Clinical use

Clozapine is an antipsychotic licensed for the management of treatment resistant schizophrenia. It may also be used for psychoses in patients with Parkinson’s disease.

Clozapine has specific prescribing, monitoring, supply, and administration requirements.

All healthcare professionals who interact with individuals on clozapine therapy should be aware of the clinical considerations for using clozapine safely and the importance of managing the risks associated with patients prescribed clozapine.

Patient harm

Unfamiliarity with the safe use of clozapine in healthcare professionals interacting with patients prescribed clozapine may lead to serious patient harm.

Harms have been reported at all stages of the patient journey and in all care settings.

A failure to adequately monitor patients or recognise and respond appropriately to symptoms associated with known adverse effects of clozapine therapy, can lead to serious patient harm.  Prescribing medicines that interact with clozapine may also lead to harm.

Prescribing

Initiation

Initiation should only be by a consultant psychiatrist registered with a clozapine service.

The therapeutic dose for clozapine is patient specific and dosage is adjusted based on response, tolerance, and plasma level.

It is good practice to include the brand name when prescribing clozapine.  The patient can only be supplied the brand for which they are registered.

Formulations

Clozapine is usually administered orally and there are three licensed brands available in the UK.  Guidance where tablet formulations are unsuitable is available

Intramuscular clozapine is unlicensed in the UK; it is occasionally used in a mental health inpatient setting under local protocol.

Monitoring

It is a requirement that people taking clozapine have full blood counts (FBC) (particularly white cell count, neutrophils, and platelets) monitored by the manufacturer. This is because clozapine can rarely cause fatal agranulocytosis, neutropenia, and thrombocytopenia.

The method of blood sampling is agreed locally and the sample is either sent directly to the monitoring service for analysis, or the results are communicated to the monitoring service.

Monitoring services

The use of clozapine is restricted to patients registered with a monitoring service specific to the brand prescribed.

The following three brands of clozapine with their own monitoring service are available in the UK:

• UK Clozaril Patient Monitoring Service (CPMS) for Clozaril® tablets
• Denzapine Monitoring Service (DMS) for Denzapine® tablets and oral suspension
• Zaponex Treatment Access System (ZTAS) for Zaponex® tablets and orodispersible tablets

Registration

Patients can only be registered with one service at any one time.

The patient, prescriber, a nominated pharmacist, and the pharmacy that supplies clozapine must all be registered with the relevant monitoring service.  Organisations are unlikely to be registered with monitoring services for all three brands.

Monitoring frequency

The frequency of monitoring depends on previous results and the length of time the individual has been taking clozapine.  The risks of developing neutropenia or agranulocytosis decreases with time therefore blood test frequency reduces.

Monitoring is usually performed weekly for 18 weeks, then every 2 weeks for the rest of the first year then every 4 weeks thereafter.

If doses are missed, or if results are outside the required limits, the frequency of monitoring may be increased.

Response to results

The monitoring service assigns the result:

Green

Continue clozapine at the current does and monitoring frequency.

Amber

Amber results indicate a warning, requiring additional monitoring and a reduced clozapine supply.

Red

Stop clozapine and follow the patient specific Red Alert Advice issued by the clozapine company to the registered prescriber and pharmacy.

If a patient has repeated red results this information is shared via the Central Non Re-challenge Database (CNRD) to support future prescribing decisions.

Clozapine can only be continued if the patient has a current green or amber blood result.

Supply

Clozapine can only be supplied for patients whose blood results are green or amber.

The quantity is based on the authorisation given by the brand monitoring service and is dependent on the required frequency of blood tests.  Supply is usually between one and four weeks.

Clozapine is not normally prescribed or supplied in primary care but there are exceptions.

Plasma level monitoring

Clozapine monitoring services are not responsible for monitoring clozapine plasma levels.

Practice for analysing clozapine plasma levels varies between organisations, some use offsite laboratories, others utilise point of care testing. Contact the local mental health trust for specific information.

Mental health organisations should have their own guidelines on when monitoring is indicated.

The MHRA recommends monitoring plasma levels of clozapine for toxicity in certain clinical situations such as when:

• a patient stops smoking or switches to an e-cigarette/NRT
• concomitant medicines may interact to increase blood clozapine levels
• a patient has pneumonia or other serious infection
• reduced clozapine metabolism is suspected
• toxicity is suspected

The clozapine dose may need to be reduced in the case of stopping smoking or severe infection to reduce the risk of toxicity.

