Clozapine Orifarm 25 mg Tablett

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

06-11-2020

Produktens egenskaper Produktens egenskaper (SPC)

16-01-2020

Aktiva substanser:
klozapin
Tillgänglig från:
Orifarm AB
ATC-kod:
N05AH02
INN (International namn):
clozapine
Dos:
25 mg
Läkemedelsform:
Tablett
Sammansättning:
klozapin 25 mg Aktiv substans; laktosmonohydrat Hjälpämne
Receptbelagda typ:
Receptbelagt
Bemyndigande status:
Avregistrerad
Godkännandenummer:
54638
Tillstånd datum:
2017-02-22

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

16-01-2020

Produktens egenskaper Produktens egenskaper - engelska

16-01-2020

Läs hela dokumentet

Bipacksedel: Information till patienten

Clozapine Actavis 25 mg tabletter eller 100 mg tabletter

klozapin

Läs noga igenom denna bipacksedel innan du börjar använda detta läkemedel. Den

innehåller information som är viktig för dig.

Spara denna information, du kan behöva läsa den igen.

Om du har ytterligare frågor vänd dig till läkare eller apotekspersonal.

Detta läkemedel har ordinerats enbart åt dig. Ge det inte till andra. Det kan skada dem, även

om de uppvisar sjukdomstecken som liknar dina.

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

som inte nämns i denna information. Se avsnitt 4.

I denna bipacksedel finns information om följande:

Vad är Clozapine Actavis och vad används det för?

Vad du behöver veta innan du innan du tar Clozapine Actavis

Hur du tar Clozapine Actavis

Eventuella biverkningar

Hur Clozapine Actavis ska förvaras

Förpackningens innehåll och övriga upplysningar

1

Vad är Clozapine Actavis och vad det används för?

Clozapine Actavis hör till typen av läkemedel som kallas antipsykotiska läkemedel som verkar på

det centrala nervsystemet.

Clozapine Actavis används vid schizofreni.

Clozapine Actavis kan också användas för psykotiska besvär, som uppkommit under behandling

av Parkinsons sjukdom.

2

Vad du behöver veta innan du tar Clozapine Actavis

Innan du påbörjar behandling med Clozapine Actavis tas ett blodprov för att undersöka

blodbilden och besluta om du kan behandlas med Clozapine Actavis.

Det är mycket viktigt att du infinner dig till de blodkontroller som skall utföras varje vecka de

första 18 veckorna och därefter åtminstone var fjärde vecka så länge behandlingen pågår samt

ytterligare 4 veckor efter avslutad behandling.

Blodkontrollerna sker för att kontrollera mängden vita blodkroppar (leukocyter och neutrofila

granulocyter) i blodet för att minimera risken att du drabbas av blodbiverkningar (lågt antal vita

blodkroppar).

Informera din läkare om du tidigare har tagit Clozapine Actavis och har blivit tvungen att avbryta

behandlingen på grund av blodbiverkningar.

Använd inte Clozapine Actavis:

om du är allergisk mot klozapin eller något hjälpämne i detta läkemedel (anges i avsnitt 6).

om du inte har möjlighet att medverka i regelbundna blodkontroller

om du har obehandlad epilepsi

om du har eller har haft försämrad benmärgsfunktion

om du har haft lågt antal vita blodkroppar (t.ex. leukopeni

eller agranulocytos), i synnerhet om orsaken är läkemedel och det inte är ett resultat av

cancerbehandling

om du tar något läkemedel som hindrar din benmärg från att fungera som den ska.

om du tar något läkemedel som minskar antalet vita blodkroppar i ditt blod.

om du tidigare tvingats sluta ta Clozapine Actavis på grand av allvarliga biverkningar (t.ex.

agranulocytos) eller problem med hjärtat.

om du har myokardit (inflammation av hjärtmuskeln)

om du har någon annan allvarlig hjärtsjukdom

om du har haft psykiska förändringar som utlösts av alkohol, läkemedel eller annan

förgiftning

om du har allvarlig njursjukdom

om du har aktiv leversjukdom med illamående, aptitlöshet eller gulsot

om du har någon annan allvarlig leversjukdom.

om du har nedsatt tarmaktivitet.

om du behandlas eller har behandlats med långverkande depotinjektioner med antipsykotika

Om något av ovanstående gäller dig, tala med din läkare och ta inte Clozapine

Actavis.Clozapine Actavis skall inte ges till medvetslösa personer eller personer i koma.

Varningar och försiktighet

Tala med läkare eller apotekspersonal innan du tar

Clozapine Actavis:

om du har för höga blodsockerhalter som kan ge sig till känna som viktminskning, ökad törst

och trötthet

om du har prostataförstoring kan Clozapine Actavis försämra detta tillstånd.

Om du har trångkammarvinkelglaukom (en sjukdom i ögat), eftersom Clozapine Actavis kan

försämra dessa tillstånd

om du eller någon i din familj tidigare har haft blodpropp, eftersom läkemedel som dessa har

förknippats med blodproppsbildning.

om du samtidigt tar läkemedel som kan ge förstoppning (antipsykotiska läkemedel, medel

mot depression och medel mot parkinsonism), då detta kan leda till ytterligare förstärkning av

effekterna av Clozapine Actavis, vilket kan medföra förstoppning (till och med tarmvred).

om du tidigare haft sjukdom i tjocktarmen eller genomgått operation i nedre delen av buken.

Om du får förstoppning bör du kontakta din läkare, eftersom detta bör behandlas aktivt.

När någon infektion utbryter skall du omedelbart informera din läkare. Var särskilt

uppmärksam på om du har influensaliknande symtom som feber eller ont i

halsen/svalget/munnen eller andra tecken på infektion. Blodkontroll skall genast göras för att

utesluta brist på vita blodkroppar.

Då du börjar din medicinering kommer du noggrant att observeras för att upptäcka om du får

blodtrycksfall när du reser dig hastigt (ortostatisk hypotension). Om du har Parkinsons

sjukdom kommer ditt blodtryck att kontrolleras både i liggande och stående ställning under de

första behandlingsveckorna.

Kontakta din läkare om du inte tål vissa sockerarter som t.ex. galaktos innan du tar detta

läkemedel.

Om du under de första 2 behandlingsmånaderna får ihållande ökning av hjärtfrekvensen i vila

och/eller rubbningar i hjärtrytmen, bröstsmärta och andra tecken på hjärtsvikt (t ex oförklarlig

trötthet, andnöd, andfåddhet) skall du omedelbart kontakta din läkare.

Om du har uttalad bradykardi (mycket långsam hjärtrytm), hjärtkärl-sjukdom eller ärftlig

störning av hjärtrytmen (förlängning av QT-intervallet) ska du tala om det för din läkare.

Samtidig behandling med andra läkemedel mot psykiska sjukdomar bör då undvikas.

Eftersom Clozapine Actavis kan medföra muntorrhet, vilket kan medföra ökad risk för karies,

bör rengöring av tänderna med fluortandkräm göras 2 gånger per dag.

Patienter som behandlas med Clozapine Actavis skall vid feber, ont i halsen/svalgen/munnen

eller vid andra tecken på infektion, genast kontakta läkare så att blodbildskontroll kan

genomföras för att utesluta brist på vita blodkroppar.

Kontakta din läkare om du planerar att sluta röka, då detta kan leda till ökade biverkningar.

Kontakta din läkare om du tar andra antipsykotiska läkemedel.

Barn och ungdomar

Säkerheten och effektiviteten för Clozapine Actavis för barn och ungdomar under 16 år har

inte fastställts. Läkemedlet bör inte användas för denna grupp innan det finns mer data.

