1.
Summary
Clozapine is
an atypical antipsychotic used in the treatment of people’s schizophrenia who
have had an inadequate response to at least two other antipsychotics, or who
cannot tolerate the side effects of these. There is a small risk of
neutropenia, the detection of which is achieved by regular haematological
monitoring through the Clozaril Patient Monitoring Service.
Until recently
the drug has only been available from a hospital pharmacy, however shared care
with general practitioners has recently been introduced for those who have been
on the drug for over a year with satisfactory blood results. As patients on
clozapine are living in the community it is appropriate that their general
practitioner should be involved in monitoring their care if their mental state
is stable.
2.
Introduction
Currently
clozapine is rarely used. FFFFFFFF Healthcare Trust have a budget for (n)
patients to be treated with this medication. It can however be remarkably effective
in treating people with chronic schizophrenia who have not responded to. other
antipsychotic medication. A number of people are now able to live in the
community who were previously long term patients in hospital. Within the Trust
there is a lead consultant (Dr. BBBBBB) who keeps a central register of those
patients on clozapine and assesses the appropriateness of the treatment prior
to the person starting the drug.
3.
Indications
Management of
patients and prescribing of clozapine in the community by the GP may be
appropriate after one year of treatment and once the patient’s blood monitoring
frequency has been reduced to four weekly. The consultant may consider
approaching the GP with a view to them participating in a shared care
arrangement when all the following conditions are met.
1.
Patient’s
mental state is stable.
2.
Suitable
arrangements for community care are in place.
3.
The patient has had a stable haematological
profile for one year with blood results in the normal (green) range for at least
the last three months and where agreement to reduce monitoring frequency to
four weekly has been obtained from the Clozaril Patient Monitoring Service.
4.
The
patient's dose is stable
5.
The
GP is happy under the arrangements 1 - 4 that he/she is able to monitor the
patient, take blood every four weeks, competent in dose adjustments when agreed
with the psychiatrist and where a community pharmacist is nominated by the
patient, is agreeable to dispensing clozapine.
4.
Dose and Route of Administration
Initiation of
Clozapine treatment must be in hospital in-patients and is restricted to those
patients with a normal white blood cell count and differential count. Initially
12.5 mg once or twice on first day,
followed by one or two 25 mg tablets on second day. Increase slowly, initially
by daily increments of 25 mg to 50
mg, followed by increments of 50 to 100 mg to reach a therapeutic dose within
the range of 200 to 450 mg daily. Once control is achieved a maintenance dose
of 150 to 300 mg daily may suffice. Exceptionally, doses up to 900 mg daily may
be used. The total daily dose should be divided and a larger portion of the
dose may be given at night.
Patients with
a history of epilepsy should be closely monitored during Clozapine therapy
since dose-related convulsions have been reported. Therefore, patients with a
history of seizures, as well as those suffering from cardiovascular, renal or
hepatic disorders, together with the elderly, need lower doses (12.5 mg given
once on the first day) and more gradual titration.
5.
Clinical Monitoring
By mid-1995
over 7,000 patients have been treated with Clozapine in the U.K. Approximately
4% of treated patients will develop neutropenia or agranulocytosis. If this is
not detected the neutropenia can develop into the more serious condition
agranulocytosis, which may leave the patient vulnerable to infection. Detection
of neutropenia is achieved by regular haematological monitoring, through the
Clozapine Patient Monitoring Service.
Neutropenia
occurs most commonly in the first eighteen weeks of therapy. The incidence of
neutropenia, after one year of monitoring, is 0.45 - 0.74%. The risk of
agranulocytosis developing after one year is in one patient in 1429. The risk
of agranulocytosis is of the same order as that caused by some phenothiazines,
which are not currently monitored.
The Clozaril
Patient Monitoring Service operated by the manufacturer. Novartis
Pharmaceuticals (UK) Ltd. oversees the use of Clozapine. The function of this
is to ensure the necessary blood monitoring and collation of patient details
onto a centralised database. Clozapine is only supplied to patients via a
pharmacist after a satisfactory blood result is obtained. The system works on
the principle “no blood result, no drug". This is effective in detecting neutropenia
and minimising the risk of fatal agranulocytosis.
The Clozaril
Patient Monitoring Service provides routine information on the use of
Clozapine. and provides 24 hour emergency medical advice.
Where a psychiatrist and (GP are happy
with the overall clinical and haematological stability of the patient, the OP
may, in collaboration with a community pharmacy of the patient’s choice, and
subsequently registered with the Clozaril Patient Monitoring Service, take on
the monitoring and care of the patient in the community under a shared-care
protocol agreed with the psychiatrist.
5. Community Monitoring Requirements
A blood sample will need to be taken at
least every four weeks and sent to the Clozaril Patient Monitoring Service
laboratory, where a full blood count will be performed. The specimen tubes and
forms are supplied by the Monitoring Service. Blood samples should be taken and
sent for analysis approximately two weeks prior to the next anticipated
dispensing day, i.e. two weeks before the patient is about to run out of
tablets.
