Caspofungin Orion 70 mg Pulver till koncentrat till infusionsvätska, lösning

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

14-01-2021

Produktens egenskaper Produktens egenskaper (SPC)

14-08-2019

Aktiva substanser:
kaspofunginacetat
Tillgänglig från:
Orion Corporation
ATC-kod:
J02AX04
INN (International namn):
kaspofunginacetat
Dos:
70 mg
Läkemedelsform:
Pulver till koncentrat till infusionsvätska, lösning
Sammansättning:
sackaros Hjälpämne; mannitol Hjälpämne; kaspofunginacetat 77,69 mg Aktiv substans
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Injektionsflaska, 1 st
Bemyndigande status:
Godkänd
Godkännandenummer:
53783
Tillstånd datum:
2017-01-30

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14-01-2021

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09-02-2017

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Bipacksedel: Information till patienten

Caspofungin Orion 50 mg pulver till koncentrat till infusionsvätska, lösning

Caspofungin Orion 70 mg pulver till koncentrat till infusionsvätska, lösning

kaspofungin

Läs noga igenom denna bipacksedel innan du eller ditt barn får 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.

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 Caspofungin Orion är och vad det används för

Vad du behöver veta innan du får Caspofungin Orion

Hur Caspofungin Orion ges

Eventuella biverkningar

Hur Caspofungin Orion ska förvaras

Förpackningens innehåll och övriga upplysningar

1.

Vad Caspofungin Orion är och vad det används för

Vad Caspofungin Orion är

Caspofungin Orion innehåller ett läkemedel som kallas kaspofungin. Det tillhör en grupp läkemedel

som kallas antimykotikum (medel mot svamp).

Vad Caspofungin Orion används för

Caspofungin Orion används för att behandla följande infektioner hos barn, ungdomar och vuxna:

allvarliga svampinfektioner i vävnader eller organ (kallad "invasiv candidiasis"). Infektionen

orsakas av svamp(jäst)celler som kallas Candida. Personer som kan få den här typen av

infektion inkluderar nyopererade patienter eller de med nedsatt immunförsvar. Feber och frossa

som inte går över med antibiotikabehandling är de vanligaste symtomen vid denna typ av

infektion.

svampinfektioner i näsan, bihålorna eller lungorna (kallad "invasiv apergillos") om andra medel

mot svamp inte har haft förväntad effekt eller har orsakat biverkningar. Denna infektion orsakas

av en organism som kallas Aspergillus. Personer som kan få den här typen av infektion

inkluderar de som behandlas med kemoterapi, de som har genomgått en transplantation och de

med nedsatt immunförsvar.

misstänkta svampinfektioner om du har feber och lågt antal vita blodkroppar som inte går över

med antibiotikabehandling. Personer med risk att få en svampinfektion inkluderar de som

nyligen genomgått en operation eller de med nedsatt immunförsvar.

Hur Caspofungin Orion fungerar

Caspofungin Orion gör svampceller sköra och hindrar svampen från att växa ordentligt. Detta hindrar

infektionen från att sprida sig och ger kroppens naturliga försvar en chans att helt göra sig av med

infektionen.

Kaspofungin som finns i Caspofungin Orion kan också vara godkänd för att behandla andra sjukdomar

som inte nämns i denna produktinformation. 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 får Caspofungin Orion

Du ska inte ges Caspofungin Orion

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

avsnitt 6).

Om du är osäker, rådfråga läkare, apotekspersonal eller sjuksköterska innan du får detta läkemedel.

Varningar och försiktighet

Tala med läkare, apotekspersonal eller sjuksköterska innan du får Caspofungin Orion

om du är allergisk mot några andra läkemedel

om du någon gång har haft leverproblem - du kan behöva en annan dos av detta läkemedel

om du redan tar ciklosporin (hjälper till att förebygga avstötning av transplanterade organ eller

för att undertrycka immunsystemet) - eftersom din läkare kan behöva ta ytterligare blodprover

under din behandling

om du någon gång haft andra medicinska problem.

Om något av ovanstående stämmer in på dig (eller om du är osäker), tala med läkare, apotekspersonal

eller sjuksköterska innan du får Caspofungin Orion.

Caspofungin Orion kan också orsaka allvarliga hudbiverkningar som Stevens-Johnson syndrom (SJS)

och toxisk epidermal nekrolys (TEN).

Andra läkemedel och Caspofungin Orion

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

andra läkemedel. Detta på grund av att Caspofungin Orion kan påverka sättet som andra läkemedel

verkar på. Andra läkemedel kan även påverka sättet Caspofungin Orion verkar på.

Tala om för läkare, apotekspersonal eller sjuksköterska om du tar något av följande läkemedel:

ciklosporin eller takrolimus (hjälper till att förebygga avstötning av transplanterade organ eller

för att undertrycka immunsystemet) eftersom din läkare kan behöva ta ytterligare blodprover

under din behandling

vissa läkemedel mot HIV som efavirenz eller nevirapin

fenytoin eller karbamazepin (används för behandling av kramper)

dexametason (kortisonpreparat)

rifampicin (ett antibiotikum).

Om något av ovanstående stämmer in på dig (eller om du är osäker), tala med läkare, apotekspersonal

eller sjuksköterska innan du får Caspofungin Orion

Graviditet och amning

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

innan du får detta läkemedel.

Caspofungin Orion har inte studerats hos gravida kvinnor. Det bör endast användas under

graviditet om den potentiella nyttan överväger den potentiella risken för det ofödda barnet.

Kvinnor som får Caspofungin Orion bör inte amma.

Körförmåga och användning av maskiner

Det finns ingen information som tyder på att Caspofungin Orion påverkar din förmåga att köra bil och

handha maskiner.

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.

Innehållsämnen

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

”natriumfritt”.

3.

Hur Caspofungin Orion ges

Caspofungin Orion kommer alltid förberedas och ges av sjukvårdspersonal.

Du kommer få Caspofungin Orion:

en gång om dagen

med långsam injektion i en ven (intravenös infusion)

under ungefär 1 timme.

Din läkare kommer att bestämma längden av behandlingen och hur mycket Caspofungin Orion du

kommer att få per dag. Din läkare kommer att kontrollera hur väl läkemedlet fungerar för dig. Om du

väger mer än 80 kg kan du behöva en annan dos.

Användning för barn och ungdomar

Dosen för barn och ungdomar kan skilja sig från dosen till vuxna.

Om du har fått för stor mängd av Caspofungin Orion

Din läkare kommer att bestämma hur mycket Caspofungin Orion du behöver och längden av

behandlingen per dag. Om du är orolig över att du fått för mycket Caspofungin Orion, tala med läkare

eller sjuksköterska omedelbart.

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.

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

4.

Eventuella biverkningar

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

dem.

Om du får någon av följande biverkningar, tala omedelbart med läkare eller sjuksköterska - du

kan behöva akut sjukvårdsbehandling:

utslag, klåda, värmekänsla, svullnad av ansikte, läppar eller hals eller andningssvårigheter – du

kan ha fått en histaminreaktion av läkemedlet

andningssvårigheter med väsande ljud eller förvärring av befintliga utslag – du kan ha fått en

allergisk reaktion av läkemedlet

hosta, allvarliga andningssvårigheter – om du är vuxen och har invasiv aspergillos kan du få ett

allvarligt andningsproblem som kan resultera i andningssvikt.

hudutslag, flagnande hud, ömmande slemhinnor, nässelutslag, stora områden med flagnande

hud.

Som för alla receptbelagda läkemedel kan vissa biverkningar vara allvarliga. Fråga din läkare efter mer

information.

Andra biverkningar hos vuxna inkluderar:

Vanliga

kan förekomma hos upp till 1 av 10 användare

sänkt hemoglobin (minskad mängd syretransporterande ämne i blodet), minskat antal vita

blodkroppar

sänkt albumin (ett slags protein) i blodet, sänkt kalium eller låga kaliumnivåer i blodet

huvudvärk

inflammation i venen

andnöd

diarré, illamående eller kräkningar

forändrade värden för vissa blodanalyser (gäller även förhöjda värden på vissa leverprover)

klåda, utslag, hudrodnad eller ökad svettning

ledsmärta

frossa, feber

klåda vid injektionsstället.

