller terfenadin (antihistamin för behandling av allergier)

tar cisaprid (mot magbesvär)

tar pimozid (används för behandling av psykiska besvär)

tar kinidin (används för behandling av oregelbunden hjärtrytm, ”arytmi”)

tar erytromycin (antibiotikum för behandling av infektioner)

Varningar och försiktighet

Tala med läkare eller apotekspersonal innan du tar Fluconazol Krka om du:

har lever eller njurproblem

har någon hjärtsjukdom, t.ex. oregelbunden hjärtrytm

har onormala halter av kalium, kalcium eller magnesium i blodet

Tala med din läkare om du:

utvecklar allvarliga hudreaktioner (klåda, rodnad av huden eller svårighet att andas)

någon gång har fått allvarliga hudutslag eller flagnande hud, blåsor och/eller sår i munnen

efter att ha tagit Fluconazol Krka

om du utvecklar tecken på binjurebarksinsufficiens, som innebär att binjurarna inte producerar

tillräckliga mängder av vissa steroidhormoner såsom kortisol (kronisk eller långvarig trötthet,

muskelsvaghet, minskad aptit, viktminskning, buksmärta).

om svampinfektionen inte blir bättre eftersom du kan behöva få en annan medicin mot

svampinfektion

Allvarliga hudreaktioner, däribland läkemedelsreaktion med eosinofili och systemiska symtom

(DRESS) har rapporterats i samband med behandling med Fluconazol Krka. Sluta att ta Fluconazol

Krka och uppsök omedelbart akutmottagning om du får något av de symtom på allvarliga

hudreakioner som beskrivs i avsnitt 4.

Andra läkemedel och Fluconazol Krka

Informera din läkare

omedelbart

om du tar astemizol, terfenadin (antihistamin för behandling av

allergier) eller cisaprid (mot magbesvär) eller pimozid (används för behandling av psykiska besvär)

eller kinidin (används för behandling av oregelbunden hjärtrytm, ”arytmi”) eller erytromycin

(antibiotikum för behandling av infektioner) då dessa inte ska tas tillsammans med Fluconazol Krka

(se avsnitt ”Ta inte Fluconazol Krka”).

Det finns några mediciner som kan påverkas av eller påverka Fluconazol Krka. Berätta för din läkare

om du tar någon av följande mediciner:

rifampicin, rifabutin (antibiotika mot infektioner)

alfentanil, fentanyl (används som bedövningsmedel)

amitriptylin, nortriptylin (används för behandling av depression)

amfotericin B, vorikonazol (mot svampinfektion)

blodförtunnande läkemedel (t.ex. warfarin) för att förhindra blodproppar

bensodiazepiner (t.ex. midazolam, triazolam) som används mot sömnlöshet eller ångest

karbamazepin, fenytoin (mot epilepsi)

nifedipin, isradipin, amlodipin, felodipin eller losartan (mot högt blodtryck)

olaparib (används för behandling av äggstockscancer)

ciklosporin, everolimus, sirolimus eller takrolimus (används efter transplantationer)

cyklofosfamid, vinkaalkaloider (t.ex. vinkristin, vinblastin) som används för att behandla

cancer.

halofantrim (mot malaria)

statiner (atorvastatin, simvastatin och fluvastatin) som används för att sänka kolesterolhalten i

blodet

metadon (mot smärta)

celecoxib, fluribiprofen, naproxen, ibuprofen, lornoxikam, meloxikam, diklofenak (icke-

steroida antiinflammatoriska läkemedel, NSAID)

p-piller

prednison (steroid)

zidovudin (även kallat AZT) eller sakvinavir (används vid behandling av HIV)

läkemedel mot diabetes såsom klorpropamid, glibenklamid, glipizid eller tolbutamid

teofyllin (mot astma)

tofacitinib (används för att behandla reumatoid artrit)

A-vitamin (näringstillskott)

ivakaftor (används för behandling av cystisk fibros)

amiodaron (används för behandling av oregelbunden hjärtrytm (arytmier)).

hydroklortiazid (vätskedrivande)

ibrutinib (används för behandling av blodcancer)

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

läkemedel.

Fluconazol Krka med mat och dryck

Läkemedlet kan tas oberoende av måltid

Graviditet och amning

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

eller apotekspersonal innan du använder detta läkemedel.

Du ska inte ta Fluconazol Krka om du är gravid, tror att du kan vara gravid eller planerar att skaffa

barn eller ammar, om inte din läkare har sagt åt dig att göra det.

Om flukonazol tas under den första trimestern av graviditeten kan risken för missfall öka. Om

flukonazol tas i låga doser under den första trimestern kan risken för att ett barn föds med

missbildningar som påverkar skelett och/eller muskler vara något ökad.

Du kan fortsätta amma efter intag av en engångsdos av Fluconazol Krka på 150 mg.

Du bör inte amma om du tar upprepade doser av Fluconazol Krka.

Körförmåga och användning av maskiner

Vid bilkörning eller när du använder maskiner bör du tänka på att du kan drabbas av yrsel eller

krampanfall under behandlingen.

Du är alltid 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.

Fluconazol Krka 50 mg, 100 mg och 150 mg hårda kapslar innehåller laktos och natrium

Kapslarna innehåller laktos. Om du inte tål vissa sockerarter, bör du kontakta din läkare innan du tar

denna medicin.

Detta läkemedel innehåller också mindre än 1 mmol natrium (23 mg) per kapsel, dvs det är näst intill

”natriumfritt”.

Flukonazol Krka 200 mg hårda kapslar innehåller laktos, natrium och azorubin

Kapslarna innehåller laktos. Om du inte tål vissa sockerarter, bör du kontakta din läkare innan du tar

denna medicin.

Detta läkemedel innehåller också mindre än 1 mmol natrium (23 mg) per kapsel, dvs det är näst intill

”natriumfritt”.

Fluconazol Krka 200 mg kapslar innehåller även färgämnet azorubin (E122) som kan ge allergiska

reaktioner.

3.

Hur du tar Fluconazol Krka

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

du är osäker.

Svälj kapseln hel med ett glas vatten. Du bör ta kapslarna vid samma tidpunkt varje dag.

I tabellen nedan visas de vanliga doserna för olika infektioner:

Vuxna

Infektion

För att behandla hjärnhinneinflammation

orsakad av kryptokocker

400 mg den första dagen, därefter 200 mg till

400 mg en gång dagligen under 6 till 8 veckor

eller längre vid behov. Ibland ökas dosen upp

till 800 mg

För att förebygga hjärnhinneinflammation

orsakad av kryptokocker

200 mg en gång dagligen tills läkaren säger att

du kan sluta

För att behandla koccidioidomykos

200 mg till 400 mg en gång dagligen från

11 månader upp till 24 månader eller längre vid

behov. Ibland ökas dosen upp till 800 mg

För att behandla invärtes svampinfektioner som

orsakats av

Candida

800 mg den första dagen, därefter 400 mg en

gång dagligen tills läkaren säger att du kan sluta

Svampinfektion i munnen som påverkar

slemhinnan i mun, svalg och kan ge

inflammation i munslemhinnan vid användning

av tandprotes

200 mg till 400 mg den första dagen, därefter

100 mg till 200 mg tills läkaren säger att du kan

sluta

För att behandla svampinfektion i munnen –

dosen beror på var infektionen sitter

50 mg till 400 mg en gång dagligen under 7 till

30 dagar tills läkaren säger att du kan sluta

För att förebygga svampinfektioner som

påverkar slemhinnan i mun och svalg

100 mg till 200 mg en gång dagligen eller

200 mg tre gånger per vecka så länge du löper

risk att få en infektion

För att behandla genital svampinfektion

150 mg som engångsdos

För att förebygga återkommande svampinfektion

i slidan

150 mg var tredje dag i totalt 3 doser (dag 1, 4

och 7) och sedan en gång per vecka i 6 månader

så länge du löper risk att få en infektion

För att behandla svampinfektioner på hud och

naglar

Beroende på ställe för infektionen 50 mg en

gång dagligen, 150 mg en gång per vecka, 300

till 400 mg en gång i veckan i 1 till 4 veckor

(upp till 6 veckor vid fotsvamp, vid behandling

av nagelinfektion tills den infekterade nageln

har ersatts)

För att förebygga infektioner orsakade av

Candida

(om du har försvagat immunförsvar)

200 mg till 400 mg en gång dagligen så länge du

löper risk att få en infektion

Ungdomar mellan 12 och 17 år

Använd dosen som läkaren ordinerar (enligt rekommendationerna för antingen vuxna eller barn).

