CLOZAPINE: reducing the risk of harm

Key messages
• Common side effects may lead to life-threatening conditions in people who are
prescribed clozapine:
o clozapine-induced constipation
o clinical or haematological neutropenia or agranulocytosis
o tachycardia
• Clozapine is designated as a RED drug in Cheshire and Merseyside.
• Clozapine is for specialist use only and any queries regarding treatment should be
referred to the specialist.

SAFETY
Everyone involved in the support or care of people receiving clozapine is reminded of
the importance of awareness and management of common side effects that may lead
to life-threatening conditions.
• Constipation must be actively monitored and actively treated. Clozapine carries a
serious risk of intestinal obstruction including faecal impaction and paralytic ileus
[1].
• Be cautious with signs or symptoms of a low white cell count. Clinical or
haematological neutropenia or agranulocytosis can lead to an acute
life-threatening condition.
• Monitor closely for tachycardia. Clozapine also carries a serious risk of myocarditis
and cardiomyopathy particularly in the first two months of treatment.
Also urgently inform the psychiatrist, CMHT *, care coordinator, or another lead
clinician of:
• Episodes of erratic or non-compliance with clozapine therapy.
• A break in treatment of more than 48 hours; do not restart clozapine as this will
require re-titration.
• Abrupt discontinuation of clozapine; can lead to an acute rebound psychosis.
• Any change in smoking status.
Share information across the healthcare interface:
• Mental health specialists, communicate all medication changes to the GP.
• GP practices, add clozapine to the electronic health record as repeat medication
prescribed elsewhere.

* CMHT (Community Mental Health Team) refers to the relevant, local mental health team providing care for your
service user; this may include the Recovery Team, Early Intervention Team, Health and well-being team, etc.

ICB approval date: 24 Aug 2023 Last updated: 01 Mar 2024 Version: 1.2
Review date: Aug 2025 (or earlier if there is significant new evidence relating to this recommendation)
APG administration provided by Midlands and Lancashire Commissioning Support Unit
CLOZAPINE: reducing the risk of harm

Introduction
Service users supplied with clozapine will have it prescribed, monitored and dispensed by their local mental health
trust. Where a service user is under the care of a third party, e.g., during an acute medical admission, this may lead
to a breakdown in care. This guidance is aimed at highlighting these risks and providing solutions for the
non-specialist.
Administrative action points for general practice
• DO NOT issue clozapine prescriptions.
• Ensure that clozapine is added as a ‘medication prescribed elsewhere’ on the Primary care clinical system
using the ‘hospital no print’ function to ensure it is listed under the patients medication on their Summary
Care Record (SCR) and to allow interactions to be detected. The dose should not be specified.
• Refer to the Cheshire guidance on repeat prescribing or the Merseyside guidance on the summary care
record.
Clinical action points for all prescribers and other non-mental health hospitals
• Clozapine can cause neutropenia (3% of service users) and agranulocytosis (0.5%).
• Consider urgent FBC if there are signs and symptoms of infection, e.g., sore throat, fever, or flu-like
symptoms.
• Urgently inform the psychiatrist, CMHT, care coordinator, or another lead clinician if there are:
- clinical or haematological episodes of neutropenia or agranulocytosis
- episodes of erratic or non-compliance with clozapine therapy
- a break in treatment of more than 48 hours; do not restart clozapine as this will require re-titration
- abrupt discontinuation of clozapine; this can lead to an acute rebound psychosis
- any change in smoking status
- potential clozapine-induced constipation; can be life-threatening, consider A&E referral.
• Contact your local CMHT and/or supplying pharmacy for all clozapine admissions and any clozapine-related
queries or for advice.
• Contact Psychiatry Liaison during all acute hospital in-patient user stays.
• Carefully consider the potential for drug interactions (see below) .
• Always report appropriate clozapine side effects on a Yellow Card, e .g., neutropenia and severe constipation.
• Always consider the potential for clozapine toxicity, i.e., if the patient is experiencing an increasing burden of
side effects or changes to smoking habits (see MHRA guidance 2020 on clozapine blood levels) [2]
Advice for Healthcare professionals
• Monitoring blood clozapine levels for toxicity is now advised in certain clinical situations such as when:
- a patient stops/reduces smoking or switches to an e-cigarette
- concomitant medicines may interact to increase blood clozapine levels
- a patient has pneumonia or other serious infection
- poor (reduced) clozapine metabolism is suspected
- toxicity is suspected
• If blood clozapine level monitoring is carried out, this should be in addition to the required blood tests to
manage the risk of agranulocytosis. for other antipsychotics, where assays and suggested reference values
are available, blood level monitoring for toxicity may be helpful in certain circumstances, for example in the
event of symptoms suggestive of toxicity or when concomitant medicines may interact to increase
antipsychotic drug levels.
• Refer to the full Summaries of Product Characteristics for other important warnings, interactions, and
recommendations for clozapine and other individual antipsychotics.
Action points for community pharmacists
• DO NOT dispense clozapine prescriptions (unless you are registered with the appropriate monitoring
service).