Mindre vanliga (

kan förekomma hos upp till 1 av 100 användare

förändrade värden för vissa blodanalyser (inklusive blodkoagulationssjukdomar, blodplättar,

röda blodkroppar och vita blodkroppar)

minskad aptit, ansamling av vätska i kroppen, obalans i kroppens salthalt, höga

blodsockernivåer i blodet, låga kalciumnivåer i blodet, förhöjda kalciumnivåer i blodet, låga

magnesiumnivåer i blodet, ökade syrahalter i blodet

förvirring, nervös känsla, oförmåga att sova

känsla av yrsel, nedsatt känsel och känslighet (speciellt i huden), skakningar, känsla av trötthet,

smakförändring, stickningar eller domningar

dimsyn, ökat tårmängd, svullna ögonlock, gulfärgning av ögonvitorna

känsla av snabba eller oregelbundna hjärtslag, snabba hjärtslag, oregelbundna hjärtslag, onormal

hjärtrytm, hjärtsvikt

blodvallning, värmevallning, högt blodtryck, lågt blodtryck, rodnad utmed en ven som också är

extremt öm vid beröring

åtstramning av musklerna runt luftvägarna som resulterar i väsande ljud eller hosta, snabb

andhämtning, andfåddhet som väcker dig, syrebrist i blodet, onormala andningsljud, knarrande

ljud i lungorna, väsande, nästäppa, hosta, halsont

buksmärta, smärta i övre delen av buken, väderspänning, , förstoppning, sväljsvårigheter,

muntorrhet, dålig matsmältning, gaser, magbesvär, svullnad på grund av vätskeansamling kring

buken

minskat gallflöde, leverförstoring, gulfärgning av hud och/eller ögonvitor, leverskada orsakad av

läkemedel eller kemikalie, leverstörningar

onormal hudvävnad, generell klåda, nässelutslag, olika typer av hudutslag, onormal hud, röda

och ofta kliande fläckar på armar och ben och ibland i ansiktet och på övriga kroppen

ryggsmärta, smärta i en arm eller ben, benvävnadssmärta, muskelsmärta, muskelsvaghet

nedsättning av njurfunktionen, plötslig nedsättning av njurfunktionen

smärta vid kateteringång, besvär vid injektionsstället (rodnad, förhårdnad, smärta, svullnad,

irritation, utslag, nässelutslag, vätskeläckage från katetern in i vävnaden), inflammation i venen

vid injektionsstället

förhöjt blodtryck och ändrade värden för vissa blodanalyser (inklusive njur-, elektrolyt- och

koagulationstest), förhöjda nivåer av läkemedlet du tar vilket försvagar immunförsvaret.

bröstobehag, bröstsmärta, känsla av ändrad kroppstemperatur, allmän sjukdomskänsla, allmän

smärta, svullnad av ansikte, svullnad av vrister, händer eller fötter, svullnad, ömhet, känsla av

trötthet.

Ytterligare biverkningar hos barn och ungdomar

Mycket vanliga (

kan förekomma hos fler än 1 av 10 användare

feber.

Vanliga (

kan förekomma hos upp till 1 av 10 användare

huvudvärk

snabb puls

blodvallning, lågt blodtryck

förändrade värden för vissa blodanalyser (förhöjda värden på vissa leverprover)

klåda, utslag

smärta vid kateterområdet, frossa

förändrade värden för vissa blodanalyser.

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

Webbplats: www.lakemedelsverket.se

5.

Hur Caspofungin Orion ska förvaras

Förvara detta läkemedel utom syn- och räckhåll för barn.

Används före utgångsdatum som anges på kartongen och injektionsflaskan. Utgångsdatumet är den

sista dagen i angiven månad.

Förvaras i kylskåp (2

Så snart Caspofungin Orion färdigställts bör den användas omedelbart. Detta på grund av att den inte

innehåller några ämnen som stoppar bakterietillväxt. Endast utbildad sjukvårdspersonal som har läst

hela bruksanvisningen får färdigställa detta läkemedel (se nedan ”Instruktioner för att lösa upp och

späda Caspofungin Orion”).

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 kaspofungin. Varje injektionsflaska innehåller kaspofunginacetat

motsvarande 50 mg eller 70 mg kaspofungin.

Övriga innehållsämnen är sackaros, mannitol, koncentrerad ättiksyra och natriumhydroxid.

Läkemedlets utseende och förpackningsstorlekar

Caspofungin Orion är ett sterilt, vitt till benvitt, kompakt pulver.

Caspofungin Orion pulver är förpackad i en glasinjektionsflaska med ett rött (50 mg injektionsflaska)

eller orange (70 mg injektionsflaska) lock. Injektionsflaskan är vidare förpackad i en kartong. Varje

förpackning innehåller en injektionsflaska.

Innehavare av godkännande för försäljning

Orion Corporation

Orionintie 1

FI-02200 Espoo

Finland

Tillverkare

Orion Corporation Orion Pharma

Orionintie 1

FI-02200 Espoo

Finland

Pharmathen S.A.

Dervenakion 6

Pallini 15351

Attikis

Grekland

Pharmadox Healthcare Ltd.

KW20A Kordin Industrial Park

Paola PLA 3000

Malta

ELPEN Pharmaceutical Co., Inc

Marathonos Ave. 95

Pikermi Attiki, 19009

Grekland

För ytterligare upplysningar om detta läkemedel, kontakta lokal företrädare för innehavaren av

godkännandet för försäljning i Sverige:

Orion Pharma AB, Danderyd, medinfo@orionpharma.com

Denna bipacksedel ändrades senast 2021-01-13

---------------------------------------------------------------------------------------------------------------------------

Följande uppgifter är endast avsedda för hälso- och sjukvårdspersonal :

Instruktioner för att lösa upp och späda Caspofungin Orion:

INSTRUKTIONER FÖR ANVÄNDNING HOS VUXNA PATIENTER

Steg 1 Beredning i injektionsflaska

För att lösa upp pulvret, låt injektionsflaskan anta rumstemperatur och tillsätt aseptiskt 10,5 ml vatten

för injektionsvätskor. Koncentrationerna i de upplösta injektionsflaskorna blir 5,2 mg/ml (50 mg

injektionsflaska) eller 7,2 mg/ml (70 mg injektionsflaska).

Det vita till benvita kompakta frystorkade pulvret kommer att upplösas helt. Blanda varsamt tills en

klar lösning erhålls. Kontrollera visuellt den färdiga lösningen med avseende på partiklar eller

missfärgningar. Den färdiga lösningen kan förvaras upp till 24 timmar vid förvaring i 25ºC eller lägre

(ner till 2°C – 8°C).

Steg 2 Tillsättning av upplöst Caspofungin Orion till infusionslösning för patient

Spädningsvätskor till den slutgiltiga infusionslösningen är: Natriumklorid injektionsvätska (9 mg/ml,

4.5 mg/ml eller 2.25 mg/ml) eller lakterad Ringerlösning. Infusionslösningen färdigställs genom att

aseptiskt tillsätta den rätta mängden upplöst koncentrat (enligt tabellen nedan) till en 250 ml

infusionspåse eller flaska. Reducerad infusionsvolym om 100 ml kan användas, om medicinskt

nödvändigt, till doserna 50 mg eller 35 mg dagligen. Denna infusionslösning måste användas inom 48

timmar om den förvaras vid eller under 25°C (ner till 2°C – 8°C). Använd ej om lösningen är grumlig

eller har fällningar.

FÄRDIGSTÄLLANDE AV INFUSIONSLÖSNING TILL VUXNA

DOS*

Volym upplöst

Caspofungin Orion

för överföring till

infusionspåse eller

flaska

Standardberedning

(upplöst Caspofungin

Orion tillsatt till 250

ml) slutlig

koncentration

Reducerad

infusionsvolym

(upplöst Caspofungin

Orion tillsatt till 100

ml) slutlig

koncentration

70 mg

10 ml

0,28 mg/ml

Rekommenderas inte

70 mg

(från två 50 mg

injektionsflaskor)**

14 ml

0,28 mg/ml

Rekommenderas inte

50 mg

10 ml

0,20 mg/ml

50 mg vid reducerad

volym

10 ml

0,47 mg/ml

35 mg för måttlig

leverfunktionsnedsättning

(från en 50 mg

injektionsflaska)

7 ml

0,14 mg/ml

35 mg för måttlig

leverfunktionsnedsättning

(från en

50 mg injektionsflaska)

vid reducerad volym

7 ml

0,34 mg/ml

35 mg för måttlig

leverfunktionsnedsättning

(från en 70 mg

injektionsflaska)

5 ml

0,14 mg/ml

0,34 mg/ml

* 10,5 ml bör användas för beredning av alla injektionsflaskor

** Om 70 mg injektionsflaska inte finns tillgänglig, kan 70 mg dosen förberedas från två 50 mg

injektionsflaskor

INSTRUKTION FÖR BEREDNING AV INFUSIONSLÖSNING TILL BARN

Beräkning av kroppsyta för dosering till barn

Innan beredning av infusionslösning, beräkna patientens kroppsyta enligt följande formel (Mosteller´s

formel):

𝐾𝑟𝑜𝑝𝑝𝑠𝑦𝑡𝑎 (𝑚

𝑘𝑟𝑜𝑝𝑝𝑠𝑙ä𝑛𝑔𝑑 (𝑐𝑚)𝑥 𝑣𝑖𝑘𝑡 (𝑘𝑔)

3600

Beredning av 70 mg/m

2

infusionslösning till barn >3 månaders ålder (med en 50 mg

injektionsflaska eller en 70 mg injektionsflaska)

Fastställ den aktuella engångsbolusdosen för behandling av barnet med hjälp av patientens

beräknade kroppsyta (enligt formel ovan) och följande ekvation:

Kroppsyta (m

) ×70 mg/m

= engångsbolusdos

Maximal engångsbolusdos dag 1 ska ej överstiga 70 mg oavsett patientens beräknade dos.