Barn upp till 11 år

Den maximala dosen för barn är 400 mg dagligen.

Dosen baseras på barnets vikt i kg.

Infektion

Daglig dos

Svampinfektioner i munnen och halsinfektioner

som orsakats av

Candida

– dos och

behandlingslängd beror på hur svår infektionen

är och var den sitter

3 mg per kg kroppsvikt (6 mg per kg kroppsvikt

kan ges den första dagen)

Hjärnhinneinflammation som orsakats av

kryptokocker eller invärtes svampinfektioner

som orsakats av

Candida

6 mg till 12 mg per kg kroppsvikt

För att förebygga att barnet får infektioner

orsakade av

Candida

(om barnet har försvagat

immunförsvar)

3 mg till 12 mg per kg kroppsvikt

Barn mellan 0 och 4 veckor

Barn mellan 3 och 4 veckor:

Samma dos som ovan ges varannan dag. Maximal dos är 12 mg per kg kroppsvikt varannan dag

(48 timmar).

Barn yngre än 2 veckor:

Samma dos som ovan ges var tredje dag. Maximal dos är 12 mg per kg kroppsvikt var tredje dag

(72 timmar).

Läkaren kan ordinera andra doser än de som anges här. Använd alltid Fluconazol Krka enligt läkarens

anvisningar. Rådfråga läkare eller apotekspersonal om du är osäker.

Äldre

Den vanliga dosen för vuxna kan användas såvida du inte har njurproblem.

Patienter med njurproblem

Din läkare kan ändra dosen beroende på din njurfunktion.

Om du har tagit för stor mängd av Fluconazol Krka

Du kan må dåligt om du tar för många kapslar på en gång. Om du fått i dig för stor mängd Fluconazol

Krka eller om t.ex. ett barn fått i sig läkemedel av misstag, kontakta läkare, sjukhus eller

Giftinformationscentralen (tel. 112) för bedömning av risken samt rådgivning.

Symtomen på en möjlig överdos kan vara att du börja höra, se, känna och tänka saker som inte är på

riktigt (hallucinationer och paranoida beteenden). Behandling av symtomen och magsköljning kan

behövas vid överdosering.

Om du har glömt att ta Fluconazol Krka

Ta inte dubbel dos för att kompensera för glömd dos. Om du glömmer en dos, ta den så snart du

kommer ihåg det. Om det snart är dags för nästa dos ska du inte ta den glömda dosen.

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.

Några personer utvecklar

allergiska reaktioner

, även om det är sällsynt med allvarliga allergiska

reaktioner.

Om du får några av följande symtom

ska du genast kontakta läkare.

plötslig pipande andning, svårigheter att andas eller en trång känsla i bröstet

svullnad i ögonlock, ansikte eller läppar

klåda över hela kroppen, hudrodnad eller kliande, röda fläckar

hudutslag

svåra hudreaktioner, t.ex. ett utslag med blåsbildning (detta kan påverka mun och tunga)

Fluconazol Krka kan påverka din lever. Tecken på leverpåverkan inkluderar:

trötthet

minskad aptit

kräkningar

gulaktig hud eller gulaktiga ögonvitor (gulsot)

Sluta ta Fluconazol Krka och uppsök omedelbart akutmottagning om du upplever något av följande

symtom:

utbredda utslag, feber eller svullna lymfkörtlar (DRESS eller överkänslighetsreaktion mot

läkemedel).

Om något av detta inträffar, sluta ta Fluconazol Krka och

kontakta din läkare omedelbart

Andra biverkningar

Om några biverkningar blir värre eller om du märker några biverkningar som inte nämns i denna

information, kontakta läkare eller apotekspersonal.

Vanliga biverkningar: kan förekomma hos upp till 1 av 10 användare

huvudvärk

obehagskänsla i magen, diarré, illamående, kräkningar

förhöjda levervärden

hudutslag

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

minskad mängd röda blodkroppar vilket kan leda till blek hud och orsaka svaghet och

andfåddhet

minskad aptit

sömnsvårigheter, dåsighet

krampanfall, yrsel, snurrande känsla, myrkrypningar, stickningar eller domningar,

smakförändringar

förstoppning, matsmältningsbesvär, gasspänningar, muntorrhet

muskelsmärta

leverskador och gulfärgning av hud och ögon (gulsot)

strimmor i huden, blåsbildning (nässelutslag), klåda, svettningar

trötthet, allmän olustkänsla, feber

Sällsynta biverkningar: kan förekomma hos upp till 1 av 1000 användare

minskat antal vita blodkroppar som hjälper till att försvara kroppen mot infektioner och

minskat antal blodkroppar som hjälper till att stoppa blödningar

röd eller lila missfärgning av huden som kan orsakas av minskat antal blodplättar eller andra

förändringar i blodet

förhöjda blodkolesterol- och blodfettvärden

sänkt halt av kalium i blodet

skakningar

onormalt EKG, förändringar i puls eller hjärtrytm

leversvikt

allergiska reaktioner (ibland allvarliga), däribland utbredda utslag med blåsbildning och

flagande hud, svåra hudreaktioner och svullnad av läppar eller ansikte

håravfall

Ingen känd frekvens, men kan inträffa (kan inte beräknas från tillgängliga data):

överkänslighetsreaktion med hudutslag, feber, svullna körtlar, ökad mängd av en typ av vita

blodkroppar (eosinofili) och inflammation i inre organ (lever, lungor, hjärta, njurar och

tjocktarm) (så kallad ”läkemedelsreaktion med eosinofili och systemiska symtom”, (DRESS)).

Rapportering av biverkningar

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

www.lakemedelsverket.se

5.

Hur Fluconazol Krka ska förvaras

Förvara detta läkemedel utom syn- och räckhåll för barn.

Inga speciella förvaringsanvisningar.

Används före utgångsdatum som anges på kartongen efter EXP. Utgångsdatumet är den sista dagen i

angiven månad.

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 flukonazol: 50, 100, 150 eller 200 mg.

Övriga innehållsämnen är laktosmonohydrat, natriumlaurilsulfat, magnesiumstearat, vattenfri

kolloidal kiseldioxid och majsstärkelse.

Kapselhöljet till Fluconazol Krka 50 mg, 100 mg och 150 mg innehåller patentblått V (E131),

titandioxid (E171) och gelatin. Se avsnitt 2 ”Fluconazol Krka 50 mg, 100 mg och 150 mg

hårda kapslar innehåller laktos och natrium”.

Kapselhöljet till Fluconazol Krka 200 mg innehåller titandioxid (E171), azorubin (E122),

indigokarmin (E132) och gelatin. Se avsnitt 2 ”Fluconazol Krka 200 mg hårda kapslar

innehåller laktos, natrium och azorubin”.

Läkemedlets utseende och förpackningsstorlekar

50 mg: kapsel med blå överdel och vit underdel

100 mg: kapsel med blå överdel och vit underdel

150 mg: kapsel med blå överdel och blå underdel

200 mg: kapsel med violett överdel och vit underdel

Tryckförpackning

50 mg: 100 x 1, 7, 10, 20, 28, 50 och 98 kapslar

100 mg: 100 x 1, 7, 10, 20, 28, 50, 60 kapslar

150 mg: 1, 2, 4, 6, 12 kapslar

200 mg: 100 x 1, 7, 10, 20, 28, 30, 50 kapslar

Eventuellt kommer inte alla förpackningsstorlekar att marknadsföras.

Innehavare av godkännande för försäljning och tillverkare:

Innehavare av godkännande för försäljning

KRKA Sverige AB, Göta Ark 175, 118 72 Stockholm, Sverige

Tillverkare

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenien

Denna bipacksedel ändrades senast: 2021-06-21

Läs hela dokumentet

SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Fluconazol Krka 50 mg hard capsules

Fluconazol Krka 100 mg hard capsules

Fluconazol Krka 150 mg hard capsules

Fluconazol Krka 200 mg hard capsules

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Еаch hard capsule contains: Fluconazole 50 mg, 100 mg, 150 mg or 200 mg

Excipients with known effect:

50 mg capsules

100 mg

capsules

150 mg

capsules

200 mg capsules

Lactose monohydrate

49.8 mg

99.6 mg

149.4 mg

199.2 mg

Azorubine

0.05 mg

For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Hard capsule

Fluconazol Krka 50 mg: Blue/white capsule

Fluconazol Krka 100 mg: Blue/white capsule

Fluconazol Krka 150 mg: Blue/blue capsule

Fluconazol Krka 200 mg: Violet/white capsule

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Fluconazol Krka is indicated in the following fungal infections (see section 5.1).

