CLOZARIL 25mg Tablets
CLOZARIL 100mg Tablets
Please see Summary of Product
Characteristics (SmPC) for full information before prescribing Clozaril.
The use of Clozaril is
restricted to patients, physicians and nominated pharmacists registered with
the Clozaril Patient Monitoring Service (CPMS).
In the UK a white cell count with differential count
must be monitored:
At least weekly for the first 18 weeks of
At least at 2 week intervals between weeks
18 and 52
After 1 year of treatment with stable
neutrophil counts, patients may be monitored at least at 4 week intervals
must continue throughout treatment and for at least 4 weeks after
is associated with an increased risk of myocarditis and cardiomyopathy. If
suspected Clozaril must be stopped immediately and the patient referred to a
cardiologist and not re-exposed to Clozaril.
Clozaril 25 mg Tablets
containing 25mg clozapine. Clozaril 100 mg Tablets containing 100mg clozapine.
patients and in schizophrenia patients with severe, untreatable neurological
adverse reactions to other antipsychotic agents, including an atypical
antipsychotic agent prescribed for adequate duration. Psychotic disorders
occurring during the course of Parkinson's disease, where standard treatment
Dosage and Administration
12.5 mg once or twice on the
first day, followed by 25 mg tablets once or twice on the second day. Increase
dose slowly, by increments (see SmPC). In most patients, antipsychotic efficacy
can be expected with 200 to 450 mg/day given in divided doses. If dose does not
exceed 200 mg/day, it can be given as a single administration in the evening.
Once control is achieved, a lower maintenance dose may be effective. Treatment
should be maintained for at least 6 months. Doses up to 900 mg/day can be used
but the possibility of increased adverse reactions (especially seizures)
occurring at doses over 450 mg/day must be considered.
See SmPC for details on
re-starting therapy, ending treatment or switching from another antipsychotic.
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 taken in the evening. Increase dose by 12.5 mg increments,
with a maximum of two increments a week up to a maximum of 50 mg, preferably
given as a single dose in the evening. The mean effective dose is usually
between 25 and 37.5 mg/day.
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 two weeks, an increase in
anti-parkinsonian medication is possible on the basis of motor status.
Cautious titration and a divided dosage
schedule are necessary to minimise the risks of hypotension, seizure and
Method of administrationClozaril is administered orally.
Switching from a previous antipsychotic therapy to
It is generally recommended that Clozaril should not
be used in combination with other antipsychotics. When Clozaril 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.
Hepatic impairment Patients with hepatic
impairment should receive Clozaril with caution along with regular monitoring
of liver function tests (see section 4.4 of SmPC).
No paediatric studies have been performed. The safety
and efficacy of Clozaril in children and adolescents under the age of 16 years
have not yet been established. Clozaril should not be used in this group until
further data becomes available.
Patients 60 years of age and older
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.
See SmPC for information on
Hypersensitivity to the active substance
or to any of the excipients. 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 Clozaril induced agranulocytosis. Concurrent treatment with
substances known to have a substantial potential for causing agranulocytosis;
concomitant use of depot antipsychotics is discouraged.
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.
Warnings and Precautions
: Before initiating
clozapine therapy, patients should have a blood test and a history and physical
examination. Clozaril can cause agranulocytosis, so is restricted to patients
who have initially normal leukocyte findings (White Blood Cell (WBC) count >
3.5x 109/l and Absolute Neutrophil Count (ANC) > 2.0x 109l),
and in whom regular WBC counts and ANC can be performed within 10 days prior to
starting Clozaril, weekly for first 18 weeks, thereafter at 4 week intervals
throughout treatment and for 4 weeks after complete discontinuation.
Patients with history of cardiac
illness or abnormal cardiac findings on physical examination prior to treatment
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. The treating physician should consider performing a pre-treatment ECG.
QT interval prolongation:
As with other antipsychotics, caution is
advised in patients with known cardiovascular disease or family history of QT
prolongation. As with other antipsychotics, caution should be exercised when
clozapine is prescribed with medicines known to increase QTc interval.
Cerebrovascular adverse events:
Clozapine should be used with caution in
patients with risk factors for stroke. Risk of thromboembolism: Cases of venous
thromboembolism (VTE) have been reported with antipsychotic drugs. If the
diagnosis of NMS is confirmed, Clozaril should be discontinued
immediately and appropriate medical measures should be administered.