Låt den kylda injektionsflaskan med Caspofungin Orion anta rumstemperatur.

Tillsätt aseptiskt 10,5 ml vatten för injektionsvätskor.

Denna färdigberedda lösning kan förvaras

upp till 24 timmar vid förvaring i 25 ºC eller lägre (ner till 2°C – 8°C)

. Den slutliga

koncentrationen av kaspofungin i injektionsflaskan blir 5,2 mg/ml (50 mg injektionsflaska) eller

7,2 mg/ml (70 mg injektionsflaska).

Ta ut mängden läkemedel motsvarande den beräknade engångsbolusdosen (steg 1) från

injektionsflaskan. Överför aseptiskt denna mängd (ml)

av färdigberedd Caspofungin Orion till

en 250 ml infusionspåse (eller flaska) med natriumkloridlösning 9mg/ml (0,9%), 4,5 mg/ml

(0,45%) eller 2,25 mg/ml (0,225%) för infusion eller lakterad Ringerlösning. Alternativt kan

mängden (ml)

färdigberedd Caspofungin Orion tillsättas till en reducerad infusionsvolym med

natriumkloridlösning 9 mg/ml (0,9%), 4,5 mg/ml (0,45%) eller 2,25 mg/ml (0,225%) för

infusion eller lakterad Ringerlösning, ej överstigande en slutlig koncentration om 0,5 mg/ml.

Denna infusionslösning ska användas inom 48 timmar vid förvaring i 25ºC eller lägre (ner till

2ºC till 8ºC).

Beredning av 50 mg/m

2

infusionslösning till barn >3 månaders ålder (med en 50 mg

injektionsflaska eller en 70 mg injektionsflaska)

Fastställ den aktuella dagliga underhållsdosen för behandling av barnet med hjälp av patientens

beräknade kroppsyta (enligt formel ovan) och följande ekvation:

Kroppsyta (m

) × 50 mg/m

= daglig underhållsdos

Den dagliga underhållsdosen ska ej överstiga 70 mg oavsett patientens beräknade dos.

Låt den kylda injektionsflaskan med Caspofungin Orion anta rumstemperatur.

Tillsätt aseptiskt 10,5 ml vatten för injektionsvätskor.

Denna färdigberedda lösning kan förvaras

upp till 24 timmar vid förvaring i 25 ºC eller lägre (ner till 2°C – 8°C)

. Den slutliga

koncentrationen av kaspofungin i injektionsflaskan blir 5,2 mg/ml (50 mg injektionsflaska) eller

7,2 mg/ml (70 mg injektionsflaska).

Ta ut mängden läkemedel motsvarande den beräknade dagliga underhållsdosen (steg 1) från

injektionsflaskan. Överför aseptiskt denna mängd (ml)

av färdigberedd Caspofungin Orion till

en 250 ml infusionspåse (eller flaska) med natriumkloridlösning 9 mg/ml (0,9%), 4,5 mg/ml

(0,45%) eller 2,25 mg/ml (0,225%) för infusion eller lakterad Ringerlösning. Alternativt kan

mängden (ml)c färdigberedd Caspofungin Orion tillsättas till en reducerad infusionsvolym med

natriumkloridlösning 9 mg/ml (0,9%), 4.5 mg/ml (0,45%) eller 2,25 mg/ml (0,225%) för

infusion eller lakterad Ringerlösning, ej överstigande en slutlig koncentration om 0,5 mg/ml.

Denna infusionslösning ska användas inom 48 timmar vid förvaring i 25ºC eller lägre (ner till

2ºC till 8ºC).

Mosteller RD: Simplified Calculation of Body Surface Area. N Engl J Med 1987 Oct 22;317(17):1098 (letter)

Noteringar för beredning

Det vita till benvita kompakta pulvret kommer att upplösas helt. Blanda varsamt tills en klar

lösning erhålls.

Kontrollera visuellt den färdiga lösningen efter partiklar eller missfärgningar under upplösning

och före infusion. Använd inte lösningen om den är grumlig eller har en fällning.

Caspofungin Orion är formulerad för att ge den dos som anges på injektionsflaskans etikett

(50 mg eller 70 mg) då 10 ml tas från injektionsflaskan.

Läs hela dokumentet

SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT

Caspofungin Orion 50 mg powder for concentrate for solution for infusion

Caspofungin Orion 70 mg powder for concentrate for solution for infusion

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains caspofungin acetate equivalent to 50 mg or 70 mg caspofungin.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Powder for concentrate for solution for infusion.

Before reconstitution, the product is a white to off white lyophilised powder.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Treatment of invasive candidiasis in adult or paediatric patients.

Treatment of invasive aspergillosis in adult or paediatric patients who are refractory to or

intolerant of amphotericin B, lipid formulations of amphotericin B and/or itraconazole.

Refractoriness is defined as progression of infection or failure to improve after a minimum of

7 days of prior therapeutic doses of effective antifungal therapy.

Empirical therapy for presumed fungal infections (such as

Candida

Aspergillus

) in febrile,

neutropaenic adult or paediatric patients.

4.2

Posology and method of administration

Caspofungin should be initiated by a physician experienced in the management of invasive fungal

infections.

Posology

Adult patients

A single 70 mg loading dose should be administered on Day 1, followed by 50 mg daily thereafter. In

patients weighing more than 80 kg, after the initial 70 mg loading dose, caspofungin 70 mg daily is

recommended (see section 5.2). No dosage adjustment is necessary based on gender or race (see

section 5.2).

Paediatric patients (12 months to 17 years)

In paediatric patients (12 months to 17 years of age), dosing should be based on the patient’s body

surface area (see Instructions for Use in Paediatric Patients, Mosteller

Formula). For all indications, a

single 70 mg/m

loading dose (not to exceed an actual dose of 70 mg) should be administered on

Day 1, followed by 50 mg/m

daily thereafter (not to exceed an actual dose of 70 mg daily). If the

50 mg/m

daily dose is well tolerated but does not provide an adequate clinical response, the daily

dose can be increased to 70 mg/m

daily (not to exceed an actual daily dose of 70 mg).

Mosteller RD: Simplified Calculation of Body Surface Area. N Engl J Med 1987 Oct

22;317(17):1098 (letter)

The safety and efficacy of caspofungin have not been sufficiently studied in clinical trials involving

neonates and infants below 12 months of age. Caution is advised when treating this age group.

Limited data suggest that caspofungin at 25 mg/m

daily in neonates and infants (less than 3 months

of age) and 50 mg/m

daily in young children (3 to 11 months of age) can be considered (see section

5.2).

Duration of treatment

Duration of empirical therapy should be based on the patient’s clinical response. Therapy should be

continued until up to 72 hours after resolution of neutropaenia (ANC≥500). Patients found to have a

fungal infection should be treated for a minimum of 14 days and treatment should continue for at least

7 days after both neutropaenia and clinical symptoms are resolved.

Duration of treatment of invasive candidiasis should be based upon the patient’s clinical and

microbiological response. After signs and symptoms of invasive candidiasis have improved and

cultures have become negative, a switch to oral antifungal therapy may be considered. In general,

antifungal therapy should continue for at least 14 days after the last positive culture.

Duration of treatment of invasive aspergillosis is determined on a case by case basis and should be

based upon the severity of the patient’s underlying disease, recovery from immunosuppression and

clinical response. In general, treatment should continue for at least 7 days after resolution of

symptoms.

The safety information on treatment durations longer than 4 weeks is limited. However, available data

suggest that caspofungin continues to be well tolerated with longer courses of therapy (up to 162 days

in adult patients and up to 87 days in paediatric patients).

Special populations

Elderly patients

In elderly patients (65 years of age or more), the area under the curve (AUC) is increased by

approximately 30%. However, no systematic dosage adjustment is required. There is limited treatment

experience in patients 65 years of age and older (see section 5.2).

Renal impairment

No dosage adjustment is necessary based on renal impairment (see section 5.2).

Hepatic impairment

For adult patients with mild hepatic impairment (Child-Pugh score 5 to 6), no dosage adjustment is

needed. For adult patients with moderate hepatic impairment (Child-Pugh score 7 to 9), caspofungin

35 mg daily is recommended based upon pharmacokinetic data. An initial 70 mg loading dose should

be administered on Day 1. There is no clinical experience in adult patients with severe hepatic

impairment (Child-Pugh score greater than 9) and in paediatric patients with any degree of hepatic

impairment (see section 4.4).