Fluconazol Krka is indicated in adults for the treatment of:

Cryptococcal meningitis (see section 4.4).

Coccidioidomycosis (see section 4.4).

Invasive candidiasis.

Mucosal candidiasis including oropharyngeal, oesophageal candidiasis, candiduria and chronic

mucocutaneous candidiasis.

Chronic oral atrophic candidiasis (denture sore mouth) if dental hygiene or topical treatment are

insufficient.

Vaginal candidiasis, acute or recurrent; when local therapy is not appropriate.

Candidal balanitis

when local therapy is not appropriate.

Dermatomycosis including

tinea pedis

tinea corporis

tinea cruris

tinea versicolor

and dermal

candida

infections when systemic therapy is indicated.

Tinea unguinium (onychomycosis)

when other agents are not considered appropriate.

Fluconazol Krka is indicated in adults for the prophylaxis of:

Relapse of cryptococcal meningitis in patients with high risk of recurrence.

Relapse of oropharyngeal or oesophageal candidiasis in patients infected with HIV who are at

high risk of experiencing relapse.

To reduce the incidence of recurrent vaginal candidiasis (4 or more episodes a year).

Prophylaxis of candidal infections in patients with prolonged neutropenia (such as patients with

haematological malignancies receiving chemotherapy or patients receiving Hematopoietic Stem

Cell Transplantation (see section 5.1)).

Fluconazol Krka is indicated in term newborn infants, infants, toddlers, children, and adolescents aged

from 0 to 17 years old:

Fluconazol Krka is used for the treatment of mucosal candidiasis (oropharyngeal, oesophageal),

invasive candidiasis, cryptococcal meningitis and the prophylaxis of candidal infections in

immunocompromised patients. Fluconazol Krka can be used as maintenance therapy to prevent

relapse of cryptococcal meningitis in children with high risk of reoccurrence (see section 4.4).

Therapy may be instituted before the results of the cultures and other laboratory studies are known;

however, once these results become available, anti-infective therapy should be adjusted accordingly.

Considerationshould be given to official guidance on the appropriate use of antifungals.

4.2

Posology and method of administration

Posology

The dose should be based on the nature and severity of the fungal infection. Treatment of infections

requiring multiple dosing should be continued until clinical parameters or laboratory tests indicate that

active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of

active infection.

Adults

Indications

Posology

Duration of treatment

- Treatment of

cryptococcal

meningitis.

Loading dose:

400 mg on Day 1

Subsequent dose:

200 mg to 400

mg once daily

Usually at least 6 to 8 weeks.

In life threatening infections

the daily dose can be increased

to 800 mg

Cryptococcosis

- Maintenance

therapy to prevent

relapse of

cryptococcal

meningitis in

patients with high

risk of recurrence.

200 mg once

daily

Indefinitely at a daily dose of

200 mg

Coccidioidomycosis

200 mg to 400

11 months up to 24 months or

longer depending on the

patient. 800 mg daily may be

considered for some infections

and especially for meningeal

disease

Invasive candidiasis

Loading dose:

800 mg on Day 1

Subsequent dose:

400 mg once

daily

In general, the recommended

duration of therapy for

candidemia is for 2 weeks after

first negative blood culture

result and resolution of signs

and symptoms attributable to

candidemia.

- Oropharyngeal

candidiasis

Loading dose:

200 mg to 400

mg on Day 1

Subsequent dose:

100 mg to 200

mg once daily

7 to 21 days (until

oropharyngeal candidiasis is in

remission).

Longer periods may be used in

patients with severely

compromised immune function

- Oesophageal

candidiasis

Loading dose:

200 mg to 400

mg on Day 1

Subsequent dose:

100 mg to 200

mg once daily

14 to 30 days (until

oesophageal candidiasis is in

remission).

Longer periods may be used in

patients with severely

compromised immune function

- Candiduria

200 mg to 400

mg once daily

7 to 21 days. Longer periods

may be used in patients with

severely compromised immune

function.

- Chronic atrophic

candidiasis

50 mg once daily

14 days

Treatment of

mucosal candidiasis

- Chronic

mucocutaneous

candidiasis

50 mg to 100 mg

once daily

Up to 28 days. Longer periods

depending on both the severity

of infection or underlying

immune compromisation and

infection

- Oropharyngeal

candidiasis

100 mg to 200

mg once daily or

200 mg 3 times

per week

An indefinite period for

patients with chronic immune

suppression

Prevention of

relapse of mucosal

candidiasis in

patients infected

with HIV who are at

high risk of

experiencing relapse

- Oesophageal

candidiasis

100 mg to 200

mg once daily or

200 mg 3 times

per week

An indefinite period for

patients with chronic immune

suppression

- Acute vaginal

candidiasis

- Candidal balanitis

150 mg

Single dose

Genital candidiasis

- Treatment and

prophylaxis of

recurrent vaginal

candidiasis (4 or

more episodes a

year).

150 mg every

third day for a

total of 3 doses

(day 1, 4, and 7)

followed by 150

mg once weekly

maintenance dose

Maintenance dose: 6 months.

tinea pedis,

tinea corporis,

tinea cruris,

candida

infections

150 mg once

weekly or 50 mg

once daily

2 to 4 weeks,

tinea pedis

require treatment for up to 6

weeks

300 mg to 400

mg once weekly

1 to 3 weeks

tinea versicolor

50 mg once daily

2 to 4 weeks

Dermatomycosis

tinea unguium

onychomycosis

150 mg once

weekly

Treatment should be continued

until infected nail is replaced

(uninfected nail grows in).

Regrowth of fingernails and

toenails normally requires 3 to

6 months and 6 to 12 months,

respectively. However, growth

rates may vary widely in

individuals, and by age. After

successful treatment of long-

term chronic infections, nails

occasionally remain disfigured.

Prophylaxis of

candidal infections

in patients with

prolonged

neutropenia

200 mg to 400

Treatment should start several

days before the anticipated

onset of neutropenia and

continue for 7 days after

recovery from neutropenia

after the neutrophil count rises

above 1000 cells per mm3.

Special populations

Elderly

Dosage should be adjusted based on the renal function (see “

Renal impairment

”).

Renal impairment

Fluconazol Krka is predominantly excreted in the urine as unchanged active substance.

adjustments in single dose therapy are necessary. In patients (including paediatric population) with

impaired renal function who will receive multiple doses of fluconazole, an initial dose of 50 mg to 400

mg should be given, based on the recommended daily dose for the indication. After this initial loading

dose, the daily dose (according to indication) should be based on the following table:

Creatinine clearance (ml/min)

Percent of recommended dose

> 50

100%

≤ 50 (no haemodialysis)

Haemodialysis

100% after each haemodialysis

Patients on haemodialysis should receive 100% of the recommended dose after each haemodialysis;

on non-dialysis days, patients should receive a reduced dose according to their creatinine clearance.

Hepatic impairment

Limited data are available in patients with hepatic impairment, therefore fluconazole should be

administered with caution to patients with liver dysfunction (see sections 4.4 and 4.8).

Paediatric population

A maximum dose of 400 mg daily should not be exceeded in paediatric population.

As with similar infections in adults, the duration of treatment is based on the clinical and mycological

response. Fluconazol Krka is administered as a single daily dose.

For paediatric patients with impaired renal function, see dosing in “

Renal impairment

”. The

pharmacokinetics of fluconazole has not been studied in paediatric population with renal insufficiency

(for “Term newborn infants” who often exhibit primarily renal immaturity please see below).

Infants, toddlers and children (from 28 days to 11 years old):

Indication

Posology

Recommendations

Mucosal candidiasis

Initial dose: 6 mg/kg

Subsequent dose: 3 mg/kg daily

Initial dose may be used on

the first day to achieve

steady state levels more

rapidly

Invasive candidiasis

Cryptococcal meningitis

Dose: 6 to 12 mg/kg daily

Depending on the severity

of the disease

Maintenance therapy to

prevent relapse of cryptococcal

meningitis in children with

high risk of recurrence

Dose: 6 mg/kg daily

Depending on the severity

of the disease

Prophylaxis of

Candida

immunocompromised patients

Dose: 3 to 12 mg/kg daily

Depending on the extent

and duration of the induced

neutropenia (see Adults

posology)

Adolescents (from 12 to 17 years old):

Depending on the weight and pubertal development, the prescriber would need to assess which

posology (adults or children) is the most appropriate. Clinical data indicate that children have a higher

fluconazole clearance than observed for adults. A dose of 100, 200 and 400 mg in adults corresponds

to a 3, 6 and 12 mg/kg dose in children to obtain a comparable systemic exposure.