Atypical antipsychotic drugs, including Clozaril, have been
associated with metabolic changes that may increase cardiovascular/cerebrovascular
risk. Hyperglycaemia: Patients with an established diagnosis of diabetes
mellitus who are started on atypical antipsychotics should be monitored
regularly for worsening of glucose control. Hepatic impairment: Patients
with stable pre-existing liver disorders may receive Clozaril, 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 Clozaril therapy.
Prior to treatment initiation,
physicians must ensure that the patient has not experienced an adverse
haematological reaction to clozapine that necessitated discontinuation.
Immediate discontinuation of
Clozaril is mandatory if either the WBC count is less than 3.0x109 /l
or the ANC is less than 1.5x109/l at any time during Clozaril
treatment. Patients in whom Clozaril has been discontinued as a result of
either WBC or ANC deficiencies must not be re-exposed to Clozaril. Following
discontinuation of Clozaril, haematological evaluation is required until
haematological recovery has occurred.
If Clozaril has been withdrawn and
either a further drop in the WBC count below 2.0x109 /l occurs or
the ANC falls below 1.0x109/l the management of this condition must
be guided by an experienced haematologist.
The patient should be educated
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
Low WBC count/ANC:
If, during Clozaril
therapy, either the WBC count falls to between 3.5x109/l and 3.0x109/l
or the ANC falls to between 2.0x109/l and 1.5x109/l,
haematological evaluations must be performed at least twice weekly until the
patient’s WBC count and ANC stabilise within the range 3.0-3.5x109/l
and 1.5-2.0x109/l respectively, or higher.
: Discontinuation of
Clozaril is recommended if the eosinophil count rises above 3.0x10 9/l; therapy should be restarted only after the eosinophil count has fallen
below 1.0x109/l. Discontinuation of Thrombocytopenia: Clozaril
therapy is recommended if the platelet count falls below 50x109/l.
with or without syncope, can occur during Clozaril treatment. Rarely, collapse
can be profound and may be accompanied by cardiac and/or respiratory arrest
which is more likely to occur with concurrent use of certain medications (See
SPC for more details) and during initial titration with rapid dose escalation.
Patients starting Clozaril treatment require close medical supervision.
Clozaril is associated with an increased risk of myocarditis,
pericarditis/pericardial effusion and cardiomyopathy; and if suspected,
Clozaril 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 Clozaril.
In patients who are
diagnosed with cardiomyopathy while on Clozaril treatment, there is potential
to develop mitral valve incompetence, including mild or moderate mitral
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 or symptoms mimicking
myocardial infarction. Flu-like symptoms may also be present.
Myocardial infarction (MI):
There have been post
marketing reports of MI which include fatal cases.
Patients with a
history of epilepsy should be closely observed during Clozaril therapy since dose related convulsions have been reported.
Patients with stable
pre-existing liver disorders or liver dysfunction need regular liver function
tests. If the LFTs are elevated, discontinue Clozaril and resume only if LFTs
return to normal.
alterations in lipids have been observed in patients treated with atypical
antipsychotics, including Clozaril. Clinical monitoring, including baseline and
periodic follow-up lipid evaluations in patients using clozapine, is
Use with care in
patients with a history of colonic disease, a history of lower abdominal
surgery, glaucoma, narrow angle glaucoma, prostatic enlargement and in patients
receiving concomitant medications known to cause constipation, megacolon and intestinal infarction/ischaemia, paralytic ilius.
should be evaluated carefully to rule out underlying infection, agranulocytosis
or Neuroleptic Malignant Syndrome (NMS). If NMS is confirmed, discontinue
Clozaril immediately and administer appropriate medical measures.
Patients with rare hereditary problems
of galactose intolerance should not take Clozaril.
Impaired glucose tolerance
and/or development or exacerbation of diabetes mellitus has been reported rarely
during treatment with clozapine.
Falls: Clozaril may cause seizures, somnolence and other conditions that could lead to falls. Fall risk assessments should be performed on patients with exacerbating conditions.
Risk of thromboembolism:
patients should be avoided due to reports of thromboembolism.
Increased mortality in elderly
patients with dementia.
Caution when prescribing to
. Mothers receiving Clozaril should not breast-feed. Adequate contraceptive
measures must be ensured in women of childbearing potential.