Andra läkemedel och Clozapine Actavis

Tala om för din läkare eller farmaceut om du tar, nyligen har tagit eller kommer att ta andra

läkemedel. Det gäller särskilt:

läkemedel som hämmar benmärgen (t ex karbamazepin, kloramfenikol, fenylbutazon)

läkemedel mot hjärtrytmrubbningar

metadon

meflokin (malariamedel)

vissa urindrivande läkemedel (tiaziddiuretika)

cisaprid

antihistaminer (allergiläkemedel t ex loratadin, klorfeniramin) och benzodiazepiner eller

andra psykofarmaka (läkemedel som används som lugnande medel eller sömnmedel)

karbamazepin, fenytoin, valproinsyra (epilepsiläkemedel)

litium

läkemedel mot depression (t ex fluvoxamin, fluoxetin, paroxetin, amitriptylin, klopramin)

blodtryckssänkande läkemedel (t ex metoprolol, kaptopril)

warfarin och digoxin

antikolinerga läkemedel t ex biperiden, orfenadrin

cimetidin

vissa antibiotika t ex kotrimaoxazol, erytromycin, rifampicin, moxifloxacin och svampmedel

som flukonazol

vissa antivirala medel som ritonavir, indinavir.

magläkemedel t ex omeprazol

Användning av Clozapine Actavis med mat, dryck och alkohol

Alkohol skall inte intas samtidigt med Clozapine Actavis på grund av att det förstärker

alkoholens negativa effekt. Om dina kaffevanor väsentligt förändras kan du behöva kontakta din

läkare så att din Clozapine Actavis-dos kan anpassas.

Graviditet och amning och fertilitet

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.

Följande symtom kan förekomma hos nyfödda barn till mödrar som använt Clozapine Actavis

under den sista trimestern (de sista tre månaderna av graviditeten): skakningar, muskelstelhet

och/eller svaghet, sömnighet, oro, andningsproblem och svårigheter att äta. Om ditt barn uppvisar

något av dessa symtom kan du behöva kontakta läkare.

Amning

Kvinnor som ammar skall inte ta Clozapine Actavis eftersom läkemedlet kan överföras från

moderns mjölk till barnet.

Kvinnor i fertil ålder

Om du byter från andra antipsykotiska läkemedel till Clozapine Actavis kan detta resultera i att

du får tillbaka dina normala menstruationer. Därför bör du använda lämplig preventivmetod.

Körförmåga och användning av maskiner

Clozapine Actavis har en sömngivande effekt och ger lägre kramptröskel. Kör därför inte bil eller

använd verktyg och maskiner under de första behandlingsveckorna.

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.

Clozapine Actavis innehåller laktosmonohydrat

Patienter med sällsynta ärftliga problem såsom galaktosintolerans, Lapp laktasbrist eller glukos-

galaktos malabsorption bör inte ta detta läkemedel.

3

Hur du tar Clozapine Actavis

Ta alltid Clozapine Actavis enligt din läkares och apotekets anvisningar. Rådfråga din läkare eller

apotekspersonal om du är osäker.

Rekommenderad dos för behandlingsresistenta schizofrena patienter är:

Vuxna

Startdos

12,5 mg (en halv 25 mg tablett) en eller två gånger första dagen, följt av en eller två 25 mg

tabletter andra dagen. Om du tolererar detta väl kan din läkare öka dagsdosen långsamt med

25 mg till 50 mg åt gången, tills en dosnivå på 300 mg/dag uppnåtts inom 2 – 3 veckor.

Äldre

En mycket låg dos (en engångsdos på 12,5 mg den första dagen – en halv 25 mg tablett)

rekommenderas vid start av behandlingen.

Underhållsdos

Då högsta terapeutisk effekt uppnåtts, kan man hos många patienter uppehålla denna med en

lägre dos.

Rekommenderad dos för patienter som har psykotiska besvär på grund av Parkinsons sjukdom

är:

Vuxna

Den effektiva dosen ligger normalt på i genomsnitt mellan 25 och 37,5 mg per dag.

Behandlingen påbörjas vanligen med 12,5 mg/dag (en halv 25 mg tablett) och bör intas på

kvällen. Fortsatta dosökningar brukar göras med 12,5 mg åt gången med högst två dosökningar

per vecka upp till maximalt 50 mg.

Clozapine Actavis är en behandling som bör pågå under längre tid, om den avbryts kan tidigare

symtom återkomma. Därför är det viktigt att tabletterna tas varje dag.

Om du upplever att effekten av Clozapine Actavis är för stark eller för svag vänd dig till din

läkare eller farmaceut.

Tabletten kan delas i två lika stora doser.

Hur länge du skall ta Clozapine Actavis

Din läkare avgör hur länge du ska behandlas med Clozapine Actavis. Du skall inte ändra dosen

eller behandlingen utan att tala med din läkare.

Om du använder mera Clozapine Actavis än vad du borde

Om du tagit mer Clozapine Actavis än din läkare har ordinerat, kontakta alltid läkare, sjukhus

eller Giftinformationscentralen, telefonnummer 112.

Vid överdosering ses bl a tecken som dåsighet, förvirring, hallucinationer, kramper, ryckningar i

armar och ben, dimsyn, lågt blodtryck, andnöd, snabb puls och hjärtrytm. (Se avsnittet Eventuella

biverkningar.)

Om du glömt att ta Clozapine Actavis

Om du har glömt att ta Clozapine Actavis eller har andra funderingar rörande doseringen,

kontakta din läkare. Ta inte dubbla doser för att kompensera de doser du glömt.

Effekter som kan uppträda när behandlingen med Clozapine Actavis avslutas

Om behandlingen måste avbrytas abrupt kan de psykotiska symtomen återkomma samt följande

symtom uppträda: t ex riklig svettning, huvudvärk, illamående, kräkningar och diarré.

4

Eventuella biverkningar

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

Sluta ta Clozapine Actavis och sök omedelbart vård om du upplever något av följande:

Blodproppar – särskilt i benen (symtomen är svullnad, smärta och rodnad på benen), kan

transporteras till lungorna och orsaka bröstsmärta och andningssvårigheter. Detta är sällsynt

(kan förekomma hos upp till 1 av 1000 användare).

Gulsot (gulfärgning av hud eller ögon) på grund av blockerad gallgång. Detta är sällsynt (kan

förekomma hos upp till 1 av 1000 användare).

Malignt neuroleptikasyndrom (muskelstelhet, feber, medvetslöshet). Detta är mindre vanligt

(kan förekomma hos upp till 1 av 100 användare).

Nedan följer en uppräkning av andra biverkningar som rapporterats.

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

Dåsighet, yrsel.

Förhöjd hjärtfrekvens.

Förstoppning, ökat salivflöde.

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

Minskat antal vita blodkroppar (granulocyter), ökat antal vita blodkroppar.

Viktökning.

Dimsyn.

Darrningar, stelhet, inre oro, ryckningar i armar och ben, kramper, muskelryckningar.

EKG-förändringar, högt blodtryck.

Blodtrycksfall när man reser sig hastigt, svimning.

Illamående, kräkningar, aptitlöshet, muntorrhet.

Urininkontinens, svårighet att kissa.

Trötthet, feber, värmekänsla, störningar i svettnings/temperaturregleringen.

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

Uttalad minskning av antal vita blodkroppar (granulocyter).

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

Diabetes som kan framkalla viktminskning, ökad törst, trötthet, rastlöshet, förvirring,

delirium.

Sväljsvårigheter, ”sätter i vrångstrupen”, leverinflammation, inflammation i bukspottkörteln.

Hjärtrytmstörningar, oregelbunden hjärtrytm och EKG-förändringar i samband med detta,

hjärtstillestånd, inflammation i hjärtmuskulaturen.

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

Minskat antal blodplättar, ökat antal blodplättar, mycket för hög blodsockerhalt och ökad halt

av sura ämnen i blodet (ketoacidos), ökad halt av blodfetter, ökad halt av kolesterol.

Ofrivilliga ryckningar i ben och armar.

Sjukdom i hjärtmuskulaturen.

Förstoring av öronspottkörteln.

Allvarlig njur- och leverskada.

Hudreaktioner.

Förstoppning, tarmvred.

Smärtsam, krampaktig erektion av penis.

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

Hos äldre personer med demens som behandlas med antipsykotiska läkemedel har en liten

ökning i antalet dödsfall rapporterats jämfört med de som inte får sådan behandling.