Plasma levels need to be reviewed if patients start/restart smoking.

Target range

A therapeutic window of 0.35 mg/L to 0.6 mg/L is suggested by the Maudsley Prescribing Guidelines. Some patients may benefit from levels outside of this range.

Any patient showing signs of toxicity should have the dose reviewed regardless of plasma level.

Any changes in dose should be made in consultation with the mental health team.

Physical Health Checks

Patients prescribed clozapine should be on the Severe Mental Illness (SMI) register and require annual physical health checks as a minimum due to the impact of clozapine on their physical health

Clozapine toxicity

Acute toxicity symptoms include severe sedation, tachycardia, hypotension, worsening hypersalivation, respiratory depression, delirium, difficulty in walking or talking, seizures and possible coma.

Adverse effects

Some of the serious side-effects of clozapine include agranulocytosis, neutropenia, constipation, fever, bruising, hypersalivation, myocarditis/cardiomyopathy, diabetes, raised CRP and pneumonia.

Neutropenia and agranulocytosis

Patients presenting with flu-like symptoms such as sore throat and a high temperature need to be reviewed by an urgent care service (such as via NHS 111), as this can be a sign of neutropenia.

Constipation and clozapine-induced gastrointestinal hypomotility (CIGH)

Clozapine may impair motility of the entire gastrointestinal system from the oesophagus to the rectum.  The effect can range from mild constipation to rare instances of intestinal obstruction, faecal impaction, and paralytic ileus.

Clozapine induced constipation can be fatal.

Managing constipation in people taking clozapine provides guidance on preventing and managing constipation in individuals prescribed clozapine.

Myocarditis and cardiomyopathy

These may be suspected in patients who have persistent tachycardia at rest, palpitations, arrhythmias, chest pain, and other signs/symptoms of heart failure or symptoms that mimic a myocardial infarction. Flu-like symptoms may also be present.

Interactions

There are a number of significant interactions with clozapine that can alter the plasma level.

Medicines

These include any medicines that may alter the plasma concentration of clozapine, increase risk of constipation, or cause/contribute to agranulocytosis.

The effect of interactions can occur when medicines are stopped or started.

For further information on interactions refer to the SPS article about drug interactions, the clozapine section of the BNF and the relevant Summary of Product Characteristics (SmPC).

Other specialist texts include Stockley’s and the Maudsley Prescribing Guidelines.

Other factors

Tobacco smoking, caffeine and infection can all significantly alter clozapine metabolism and require prompt referral to a specialist prescriber for a change in clozapine dose.

Alcohol and clozapine can both cause central nervous system depression and patients should be made aware of this additive risk.

Missed doses

It is important that patients do not miss doses.

If more than 48 hours has elapsed since the last dose the patient must have their dose re-titrated under specialist advice.

This is because tolerance to common side effects such as postural hypotension and tachycardia are lost very quickly. Restarting at the previous dose would result in a high risk of seizures, tachycardia, hypotension, and circulatory collapse.

If an individual misses more than three days of clozapine, their blood testing frequency may need to change.

The relevant clozapine manufacturer or mental health pharmacy should be contacted for further advice.

Swallowing difficulties

Support should be offered to individuals having difficulty or unable to swallow clozapine to prevent any missed doses. Clozapine use in adults with swallowing difficulties offers advice on options.

Pregnancy and breastfeeding

It is important that a patient prescribed clozapine is supported by their specialist mental health team if they are planning a pregnancy, find out they are pregnant or planning on breastfeeding.

SPS has breastfeeding resources to support discussions.

Patient and carer engagement

Patients should inform health care professionals they are prescribed clozapine, for example when buying over the counter medicines or at physical health appointments.

Patients should be reminded at every contact that clozapine is a regular medicine that cannot be missed, and discuss the signs of potentially serious adverse effects and what to do about them.

Patients should be reminded to always bring their supply of clozapine when they move care sectors.

Patient information leaflets should be available to all patients.

Discussions about the importance of agreeing to data sharing across the health care system are essential.

Further information

Managing the risks associated with patients prescribed clozapine

Clozapine use in adults with swallowing difficulties

Managing constipation in people taking clozapine