Neonates exposed to antipsychotic drugs
(including Clozaril), 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.
Activities such as driving or operating machinery
should be avoided, especially during the initial weeks of treatment.
Interaction with other medicinal
products and other forms of interaction
Clozaril must not be used
concomitantly with substances having a well-known potential to suppress bone
marrow function. (See Section 4.3 of the SmPC, Contraindications).
Long-acting depot antipsychotics
(with myelosuppressive potential) must not be used with Clozaril because these
cannot be removed from the body in situations where they may be required e.g.
neutropenia. Alcohol should not be used with Clozaril due to possible
potentiation of sedation.
Caution is advised if Clozaril
is used concomitantly with other CNS active agents such as, MAOIs, perazine, SSRIs
especially fluvoxamine, caffeine, CNS depressants including narcotics,
antihistamines and benzodiazepines, Caution is advised if Clozaril is used
concomitantly with antihypertensive agents, highly protein bound drugs (e.g.
warfarin and digoxin), phenytoin, lithium, rifampicin, valproic acid,
noradrenaline [norepinephrine], adrenaline [epinephrine] or omeprazole.
Cases have been reported of an interaction
between citalopram and clozapine, which may increase the risk of adverse events
associated with clozapine. The nature of this interaction has not been fully
. Hormonal contraceptives (including combinations of estrogen and
progesterone or progesterone only) are CYP 1A2, CYP 3A4 and CYP 2C19
inhibitors. Therefore initiation or discontinuation of hormonal contraceptives,
may require dose adjustment of clozapine according to the individual medical need.
In cases of sudden cessation of
smoking, the plasma clozapine concentration may be increased, thus leading to
an increase in adverse effects. See SPC for more details.
Fertility, Pregnancy and
Caution should be exercised when prescribing to
pregnant women. Neonates exposed to antipsychotics (including Clozaril) during
the third trimester 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 suggest that clozapine is
excreted in breast milk and has an effect in the nursing infant; therefore,
mothers receiving Clozaril should not breast-feed.
Limited data available on the effects of
clozapine on human fertility are inconclusive.
return to normal menstruation may occur as a result of switching from other
antipsychotics to Clozaril. Adequate contraceptive measures must therefore be
ensured in women of childbearing potential.
Ability to Drive and Operate
Owing to the ability of Clozaril 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.
Adverse reactions are ranked
under headings of frequency. Very common (≥1/10), common (≥1/100,
<1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000,
<1/1,000), very rare (<1/10,000), including isolated reports.
The most serious adverse reactions experienced with
clozapine are agranulocytosis, seizure, cardiovascular effects and fever.
dizziness, tachycardia, constipation, hypersalivation.
WBC/neutropenia, eosinophilia, leukocytosis, weight gain, blurred vision, headache,
tremor, rigidity, akathisia, extrapyramidal symptoms, seizures, convulsions,
myoclonic jerks, ECG changes, hypertension, postural hypotension, syncope,
nausea, vomiting, anorexia, dry mouth, elevated liver enzymes, urinary
incontinence, urinary retention, fatigue, fever, benign hyperthermia, disturbances
in sweating/temperature regulation, dysarthria.
neuroleptic malignant syndrome, dysphemia, falls.
For details of rare, very rare and not
known undesirable effects please refer to SmPC.”
Quantities and basic NHS price
28 x 25 mg tablets : £2.95 ; 84 x 25 mg
tablets : £6.30; 100 x 25 mg tablets : £7.50
28 x 100 mg tablets : £11.76 ; 84 x 100
mg tablets : £25.21 ; 100 x 100 mg tablets : £30.01
Supply of Clozaril is restricted
to hospital pharmacies registered with the CLOZARIL Patient Monitoring Service.
Mylan Products Limited, 20
Station Close, Potters Bar, Herts, EN6 1TL, UK.
Product Authorisation Numbers
25 mg tablets: PL 46302/0054
100 mg tablets: PL 46302/0057
Legal Category: POM
information is available in the UK from:
BGP Products Ltd.,
Building Q1, Quantum House, 60 Norden Road, Maidenhead, Berkshire, SL6
Date of last revision: July 2018
Clozaril is a registered Trade
events should be reported. Reporting forms and information can be found at
or search for MHRA Yellow Card in the
Google Play or Apple App Store. Adverse events should also be reported to