Tvångsmässiga symtom.

Rapportering av biverkningar

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

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

via Läkemedelsverket, Box 26, SE-751 03 Uppsala. Webbplats: www.lakemedelsverket.se.

Genom att rapportera biverkningar kan du bidra till att öka informationen om läkemedels

säkerhet.

Läkemedelsverket

Box 26

SE-751 03 Uppsala

Webbplats: www.lakemedelsverket.se.

5

Hur Clozapine Actavis ska förvaras

Förvaras utom syn- och räckhåll för barn.

Inga särskilda förvaringsanvisningar.

Använd inte detta läkemedel efter utgångsdatumet på förpackningen.

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 klozapin. Varje tablett innehåller 25 respektive 100 mg.

Övriga innehållsämnen är: laktosmonohydrat, magnesiumstearat, povidon, talk,

majsstärkelse, kolloidal vattenfri kiseldioxid och pregelatiniserad stärkelse.

Läkemedlets utseende och förpackningsstorlekar

Clozapine Actavis 25 mg tabletter:

Gul, rund tablett, 6 mm i diameter, med delskåra på båda sidor och präglad med ”CPN 25” på ena

sidan.

Clozapine Actavis 100 mg tabletter:

Gul, rund tablett, 10 mm i diameter, med delskåra på båda sidor och präglad med ”CPN 100” på

ena sidan.

Innehavare av godkännande för försäljning och tillverkare

Innehavare av försäljningstillstånd

Actavis Group PTC ehf.

Reykjavikurvegi 76-78

IS-220 Hafnarfjordur

Island

Lokal representant

Teva Sweden AB

Box 1070

251 10 Helsingborg

Tillverkare

Synthon Hispania S.L.

C/ Castelló, no 1, Pol. Las Salinas

Sant Boi de Llobregat

08830 Barcelona

Spanien

Balkanpharma Dupnitsa AD,

3 Samakovsko Shosse Str.

Dupnitsa, 2600

Bulgarien

Denna bipacksedel godkändes senast 2020-11-06

Läs hela dokumentet

SUMMARY OF PRODUCT CHARACTERISTICS

NAME OF THE MEDICINAL PRODUCT

Clozapine Actavis 25 mg tablets

Clozapine Actavis 100 mg tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 25 mg clozapine.

Excipient with known effect: lactose monohydrate 48 mg per tablet

Each tablet contains 100 mg clozapine

Excipient with known effect: lactose monohydrate 192 mg

per tablet

Clozapine Actavis can cause agranulocytosis. Its use should be limited to patients:

with schizophrenia who are non-responsive to or intolerant of antipsychotic medication, or

with psychosis in Parkinson’s disease when other treatment strategies have failed (see

section 4.1).

who have initially normal leukocyte findings (white blood cell count ≥3500/mm

(3.5x10

/l),

and ANC ≥2000/mm

( 2.0x10

/l)), and

in whom regular white blood cell (WBC) counts and absolute neutrophil counts (ANC) can

be performed as follows: weekly during the first 18 weeks of treatment, and at least every

4 weeks thereafter throughout treatment. Monitoring must continue throughout treatment

and for 4 weeks after complete discontinuation of Closapine Actavis.

Prescribing physicians must comply fully with the required safety measures. At each consultation,

a patient receiving Clozapine Actavis must be reminded to contact the treating physician

immediately if any kind of infection begins to develop. Particular attention must be paid to flulike

complaints such as fever or sore throat and to other evidence of infection, which may be indicative

of neutropenia.

Clozapine Actavis must be dispensed under strict medical supervision in accordance with official

recommendations.

Myocarditis

Clozapine is associated with an increased risk of myocarditis which has, in rare cases, been fatal.

The increased risk of myocarditis is greatest in the first 2 months of treatment. Fatal cases of

cardiomyopathy have also been reported rarely.

Myocarditis or cardiomyopathy should be suspected in patients who experience persistent

tachycardia at rest, especially in the first 2 months of treatment, and/or palpitations, arrhythmias,

chest pain and other signs and symptoms of heart failure (e.g. unexplained fatigue, dyspnoea,

tachypnoea) or symptoms that mimic myocardial infarction.

If myocarditis or cardiomyopathy are suspected, Clozapine Actavis treatment should be promptly

stopped and the patient immediately referred to a cardiologist.

Patients who develop clozapine-induced myocarditis or cardiomyopathy should not be re-exposed

to clozapine.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Clozapine Actavis 25 mg tablets:

Yellow, round tablet,

6 mm in diameter,

scored with a division mark on both sides and

debossed with “CPN 25” on one side.

The tablet can be divided into equal doses.

Clozapine Actavis 100 mg tablets

Yellow, round tablet,

10 mm in diameter,

scored with a division mark on both sides and

debossed with “CPN 100” on one side.

The tablet can be divided into equal doses.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Indicated in treatment-resistant schizophrenic patients and in schizophrenia patients who have severe,

untreatable neurological adverse reactions to other antipsychotic agents, including atypical

antipsychotics.

Treatment resistance is defined as a lack of satisfactory clinical improvement despite the use of

adequate doses of at least two different antipsychotic agents, including an atypical antipsychotic agent,

prescribed for adequate duration.

Clozapine Actavis is also indicated in psychotic disorders occurring during the course of Parkinson’s

disease, in cases where standard treatment has failed.

4.2

Posology and method of administration

The dosage must be adjusted individually. For each patient the lowest effective dose should be used.

Initiation of Clozapine Actavis treatment must be restricted to those patients with a WBC count

≥3500/mm

(3.5x10

/l) and an ANC ≥2000/mm

(2.0x10

/l) within standardised normal limits.

Dose adjustment is indicated in patients who are also receiving medicinal products that have

pharmacodynamic and pharmacokinetic interactions with Clozapine Actavis, such as benzodiazepines

or selective serotonin re-uptake inhibitors (see section 4.5 Interaction with other medicinal products

and other forms of interaction).

Posology

The following dosages are recommended:

Treatment-resistant schizophrenic patients

Starting therapy

12.5 mg (half a 25 mg tablet) once or twice on the first day, followed by 25 mg once or twice on the

second day. If well tolerated, the daily dose may then be increased slowly in increments of 25-50 mg

in order to achieve a dose level of up to 300 mg/day within 2-3 weeks. Thereafter, if required, the

daily dose may be further increased in increments of 50-100 mg at half-weekly or, preferably, weekly

intervals.

Elderly patients

Initiation of treatment is recommended at a particularly low dose (12.5 mg given once on the first

day), with subsequent dose increments restricted to 25 mg/day.

Paediatric population

The safety and efficacy of Clozapine Actavis in children and adolescents under the age of 16 years

have not yet been established. It should not be used in this group until further data become available.

Therapeutic dose range

In most patients, antipsychotic efficacy can be expected with 200-450 mg/day given in divided doses.

The total daily dose may be divided unevenly, with the larger portion at bedtime. For information

about maintenance dose see below.

Maximum dose

To obtain full therapeutic benefit, a few patients may require larger doses, in which case judicious

increments (not exceeding 100 mg) are permissible up to 900 mg/day. However, the possibility of

increased adverse reactions (in particular seizures) occurring at doses over 450 mg/day must be borne

in mind.

Maintenance dose

After achieving maximum therapeutic benefit, many patients can be maintained effectively on lower

doses. Careful downward titration is therefore recommended. Treatment should be maintained for at

least 6 months. If the daily dose does not exceed 200 mg, once daily administration in the evening may

be appropriate.

Ending therapy

In the event of planned termination of Clozapine Actavis therapy, a gradual reduction in dose over a

1-2 week period is recommended. If abrupt discontinuation is necessary, the patient should be

carefully observed for the occurrence of withdrawal reactions (see section 4.4 Special warnings and

precautions for use).