Safety and efficacy for genital candidiasis indication in paediatric population has not been established.

Current available safety data for other paediatric indications are described in section 4.8. If treatment

for genital candidiasis is imperative in adolescents (from 12 to 17 years old), the posology should be

the same as adults posology.

Term newborn infants (0 to 27 days):

Neonates excrete fluconazole slowly. There are few pharmacokinetic data to support this posology in

term newborn infants (see section 5.2).

Age group

Posology

Recommendations

Term newborn infants (0 to

14 days)

The same mg/kg dose as for infants,

toddlers and children should be given

every 72 hours

A maximum dose of 12

mg/kg every 72 hours

should not be exceeded

Term newborn infants (from

15 to 27 days)

The same mg/kg dose as for infants,

toddlers and children should be given

every 48 hours

A maximum dose of 12

mg/kg every 48 hours

should not be exceeded

Method of administration

Fluconazol Krka may be administered either orally or by intravenous infusion, the route being

dependent on the clinical state of the patient. On transferring from the intravenous to the oral route, or

vice versa

, there is no need to change the daily dose.

The physician should prescribe the most appropriate pharmaceutical form and strength according to

age, weight and dose. The capsule formulation is not adapted for use in infants and small children.

Oral liquid formulations of fluconazole are available that are more suitable in this population.

The capsules should be swallowed whole and independent of food intake.

4.3

Contraindications

Hypersensitivity to the active substance, to related azole substances, or to any of the excipients listed

in section 6.1.

Coadministration of terfenadine is contraindicated in patients receiving Fluconazol Krka at multiple

doses of 400 mg per day or higher based upon results of a multiple dose interaction study.

Coadministration of other medicinal products known to prolong the QT interval and which are

metabolised via the cytochrome P450 (CYP) 3A4 such as cisapride, astemizole, pimozide, quinidine

and erythromycin are contraindicated in patients receiving fluconazole (see sections 4.4 and 4.5).

4.4

Special warnings and precautions for use

Tinea capitis

Fluconazole has been studied for treatment of

tinea capitis

in children. It was shown not to be superior

to griseofulvin and the overall success rate was less than 20%. Therefore, Fluconazol Krka should not

be used for

tinea capitis.

Cryptococcosis

The evidence for efficacy of fluconazole in the treatment of cryptococcosis of other sites (e.g.

pulmonary and cutaneous cryptococcosis) is limited, which prevents dosing recommendations.

Deep endemic mycoses

The evidence for efficacy of fluconazole in the treatment of other forms of endemic mycoses such as

paracoccidioidomycosis, lymphocutaneous sporotrichosis

histoplasmosis

is limited, which

prevents specific dosing recommendations.

Candidiasis

Studies have shown an increasing prevalence of infections with

Candida

species other than

C. albicans

These are often inherently resistant (e.g.

C. krusei

C. auris

) or show reduced susceptibility to

fluconazole (

C. glabrata

). Such infections may require alternative antifungal therapy secondary to

treatment failure. Therefore, prescribers are advised to take into account the prevalence of resistance in

various

Candida

species to fluconazole.

Renal system

Fluconazol Krka should be administered with caution to patients with renal dysfunction (see section

4.2).

Hepatobiliary system

Fluconazol Krka should be administered with caution to patients with liver dysfunction.

Fluconazol Krka has been associated with rare cases of serious hepatic toxicity including fatalities,

primarily in patients with serious underlying medical conditions. In cases of fluconazole associated

hepatotoxicity, no obvious relationship to total daily dose, duration of therapy, sex or age of patient

has been observed. Fluconazole hepatotoxicity has usually been reversible on discontinuation of

therapy.

Patients who develop abnormal liver function tests during fluconazole therapy must be monitored

closely for the development of more serious hepatic injury.

The patient should be informed of suggestive symptoms of serious hepatic effect (important asthenia,

anorexia, persistent nausea, vomiting and jaundice). Treatment of fluconazole should be immediately

discontinued and the patient should consult a physician.

Cardiovascular system

Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the

electrocardiogram. Fluconazole causes QT prolongation via the inhibition of Rectifier Potassium

Channel current (I

). The QT prolongation caused by other medicinal products (such as amiodarone)

may be amplified via the inhibition of cytochrome P450 (CYP) 3A4. During post-marketing

surveillance, there have been very rare cases of QT prolongation and

torsades de pointes

in patients

taking Fluconazol Krka. These reports included seriously ill patients with multiple confounding risk

factors, such as structural heart disease, electrolyte abnormalities and concomitant treatment that may

have been contributory. Patients with hypokalaemia and advanced cardiac failure are at an increased

risk for the occurrence of life threatening ventricular arrhythmias and

torsades de pointes

Fluconazol Krka should be administered with caution to patients with these potentially proarrhythmic

conditions. Coadministration of other medicinal products known to prolong the QT interval and which

are metabolised via the cytochrome P450 (CYP) 3A4 are contraindicated (see sections 4.3 and 4.5).

Halofantrine

Halofantrine has been shown to prolong QTc interval at the recommended therapeutic dose and is a

substrate of CYP3A4. The concomitant use of fluconazole and halofantrine is therefore not

recommended (see section 4.5).

Dermatological reactions

Patients have rarely developed exfoliative cutaneous reactions, such as Stevens-Johnson syndrome and

toxic epidermal necrolysis, during treatment with fluconazole. AIDS patients are more prone to the

development of severe cutaneous reactions to many medicinal products. If a rash, which is considered

attributable to fluconazole, develops in a patient treated for a superficial fungal infection, further

therapy with this medicinal product should be discontinued. If patients with invasive/systemic fungal

infections develop rashes, they should be monitored closely and fluconazole discontinued if

bullous

lesions or

erythema

multiforme develop.

Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported.

Hypersensitivity

In rare cases anaphylaxis has been reported (see section 4.3).

Cytochrome P450

Fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole is also a

strong inhibitor of CYP2C19. Fluconazol Krka treated patients who are concomitantly treated with

medicinal products with a narrow therapeutic window metabolised through CYP2C9, CYP2C19 and

CYP3A4, should be monitored (see section 4.5).

Terfenadine

The coadministration of fluconazole at doses lower than 400 mg per day with terfenadine should be

carefully monitored (see sections 4.3 and 4.5).

Adrenal insufficiency

Ketoconazole is known to cause adrenal insufficiency and this could also, although rarely seen, be

applicable to fluconazole.

Adrenal insufficiency relating to concomitant treatment with Prednisone is described in section 4.5

"The effect of fluconazole on other medicinal products".

Special information about some of the ingredients

Fluconazol Krka 50 mg, 100 mg, and 150 mg hard capsules contain lactose and should not be given to

patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-

galactose malabsorption.

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

‘sodium-free’.

Fluconazol Krka 200 mg hard capsules contain azorubine (E122) which may cause allergic reaction.

4.5

Interaction with other medicinal products and other forms of interaction

Concomitant use of the following other medicinal products is contraindicated:

Cisapride

There have been reports of cardiac events, including torsades de pointes, in patients to whom

fluconazole and cisapride were co-administered. A controlled study found that concomitant

fluconazole 200 mg once daily and cisapride 20 mg four times a day yielded a significant increase in

cisapride plasma levels and prolongation of QTc interval. Concomitant treatment with fluconazole and

cisapride is contraindicated (see section 4.3).

Terfenadine

Because of the occurrence of serious cardiac dysrhythmias secondary to prolongation of the QTc

interval in patients receiving azole antifungals in conjunction with terfenadine, interaction studies have

been performed. One study at a 200 mg daily dose of fluconazole failed to demonstrate a prolongation

in QTc interval. Another study at a 400 mg and 800 mg daily dose of fluconazole demonstrated that

fluconazole taken in doses of 400 mg per day or greater significantly increases plasma levels of

terfenadine when taken concomitantly. The combined use of fluconazole at doses of 400 mg or greater

with terfenadine is contraindicated (see section 4.3). The coadministration of fluconazole at doses

lower than 400 mg per day with terfenadine should be carefully monitored.

Astemizole

Concomitant administration of fluconazole with astemizole may decrease the clearance of astemizole.

Resulting increased plasma concentrations of astemizole can lead to QT prolongation and rare

occurrences of

torsades de pointes

. Coadministration of fluconazole and astemizole is contraindicated

(see section 4.3).