Co-administration with inducers of metabolic enzymes

Limited data suggest that an increase in the daily dose of caspofungin to 70 mg, following the 70 mg

loading dose, should be considered when co-administering caspofungin in adult patients with certain

inducers of metabolic enzymes (see section 4.5). When caspofungin is co-administered to paediatric

patients (12 months to 17 years of age) with these same inducers of metabolic enzymes (see section

4.5), a caspofungin dose of 70 mg/m

daily (not to exceed an actual daily dose of 70 mg) should be

considered.

Method of administration

After reconstitution and dilution, the solution should be administered by slow intravenous infusion

over approximately 1 hour. For reconstitution directions see section 6.6.

Both 70 mg and 50 mg vials are available.

Caspofungin should be given as a single daily infusion.

4.3

Contraindications

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

4.4

Special warnings and precautions for use

Anaphylaxis has been reported during administration of caspofungin. If this occurs, caspofungin

should be discontinued and appropriate treatment administered. Possibly histamine-mediated adverse

reactions, including rash, facial swelling, angioedema, pruritus, sensation of warmth, or

bronchospasm have been reported and may require discontinuation and/or administration of

appropriate treatment.

Limited data suggest that less common non-

Candida

yeasts and non-

Aspergillus

moulds are not

covered by caspofungin. The efficacy of caspofungin against these fungal pathogens has not been

established.

Concomitant use of caspofungin with cyclosporin has been evaluated in healthy adult volunteers and

in adult patients. Some healthy adult volunteers who received two 3 mg/kg doses of cyclosporin with

caspofungin showed transient increases in alanine transaminase (ALT) and aspartate transaminase

(AST) of less than or equal to 3-fold the upper limit of normal (ULN) that resolved with

discontinuation of the treatment. In a retrospective study of 40 patients treated during marketed use

with caspofungin and cyclosporin for 1 to 290 days (median 17.5 days), no serious hepatic adverse

reactions were noted. These data suggest that caspofungin can be used in patients receiving

cyclosporin when the potential benefit outweighs the potential risk. Close monitoring of liver

enzymes should be considered if caspofungin and cyclosporin are used concomitantly.

In adult patients with mild and moderate hepatic impairment, the AUC is increased about 20% and

75%, respectively. A reduction of the daily dose to 35 mg is recommended for adults with moderate

hepatic impairment. There is no clinical experience in adults with severe hepatic impairment or in

paediatric patients with any degree of hepatic impairment. A higher exposure than in moderate hepatic

impairment is expected and caspofungin should be used with caution in these patients (see sections

4.2 and 5.2).

Laboratory abnormalities in liver function tests have been seen in healthy volunteers and adult and

paediatric patients treated with caspofungin. In some adult and paediatric patients with serious

underlying conditions who were receiving multiple concomitant medications with caspofungin, cases

of clinically significant hepatic dysfunction, hepatitis and hepatic failure have been reported; a causal

relationship to caspofungin has not been established. Patients who develop abnormal liver function

tests during caspofungin therapy should be monitored for evidence of worsening hepatic function and

the risk/benefit of continuing caspofungin therapy should be re-evaluated.

Cases of Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported

after post-marketing use of caspofungin. Caution should apply in patients with history of allergic skin

reaction (see section 4.8).

Excipients

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

‘sodium-free’.

4.5

Interaction with other medicinal products and other forms of interaction

Studies

in vitro

show that caspofungin is not an inhibitor of any enzyme in the cytochrome P450

(CYP) system. In clinical studies, caspofungin did not induce the CYP3A4 metabolism of other

substances. Caspofungin is not a substrate for P-glycoprotein and is a poor substrate for cytochrome

P450 enzymes. However, caspofungin has been shown to interact with other medicinal products in

pharmacological and clinical studies (see below).

In two clinical studies performed in healthy adult subjects, cyclosporin A (one 4 mg/kg dose or two

3 mg/kg doses 12 hours apart) increased the AUC of caspofungin by approximately 35%. These AUC

increases are probably due to reduced uptake of caspofungin by the liver. Caspofungin did not

increase the plasma levels of cyclosporin. There were transient increases in liver ALT and AST of

less than or equal to 3-fold the upper limit of normal (ULN) when caspofungin and cyclosporin were

co-administered, that resolved with discontinuation of the medicinal products. In a retrospective study

of 40 patients treated during marketed use with caspofungin and cyclosporin for 1 to 290 days

(median 17.5 days), no serious hepatic adverse reactions were noted (see section 4.4). Close

monitoring of liver enzymes should be considered if the two medicinal products are used

concomitantly.

Caspofungin reduced the trough concentration of tacrolimus by 26% in healthy adult volunteers. For

patients receiving both therapies, standard monitoring of tacrolimus blood concentrations and

appropriate tacrolimus dosage adjustments are mandatory.

Clinical studies in healthy adult volunteers show that the pharmacokinetics of caspofungin are not

altered to a clinically relevant extent by itraconazole, amphotericin B, mycophenolate, nelfinavir, or

tacrolimus. Caspofungin did not influence the pharmacokinetics of amphotericin B, itraconazole,

rifampicin or mycophenolate mofetil. Although safety data are limited it appears that no special

precautions are needed when amphotericin B, itraconazole, nelfinavir or mycophenolate mofetil are

co-administered with caspofungin.

Rifampicin caused a 60% increase in AUC and 170% increase in trough concentration of caspofungin

on the first day of co-administration when both medicinal products were initiated together in healthy

adult volunteers. Caspofungin trough levels gradually decreased upon repeated administration. After

two weeks’ administration rifampicin had limited effect on AUC, but trough levels were 30% lower

than in adult subjects who received caspofungin alone. The mechanism of interaction could possibly

be due to an initial inhibition and subsequent induction of transport proteins. A similar effect could be

expected for other medicinal products that induce metabolic enzymes. Limited data from population

pharmacokinetics studies indicate that concomitant use of caspofungin with the inducers efavirenz,

nevirapine, rifampicin, dexamethasone, phenytoin, or carbamazepine may result in a decrease in

caspofungin AUC. When co-administering inducers of metabolic enzymes, an increase in the daily

dose of caspofungin to 70 mg, following the 70 mg loading dose, should be considered in adult

patients (see section 4.2).

All adult drug-drug interaction studies described above were conducted at a 50 or 70 mg daily

caspofungin dose. The interaction of higher doses of caspofungin with other medicinal products has

not been formally studied.

In paediatric patients, results from regression analyses of pharmacokinetic data suggest that co-

administration of dexamethasone with caspofungin may result in clinically meaningful reductions in

caspofungin trough concentrations. This finding may indicate that paediatric patients will have similar

reductions with inducers as seen in adults. When caspofungin is co-administered to paediatric patients

(12 months to 17 years of age) with inducers of drug clearance, such as rifampicin, efavirenz,

nevirapine, phenytoin, dexamethasone, or carbamazepine, a caspofungin dose of 70 mg/m

daily (not

to exceed an actual daily dose of 70 mg) should be considered.

4.6

Fertility, pregnancy and lactation

Pregnancy

There are no or limited data from the use of caspofungin in pregnant women. Caspofungin should not

be used during pregnancy unless clearly necessary. Animal studies have shown developmental

toxicity (see section 5.3). Caspofungin has been shown to cross the placental barrier in animal studies.

Breastfeeding

It is unknown whether caspofungin is excreted in human milk. Available pharmacodynamic/

toxicological data in animals have shown excretion of caspofungin in milk. Women receiving

caspofungin should not breastfeed.

Fertility

For caspofungin, there were no effects on fertility in studies conducted in male and female rats (see

section 5.3). There are no clinical data for caspofungin to assess its impact on fertility.

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.

4.8

Undesirable effects

Hypersensitivity reactions (anaphylaxis and possibly histamine-mediated adverse reactions) have been

reported (see section 4.4).

Also reported in patients with invasive aspergillosis were pulmonary oedema, adult respiratory

distress syndrome (ARDS) and radiographic infiltrates.

Adult patients

In clinical studies, 1,865 adult individuals received single or multiple doses of caspofungin:

564 febrile neutropaenic patients (empirical therapy study), 382 patients with invasive candidiasis,

228 patients with invasive aspergillosis, 297 patients with localised

Candida

infections, and

394 individuals enrolled in Phase I studies. In the empirical therapy study patients had received

chemotherapy for malignancy or had undergone hematopoietic stem-cell transplantation (including

39 allogeneic transplantations). In the studies involving patients with documented

Candida

infections,

the majority of the patients with invasive

Candida

infections had serious underlying medical

conditions (e.g., haematologic or other malignancy, recent major surgery, HIV) requiring multiple

concomitant medications. Patients in the non-comparative

Aspergillus

study often had serious

predisposing medical conditions (e.g., bone marrow or peripheral stem cell transplants, haematologic

malignancy, solid tumours or organ transplants) requiring multiple concomitant medications.

Phlebitis was a commonly reported local injection-site adverse reaction in all patient populations.

Other local reactions included erythema, pain/tenderness, itching, discharge and a burning sensation.