Re-starting therapy

In patients in whom the interval since the last dose of Clozapine Actavis exceeds 2 days, treatment

should be re-initiated with 12.5 mg (half a 25 mg tablet) given once or twice on the first day. If this

dose is well tolerated, it may be feasible to titrate the dose to the therapeutic level more quickly than is

recommended for initial treatment. However, in any patient who has previously experienced

respiratory or cardiac arrest with initial dosing (see section 4.4 Special warnings and precautions for

use), but was then able to be successfully titrated to a therapeutic dose, re-titration should be carried

out with extreme caution.

Switching from a previous antipsychotic therapy to Clozapine Actavis

It is generally recommended that Clozapine Actavis should not be used in combination with other

antipsychotics. When Clozapine Actavis therapy is to be initiated in a patient undergoing oral

antipsychotic therapy, it is recommended that the other antipsychotic should first be discontinued by

tapering the dosage downwards.

Psychotic disorders occurring during the course of Parkinson's disease, in cases where

standard treatment has failed

The starting dose must not exceed 12.5 mg/day (half a 25 mg tablet), taken in the evening. Subsequent

dose increases must be by 12.5 mg increments, with a maximum of two increments a week up to a

maximum of 50 mg, a dose that cannot be reached until the end of the second week. The total daily

amount should preferably be given as a single dose in the evening.

The mean effective dose is usually between 25-37.5 mg/day. In the event that treatment for at least one

week with a dose of 50 mg fails to provide a satisfactory therapeutic response, dosage may be

cautiously increased by increments of 12.5 mg/week.

The dose of 50 mg/day should only be exceeded in exceptional cases, and the maximum dose of

100 mg/day must never be exceeded.

Dose increases should be limited or deferred if orthostatic hypotension, excessive sedation or

confusion occurs. Blood pressure should be monitored during the first weeks of treatment.

When there has been complete remission of psychotic symptoms for at least 2 weeks, an increase in

anti-parkinsonian medication is possible if indicated on the basis of motor status. If this approach

results in the recurrence of psychotic symptoms, Clozapine Actavis dosage may be increased by

increments of 12.5 mg/week up to a maximum of 100 mg/day, taken in one or two divided doses (see

above).

Ending therapy: A gradual reduction in dose by steps of 12.5 mg over a period of at least one week

(preferably two) is recommended.

Treatment must be discontinued immediately in the event of neutropenia or agranulocytosis (see

section 4.4 Special warnings and precautions for use). In this situation, careful psychiatric monitoring

of the patient is essential since symptoms may recur quickly.

4.3

Contraindications

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

Patients unable to undergo regular blood tests.

History of toxic or idiosyncratic granulocytopenia/agranulocytosis (with the exception of

granulocytopenia/agranulocytosis from previous chemotherapy).

History of Clozapine Actavis-induced agranulocytosis.

Impaired bone marrow function.

Uncontrolled epilepsy.

Alcoholic and other toxic psychoses, drug intoxication, comatose conditions.

Circulatory collapse and/or CNS depression of any cause.

Severe renal or cardiac disorders (e.g. myocarditis).

Active liver disease associated with nausea, anorexia or jaundice; progressive liver disease,

hepatic failure.

Paralytic ileus.

Clozapine Actavis treatment must not be started concurrently with substances known to have a

substantial potential for causing agranulocytosis; concomitant use of depot antipsychotics is to

be discouraged.

4.4

Special warnings and precautions for use

Clozapine Actavis can cause agranulocytosis. The incidence of agranulocytosis and the fatality rate in

those developing agranulocytosis have decreased markedly since the institution of white blood cell

(WBC) counts and absolute neutrophil count (ANC) monitoring. The following precautionary

measures are therefore mandatory and should be carried out in accordance with official

recommendations.

Because of the risks associated with Clozapine Actavis, its use is limited to patients in whom therapy

is indicated as set out in section 4.1 and:

who have initially normal leukocyte findings (WBC count ≥3500/mm

(3.5x10

/l) and

ANC ≥2000/mm

(2.0x10

/l), and

in whom regular WBC counts and ANC can be performed weekly for the first 18 weeks and at

least 4 week intervals thereafter. Monitoring must continue throughout treatment and for

4 weeks after complete discontinuation of Clozapine Actavis.

Before initiating clozapine therapy patients should have a blood test (see “agranulocytosis”) and a

history and physical examination. Patients with history of cardiac illness or abnormal cardiac findings

on physical examination should be referred to a specialist for other examinations that might include an

ECG, and the patient treated only if the expected benefits clearly outweigh the risks (see section 4.3).

The treating physician should consider performing a pre-treatment ECG.

White Blood Cell (WBC) counts and Absolute Neutrophil Count (ANC) monitoring

WBC and differential blood counts must be performed within 10 days prior to initiating Clozapine

Actavis treatment to ensure that only patients with normal WBC counts and ANC (WBC count

3500/mm

(3.5x10

/l) and ANC ≥

2000/mm

(2.0x10

/l)) will receive Clozapine Actavis. After the

start of Clozapine Actavis treatment regular WBC count and ANC must be performed and monitored

weekly for the first 18 weeks, and at least at 4 weeks intervals thereafter.

Monitoring must continue throughout treatment and for 4 weeks after complete discontinuation of

Clozapine Actavis or until haematological recovery has occurred (see “Low WBC count/ANC”

below). At each consultation, the patient must be reminded to contact the treating physician

immediately if any kind of infection, fever, sore throat or other flu-like symptoms develop. WBC and

differential blood counts must be performed immediately if any symptoms or signs of an infection

occur.

Low WBC count/ANC

If, during Clozapine Actavis therapy, either the WBC count falls to between 3500/mm

(3.5x10

/l) and

3000/mm

(3.0x10

/l) or the ANC falls to between 2000/mm

(2.0x10

/l) and 1500/mm

(1.5x10

/l),

haematological evaluations must be performed at least twice weekly until the patient’s WBC count

Prescribing physicians must comply fully with the required safety measures.

Prior to treatment initiation, physicians must ensure, to the best of their knowledge, that the patient has

not previously experienced an adverse haematological reaction to clozapine that necessitated its

discontinuation. Prescriptions should not be issued for periods longer than the interval between two

blood counts.

Immediate discontinuation of Clozapine Actavis is mandatory if either the WBC count is less than

3000/mm

(3.0x10

/l) or the ANC is less than 1500/mm

(1.5x10

/l) at any time during Clozapine

Actavis treatment. Patients in whom Clozapine Actavis has been discontinued as a result of either WBC

or ANC deficiencies must not be re-exposed to Closapine Actavis.

At each consultation, a patient receiving Clozapine Actavis must be reminded to contact the treating

physician immediately if any kind of infection begins to develop. Particular attention should be paid to

flu-like complaints such as fever or sore throat and to other evidence of infection, which may be

indicative of neutropenia. Patients and their caregivers must be informed that, in the event of any of

these symptoms, they must have a blood cell count performed immediately. Prescribers are encouraged

to keep a record of all patients’ blood results and to take any steps necessary to prevent these patients

from accidentally being rechallenged in the future.

Patients with a history of primary bone marrow disorders may be treated only if the benefit outweighs

the risk. They should be carefully reviewed by a haematologist prior to starting Closapine Actavis.

Patients who have low WBC counts because of benign ethnic neutropenia should be given special

consideration and may only be started on Clozapine Actavis with the agreement of a haematologist.

and ANC stabilise within the range 3000-3500/mm

(3.0-3.5x10

/l) and 1500-2000/mm

(1.5-

2.0x10

/l), respectively, or higher.

Immediate discontinuation of Clozapine Actavis treatment is mandatory if either the WBC count is

less than 3000/mm

(3.0x10

/l) or the ANC is less than 1500/mm

(1.5x10

/l) during Clozapine

Actavis treatment. WBC counts and differential blood counts should then be performed daily and

patients should be carefully monitored for flu-like symptoms or other symptoms suggestive of

infection. Confirmation of the haematological values is recommended by performing two blood counts

on two consecutive days; however, Clozapine Actavis should be discontinued after the first blood

count. Following discontinuation of Clozapine Actavis, haematological evaluation is required until

haematological recovery has occurred.