Pimozide

Although not studied in vitro or in vivo, concomitant administration of fluconazole with pimozide may

result in inhibition of pimozide metabolism. Increased pimozide plasma concentrations can lead to QT

prolongation and rare occurrences of

torsades de pointes

. Coadministration of fluconazole and

pimozide is contraindicated (see section 4.3).

Quinidine

Although not studied

in vitro

in vivo

, concomitant administration of fluconazole with quinidine may

result in inhibition of quinidine metabolism. Use of quinidine has been associated with QT

prolongation and rare occurrences of

torsades de pointes

. Coadministration of fluconazole and

quinidine is contraindicated (see section 4.3).

Erythromycin

Concomitant use of fluconazole and erythromycin has the potential to increase the risk of

cardiotoxicity (prolonged QT interval,

torsades de pointes

) and consequently sudden heart death.

Coadministration of fluconazole and erythromycin is contraindicated (see section 4.3).

Concomitant use of the following other medicinal products cannot be recommended

Amiodarone

Concomitant administration of fluconazole with amiodarone may increase QT prolongation. Therefore,

caution should be taken when both drugs are combined, notably with high dose fluconazole (800 mg).

Halofantrine

Fluconazole can increase halofantrine plasma concentration due to an inhibitory effect on CYP3A4.

Concomitant use of fluconazole and halofantrine has the potential to increase the risk of cardiotoxicity

(prolonged QT interval,

torsades de pointes

) and consequently sudden heart death. This combination

should be avoided (see section 4.4).

Concomitant use of the following other medicinal products lead to precautions and dose adjustments:

The effect of other medicinal products on fluconazole

Hydrochlorothiazide

In a pharmacokinetic interaction study, coadministration of multiple-dose hydrochlorothiazide to

healthy volunteers receiving fluconazole increased plasma concentration of fluconazole by 40%. An

effect of this magnitude should not necessitate a change in the fluconazole dose regimen in subjects

receiving concomitant diuretics.

Rifampicin

Concomitant administration of fluconazole and rifampicin resulted in a 25% decrease in the AUC and

a 20% shorter half-life of fluconazole. In patients receiving concomitant rifampicin, an increase of the

fluconazole dose should be considered.

Interaction studies have shown that when oral fluconazole is coadministered with food, cimetidine,

antacids or following total body irradiation for bone marrow transplantation, no clinically significant

impairment of fluconazole absorption occurs.

The effect of fluconazole on other medicinal products

Fluconazole is a moderate inhibitor of cytochrome P450 (CYP) isoenzyme 2C9 and 3A4. Fluconazole

is also a strong inhibitor of the isozyme CYP2C19. In addition to the observed/documented

interactions mentioned below, there is a risk of increased plasma concentration of other compounds

metabolized by CYP2C9, CYP2C19 and CYP3A4 co-administered with fluconazole. Therefore

caution should be exercised when using these combinations and the patients should be carefully

monitored. The enzyme inhibiting effect of fluconazole persists 4- 5 days after discontinuation of

fluconazole treatment due to the long half-life of fluconazole (see section 4.3).

Alfentanil

During concomitant treatment with fluconazole (400 mg) and intravenous alfentanil (20 µg/ kg) in

healthy volunteers the alfentanil AUC

increased 2-fold probably through inhibition of CYP3A4.

Dose adjustment of alfentanil may be necessary.

Amitriptylin, nortryptiline

Fluconazole increases the effect of amitriptyline and nortriptyline. 5- nortriptyline and/or S-

amitnptyline may be measured at initiation of the combination therapy and after one week. Dose of

amitriptyline/nortriptyline should be adjusted, if necessary.

Amphotericine B

Concurrent administration of fluconazole and amphotericin B in infected normal and

immunosuppressed mice showed the following results: a small additive antifungal effect in systemic

infection with C. albicans, no interaction in intracranial infection with Cryptococcus neoformans, and

antagonism of the two medicinal products in systemic infection with A. fumigatus. The clinical

significance of results obtained in these studies is unknown.

Anticoagulants

In post-marketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis,

gastrointestinal bleeding, hematuria, and melena) have been reported, in association with increases in

prothrombin time in patients receiving fluconazole concurrently with warfarin. During concomitant

treatment with fluconazole and warfarin the prothrombin time was prolonged up to 2-fold, probably

due to an inhibition of the warfarin metabolism through CYP2C9. In patients receiving coumarin-type

or indanedione anticoagulants concurrently with fluconazole the prothrombin time should be carefully

monitored. Dose adjustment of the anticoagulant may be necessary.

Benzodiazepines (short acting), i.e. midazolam, triazolam

Following oral administration of midazolam, fluconazole resulted in substantial increases in

midazolam concentrations and psychomotor effects. Concomitant intake of fluconazole 200 mg and

midazolam 7.5 mg orally increased the midazolam AUC and half-life 3.7-fold and 2.2-fold,

respectively. Fluconazole 200 mg daily given concurrently with triazolam 0.25 mg orally increased the

triazolam AUC and half-life 4.4-fold and 2.3-fold, respectively. Potentiated and prolonged effects of

triazolam have been observed at concomitant treatment with fluconazole. If concomitant

benzodiazepine therapy is necessary in patients being treated with fluconazole, consideration should

be given to decreasing the benzodiazepine dose, and the patients should be appropriately monitored.

Carbamazepine

Fluconazole inhibits the metabolism of carbamazepine and an increase in serum carbamazepine of

30 % has been observed. There is a risk of developing carbamazepine toxicity. Dose adjustment of

carbamazepine may be necessary depending on concentration measurements/effect.

Calcium Channel Blockers

Certain calcium channel antagonists (nifedipine, isradipine, amlodipine, verapamil and felodipine) are

metabolized by CYP3A4. Fluconazole has the potential to increase the systemic exposure of the

calcium channel antagonists. Frequent monitoring for adverse events is recommended.

Celecoxib

During concomitant treatment with fluconazole (200 mg daily) and celecoxib (200 mg) the celecoxib

and AUC increased by 68 % and 134 % respectively. Half of the celecoxib dose may be

necessary when combined with fluconazole.

Cyclophosphamide

Combination therapy with cyclophosphamide and fluconazole results in an increase in serum bilirubin

and serum creatinine. The combination may be used while taking increased consideration to the risk of

increased serum bilirubin and serum creatinine.

Fentanyl

One fatal case of fentanyl intoxication due to possible fentanyl fluconazole interaction was reported.

Furthermore, it was shown in healthy volunteers that fluconazole delayed the elimination of fentanyl

significantly. Elevated fentanyl concentration may lead to respiratory depression. Patients should be

monitored closely for the potential risk of respiratory depression. Dosage adjustment of fentanyl may

be necessary.

HMG-CoA reductase inhibitors

The risk of myopathy and rhabdomyolysis increases when fluconazole is coadministered with HMG-

CoA reductase inhibitors metabolised through CYP3A4, such as atorvastatin and simvastatin, or

through CYP2C9, such as fluvastatin. If concomitant therapy is necessary, the patient should be

observed for symptoms of myopathy and rhabdomyolysis and creatinine kinase should be monitored.

HMG-CoA reductase inhibitors should be discontinued if a marked increase in creatinine kinase is

observed or myopathy/rhabdomyolysis is diagnosed or suspected.

Ibrutinib

Moderate inhibitors of CYP3A4 such as fluconazole increase plasma ibrutinib concentrations and may

increase risk of toxicity. If the combination cannot be avoided, reduce the dose of ibrutinib to 280 mg

once daily (two capsules) for the duration of the inhibitor use and provide close clinical monitoring.

Ivacaftor

Coadministration

with

ivacaftor,

cystic

fibrosis

transmembrane

conductance

regulator

(CFTR)

potentiator, increased ivacaftor exposure by 3fold and hydroxymethyl-ivacaftor (M1) exposure by 1.9 fold.

A reduction of the ivacaftor dose to 150 mg once daily is recommended for patients taking concomitant

moderate CYP3A inhibitors, such as fluconazole and erythromycin.

Olaparib

Moderate

inhibitors

CYP3A4

such

fluconazole

increase

olaparib

plasma

concentrations;

concomitant use is not recommended. If the combination cannot be avoided, limit the dose of olaparib

to 200 mg twice daily.

Immunosuppresors (i.e. ciclosporin, everolimus, sirolimus and tacrolimus)

Ciclosporin

Fluconazole significantly increases the concentration and AUC of ciclosporin. During concomitant

treatment with fluconazole 200 mg daily and ciclosporin (2.7 mg/kg/day) there was a 1.8-fold increase

in ciclosporin AUC. This combination may be used by reducing the dose of ciclosporin depending on

ciclosporin concentration.