Reported clinical and laboratory abnormalities among all adults treated with caspofungin (total 1,780)

were typically mild and rarely led to discontinuation.

The following adverse reactions were reported:

MedDRA system

organ class

Common

≥1/100 to <1/10

Uncommon

≥1/1,000 to <1/100

Not known

(cannot

be estimated from

available data)

Blood and

lymphatic system

disorders

Haemoglobin

decreased,

haematocrit

decreased, white

blood cell count

decreased

Anaemia,

thrombocytopaenia,

coagulopathy, leukopaenia,

eosinophil count increased,

platelet count decreased,

platelet count increased,

MedDRA system

organ class

Common

≥1/100 to <1/10

Uncommon

≥1/1,000 to <1/100

Not known

(cannot

be estimated from

available data)

lymphocyte count decreased,

white blood cell count

increased, neutrophil count

decreased

Metabolism and

nutrition

disorders

Hypokalemia

Fluid overload,

hypomagnesaemia, anorexia,

electrolyte imbalance,

hyperglycaemia,

hypocalcaemia, metabolic

acidosis

Psychiatric

disorders

Anxiety, disorientation,

insomnia

Nervous system

disorders

Headache

Dizziness, dysgeusia,

paraesthesia, somnolence,

tremor, hypoaesthesia

Eye disorders

Ocular icterus, vision

blurred, eyelid oedema,

lacrimation increased

Cardiac disorders

Palpitations, tachycardia,

arrhythmia, atrial fibrillation,

cardiac failure congestive

Vascular

disorders

Phlebitis

Thrombophlebitis, flushing,

hot flush, hypertension,

hypotension

Respiratory,

thoracic and

mediastinal

disorders

Dyspnoea

Nasal congestion,

pharyngolaryngeal pain,

tachypnoea, bronchospasm,

cough, dyspnoea paroxysmal

nocturnal, hypoxia, rales,

wheezing

Gastrointestinal

disorders

Nausea, diarrhoea,

vomiting

Abdominal pain, abdominal

pain upper, dry mouth,

dyspepsia, stomach

discomfort, abdominal

distension, ascites,

constipation, dysphagia,

flatulence

Hepatobiliary

disorders

Elevated liver

values (alanine

aminotransferase,

aspartate

aminotransferase,

blood alkaline

phosphatase,

bilirubin

conjugated, blood

bilirubin)

Cholestasis, hepatomegaly,

hyperbilirubinaemia,

jaundice, hepatic function

abnormal, hepatotoxicity,

liver disorder, gamma-

glutamyltransferase

increased

Skin and

subcutaneous

tissue disorders

Rash, pruritus,

erythema,

hyperhidrosis

Erythema multiforme, rash

macular, rash maculo-

papular, rash pruritic,

urticaria, dermatitis allergic,

pruritus generalised, rash

Toxic epidermal

necrolysis and

Stevens-Johnson

syndrome (see

section 4.4)

MedDRA system

organ class

Common

≥1/100 to <1/10

Uncommon

≥1/1,000 to <1/100

Not known

(cannot

be estimated from

available data)

erythematous, rash

generalised, rash

morbilliform, skin lesion

Musculoskeletal

and connective

tissue disorders

Arthralgia

Back pain, pain in extremity,

bone pain, muscular

weakness, myalgia

Renal and urinary

disorders

Renal failure, renal failure

acute

General disorders

and

administration

site conditions

Pyrexia, chills,

infusion-site

pruritus

Pain, catheter site pain,

fatigue, feeling cold, feeling

hot, infusion site erythema,

infusion site induration,

infusion site pain, infusion

site swelling, injection site

phlebitis, oedema peripheral,

tenderness, chest discomfort,

chest pain, face oedema,

feeling of body temperature

change, induration, infusion

site extravasation, infusion

site irritation, infusion site

phlebitis, infusion site rash,

infusion site urticaria,

injection site erythema,

injection site oedema,

injection site pain, injection

site swelling, malaise,

oedema

Investigations

Blood potassium

decreased, blood

albumin decreased

Blood creatinine increased,

red blood cells urine

positive, protein total

decreased, protein urine

present, prothrombin time

prolonged, prothrombin time

shortened, blood sodium

decreased, blood sodium

increased, blood calcium

decreased, blood calcium

increased, blood chloride

decreased, blood glucose

increased, blood magnesium

decreased, blood phosphorus

decreased, blood phosphorus

increased, blood urea

increased, activated partial

thromboplastin time

prolonged, blood bicarbonate

decreased, blood chloride

increased, blood potassium

increased, blood pressure

increased, blood uric acid

decreased, blood urine

MedDRA system

organ class

Common

≥1/100 to <1/10

Uncommon

≥1/1,000 to <1/100

Not known

(cannot

be estimated from

available data)

present, breath sounds

abnormal, carbon dioxide

decreased,

immunosuppressant drug

level increased, international

normalised ratio increased,

urinary casts, white blood

cells urine positive and pH

urine increased

Caspofungin has also been evaluated at 150 mg daily (for up to 51 days) in 100 adult patients (see

section 5.1). The study compared caspofungin at 50 mg daily (following a 70 mg loading dose on Day

1) versus 150 mg daily in the treatment of invasive candidiasis. In this group of patients, the safety of

caspofungin at this higher dose appeared generally similar to patients receiving the 50 mg daily dose

of caspofungin. The proportion of patients with a serious drug-related adverse reaction or a drug-

related adverse reaction leading to caspofungin discontinuation was comparable in the 2 treatment

groups.

Paediatric population

Data from 5 clinical studies completed in 171 paediatric patients suggest that the overall incidence of

clinical adverse experiences (26.3%; 95% CI -19.9, 33.6) is not worse than reported for adults treated

with caspofungin (43.1%; 95% CI -40.0, 46.2). However, paediatric patients probably have a different

adverse event profile compared to adult patients. The most common drug-related clinical adverse

experiences reported in paediatric patients treated with caspofungin were pyrexia (11.7%), rash

(4.7%) and headache (2.9%).

The following adverse reactions were reported:

MedDRA system

organ class

Very

common

≥1/10

Common

≥1/100 to <1/10

Blood and

lymphatic system

disorders

Eosinophil count

increased

Nervous system

disorders

Headache

Cardiac disorders

Tachycardia

Vascular

disorders

Flushing, hypotension

Hepatobiliary

disorders

Elevated liver enzyme

levels (AST, ALT)

Skin and

subcutaneous

tissue disorders

Rash, pruritus

General disorders

and

administration

site conditions

Fever

Chills, catheter site pain

Investigations

Decreased potassium,

hypomagnesemia,

increased glucose,

decreased phosphorus,

MedDRA system

organ class

Very

common

≥1/10

Common

≥1/100 to <1/10

increased phosphorus

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

Inadvertent administration of up to 400 mg of caspofungin in one day has been reported. These

occurrences did not result in clinically important adverse reactions. Caspofungin is not dialysable.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: antimycotics for systemic use, ATC Code: J02AX04

Mechanism of action

Caspofungin acetate is a semi-synthetic lipopeptide (echinocandin) compound synthesised from a

fermentation product of

Glarea lozoyensis

. Caspofungin acetate inhibits the synthesis of beta (1,3)-D-

glucan, an essential component of the cell wall of many filamentous fungi and yeast. Beta (1,3)-D-

glucan is not present in mammalian cells.

Fungicidal activity with caspofungin has been demonstrated against

Candida

yeasts. Studies

in vitro

in vivo

demonstrate that exposure of

Aspergillus

to caspofungin results in lysis and death of

hyphal apical tips and branch points where cell growth and division occur.

Pharmacodynamic effects

Caspofungin has

in vitro

activity against

Aspergillus

species (

Aspergillus fumigatus

[N = 75],

Aspergillus flavus

[N = 111],

Aspergillus niger

[N = 31],

Aspergillus nidulans

[N = 8],

Aspergillus

terreus

[N = 52] and

Aspergillus candidus

[N = 3]). Caspofungin also has

in vitro

activity against

Candida

species (

Candida albicans

[N = 1,032],

Candida dubliniensis

[N = 100],

Candida

glabrata

[N = 151],

Candida guilliermondii

[N = 67],

Candida kefyr

[N = 62],

Candida krusei

[N = 147], C

andida lipolytica

[N = 20],

Candida lusitaniae

[N = 80],

Candida parapsilosis

[N = 215],

Candida rugosa

[N = 1] and

Candida tropicalis

[N = 258]), including isolates with

multiple resistance transport mutations and those with acquired or intrinsic resistance to fluconazole,

amphotericin B and 5-flucytosine. Susceptibility testing was performed according to a modification of

both the Clinical and Laboratory Standards Institute (CLSI, formerly known as the National

Committee for Clinical Laboratory Standards [NCCLS]) method M38-A2 (for

Aspergillus

species)

and method M27-A3 (for

Candida

species).

Standardised techniques for susceptibility testing have been established for yeasts by EUCAST.