Blood cell count

WBC/mm

(/l)

ANC/mm

(/l)

Action required

≥3500 (≥3.5x10

≥2000 (≥2.0x10

Continue Clozapine Actavis

treatment

Between ≥3000 and

<3500 (≥3.0x10

<3.5x10

Between ≥1500 and

<2000 (≥1.5x10

<2.0x10

Continue Clozapine Actavis

treatment, sample blood twice

weekly until counts stabilise or

increase

<3000 (<3.0x10

<1500 (<1.5x10

Immediately stop Clozapine

Actavis treatment, sample blood

daily until haematological

abnormality is resolved, monitor

for infection. Do not reexpose

the patient.

If Clozapine Actavis has been withdrawn and either a further drop in the WBC count below

2000/mm

3

(2.0x10

/l) occurs or the ANC falls below 1000/mm

3

(1.0x10

/l), the management of

this condition must be guided by an experienced haematologist.

Discontinuation of therapy for haematological reasons

Patients in whom Clozapine Actavis has been discontinued as a result of either WBC or ANC

deficiencies (see above) must not be re-exposed to Clozapine Actavis. Prescribers are encouraged to

keep a record of all patients’ blood results and to take any steps necessary to prevent the patient being

accidentally rechallenged in the future.

Discontinuation of therapy for other reasons

Patients who have been on Clozapine Actavis for more than 18 weeks and have had their treatment

interrupted for more than 3 days but less than 4 weeks should have their WBC count and ANC

monitored weekly for an additional 6 weeks. If no haematological abnormality occurs, monitoring at

intervals not exceeding 4 weeks may be resumed. If Clozapine Actavis treatment has been interrupted

for 4 weeks or longer, weekly monitoring is required for the next 18 weeks of treatment and the dose

should be re-titrated (see section 4.2).

Other precautions

This medicinal product contains lactose monohydrate. Patients with rare hereditary problems of

galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take

this medicine.

Eosinophilia

Discontinuation of Clozapine Actavis is recommended if the eosinophil count rises above 3000/mm

(3.0x10

/l); therapy should be restarted only after the eosinophil count has fallen below 1000/mm

(1.0x10

/l).

Thrombocytopenia

Discontinuation of Clozapine Actavis therapy is recommended if the platelet count falls below

50,000/mm

(50x10

/l).

Orthostatic hypotension

Orthostatic hypotension with or without syncope, can occur during Clozapine Actavis treatment.

Rarely, collapse can be profound and may be accompanied by cardiac and/or respiratory arrest. Such

events are more likely to occur with concurrent use of a benzodiazepine or any other psychotropic

agent (see section 4.5) and during initial titration in association with rapid dose escalation; on very

rare occasions they may occur even after the first dose. Therefore, patients starting Clozapine Actavis

treatment require close medical supervision. Monitoring of standing and supine blood pressure is

necessary during the first weeks of treatment in patients with Parkinson’s disease.

Myocarditis

Analysis of safety databases suggests that the use of Clozapine Actavis is associated with an increased

risk of myocarditis especially during, but not limited to, the first two months of treatment. Some cases

of myocarditis have been fatal. Pericarditis/pericardial effusion and cardiomyopathy have also been

reported in association with Clozapine Actavis use; these reports also include fatalities. Myocarditis or

cardiomyopathy should be suspected in patients who experience persistent tachycardia at rest,

especially in the first two months of treatment, and/or palpitations, arrhythmias, chest pain and other

signs and symptoms of heart failure (e.g. unexplained fatigue, dyspnoea, tachypnoea), or symptoms

that mimic myocardial infarction. Other symptoms which may be present in addition to the above

include flu-like symptoms. If myocarditis or cardiomyopathy is suspected, Clozapine Actavis

treatment should be promptly stopped and the patient immediately referred to a cardiologist.

Patients with clozapine-induced myocarditis or cardiomyopathy should not be re-exposed to Clozapine

Actavis.

An approximately 3-fold increased risk of cerebrovascular adverse events

has been seen in randomised

placebo controlled clinical trials in the dementia population with some atypical antipsychotics. The

mechanism for this increased risk is not known. An increased risk cannot be excluded for other

antipsychotics or other patient populations. Clozapine should be used with caution in patients with risk

factors for stroke.

QT interval

As clozapine can cause QT prolongation caution is advised in patients with bradycardia,

cardiovascular disease and family history of QT prolongation. Concomitant use with other

antipsychotics should be avoided.

Epilepsy

Patients with a history of epilepsy should be closely observed during Clozapine Actavis therapy since

dose-related convulsions have been reported. In such cases, the dose should be reduced (see section

4.2) and, if necessary, an anti-convulsant treatment should be initiated.

Liver dysfunction

Patients with stable pre-existing liver disorders may receive Clozapine Actavis, but need regular liver

function tests. Liver function tests should be performed in patients in whom symptoms of possible

liver dysfunction, such as nausea, vomiting and/or anorexia, develop during Clozapine Actavis

therapy. If the elevation of the values is clinically relevant (more than 3 times the UNL) or if

symptoms of jaundice occur, treatment with Clozapine Actavis must be discontinued. It may be

resumed (see section 4.2) only when the results of liver function tests are normal. In such cases, liver

function should be closely monitored after re-introduction of Clozapine Actavis.

Intestinal function

Clozapine Actavis exerts anticholinergic activity, which may produce undesirable effects throughout

the body. Careful supervision is indicated in the presence of prostatic enlargement and narrow-angle

glaucoma. Probably on account of its anticholinergic properties, Clozapine Actavis has been

associated with varying degrees of impairment of intestinal peristalsis, ranging from constipation to

intestinal obstruction, faecal impaction and paralytic ileus (see section 4.8). On rare occasions these

cases have been fatal. Particular care is necessary in patients who are receiving concomitant

medications known to cause constipation (especially those with anticholinergic properties such as

some antipsychotic

s

, antidepressants and antiparkinsonian treatments), have a history of colonic

disease or a history of lower abdominal surgery as these may exacerbate the situation. It is vital that

constipation is recognized and actively treated.

Fever and NMS

During Clozapine Actavis therapy, patients may experience transient temperature elevations above

38°C, with the peak incidence within the first 3 weeks of treatment. This fever is generally benign.

Occasionally, it may be associated with an increase or decrease in the WBC count. Patients with fever

should be carefully evaluated to rule out the possibility of an underlying infection or the development

of agranulocytosis. In the presence of high fever, the possibility of neuroleptic malignant syndrome

(NMS) must be considered.

Diabetes

Impaired glucose tolerance and/or development or exacerbation of diabetes mellitus has been reported

rarely during treatment with clozapine. A mechanism for this possible association has not yet been

determined. Cases of severe hyperglycaemia with ketoacidosis or hyperosmolar coma have been

reported very rarely in patients with no prior history of hyperglycaemia, some of which have been

fatal. When follow-up data were available, discontinuation of clozapine resulted mostly in resolution

of the impaired glucose tolerance, and reinstitution of clozapine resulted in its reoccurrence. The

discontinuation of clozapine should be considered in patients where active medical management of

their hyperglycaemia has failed.

VTE

Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients

treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors

for VTE should be identified before and during treatment with Clozapine Actavis and preventive

measures undertaken.

Acute withdrawal reactions have been reported following abrupt cessation of clozapine therefore

gradual withdrawal is recommended. If abrupt discontinuation is necessary (e.g. because of

leucopenia), the patient should be carefully observed for the recurrence of psychotic symptoms and

symptoms related to cholinergic rebound, such as profuse sweating, headache, nausea, vomiting and

diarrhoea.

Elderly patient

Initiation of treatment in elderly patients is recommended at a lower dose (see section 4.2).

Orthostatic hypotension can occur with Clozapine Actavis treatment and there have been reports of

tachycardia, which may be sustained. Patients aged 60 years and older, particularly those with

compromised cardiovascular function, may be more susceptible to these effects.

Elderly patients may also be particularly susceptible to the anticholinergic effects of Clozapine

Actavis, such as urinary retention and constipation.