Blood results will be sent by the
Clozaril Patient Monitoring Service to the prescribing GP, the consultant
psychiatrist, and the hospital pharmacist. The community pharmacist will also
receive notification of the blood result and whether Clozapine can be
dispensed.
Assuming the blood test results are
satisfactory (i.e. green/normal) the OP can write a prescription for 28 days
supply of tablets.
A maximum of four weeks supply of
Clozapine can then be dispensed by the nominated community pharmacist
previously chosen by the patient. The community pharmacist like the hospital
pharmacist, will need to agree to register with the Clozaril Patient Monitoring
Service and follow all dispensing guidelines.
If the community pharmacist, of the
patient’s choosing, dose not wish to dispense Clozapine or register with the
Clozaril Patient Monitoring Service, it will be necessary for the patient to
choose another pharmacist.
In the event of a red alert’ Novartis
will immediately contact the care team and advise on the appropriate actions.
(Further details on the use of
Clozapine in the community are available from the Clozaril Patient Monitoring
Service, Tel: 01345 698269).
A brief examination of the patient’s
mental state should be performed at the time the blood sample is taken. A CPN.
either from the hospital or OP surgery, should endeavor to see the patient
regularly, ideally once a fortnight.
Like any patient on long term
antipsychotic treatment, all else being well, the patient will need regular
out-patient appointments every 3 - 6 months.
6.
Side Effects
Neutropenia
leading to agranulocytosis. Rare reports of leucocytosis including
eosinophilia.
Most commonly
drowsiness, sedation, hypersalivation. Dizziness or headache may occur.
Clozapine lowers the seizure threshold and may cause EEG changes and delirium.
Convulsions may be precipitated in individuals who have epileptogenic potential
but no previous history of epilepsy.
Extrapyramidal
symptoms are limited mainly to tremor, akathisia and ridigity.
Neuroleptic
malignant syndrome has been reported.
Transient
autonomic effects e.g. dry mouth, disturbances of accommodation and
disturbances in sweating and temperature regulation. Hypersalivation.
Tachycardia
and postural hypotension, with or without syncope, and less commonly
hypertension may occur. In rare cases profound circulatory collapse has
occurred, EGG changes, arrhythmias, pericarditis and myocarditis (with or
without eosinophilia) have been reported, some of which have been fatal.
GI disturbances
and increases in hepatic enzymes and, in rare cases, cholestasis have been
reported.
Both urinary
incontinence and retention and priapism have been reported.
Benign
hyperthermia may occur and isolated reports of skin reactions have been
received.
Rarely,
hyperglycaemia has been reported.
With prolonged
treatment considerable weight gain has been observed.
Sudden
unexplained deaths have been reported in patients receiving Clozapine.
7.
Drug Interactions
Clozapine
should not be given with other drugs with a substantial potential to depress
bone marrow function. Clozapine may enhance the effects of alcohol, MAO
inhibitors, CNS depressants and drugs with anticholinergic, hypotensive or
respiratory depressant effects. Caution is advised when Clozapine therapy is
initiated in patients who are receiving (or have recently received) a
benzodiazepine or any other psychotropic drug as 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.
Caution is advised
with concomitant administration of therapeutic agents which are highly bound to
plasma proteins or which induce or inhibit hepatic enzymes.
Concomitant
use of lithium or other CNS-active agents may increase the risk of neuroleptic
malignant syndrome.
The
hypertensive effect of adrenaline and its derivatives may be reversed.
Do
not use in pregnant or nursing women. Use adequate contraceptive measures in
women of child bearing potential.
8. Shared
Care Responsibilities
Indications for referral back to
consultant
· Amber
or red blood result (note OP will have to take initial action in the case of a
red).
· Any
spontaneous deterioration in mental state which cannot be managed by the OP.
· Restarting
therapy after a 48 hour break in treatment, as the dose of Clozapine must be
gradually re-built again.
· Intolerance
of side effects.
· In
consideration of concomitant psychotropic prescribing.
· Ongoing
difficulty in securing monthly blood samples
· Non-compliance
with medication.
9. Patient Information
Education
for patients about clozapine will be carried out by hospital staff during their
first year on the medication.
The
patient, and if appropriate their carer, should be regularly reminded to remain
vigilent for any signs of infection, e.g. fever or sore throat, which may
indicate the presence of agranulocytosis. While it is unlikely that such
symptoms are related to the development of Clozapine induced agranulocytosis.
an immediate blood test will be necessary to exclude the possibility. The
patient should, therefore, be regularly advised to return to either their GP.
or their hospital team, to seek immediate attention, if symptoms suggestive of
fever occur.
10. Support and Contacts
Currently most of the patients who are on Clozapine are the
responsibility of Dr.. BBBBBBBb and the
Rehabilitation Team, who can be contacted on ****** in office hours, ******
between 8.30 a.m. - 5.00 p.m. and ******** out of hours. However, other
consultants may use the drug and can be contacted on the following numbers:
11. Cost
Five patients on an average dose of 300
mg per day cost £10,350 per year.
12. Proposals
To be reviewed: (date)
Donated
by North West Anglia Trust. May 2001.