EUCAST breakpoints have not yet been established for caspofungin, due to significant inter-

laboratory variation in MIC ranges for caspofungin. In lieu of breakpoints,

Candida

isolates that are

susceptible to anidulafungin as well as micafungin should be considered susceptible to caspofungin.

Similarly,

C. parapsilosis

isolates intermediate to anidulafungin and micafungin can be regarded

intermediate to caspofungin.

Mechanism of resistance

Isolates of

Candida

with reduced susceptibility to caspofungin have been identified in a small number

of patients during treatment (MICs for caspofungin >2 mg/L (4- to 30-fold MIC increases) have been

reported using standardized MIC testing techniques approved by the CLSI). The mechanism of

resistance identified is FKS1 and/or FKS2 (for

C. glabrata

) gene mutations. These cases have been

associated with poor clinical outcomes.

Development of

in vitro

resistance to caspofungin by

Aspergillus

species has been identified. In

limited clinical experience, resistance to caspofungin in patients with invasive aspergillosis has been

observed. The mechanism of resistance has not been established. The incidence of resistance to

caspofungin by various clinical isolates of

Aspergillus

is rare. Caspofungin resistance in

Candida

been observed but the incidence may differ by species or region.

Clinical efficacy and safety

Invasive Candidiasis in Adult Patients:

Two hundred thirty-nine patients were enrolled in an initial

study to compare caspofungin and amphotericin B for the treatment of invasive candidiasis. Twenty-

four patients had neutropaenia. The most frequent diagnoses were bloodstream infections

(candidaemia) (77%, n=186) and

Candida

peritonitis (8%, n=19); patients with

Candida

endocarditis,

osteomyelitis, or meningitis were excluded from this study. Caspofungin 50 mg once daily was

administered following a 70 mg loading dose, while amphotericin B was administered at 0.6 to 0.7

mg/kg/day to non-neutropaenic patients or 0.7 to 1.0 mg/kg/day to neutropaenic patients. The mean

duration of intravenous therapy was 11.9 days, with a range of 1 to 28 days. A favourable response

required both symptom resolution and microbiological clearance of the

Candida

infection. Two

hundred twenty-four patients were included in the primary efficacy analysis (MITT analysis) of

response at the end of IV study therapy; favourable response rates for the treatment of invasive

candidiasis were comparable for caspofungin (73% [80/109]) and amphotericin B (62% [71/115]) [%

difference 12.7 (95.6% CI -0.7, 26.0)]. Among patients with candidaemia, favourable response rates at

the end of IV study therapy were comparable for caspofungin (72% [66/92]) and amphotericin B

(63% [59/94]) in the primary efficacy analysis (MITT analysis) [% difference 10.0 (95.0% CI -4.5,

24.5)]. Data in patients with non-blood sites of infection were more limited. Favourable response rates

in neutropaenic patients were 7/14 (50%) in the caspofungin group and 4/10 (40%) in the

amphotericin B group. These limited data are supported by the outcome of the empirical therapy

study.

In a second study, patients with invasive candidiasis received daily doses of caspofungin at 50 mg/day

(following a 70 mg loading dose on Day 1) or caspofungin at 150 mg/day (see section 4.8). In this

study, the caspofungin dose was administered over 2 hours (instead of the routine 1-hour

administration). The study excluded patients with suspected

Candida

endocarditis, meningitis, or

osteomyelitis. As this was a primary therapy study, patients who were refractory to prior antifungal

agents were also excluded. The number of neutropenic patients enrolled in this study was also limited

(8.0%). Efficacy was a secondary endpoint in this study. Patients who met the entry criteria and

received one or more doses of caspofungin study therapy were included in the efficacy analysis. The

favorable overall response rates at the end of caspofungin therapy were similar in the 2 treatment

groups: 72% (73/102) and 78% (74/95) for the caspofungin 50 mg and 150-mg treatment groups,

respectively (difference 6.3% [95% CI -5.9, 18.4]).

Invasive Aspergillosis in Adult Patients:

Sixty-nine adult patients (age 18-80) with invasive

aspergillosis were enrolled in an open-label, non-comparative study to evaluate the safety, tolerability

and efficacy of caspofungin. Patients had to be either refractory to (disease progression or failure to

improve with other antifungal therapies given for at least 7 days) (84% of the enrolled patients) or

intolerant of (16% of enrolled patients) other standard antifungal therapies. Most patients had

underlying conditions (haematologic malignancy [N = 24], allogeneic bone marrow transplant or stem

cell transplant [N = 18], organ transplant [N = 8], solid tumour [N = 3], or other conditions [N = 10]).

Stringent definitions, modelled after the Mycoses Study Group Criteria, were used for diagnosis of

invasive aspergillosis and for response to therapy (favourable response required clinically significant

improvement in radiographs as well as in signs and symptoms). The mean duration of therapy was

33.7 days, with a range of 1 to 162 days. An independent expert panel determined that 41% (26/63) of

patients receiving at least one dose of caspofungin had a favourable response. For those patients who

received more than 7 days of therapy with caspofungin, 50% (26/52) had a favourable response. The

favourable response rates for patients who were either refractory to or intolerant of previous therapies

were 36% (19/53) and 70% (7/10), respectively. Although the doses of prior antifungal therapies in 5

patients enrolled as refractory were lower than those often administered for invasive aspergillosis, the

favourable response rate during therapy with caspofungin was similar in these patients to that seen in

the remaining refractory patients (2/5 versus 17/48, respectively). The response rates among patients

with pulmonary disease and extrapulmonary disease were 47% (21/45) and 28% (5/18), respectively.

Among patients with extrapulmonary disease, 2 of 8 patients who also had definite, probable, or

possible CNS involvement had a favourable response.

Empirical Therapy in Febrile, Neutropaenic Adult Patients:

A total of 1,111 patients with persistent

fever and neutropaenia were enrolled in a clinical study and treated with either caspofungin 50 mg

once daily following a 70 mg loading dose or liposomal amphotericin B 3.0 mg/kg/day. Eligible

patients had received chemotherapy for malignancy or had undergone hematopoietic stem-cell

transplantation and presented with neutropaenia (<500 cells/mm

for 96 hours) and fever (>38.0°C)

not responding to ≥96 hours of parenteral antibacterial therapy. Patients were to be treated until up to

72 hours after resolution of neutropaenia, with a maximum duration of 28 days. However, patients

found to have a documented fungal infection could be treated longer. If the drug was well tolerated

but the patient’s fever persisted and clinical condition deteriorated after 5 days of therapy, the dosage

of study drug could be increased to 70 mg/day of caspofungin (13.3% of patients treated) or to

5.0 mg/kg/day of liposomal amphotericin B (14.3% of patients treated). There were 1,095 patients

included in the primary Modified Intention-To-Treat (MITT) efficacy analysis of overall favourable

response; caspofungin (33.9%) was as effective as liposomal amphotericin B (33.7%) [% difference

0.2 (95.2% CI –5.6, 6.0)]. An overall favourable response required meeting each of 5 criteria:

(1) successful treatment of any baseline fungal infection (caspofungin 51.9% [14/27], liposomal

amphotericin B 25.9% [7/27]), (2) no breakthrough fungal infections during administration of study

drug or within 7 days after completion of treatment (caspofungin 94.8% [527/556], liposomal

amphotericin B 95.5% [515/539]), (3) survival for 7 days after completion of study therapy

(caspofungin 92.6% [515/556], liposomal amphotericin B 89.2% [481/539]), (4) no discontinuation

from the study drug because of drug-related toxicity or lack of efficacy (caspofungin 89.7%

[499/556], liposomal amphotericin B 85.5% [461/539]) and (5) resolution of fever during the period

of neutropaenia (caspofungin 41.2% [229/556], liposomal amphotericin B 41.4% [223/539]).

Response rates to caspofungin and liposomal amphotericin B for baseline infections caused by

Aspergillus

species were, respectively, 41.7% (5/12) and 8.3% (1/12) and by

Candida

species were

66.7% (8/12) and 41.7% (5/12). Patients in the caspofungin group experienced breakthrough

infections due to the following uncommon yeasts and moulds:

Trichosporon

species (1),

Fusarium

species (1),

Mucor

species (1) and

Rhizopus

species (1).

Paediatric population

The safety and efficacy of caspofungin was evaluated in paediatric patients 3 months to 17 years of

age in two prospective, multicenter clinical trials. The study design, diagnostic criteria and criteria for

efficacy assessment were similar to the corresponding studies in adult patients (see section 5.1).

The first study, which enrolled 82 patients between 2 to 17 years of age, was a randomized, double-

blind study comparing caspofungin (50 mg/m

IV once daily following a 70 mg/m

loading dose on

Day 1 [not to exceed 70 mg daily]) to liposomal amphotericin B (3 mg/kg IV daily) in a 2:1 treatment

fashion (56 on caspofungin, 26 on liposomal amphotericin B) as empirical therapy in paediatric

patients with persistent fever and neutropenia. The overall success rates in the MITT analysis results,

adjusted by risk strata, were as follows: 46.6% (26/56) for caspofungin and 32.2% (8/25) for

liposomal amphotericin B.