Increased mortality in elderly people with dementia

Data from two large observational studies showed that elderly people with dementia who are treated

with antipsychotics are at a small increased risk of death compared with those who are not treated.

There are insufficient data to give a firm estimate of the precise magnitude of the risk and the cause of

the increased risk is not known.

Clozapine Actavis is not approved for the treatment of dementia-related behavioural disturbances.

4.5

Interaction with other medicinal products and other forms of interaction

Contraindication of concomitant use

Substances known to have a substantial potential to depress bone marrow function must not be used

concurrently with Clozapine Actavis (see section 4.3).

Long-acting depot antipsychotics (which have myelosuppressive potential) must not be used

concurrently with Clozapine Actavis because these cannot be rapidly removed from the body in

situations where this may be required, e.g. neutropenia (see section 4.3).

Alcohol should not be used concomitantly with Clozapine Actavis due to possible potentiation of

sedation.

Precautions including dose adjustment

Clozapine Actavis may enhance the central effects of CNS depressants such as narcotics,

antihistamines and benzodiazepines. Particular caution is advised when Clozapine Actavis therapy is

initiated in patients who are receiving a benzodiazepine or any other psychotropic agent. These

patients may have an increased risk of circulatory collapse, which, on rare occasions, can be profound

and may lead to cardiac and/or respiratory arrest. It is not clear whether cardiac or respiratory collapse

can be prevented by dose adjustment. Because of the possibility of additive effects, caution is essential

in the concomitant administration of substances possessing anticholinergic, hypotensive, or respiratory

depressant effects.

Owing to its anti alpha-adrenergic properties, Clozapine Actavis may reduce the blood-pressure

increasing effect of norepinephrine or other predominantly alpha-adrenergic agents and reverse the

pressor effect of epinephrine.

Concomitant administration of substances known to inhibit the activity of some cytochrome P450

isozymes may increase the plasma levels of clozapine, and the dose of clozapine may need to be

reduced to prevent undesirable effects. This is more important for CYP1A2 inhibitors such as caffeine

(see below) and the selective serotonin reuptake inhibitor fluvoxamine and (more controversial)

paroxetin. Some of the other serotonin reuptake inhibitors such as fluoxetine and sertraline are

CYP2D6 inhibitors and, as a consequence, major pharmacokinetic interactions with clozapine are less

likely. Similarly, pharmacokinetic interactions with CYP3A4 inhibitors such as azole antimycotics,

cimetidine, erythromycin and protease inhibitors are unlikely, although some have been reported.

Because the plasma concentration of clozapine is increased by caffeine intake (1A2) and decreased by

nearly 50% following a 5-day caffeine-free period, dosage changes of clozapine may be necessary

when there is a change in caffeine drinking habit. In cases of sudden cessation of smoking, the plasma

clozapine concentration may be increased, thus leading to an increase in adverse effects. Azole

antimycotics, potent CYP3A4 inhibitors may also increase plasma levels of clozapine.

Concomitant administration of substances known to induce cytochrome P450 enzymes may decrease

the plasma levels of clozapine, leading to reduced efficacy. Substances known to induce the activity of

cytochrome P450 enzymes and with reported interactions with clozapine include, for instance,

carbamazepine (not to be used concomitantly with clozapine, due to its myelosuppresive potential),

phenytoin and rifampicin.

Known inducers of CYP1A2, such as omeprazole, may lead to decreased clozapine levels. The

potential for reduced efficacy of clozapine should be considered when it is used in combination with

these substances.

Caution should be exercised when clozapine is prescribed with other medicines known to increase QT

interval, such as other antipsychotics, class IA and III antiarrhythmics, moxifloxacin, erythromycin,

methadone, mefloquine, tricyclic antidepressants, lithium or cisapride. Concomitant use with

medicines causing electrolyte imbalance, such as thiazide diuretics (hypokalemia), should be

considered as it increase the risk for malignant arrhythmias

(see section 4.4). In this regard

concomitant treatment with drugs that may increase the concentration of clozapine in the blood should

also be considered

Other

Concomitant use of lithium or other CNS-active agents may increase the risk of development of

neuroleptic malignant syndrome (NMS).

Rare but serious reports of seizures, including onset of seizures in non-epileptic patients, and isolated

cases of delirium where Clozapine Actavis was co-administered with valproic acid have been reported.

These effects are possibly due to a pharmacodynamic interaction, the mechanism of which has not

been determined.

Caution is called for in patients receiving concomitant treatment with other substances which are

either inhibitors or inducers of the cytochrome P450 isozymes. With tricyclic antidepressants,

phenothiazines and type 1C anti-arrhythmics, which are known to bind to cytochrome P450 2D6, no

clinically relevant interactions have been observed thus far.

An outline of drug interactions believed to be most important with Clozapine Actavis is given in Table

1 below. The list is not exhaustive.

Table 1: Reference to the most common drug interactions with Clozapine Actavis

Drug

Interactions

Comments

Bone marrow suppressants (e.g.

carbamazapine,

chloramphenicol),

sulphonamides (e.g.

cotrimoxazole), pyrazolone

analgesics (e.g.

phenylbutazone), penicillamine,

cytotoxic agents and long-acting

depot injections of

antipsychotics

Interact to increase the risk

and/or severity of bone marrow

suppression.

Clozapine Actavis

must not be

used

concomitantly with other

agents having a well known

potential to suppress bone

marrow function (see section

4.3).

Benzodiazepines

Concomitant use may increase

risk of circulatory collapse,

which may lead to cardiac

and/or respiratory arrest.

Whilst the occurrence is rare,

caution is advised when using

these agents together. Reports

suggest that respiratory

depression and collapse are

more likely to occur at the start

of this combination or when

Clozapine Actavis is added to

an established benzodiazepine

regimen.

Anticholinergics

Clozapine Actavis potentiates

the action of these agents

through additive anticholinergic

activity.

Observe patients for

anticholinergic side-effects, e.g.

constipation, especially when

using to help control

hypersalivation.

Antihypertensives

Clozapine Actavis can

potentiate the hypotensive

effects of these agents due to its

sympathomimetic antagonistic

effects.

Caution is advised if Clozapine

Actavis is used concomitantly

with antihypertensive agents.

Patients should be advised of

the risk of hypotension,

especially during the period of

initial dose titration.

Alcohol, MAOIs, CNS

depressants, benzodiazepines

Enhanced central effects.

Additive CNS depression and

cognitive and motor

performance interference when

used in combination with these

Caution is advised if Clozapine

Actavis is used concomitantly

with other CNS active agents.

Advise patients of the possible

additive sedative effects and

substances.

caution them not to drive or

operate machinery.

Highly protein bound

substances

(e.g. warfarin and digoxin)

Clozapine Actavis may cause an

increase in plasma concentration

of these substances due to

displacement from plasma

proteins.

Patients should be monitored

for the occurrence of side

effects associated with these

substances, and doses of the

protein bound substance

adjusted, if necessary.

Phenytoin

Addition of phenytoin to

Clozapine Actavis regimen may

cause a decrease in the

clozapine plasma

concentrations.

If phenytoin must be used, the

patient should be monitored

closely for a worsening or

recurrence of psychotic

symptoms.

Lithium

Concomitant use can increase

the risk of development of

neuroleptic malignant syndrome

(NMS).

Observe for signs and

symptoms of NMS.

4.6

Fertility, pregnancy and lactation

Pregnancy

For clozapine, there are only limited clinical data on exposed pregnancies. Neonates exposed to

antipsychotics (including Clozapine Actavis) during the third trimester of pregnancy are at risk of

adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and

duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor,

somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored

carefully.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy

,

embryonal/foetal development, parturition or postnatal development (see section 5.3). Caution should

be exercised when prescribing to pregnant women.

Breastfeeding

Animal studies suggest that clozapine is excreted in breast milk and has an effect in the nursing infant;

therefore, mothers receiving Clozapine Actavis should not breast-feed.

Fertility

A return to normal menstruation may occur as a result of switching from other antipsychotics to

Clozapine Actavis. Adequate contraceptive measures must therefore be ensured in women of

childbearing potential.