Everolimus

Although not studied

in vivo

in vitro

, fluconazole may increase serum concentrations of everolimus

through inhibition of CYP3A4.

Sirolimus

Fluconazole increases plasma concentrations of sirolimus presumably by inhibiting the metabolism of

sirolimus via CYP3A4 and P-glycoprotein. This combination may be used with a dose adjustment of

sirolimus depending on the effect/concentration measurements.

Tacrolimus

Fluconazole may increase the serum concentrations of orally administered tacrolimus up to 5 times

due to inhibition of tacrolimus metabolism through CYP3A4 in the intestine. No significant

pharmacokinetic changes have been observed when tacrolimus is given intravenously. Increased

tacrolimus levels have been associated with nephrotoxicity. Dose of orally administered tacrolimus

should be decreased depending on tacrolimus concentration.

Losartan

Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74) which is responsible

for most of the angiotensin Il-receptor antagonism which occurs during treatment with losartan.

Patients should have their blood pressure monitored continuously.

Methadone

Fluconazole may enhance the serum concentration of methadone. Dose adjustment of methadone may

be necessary.

Non-steroidal anti-inflammatory drugs

The C

and AUC of flurbiprofen was increased by 23% and 81%, respectively, when coadministered

with fluconazole compared to administration of flurbiprofen alone. Similarly, the C

and AUC of the

pharmacologically active isomer [S-(+)-ibuprofen] was increased by 15% and 82%, respectively,

when fluconazole was coadministered with racemic ibuprofen (400 mg) compared to administration of

racemic ibuprofen alone.

Although not specifically studied, fluconazole has the potential to increase the systemic exposure of

other NSAIDs that are metabolized by CYP2C9 (e.g. naproxen, lornoxicam, meloxicam, diclofenac).

Frequent monitoring for adverse events and toxicity related to NSAIDs is recommended. Adjustment

of dose of NSAIDs may be needed.

Phenytoin

Fluconazole inhibits the hepatic metabolism of phenytoin. Concomitant repeated administration of 200

mg fluconazole and 250 mg phenytoin intravenously, caused an increase of the phenytoin AUC

75 % and C

by 128 %. With coadministration, serum phenytoin concentration levels should be

monitored in order to avoid phenytoin toxicity.

Prednisone

There was a case report that a liver-transplanted patient treated with prednisone developed acute

adrenal cortex insufficiency when a three month therapy with fluconazole was discontinued. The

discontinuation of fluconazole presumably caused an enhanced CYP3A4 activity which led to

increased metabolism of prednisone. Patients on long-term treatment with fluconazole and prednisone

should be carefully monitored for adrenal cortex insufficiency when fluconazole is discontinued.

Rifabutin

Fluconazole increases serum concentrations of rifabutin, leading to increase in the AUC of rifabutin

up to 80%. There have been reports of uveitis in patients to whom fluconazole and rifabutin were

coadministered. In combination therapy, symptoms of rifabutin toxicity should be taken into

consideration.

Saquinavir

Fluconazole increases the AUC and C

of saquinavir with approximately 50% and 55% respectively,

due to inhibition of saquinavir’s hepatic metabolism by CYP3A4 and inhibition of P- glycoprotein.

Interaction with saquinavir/ritonavir has not been studied and might be more marked. Dose adjustment

of saquinavir may be necessary.

Sulfonylureas

Fluconazole has been shown to prolong the serum half-life of concomitantly administered oral

sulfonylureas (e.g., chlorpropamide, glibenclamide, glipizide, tolbutamide) in healthy volunteers.

Frequent monitoring of blood glucose and appropriate reduction of sulfonylurea dose is recommended

during coadministration.

Theophylline

In a placebo controlled interaction study, the administration of fluconazole 200 mg for 14 days resulted in

an 18% decrease in the mean plasma clearance rate of theophylline. Patients who are receiving high dose

theophylline or who are otherwise at increased risk for theophylline toxicity should be observed for signs

of theophylline toxicity while receiving fluconazole. Therapy should be modified if signs of toxicity

develop.

Tofacitinib

Exposure of tofacitinib is increased when tofacitinib is co-administered with medications that result in

both moderate inhibition of CYP3A4 and strong inhibition of CYP2C19 (e.g., fluconazole). Therefore,

it is recommended to reduce tofacitinib dose to 5 mg once daily when it is combined with these drugs.

Vinca Alkaloids

Although not studied, fluconazole may increase the plasma levels of the vinca alkaloids (e.g. vincristine

and vinblastine) and lead to neurotoxicity, which is possibly due to an inhibitory effect on CYP3A4.

Vitamin A

Based on a case-report in one patient receiving combination therapy with all-trans-retinoid acid (an

acid form of vitamin A) and fluconazole, CNS related undesirable effects have developed in the form

of pseudotumour cerebri, which disappeared after discontinuation of fluconazole treatment. This

combination may be used but the incidence of CNS related undesirable effects should be borne in

mind.

Voriconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitor)

Coadministration of oral voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for 2.5 days) and

oral fluconazole (400 mg on day 1, then 200 mg Q24h for 4 days) to 8 healthy male subjects resulted

in an increase in C

and AUCτ of voriconazole by an average of 57% (90% CI: 20%, 107%) and

79% (90% CI: 40%, 128%), respectively. The reduced dose and/or frequency of voriconazole and

fluconazole that would eliminate this effect have not been established. Monitoring for voriconazole

associated adverse events is recommended if voriconazole is used sequentially after fluconazole.

Zidovudine

Fluconazole increases C

and AUC of zidovudine by 84% and 74%, respectively, due to an approx.

45% decrease in oral zidovudine clearance. The half-life of zidovudine was likewise prolonged by

approximately 128% following combination therapy with fluconazole. Patients receiving this

combination should be monitored for the development of zidovudine-related adverse reactions. Dose

reduction of zidovudine may be considered.

Azithromycin

An open-label, randomized, three-way crossover study in 18 healthy subjects assessed the effect of a

single 1200 mg oral dose of azithromycin on the pharmacokinetics of a single 800 mg oral dose of

fluconazole as well as the effects of fluconazole on the pharmacokinetics of azithromycin. There was

no significant pharmacokinetic interaction between fluconazole and azithromycin.

Oral contraceptives

Two pharmacokinetic studies with a combined oral contraceptive have been performed using multiple

doses of fluconazole. There were no relevant effects on hormone level in the 50 mg fluconazole study,

while at 200 mg daily, the AUCs of ethinyl estradiol and levonorgestrel were increased 40% and 24%,

respectively. Thus, multiple dose use of fluconazole at these doses is unlikely to have an effect on the

efficacy of the combined oral contraceptive.

4.6

Fertility, pregnancy and lactation

Pregnancy

An observational study has suggested an increased risk of spontaneous abortion in women treated with

fluconazole during the first trimester.

There have been reports of multiple congenital abnormalities (including brachycephalia, ears

dysplasia, giant anterior fontanelle, femoral bowing and radio-humeral synostosis) in infants whose

mothers were treated for at least three or more months with high doses (400-800 mg daily) of

fluconazole for coccidioidomycosis. The relationship between fluconazole use and these events is

unclear.

Data from several thousand pregnant women treated with a cumulative dose of ≤ 150 mg of fluconazole,

administered in the first trimester, show no increase in the overall risk of malformations in the foetus.

In one large observational cohort study, first trimester exposure to oral fluconazole was associated with

a small increased risk of musculoskeletal malformations, corresponding to approximately 1 additional

case per 1000 women treated with cumulative doses ≤450 mg compared with women treated with topical

azoles and to approximately 4 additional cases per 1000 women treated with cumulative doses over 450

mg. The adjusted relative risk was 1.29 (95% CI 1.05 to 1.58) for 150 mg oral fluconazole and 1.98

(95% CI 1.23 to 3.17) for doses over 450 mg fluconazole.

Studies in animals have shown reproductive toxicity (see section 5.3).

Fluconazole in standard doses and short-term treatments should not be used in pregnancy unless

clearly necessary.

Fluconazole in high dose and/or in prolonged regimens should not be used during pregnancy except

for potentially life-threatening infections.

Breast-feeding

Fluconazole passes into breast milk to reach concentrations similar to those in plasma (see section

5.2). Breast-feeding may be maintained after a single use of 150 mg fluconazole. Breast-feeding is not

recommended after repeated use or after high dose fluconazole.