The second study was a prospective, open-label, non-comparative study estimating the safety and

efficacy of caspofungin in paediatric patients (ages 6 months to 17 years) with invasive candidiasis,

esophageal candidiasis and invasive aspergillosis (as salvage therapy). 49 patients were enrolled and

received caspofungin at 50 mg/m

IV once daily following a 70 mg/m

loading dose on Day 1 (not to

exceed 70 mg daily), of whom 48 were included in the MITT analysis. Of these, 37 had invasive

candidiasis, 10 had invasive aspergillosis and 1 patient had esophageal candidiasis. The favorable

response rate, by indication, at the end of caspofungin therapy was as follows in the MITT analysis:

81% (30/37) in invasive candidiasis, 50% (5/10) in invasive aspergillosis and 100% (1/1) in

esophageal candidiasis.

In a double-blind, randomized (2:1) comparator-controlled study safety, tolerability and efficacy of

caspofungin (2 mg/kg/d intravenously, infused over 2 hours) vs amphotericin B deoxycholate

(1 mg/kg/d) was evaluated in neonates and infants less than 3 months of age with (culture-confirmed)

invasive candidiasis. Due to poor enrolment, the study was terminated early and only 51 patients were

randomized. The proportion of patients with fungal-free survival at 2 weeks post-therapy in the

caspofungin treatment group (71.0%) was similar to that seen in the amphotericin B deoxycholate

treatment group (68.8%). Based on this study, no posology recommendations for neonates and infants

can be made.

5.2

Pharmacokinetic properties

Distribution

Caspofungin is extensively bound to albumin. The unbound fraction of caspofungin in plasma varies

from 3.5% in healthy volunteers to 7.6% in patients with invasive candidiasis. Distribution plays the

prominent role in caspofungin plasma pharmacokinetics and is the rate-controlling step in both the

alpha- and beta-disposition phases. The distribution into tissues peaked at 1.5 to 2 days after dosing

when 92% of the dose was distributed into tissues. It is likely that only a small fraction of the

caspofungin taken up into tissues later returns to plasma as parent compound. Therefore, elimination

occurs in the absence of a distribution equilibrium and a true estimate of the volume of distribution of

caspofungin is currently impossible to obtain.

Biotransformation

Caspofungin undergoes spontaneous degradation to an open ring compound. Further metabolism

involves peptide hydrolysis and N-acetylation. Two intermediate products, formed during the

degradation of caspofungin to this open ring compound, form covalent adducts to plasma proteins

resulting in a low-level, irreversible binding to plasma proteins.

In vitro

studies show that caspofungin is not an inhibitor of cytochrome P450 enzymes 1A2, 2A6,

2C9, 2C19, 2D6 or 3A4. In clinical studies, caspofungin did not induce or inhibit the CYP3A4

metabolism of other medicinal products. Caspofungin is not a substrate for P-glycoprotein and is a

poor substrate for cytochrome P450 enzymes.

Elimination

The elimination of caspofungin from plasma is slow with a clearance of 10-12 ml/min. Plasma

concentrations of caspofungin decline in a polyphasic manner following single 1-hour intravenous

infusions. A short alpha-phase occurs immediately post-infusion, followed by a beta-phase with a

half-life of 9 to 11 hours. An additional gamma-phase also occurs with a half-life of 45 hours.

Distribution, rather than excretion or biotransformation, is the dominant mechanism influencing

plasma clearance.

Approximately 75% of a radioactive dose was recovered during 27 days: 41% in urine and 34% in

faeces. There is little excretion or biotransformation of caspofungin during the first 30 hours after

administration. Excretion is slow and the terminal half-life of radioactivity was 12 to 15 days. A small

amount of caspofungin is excreted unchanged in urine (approximately 1.4% of dose).

Caspofungin displays moderate non-linear pharmacokinetics with increased accumulation as the dose

is increased and a dose dependency in the time to reach steady state upon multiple-dose

administration.

Special populations

Increased caspofungin exposure was seen in adult patients with renal impairment and mild liver

impairment, in female subjects and in the elderly. Generally the increase was modest and not large

enough to warrant dosage adjustment. In adult patients with moderate liver impairment or in higher

weight patients, a dosage adjustment may be necessary (see below).

Weight

Weight was found to influence caspofungin pharmacokinetics in the population pharmacokinetic

analysis in adult candidiasis patients. The plasma concentrations decrease with increasing weight. The

average exposure in an adult patient weighing 80 kg was predicted to be about 23% lower than in an

adult patient weighing 60 kg (see section 4.2).

Hepatic impairment

In adult patients with mild and moderate hepatic impairment, the AUC is increased about 20% and

75%, respectively. There is no clinical experience in adult patients with severe hepatic impairment

and in paediatric patients with any degree of hepatic impairment. In a multiple-dose study, a dose

reduction of the daily dose to 35 mg in adult patients with moderate hepatic impairment has been

shown to provide an AUC similar to that obtained in adult subjects with normal hepatic function

receiving the standard regimen (see section 4.2).

Renal impairment

In a clinical study of single 70 mg doses, caspofungin pharmacokinetics were similar in adult

volunteers with mild renal impairment (creatinine clearance 50 to 80 ml/min) and control subjects.

Moderate (creatinine clearance 31 to 49 ml/min), advanced (creatinine clearance 5 to 30 ml/min) and

end-stage (creatinine clearance <10 ml/min and dialysis dependent) renal impairment moderately

increased caspofungin plasma concentrations after single-dose administration (range: 30 to 49% for

AUC). However, in adult patients with invasive candidiasis, oesophageal candidiasis, or invasive

aspergillosis who received multiple daily doses of caspofungin 50 mg, there was no significant effect

of mild to advanced renal impairment on caspofungin concentrations. No dosage adjustment is

necessary for patients with renal impairment. Caspofungin is not dialysable, thus supplementary

dosing is not required following haemodialysis.

Gender

Caspofungin plasma concentrations were on average 17-38% higher in women than in men.

Elderly

A modest increase in AUC (28%) and C

(32%) was observed in elderly male subjects compared

with young male subjects. In patients who were treated empirically or who had invasive candidiasis, a

similar modest effect of age was seen in older patients relative to younger patients.

Race

Patient pharmacokinetic data indicated that no clinically significant differences in the

pharmacokinetics of caspofungin were seen among Caucasians, Blacks, Hispanics and Mestizos.

Paediatric Patients

In adolescents (ages 12 to 17 years) receiving caspofungin at 50 mg/m

daily (maximum 70 mg daily),

the caspofungin plasma AUC

0-24 hr

was generally comparable to that seen in adults receiving

caspofungin at 50 mg daily. All adolescents received doses >50 mg daily, and, in fact, 6 of 8 received

the maximum dose of 70 mg/day. The caspofungin plasma concentrations in these adolescents were

reduced relative to adults receiving 70 mg daily, the dose most often administered to adolescents.

In children (ages 2 to 11 years) receiving caspofungin at 50 mg/m

daily (maximum 70 mg daily), the

caspofungin plasma AUC

0-24 hr

after multiple doses was comparable to that seen in adults receiving

caspofungin at 50 mg/day.

In young children and toddlers (ages 12 to 23 months) receiving caspofungin at 50 mg/m

daily

(maximum 70 mg daily), the caspofungin plasma AUC

0-24 hr

after multiple doses was comparable to

that seen in adults receiving caspofungin at 50 mg daily and to that in older children (2 to 11 years of

age) receiving the 50 mg/m

daily dose.

Overall, the available pharmacokinetic, efficacy and safety data are limited in patients 3 to 10 months

of age. Pharmacokinetic data from one 10-month old child receiving the 50 mg/m

daily dose

indicated an AUC

0-24 hr

within the same range as that observed in older children and adults at the

50 mg/m

and the 50 mg dose, respectively, while in one 6-month old child receiving the 50 mg/m

dose, the AUC

0-24 hr

was somewhat higher.

In neonates and infants (<3 months) receiving caspofungin at 25 mg/m

daily (corresponding mean

daily dose of 2.1 mg/kg), caspofungin peak concentration (C

1 hr

) and caspofungin trough concentration

24 hr

) after multiple doses were comparable to that seen in adults receiving caspofungin at 50 mg

daily. On Day 1, C

1 hr

was comparable and C

24 hr

modestly elevated (36%) in these neonates and

infants relative to adults. However, variability was seen in both C

1 hr

(Day 4 geometric mean

11.73 µg/ml, range 2.63 to 22.05 µg/ml) and C

24 hr

(Day 4 geometric mean 3.55 µg/ml, range 0.13 to

7.17 µg/ml). AUC

0-24 hr

measurements were not performed in this study due to the sparse plasma

sampling. Of note, the efficacy and safety of caspofungin have not been adequately studied in

prospective clinical trials involving neonates and infants under 3 months of age.