4.7

Effects on ability to drive and use machines

Owing to the ability of Clozapine Actavis to cause sedation and lower the seizure threshold, activities

such as driving or operating machinery should be avoided, especially during the initial weeks of

treatment.

4.8

Undesirable effects

For the most part, the adverse event profile of clozapine is predictable from its pharmacological

properties. An important exception is its propensity to cause agranulocytosis (see section 4.4). Because

of this risk, its use is restricted to treatment-resistant schizophrenia and psychosis occurring during the

course of Parkinson’s disease in cases where standard treatment has failed. While blood monitoring is

an essential part of the care of patients receiving clozapine, the physician should be aware of other rare

but serious adverse reactions, which may be diagnosed in the early stages only by careful observation

and questioning of the patient in order to prevent morbidity and mortality.

Blood and lymphatic system

Development of granulocytopenia and agranulocytosis is a risk inherent to Clozapine Actavis

treatment. Although generally reversible on withdrawal of treatment, agranulocytosis may result in

sepsis and can prove fatal. Because immediate withdrawal of treatment is required to prevent the

development of life-threatening agranulocytosis, monitoring of the WBC count is mandatory (see

section 4.4). Table 2 below summarises the estimated incidence of agranulocytosis for each Clozapine

Actavis treatment period.

Table 2:

Estimated incidence of agranulocytosis

Treatment period

Incidence of agranulocytosis per 100,000

person-weeks

2

of observation

Weeks 0-18

32.0

Weeks 19-52

Weeks 53 and higher

From the UK Clozapine Actavis Patient Monitoring Service lifetime registry experience

between 1989 and 2001.

Person-time is the sum of individual units of time that the patients in the registry were exposed

to Clozapine Actavis before experiencing agranulocytosis. For example, 100,000 person-weeks

could be observed in 1,000 patients who were in the registry for 100 weeks

(100*1000=100,000), or in 200 patients who were in the registry for 500 weeks

(200*500=100,000) before experiencing agranulocytosis.

The cumulative incidence of agranulocytosis in the UK Clozaril Patient Monitoring Service lifetime

registry experience (0-11.6 years between 1989 and 2001) is 0.78%. The majority of cases

(approximately 70%) occur within the first 18 weeks of treatment.

Metabolic and nutritional disorders

Impaired glucose tolerance and/or development or exacerbation of diabetes mellitus has been reported

rarely during treatment with clozapine. On very rare occasions, severe hyperglycaemia, sometimes

leading to ketoacidosis/hyperosmolar coma, has been reported in patients on Clozapine Actavis

treatment with no prior history of hyperglycaemia. Glucose levels normalised in most patients after

discontinuation of Clozapine Actavis and in a few cases hyperglycaemia recurred when treatment was

reinitiated. Although most patients had risk factors for non-insulin-dependent diabetes mellitus,

hyperglycaemia has also been documented in patients with no known risk factors (see section 4.4).

Nervous system disorders

The very common adverse reactions observed include drowsiness/sedation, and dizziness.

Clozapine Actavis can cause EEG changes, including the occurrence of spike and wave complexes. It

lowers the seizure threshold in a dose-dependent manner and may induce myoclonic jerks or

generalised seizures. These symptoms are more likely to occur with rapid dose increases and in

patients with pre-existing epilepsy. In such cases the dose should be reduced and, if necessary,

anticonvulsant treatment initiated. Carbamazepine should be avoided because of its potential to

depress bone marrow function, and with other anticonvulsant the possibility of a pharmacokinetic

interaction should be considered. In rare cases, patients treated with Clozapine Actavis may

experience delirium.

Very rarely, tardive dyskinesia has been reported in patients on Clozapine Actavis who had been

treated with other antipsychotic agents. Patients in whom tardive dyskinesia developed with other

antipsychotics have improved on Clozapine Actavis.

Cardiac disorders

Tachycardia and postural hypotension with or without syncope may occur, especially in the initial

weeks of treatment. The prevalence and severity of hypotension is influenced by the rate and

magnitude of dose titration. Circulatory collapse as a result of profound hypotension, in particular

related to aggressive titration, with the possible serious consequences of cardiac or pulmonary arrest,

has been reported with Clozapine Actavis.

A minority of Clozapine Actavis-treated patients experience ECG changes similar to those seen with

other antipsychotics, including S-T segment depression and flattening or inversion of T waves, which

normalise after discontinuation of Clozapine Actavis. The clinical significance of these changes is

unclear. However, such abnormalities have been observed in patients with myocarditis, which should

therefore be considered.

Isolated cases of cardiac arrhythmias (see section 4.4), pericarditis/pericardial effusion and

myocarditis have been reported, some of which have been fatal. The majority of the cases of

myocarditis occurred within the first 2 months of initiation of therapy with Clozapine Actavis.

Cardiomyopathy generally occurred later in the treatment. Eosinophilia has been co-reported with

some cases of myocarditis (approximately 14%) and pericarditis/pericardial effusion; it is not known,

however, whether eosinophilia is a reliable predictor of carditis.

Signs and symptoms of myocarditis or cardiomyopathy include persistent tachycardia at rest,

palpitations, arrhythmias, chest pain and other signs and symptoms of heart failure (e.g. unexplained

fatigue, dyspnoea, tachypnoea), or symptoms that mimic myocardial infarction. Other symptoms

which may be present in addition to the above include flu-like symptoms.

Sudden, unexplained deaths are known to occur among psychiatric patients who receive conventional

antipsychotic medication but also among untreated psychiatric patients. Such deaths, that can be

caused by cardiac disorders, have been reported very rarely in patients receiving clozapine (see section

4.4).

Vascular disorders

Rare cases of thromboembolism have been reported.

Respiratory system

Respiratory depression or arrest has occurred very rarely, with or without circulatory collapse (see

sections 4.4 and 4.5).

Gastrointestinal system

Constipation and hypersalivation have been observed very frequently, and nausea and vomiting

frequently. Very rarely ileus may occur (see section 4.4). Rarely Clozapine Actavis treatment may be

associated with dysphagia. Aspiration of ingested food may occur in patients presenting with

dysphagia or as a consequence of acute overdosage.

Hepatobiliary disorders

Transient, asymptomatic elevations of liver enzymes and, rarely, hepatitis and cholestatic jaundice

may occur. Very rarely, fulminant hepatic necrosis has been reported. If jaundice develops, Clozapine

Actavis should be discontinued (see section 4.4). In rare cases, acute pancreatitis has been reported.

Renal disorders

Isolated cases of acute interstitial nephritis have been reported in association with Clozapine Actavis

therapy.

Pregnancy, puerperium and perinatal conditions

Neonatal withdrawal syndrome has been reported (see section 4.6).

Reproductive and breast disorders

Very rare reports of priapism have been received.

General disorders

Cases of neuroleptic malignant syndrome (NMS) have been reported in patients receiving Clozapine

Actavis either alone or in combination with lithium or other CNS-active agents. Acute withdrawal

reactions have been reported (see section 4.4).

The table below (Table 3) summarizes the adverse reactions accumulated from reports made

spontaneously and during clinical studies.

Table 3: Treatment-emergent adverse experience frequency estimate from spontaneous and clinical

trial reports

Adverse reactions are ranked under headings of frequency, using the following convention: 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).

Blood and lymphatic system disorders

Common

Leukopenia/decreased WBC/neutropenia, eosinophilia, leukocytosis

Unommon

Agranulocytosis

Very rare

Thrombocytopenia, thrombocythaemia

Metabolism and nutrition disorders

Common

Weight gain

Rare

impaired glucose tolerance and diabetes mellitus

Very rare

Ketoacidosis, hyperosmolar coma, severe hyperglycaemia, hypertriglyceridemia

and hypercholesterolemia

Psychiatric disorders

Rare

Agitation, restlessness

Not known

Obsessive compulsive symptoms.