The developmental and health

benefits of breast-feeding should be considered along with the mother's clinical need for

fluconazole and any potential adverse effects on the breast-fed child from fluconazole or from the

underlying maternal condition.

Fertility

Fluconazole did not affect the fertility of male or female rats (see section 5.3).

4.7

Effects on ability to drive and use machines

No studies have been performed on the effects of Fluconazol Krka on the ability to drive or use

machines.

Patients should be warned about the potential for dizziness or seizures (see section 4.8) while taking

Fluconazol Krka and should be advised not to drive or operate machines if any of these symptoms

occur.

4.8

Undesirable effects

The most frequently (>1/10) reported adverse reactions are headache, abdominal pain, diarrhoea,

nausea, vomiting, alanine aminotransferase increased, aspartate aminotransferase increased, blood

alkaline phosphatase increased and rash.

Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported in association

with fluconazole treatment (see section 4.4).

The following adverse reactions have been observed and reported during treatment with Fluconazol

Krka with the following frequencies: 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)

System Organ

Class

Common

Uncommon

Rare

Not known

Blood and the

lymphatic

system

disorders

Anaemia

Agranulocytosis,

leukopenia,

thrombocytopenia,

neutropenia

Immune system

disorders

Anaphylaxis

Metabolism

and nutrition

disorders

Decreased

appetite

Hypercholesterolaemia,

hypertriglyceridaemia,

hypokalemia

Psychiatric

disorders

Somnolence,

insomnia

Nervous system

disorders

Headache

Seizures,

paraesthesia,

dizziness,

taste

perversion

Tremor

Ear and

labyrinth

disorders

Vertigo

Cardiac

disorders

Torsade de pointes

(see

section 4.4), QT

prolongation (see

section 4.4)

Gastrointestinal

disorders

Abdominal pain,

vomiting,

diarrhoea, nausea

Constipation

dyspepsia,

flatulence,

dry mouth

Hepatobiliary

disorders

Alanine

aminotransferase

increased (see

section 4.4),

aspartate

aminotransferase

increased (see

section 4.4),

blood alkaline

phosphatase

increased (see

section 4.4)

Cholestasis

(see section

4.4), jaundice

(see section

4.4), bilirubin

increased (see

section 4.4)

Hepatic failure (see

section 4.4),

hepatocellular necrosis

(see section 4.4),

hepatitis (see section

4.4), hepatocellular

damage (see section

4.4)

Skin and

subcutaneous

tissue disorders

Rash (see section

4.4)

Drug

eruption*

(see section

4.4), urticaria

(see section

4.4), pruritus,

Toxic epidermal

necrolysis, (see section

4.4), Stevens-Johnson

syndrome (see section

4.4), acute generalised

exanthematous-

Drug reaction

with eosinophilia

and systemic

symptoms

(DRESS)

increased

sweating

pustulosis (see section

4.4), dermatitis

exfoliative,

angioedema, face

oedema, alopecia

Musculoskeletal

and connective

tissue disorders

Myalgia

General

disorders and

administration

site conditions

Fatigue,

malaise,

asthenia,

fever

* including Fixed Drug Eruption

Paediatric population

The pattern and incidence of adverse reactions and laboratory abnormalities recorded during paediatric

clinical trials, excluding the genital candidiasis indication, are comparable to those seen in adults.

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

Symptoms

There have been reports of overdose with Fluconazol Krka and hallucination and paranoid behaviour

have been concomitantly reported.

Management

In the event of overdose, symptomatic treatment (with supportive measures and gastric lavage if

necessary) may be adequate.

Fluconazole is largely excreted in the urine; forced volume diuresis would probably increase the

elimination rate. A three-hour haemodialysis session decreases plasma levels by approximately 50%.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

ATC classification

Pharmacotherapeutic group: Antimycotics for systemic use, triazole derivatives, ATC code: J02AC01.

Mode of action

Fluconazole is a triazole antifungal agent. Its primary mode of action is the inhibition of fungal

cytochrome P-450-mediated 14 alpha-lanosterol demethylation, an essential step in fungal ergosterol

biosynthesis. The accumulation of 14 alpha-methyl sterols correlates with the subsequent loss of

ergosterol in the fungal cell membrane and may be responsible for the antifungal activity of

fluconazole. Fluconazole has been shown to be more selective for fungal cytochrome P-450 enzymes

than for various mammalian cytochrome P-450 enzyme systems.

Fluconazole 50 mg daily given up to 28 days has been shown not to effect testosterone plasma

concentrations in males or steroid concentration in females of child-bearing age. Fluconazole 200 mg

to 400 mg daily has no clinically significant effect on endogenous steroid levels or on ACTH

stimulated response in healthy male volunteers. Interaction studies with antipyrine indicate that single

or multiple doses of fluconazole 50 mg do not affect its metabolism.

Susceptibility

in vitro

n vitro

, fluconazole displays antifungal activity against most clinically common

Candida

species

(including

C. albicans, C. parapsilosis, C. tropicalis). C. glabrata

shows reduced susceptibility to

fluconazole while

C. krusei

C. auris

are resistant to fluconazole.

Fluconazole also exhibits activity

in vitro

against

Cryptococcus neoformans

Cryptococcus. gattii

as well as the endemic moulds

Blastomyces dermatiditis

Coccidioides immitis

Histoplasma

capsulatum

Paracoccidioides brasiliensis

PK/PD relationship

In animal studies, there is a correlation between MIC values and efficacy against experimental

mycoses due to

Candida

spp. In clinical studies, there is an almost 1:1 linear relationship between the

AUC and the dose of fluconazole. There is also a direct though imperfect relationship between the

AUC or dose and a successful clinical response of oral candidosis and to a lesser extent candidaemia

to treatment. Similarly cure is less likely for infections caused by strains with a higher fluconazole

MIC.

Mechanism(s) of resistance

Candida

spp have developed a number of resistance mechanisms to azole antifungal agents. Fungal

strains which have developed one or more of these resistance mechanisms are known to exhibit high

minimum inhibitory concentrations (MICs) to fluconazole which impacts adversely efficacy

in vivo

and clinically.

There have been reports of superinfection with

Candida

species other than

C. albicans

, which often

have inherently reduced susceptibility (

C. glabrata

) or resistance to fluconazole (e.g.

C. krusei, C.

auris

). Such infections may require alternative antifungal therapy.

Breakpoints (according to EUCAST)

Based on analyses of pharmacokinetic/pharmacodynamic (PK/PD) data, susceptibility

in vitro

clinical response EUCAST-AFST (European Committee on Antimicrobial susceptibility Testing-

subcommittee on Antifungal Susceptibility Testing) has determined breakpoints for fluconazole for

Candida

species (EUCAST Fluconazole rational document (2007)-version 2). These have been

divided into non-species related breakpoints; which have been determined mainly on the basis of

PK/PD data and are independent of MIC distributions of specific species, and species related

breakpoints for those species most frequently associated with human infection. These breakpoints are

given in the table below:

Antifungal

Species-related breakpoints (S ≤/ R >)

Non-species

related

breakpoints

S ≤/ R >

Candida

albicans

Candida

glabrata

Candida

krusei

Candida

parapsilosis

Candida

tropicalis

Fluconazole

S = Susceptible, R = Resistant

A = Non-species related breakpoints have been determined mainly on the basis of PK/PD data and are

independent of MIC distributions of specific species. They are for use only for organisms that do not

have specific breakpoints.

--

= Susceptibility testing not recommended as the species is a poor target for therapy with the

medicinal product.

IE = There is insufficient evidence that the species in question is a good target for therapy with the

medicinal product

5.2

Pharmacokinetic properties

The pharmacokinetic properties of fluconazole are similar following administration by the intravenous

or oral route.

Absorption

After oral administration fluconazole is well absorbed, and plasma levels (and systemic

bioavailability) are over 90% of the levels achieved after intravenous administration. Oral absorption

is not affected by concomitant food intake. Peak plasma concentrations in the fasting state occur

between 0.5 and 1.5 hours post-dose. Plasma concentrations are proportional to dose. Ninety percent

steady state levels are reached by day 4-5 with multiple once daily dosing. Administration of a loading

dose (on day 1) of twice the usual daily dose enables plasma levels to approximate to 90% steady-state

levels by day 2.

Distribution

The apparent volume of distribution approximates to total body water. Plasma protein binding is low

(11-12%).

Fluconazole achieves good penetration in all body fluids studied. The levels of fluconazole in saliva

and sputum are similar to plasma levels. In patients with fungal meningitis, fluconazole levels in the

CSF are approximately 80% the corresponding plasma levels.