5.3

Preclinical safety data

Repeated dose toxicity studies in rats and monkeys using doses up to 7-8 mg/kg given intravenously

showed injection site reactions in rats and monkeys, signs of histamine release in rats and evidence of

adverse effects directed at the liver in monkeys. Developmental toxicity studies in rats showed that

caspofungin caused decreases in foetal body weights and an increase in the incidence of incomplete

ossification of vertebra, sternebra and skull bone at doses of 5 mg/kg that were coupled to adverse

maternal effects such as signs of histamine release in pregnant rats. An increase in the incidence of

cervical ribs was also noted. Caspofungin was negative in

in vitro

assays for potential genotoxicity as

well as in the

in vivo

mouse bone marrow chromosomal test. No long-term studies in animals have

been performed to evaluate the carcinogenic potential. For caspofungin, there were no effects on

fertility in studies conducted in male and female rats up to 5 mg/kg/day.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Sucrose

Mannitol

Acetic acid, glacial

Sodium hydroxide (for pH-adjustment)

6.2

Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in

section 6.6.

6.3

Shelf life

Unopened vials:

2 years

Reconstituted concentrate:

Chemical and physical in-use stability has been demonstrated for 24 hours at room temperature and at

2°C – 8°C when reconstituted with water for injection.

From a microbiological point of view the

product should be used immediately. If not used immediately, in-use storage conditions prior to use

are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless

reconstitution has taken place in controlled and validated aseptic conditions.

Diluted patient infusion solution:

Chemical and physical in-use stability has been demonstrated for 48 hours when stored at 25°C or

2°C – 8°C and diluted with sodium chloride solution 9 mg/ml (0.9%), 4.5 mg/ml (0.45%) or

2.25 mg/ml (0.225%) for infusion or with Lactated Ringer’s solution. From a microbiological point of

view, the product should be used immediately. If not used immediately, in-use storage times and

conditions prior to use are the responsibility of the user and would normally not be longer than 24

hours at 2 to 8°C, unless reconstitution and dilution have taken place in controlled validated aseptic

conditions.

6.4

Special precautions for storage

Unopened vials: store in a refrigerator (2°C – 8°C).

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

6.5

Nature and contents of container

10 ml transparent Type I glass vial with a grey bromobutyl rubber stopper and aluminium band with a

red (50 mg) or orange (70 mg) plastic flip-off cap. Supplied in packs of 1 vial.

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.

INSTRUCTIONS FOR USE IN ADULT PATIENTS

Step 1 Reconstitution of vials

To reconstitute the powder, bring the vial to room temperature and aseptically add 10.5 ml of water

for injection. The concentrations of the reconstituted vials will be 5.2 mg/ml (50 mg vial) or

7.2 mg/ml (70 mg vial).

The white to off-white compact lyophilised powder will dissolve completely. Mix gently until a clear

solution is obtained. Reconstituted solutions should be visually inspected for particulate matter or

discolouration. This reconstituted solution may be stored for up to 24 hours at or below 25°C (down

to 2°C – 8°C).

Step 2 Addition of reconstituted Caspofungin Orion to patient infusion solution

Diluents for the final solution for infusion are: sodium chloride solution for injection (9 mg/ml,

4.5 mg/ml or 2.25 mg/ml), or Lactated Ringer’s solution. The solution for infusion is prepared by

aseptically adding the appropriate amount of reconstituted concentrate (as shown in the table below)

to a 250 ml infusion bag or bottle. Reduced volume infusions in 100 ml may be used, when medically

necessary, for 50 mg or 35 mg daily doses. This infusion solution must be used within 48 hours if

stored at or below 25°C (down to 2°C – 8°C). Do not use if the solution is cloudy or has precipitated.

PREPARATION OF THE SOLUTION FOR INFUSION IN ADULTS

DOSE*

Volume of

reconstituted

Caspofungin

Orion for

transfer to

intravenous

Standard

preparation

(reconstituted

Caspofungin

Orion added to

250 ml) final

Reduced volume

infusion

(reconstituted

Caspofungin

Orion added to

100 ml) final

bag or bottle

concentration

concentration

70 mg

10 ml

0.28 mg/ml

Recommended

70 mg

(from two 50

mg vials)**

14 ml

0.28 mg/ml

Recommended

50 mg

10 ml

0.20 mg/ml

50 mg at

reduced

volume

10 ml

0.47 mg/ml

35 mg for

moderate

hepatic

impairment

(from one

50 mg vial)

7 ml

0.14 mg/ml

35 mg for

moderate

hepatic

impairment

(from one

50 mg vial) at

reduced

volume

7 ml

0.34 mg/ml

35 mg for

moderate

hepatic

impairment

(from one

70 mg vial)

5 ml

0.14 mg/ml

0.34 mg/ml

* 10.5 ml should be used for reconstitution of all vials

** If 70 mg vial is not available, the 70 mg dose can be prepared from two 50 mg vials

INSTRUCTIONS FOR USE IN PAEDIATRIC PATIENTS

Calculation of Body Surface Area (BSA) for paediatric dosing

Before preparation of infusion, calculate the body surface area (BSA) of the patient using the

following formula (Mosteller Formula):

Preparation of the 70 mg/m

2

infusion for paediatric patients >3 months of age (using a 50 mg vial

or a 70 mg vial)

Determine the actual loading dose to be used in the paediatric patient by using the patient's

BSA (as calculated above) and the following equation:

BSA (m

) X 70 mg/m

= Loading Dose

The maximum loading dose on Day 1 should not exceed 70 mg regardless of the patient's

calculated dose.

Equilibrate the refrigerated vial of Caspofungin Orion to room temperature.

Aseptically add 10.5 ml of water for injection.

This reconstituted solution may be stored for up

to 24 hours at or below 25°C (down to 2°C – 8°C).

This will give a final caspofungin

concentration in the vial of 5.2 mg/ml (50 mg vial) or 7.2 mg/ml (70 mg vial).

Remove the volume of medicinal product equal to the calculated loading dose (Step 1) from the

vial. Aseptically transfer this volume (ml)

of reconstituted Caspofungin Orion to an IV bag (or

bottle) containing 250 ml of 9 mg/ml (0.9%), 4.5 mg/ml (0.45%) or 2.25 mg/ml (0.225%)

sodium chloride solution or Lactated Ringer’s solution. Alternatively, the volume (ml)

reconstituted Caspofungin Orion can be added to a reduced volume of 9 mg/ml (0.9%),

4.5 mg/ml ( 0.45%) or 2.25 mg/ml (0.225%) sodium chloride solution or Lactated Ringer’s

solution, not to exceed a final concentration of 0.5 mg/ml. This infusion solution must be used

within 48 hours if stored at or below 25°C (down to 2°C – 8°C).

Preparation of the 50 mg/m

2

infusion for paediatric patients >3 months of age (using a 50 mg vial

or a 70 mg vial)

Determine the actual daily maintenance dose to be used in the paediatric patient by using the

patient's BSA (as calculated above) and the following equation:

BSA (m

) X 50 mg/m

= Daily Maintenance Dose

The daily maintenance dose should not exceed 70 mg regardless of the patient's calculated

dose.

Equilibrate the refrigerated vial of Caspofungin Orion to room temperature.

Aseptically add 10.5 ml of water for injection.

This reconstituted solution may be stored for up

to 24 hours at or below 25°C (down to 2°C – 8°C).

This will give a final caspofungin

concentration in the vial of 5.2 mg/ml (50 mg vial) or 7.2 mg/ml (70 mg vial).

Remove the volume of medicinal product equal to the calculated daily maintenance dose

(Step 1) from the vial. Aseptically transfer this volume (ml)

of reconstituted Caspofungin

Orion to an IV bag (or bottle) containing 250 ml of 9 mg/ml (0.9%), 4.5 mg/ml (0.45%) or

2.25 mg/ml (0.225%) sodium chloride solution or Lactated Ringer’s solution. Alternatively, the

volume (ml)

of reconstituted Caspofungin Orion can be added to a reduced volume of 9 mg/ml

(0.9%), 4.5 mg/ml (0.45%) or 2.25 mg/ml (0.225%) sodium chloride solution or Lactated

Ringer’s solution, not to exceed a final concentration of 0.5 mg/ml. This infusion solution must

be used within 48 hours if stored at or below 25°C (down to 2°C – 8°C).

Preparation notes:

The white to off-white cake will dissolve completely. Mix gently until a clear solution is

obtained.

Visually inspect the reconstituted solution for particulate matter or discolouration during

reconstitution and prior to infusion. Do not use if the solution is cloudy or has precipitated.

Caspofungin Orion is formulated to provide the full labelled vial dose (50 mg or 70 mg) when

10 ml is withdrawn from the vial.

7.

MARKETING AUTHORISATION HOLDER

Orion Corporation

Orionintie 1

FI-02200 Espoo

Finland

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

2021-01-13

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