Nervous system disorders

Very common

Drowsiness/sedation, dizziness

Common

Blurred vision, headache, tremor, rigidity, agitation, akathisia, extrapyramidal

symptoms, seizures/convulsions/myoclonic jerks

Uncommon

Confusion, delirium

Very rare

Tardive dyskinesia

Cardiac disorders

Very common

Tachycardia

Common

ECG changes

Rare

Circulatory collapse, ventricular arrhythmias, Ventricular fibrillation, ventricular

tachycardia, myocarditis, pericarditis/ pericardial effusion, QT prolongation,

Torsade de Pointes, cardiac arrest

Very rare

Cardiomyopathy

Vascular disorders

Common

Hypertension, postural hypotension, syncope

Rare

Venous thromboembolism (including pulmonary embolism and deep vein

thrombosis)

Respiratory, thoracic and mediastinal disorders

Rare:

Aspiration of ingested food

Very rare

Respiratory depression/arrest

Gastrointestinal disorders

Very common

Constipation, hypersalivation

Common:

Nausea, vomiting, anorexia, dry mouth

Rare

Dysphagia

Very rare

Parotid gland enlargement,intestinal obstruction/paralytic ileus/faecal impaction

Hepatobiliary disorders

Common

Elevated liver enzymes

Rare:

Hepatitis, cholestatic jaundice, pancreatitis

Very rare

Fulminant hepatic necrosis

Skin and subcutaneous tissue disorders

Very rare

Skin reactions

Renal and urinary disorders

Common

Urinary retention, urinary incontinence

Very rare

Interstitial nephritis

Pregnancy, puerperium and perinatal conditions

Not known

Drug withdrawal syndrome neonatal (see 4.6 Fertility, pregnancy and lactation)

Reproductive system and breast disorders

Very rare

Priapism

General disorders and administration site conditions

Common:

Fatigue, fever, benign hyperthermia, disturbances in sweating/temperature

regulation,

Uncommon

Neuroleptic malignant syndrome

Very rare

Sudden unexplained death

Investigations

Rare

Increased creatine kinase (CPK)

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

In cases of acute intentional or accidental Clozapine Actavis overdose for which information on the

outcome is available, mortality to date is about 12%. Most of the fatalities were associated with

cardiac failure or pneumonia caused by aspiration and occurred at doses above 2000 mg. There have

been reports of patients recovering from an overdose in excess of 10,000 mg. However, in a few adult

individuals, primarily those not previously exposed to Clozapine Actavis, the ingestion of doses as low

as 400 mg led to life-threatening comatose conditions and, in one case, to death. In young children, the

intake of 50-200 mg resulted in strong sedation or coma without being lethal.

Signs and symptoms

Drowsiness, lethargy, areflexia, coma, confusion, hallucinations, agitation, delirium, extrapyramidal

symptoms, hyperreflexia, convulsions; hypersalivation, mydriasis, blurred vision, thermolability;

hypotension, collapse, tachycardia, cardiac arrhythmias; aspiration pneumonia, dyspnoea, respiratory

depression or failure.

Treatment

Gastric lavage and/or administration of activated charcoal within the first 6 hours after the ingestion of

the drug. Peritoneal dialysis and haemodialysis are unlikely to be effective. Symptomatic treatment

under continuous cardiac monitoring, surveillance of respiration, monitoring of electrolytes and acid-

base balance. The use of epinephrine should be avoided in the treatment of hypotension because of the

possibility of a “reverse epinephrine” effect.

Close medical supervision is necessary for at least 5 days because of the possibility of delayed

reactions.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Antipsychotics; Diazepines, oxazepines and thiazepines, ATC code

N05A H02

Clozapine Actavis has been shown to be an antipsychotic agent that is different from classic

antipsychotics.

Mechanism of action

In pharmacological experiments, the compound does not induce catalepsy or inhibit apomorphine- or

amphetamine-induced stereotyped behaviour. It has only weak dopaminereceptor- blocking activity at

and D

receptors, but shows high potency for the D

receptor, in addition to potent anti-

alpha-adrenergic, anticholinergic, antihistaminic, and arousal-reaction-inhibiting effects. It has also

been shown to possess antiserotoninergic properties.

Pharmacodynamic effects

Clinically Clozapine Actavis produces rapid and marked sedation and exerts antipsychotic effects in

schizophrenic patients resistant to other drug treatment. In such cases, Clozapine Actavis has proven

effective in relieving both positive and negative schizophrenic symptoms mainly in short-term trials.

In an open clinical trial performed in 319 treatment resistant patients treated for 12 months, a clinically

relevant improvement was observed in 37% of patients within the first week of treatment and in an

additional 44% by the end of 12 months. The improvement was defined as about 20% reduction from

baseline in Brief Psychiatric Rating Scale Score. In addition, improvement in some aspects of

cognitive dysfunction has been described.

Clinical efficacy and safety

Compared to classic antipsychotics, Clozapine Actavis produces fewer major extrapyramidal reactions

such as acute dystonia, parkinsonian-like side effects and akathisia. In contrast to classic

antipsychotics, Clozapine Actavis produces little or no prolactin elevation, thus avoiding adverse

effects such as gynaecomastia, amenorrhoea, galactorrhoea and impotence.

A potentially serious adverse reaction caused by Clozapine Actavis therapy is granulocytopenia and

agranulocytosis occurring at an estimated incidence of 3% and 0.7%, respectively. In view of this risk,

the use of Clozapine Actavis should be limited to patients who are treatment-resistant or patients with

psychosis in Parkinson’s disease when other treatment strategies have failed (see section 4.1

Therapeutic indications) and in whom regular haematological examinations can be performed (see

sections 4.4 and 4.8 ).

5.2

Pharmacokinetic properties

Absorption

The absorption of orally administered Clozapine Actavis is 90-95%; neither the rate nor the extent of

absorption is influenced by food.

Distribution

Clozapine Actavis is subject to moderate first-pass metabolism, resulting in an absolute bioavailability

of 50-60%. In steady-state conditions, when given twice daily, peak blood levels occur on an average

at 2.1 hours (range: 0.4-4.2 hours), and the volume of distribution is 1.6 l/kg.

Biotransformation

Clozapine Actavis is approximately 95% bound to plasma proteins. Its elimination is biphasic, with a

mean terminal half-life of 12 hours (range: 6-26 hours). After single doses of 75 mg the mean terminal

half-life was 7.9 hours; it increased to 14.2 hours when steady-state conditions were reached by

administering daily doses of 75 mg for at least 7 days.

Elimination

Clozapine Actavis is almost completely metabolised before excretion. Of the main metabolites only

the demethyl metabolite was found to be active. Its pharmacological actions resemble those of

clozapine, but are considerably weaker and of short duration. Only trace amounts of unchanged drug

are detected in the urine and faeces, approximately 50% of the administered dose being excreted as

metabolites in the urine and 30% in the faeces.

Linearity/non linearity

Dosage increases from 37.5-75 mg and 150 mg given twice daily were found to result during steady

state in linearly dose-proportional increases in the area under the plasma concentration/time curve

(AUC), and in the peak and minimum plasma concentrations.

5.3

Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of safety

pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential (for reproductive

toxicity, see section 4.6).

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Lactose monohydrate 48 mg resp. 192 mg

Magnesium stearate

Povidone

Talc

Maize starch

Silica, colloidal anhydrous

Pregelatinised starch

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

5 years.

6.4

Special precautions for storage

This medicinal product does not require any special storage precautions.

6.5

Nature and contents of container

25 mg tablets: 50x1 monodose, 100 tabl blisterpack, 100 tabl plastic bottle for dose dispensing and

hospital use only

100 mg tablets: 50x1 monodose, 100 tabl blisterpack, 500 tabl plastic bottle for dose dispensing and

hospital use only

6.6

Special precautions for disposal <and other handling>

No special requirements.

7.

MARKETING AUTHORISATION HOLDER

[To be completed nationally]

8.

MARKETING AUTHORISATION NUMBER(S)

[To be completed nationally]

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

25 mg: 1998-12-18/2008-12-18

100 mg: 1998-12-18/2008-12-18

10.

DATE OF REVISION OF THE TEXT

2020-01-09

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