High skin concentration of fluconazole, above serum concentrations, are achieved in the stratum

corneum, epidermis-dermis and eccrine sweat. Fluconazole accumulates in the stratum corneum. At a

dose of 50 mg once daily, the concentration of fluconazole after 12 days was 73 μg/g and 7 days after

cessation of treatment the concentration was still 5.8 μg/g. At the 150 mg once-a-week dose, the

concentration of fluconazole in stratum corneum on day 7 was 23.4 μg/g and 7 days after the second

dose was still 7.1 μg/g.

Concentration of fluconazole in nails after 4 months of 150 mg once-a-week dosing was 4.05 μg/g in

healthy and 1.8 μg/g in diseased nails; and, fluconazole was still measurable in nail samples 6 months

after the end of therapy.

Biotransformation

Fluconazole is metabolised only to a minor extent. Of a radioactive dose, only 11% is excreted in a

changed form in the urine. Fluconazole is a moderate inhibitor of the isozymes CYP2C9 and CYP3A4

(see section 4.5). Fluconazole is also a strong inhibitor of the isozyme CYP2C19.

Elimination

Plasma elimination half-life for fluconazole is approximately 30 hours. The major route of excretion is

renal, with approximately 80% of the administered dose appearing in the urine as unchanged

medicinal product. Fluconazole clearance is proportional to creatinine clearance. There is no evidence

of circulating metabolites.

The long plasma elimination half-life provides the basis for single dose therapy for vaginal

candidiasis, once daily and once weekly dosing for other indications.

Pharmacokinetics in renal impairment

In patients with severe renal insufficiency, (GFR < 20 ml/min) half life increased from 30 to 98 hours.

Consequently, reduction of the dose is needed. Fluconazole is removed by haemodialysis and to a

lesser extent by peritoneal dialysis. After three hours of haemodialysis session, around 50% of

fluconazole is eliminated from blood.

Pharmacokinetics during lactation

A pharmacokinetic study in ten lactating women, who had temporarily or permanently stopped breast-

feeding their infants, evaluated fluconazole concentrations in plasma and breast milk for 48 hours

following a single 150 mg dose of fluconazole. Fluconazole was detected in breast milk at an average

concentration of approximately 98% of those in maternal plasma. The mean peak breast milk

concentration was 2.61 mg/L at 5.2 hours post-dose. The estimated daily infant dose of fluconazole

from breast milk (assuming mean milk consumption of 150 ml/kg/day) based on the mean peak milk

concentration is 0.39 mg/kg/day, which is approximately 40% of the recommended neonatal dose (<2

weeks of age) or 13% of the recommended infant dose for mucosal candidiasis.

Pharmacokinetics in children

Pharmacokinetic data were assessed for 113 paediatric patients from 5 studies; 2 single-dose studies, 2

multiple-dose studies, and a study in premature neonates. Data from one study were not interpretable

due to changes in formulation pathway through the study. Additional data were available from a

compassionate use study.

After administration of 2-8 mg/kg fluconazole to children between the ages of 9 months to 15 years,

an AUC of about 38 μg·h/ml was found per 1 mg/kg dose units. The average fluconazole plasma

elimination half-life varied between 15 and 18 hours and the distribution volume was approximately

880 ml/kg after multiple doses. A higher fluconazole plasma elimination half-life of approximately 24

hours was found after a single dose. This is comparable with the fluconazole plasma elimination half-

life after a single administration of 3 mg/kg i.v. to children of 11 days-11 months old. The distribution

volume in this age group was about 950 ml/kg.

Experience with fluconazole in neonates is limited to pharmacokinetic studies in premature newborns.

The mean age at first dose was 24 hours (range 9-36 hours) and mean birth weight was 0.9 kg (range

0.75-1.10 kg) for 12 pre-term neonates of average gestation around 28 weeks. Seven patients

completed the protocol; a maximum of five 6 mg/kg intravenous infusions of fluconazole were

administered every 72 hours. The mean half-life (hours) was 74 (range 44-185) on day 1 which

decreased, with time to a mean of 53 (range 30-131) on day 7 and 47 (range 27-68) on day 13. The

area under the curve (μg h/ml) was 271 (range 173-385) on day 1 and increased with a mean of 490

(range 292-734) on day 7 and decreased with a mean of 360 (range 167-566) on day 13. The volume

of distribution (ml/kg) was 1183 (range 1070-1470) on day 1 and increased, with time, to a mean of

1184 (range 510-2130) on day 7 and 1328 (range 1040-1680) on day 13.

Pharmacokinetics in elderly

A pharmacokinetic study was conducted in 22 subjects, 65 years of age or older receiving a single 50

mg oral dose of fluconazole. Ten of these patients were concomitantly receiving diuretics. The C

was 1.54 μg/ml and occurred at 1.3 hours post-dose. The mean AUC was 76.4 ± 20.3 μg·h/ml, and the

mean terminal half-life was 46.2 hours. These pharmacokinetic parameter values are higher than

analogous values reported for normal young male volunteers. Coadministation of diuretics did not

significantly alter AUC or C

. In addition, creatinine clearance (74 ml/min), the percent of medicinal

product recovered unchanged in urine (0-24 h, 22%) and the fluconazole renal clearance estimates

(0.124 ml/min/kg) for the elderly were generally lower than those of younger volunteers. Thus, the

alteration of fluconazole disposition in the elderly appears to be related to reduced renal function

characteristics of this group.

5.3

Preclinical safety data

Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the

human exposure indicating little relevance to clinical use.

Carcinogenesis

Fluconazole showed no evidence of carcinogenic potential in mice and rats treated orally for 24

months at doses of 2.5, 5, or 10 mg/kg/day (approximately 2 to 7 times the recommended human

dose). Male rats treated with 5 and 10 mg/kg/day had an increased incidence of hepatocellular

adenomas.

Mutagenesis

Fluconazole, with or without metabolic activation, was negative in tests for mutagenicity in 4 strains of

Salmonella typhimurium, and in the mouse lymphoma L5178Y system. Cytogenetic studies in vivo

(murine bone marrow cells, following oral administration of fluconazole) and in vitro (human

lymphocytes exposed to fluconazole at 1000 μg/ml) showed no evidence of chromosomal mutations.

Reproductive toxicity

Fluconazole did not affect the fertility of male or female rats treated orally with daily doses of 5, 10, or

20 mg/kg or with parenteral doses of 5, 25, or 75 mg/kg.

There were no foetal effects at 5 or 10 mg/kg; increases in foetal anatomical variants (supernumerary

ribs, renal pelvis dilation) and delays in ossification were observed at 25 and 50 mg/kg and higher

doses. At doses ranging from 80 mg/kg to 320 mg/kg embryolethality in rats was increased and foetal

abnormalities included wavy ribs, cleft palate, and abnormal cranio-facial ossification.

The onset of parturition was slightly delayed at 20 mg/kg orally and dystocia and prolongation of

parturition were observed in a few dams at 20 mg/kg and 40 mg/kg intravenously. The disturbances in

parturition were reflected by a slight increase in the number of still-born pups and decrease of neonatal

survival at these dose levels. These effects on parturition are consistent with the species specific

oestrogen-lowering property produced by high doses of fluconazole. Such a hormone change has not

been observed in women treated with fluconazole (see section 5.1).

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Capsule content:

Lactose monohydrate

Sodium laurilsulphate

Magnesium stearate

Colloidal anhydrous silica

Maize starch

Capsule shell, 50mg, 100 mg and 150mg:

Patent Blue V (E131)

Titanium dioxide (E171)

Gelatin

Capsule shell, 200 mg:

Titanium dioxide (E171)

Azo rubine (E122)

Indigo Carmine (E132)

Gelatin

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

5 years

6.4

Special precautions for storage

This medical product does not require any special storage conditions.

6.5

Nature and contents of container

Blister (Alu/PVC-PVDC)

50 mg: 100x1, 7, 10, 20, 28, 50 and 98 capsules

100 mg: 100x1, 7, 10, 20, 28, 50, 60 capsules

150 mg: 1, 2, 4, 6, 12 capsules

200 mg: 100x1, 7, 10, 20, 28, 30, 50 capsules

Not all pack sizes may be marketed.

6.6

Special precautions for disposal and other handling

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

requirements.

7.

MARKETING AUTHORISATION HOLDER

KRKA Sverige AB

Göta Ark 175

118 72 Stockholm

8.

MARKETING AUTHORISATION NUMBER(S)

To be completed nationally.

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

2003-10-17

10.

DATE OF REVISION OF THE TEXT

2021-06-10

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