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CLOZAPINE: reducing the risk of harm

Information for healthcare professionals

Background information
Clozapine is an atypical antipsychotic indicated for treatment-resistant schizophrenia (TRS) or psychotic disorder in
Parkinson’s disease.

There are 3 brands of clozapine (see below for manufacturer contact details):
• Clozaril (Viatris) prescribed by Cheshire and Wirral Partnership NHS FT, Lancashire and South Cumbria NHS
FT, Mersey Care NHS FT.
• Denzapine (Britannia Pharmaceuticals Ltd) prescribed by Mersey Care NHS FT; only oral suspension
prescribed by Cheshire and Wirral Partnership NHS FT.
• Zaponex (Leyden Delta) is not prescribed within Cheshire or Merseyside.

Patient registration
Every service user prescribed clozapine must be registered with one of the three manufacturers before they can be
prescribed and dispensed clozapine; this is arranged by the secondary care psychiatric team.

The CMHT and/or supplying pharmacy will monitor the efficacy and tolerance of clozapine, manage the ongoing
mandatory full blood count testing required and prescribe and supply the clozapine.

Clozapine is usually dispensed only by appropriately registered pharmacies; this is usually the local mental health
Trust’s dispensary.
Side Effects
Very common side effects include (≥10%)
Constipation – can be life-threatening (see below) * ‡ Tachycardia †
Drowsiness or sedation ‡ Dizziness
Common side effects include (≥1% and <10%)
Urinary incontinence Urinary retention Weight gain ‡
ECG changes ‡ Postural hypotension Syncope
Akathisia ‡ Extrapyramidal symptoms Seizures, convulsions, or myoclonic jerks
Tremor ‡ Rigidity Blurred vision
Headache Fatigue Anorexia
Hypersalivation ‡ Dry mouth Nausea
Vomiting Leucocytosis Eosinophilia
Leucopenia Agranulocytosis * Elevated liver enzymes
Fever or benign hyperthermia (if associated with leucopenia or Disturbances in sweating or temperature
neutropenia or cardiac symptoms or temperature > 38 °C) * regulation (if associated with cardiac
symptoms) *
* These side effects can lead to an acute life-threatening condition; consider urgent referral to A&E
†
May persist and indicate the development of myocarditis * or cardiomyopathy *
‡
Management of these side effects would usually be led by the local mental health team

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CLOZAPINE: reducing the risk of harm

Service users taking clozapine may present at your GP surgery with side effects of clozapine. These can generally be
managed symptomatically; however, some will require referral back to the CMHT.

Always inform the CMHT if a service user develops any suspected clozapine -related side-effects.

Clinically significant side effects

Agranulocytosis
Clozapine can cause neutropenia AND agranulocytosis.
• Be cautious if any signs or symptoms of a low white cell count are present; consider taking urgent FBC or
refer to A&E.
• Other drugs that cause neutropenia are contraindicated, see drug interactions below.
• Always report clozapine-associated neutropenia on a Yellow Card.

Constipation
Clozapine can cause constipation (commonly) and exacerbate drug-induced constipation. This can (rarely) lead to
intestinal obstruction, faecal impaction, and paralytic ileus. This can be fatal.
• Always ask about constipation in anyone taking clozapine.
• Always consider lifestyle factors in managing clozapine-associated constipation, e.g., improving fluid and
fibre intake, and exercise.
• Always actively treat constipation in anyone taking clozapine to prevent it from deteriorating.
• Avoid bulk-forming laxatives.
• Always assess anyone taking clozapine for constipation if they are also taking antimuscarinics, e.g., hyoscine
or pirenzepine (an unlicensed anti-muscarinic for hypersalivation), etc. Review the prescribed laxatives. Ask
the CMHT to review causative medication.
• If you are concerned about the risk of impaction or bowel infarction, immediately refer to A&E for (a
surgical) assessment.
• Always inform the CMHT of acute constipation and primary care actions.
• Always report clozapine-associated severe constipation on a Yellow Card.
Tachycardia
Tachycardia may persist and indicate the development of myocarditis or cardiomyopathy. Clozapine carries a serious
risk of myocarditis and cardiomyopathy particularly in the first two months of treatment.
• Always ask about signs and symptoms of tachycardia in anyone taking clozapine.
• Always inform the CMHT of tachycardia.

Hypersalivation
• Clozapine can cause profound hypersalivation, severely impacting the quality of life.
• Specialists often initiate an off label antimuscarinic like hyoscine (Kwells®) or atropine 1% eye drops (sub-
lingual) to help manage hypersalivation.
• Unlicensed pirenzepine is sometimes prescribed by the mental health trust with the clozapine .
• Always consider the impact these additional antimuscarinics will have on constipation.
• Refer to local guidance for advice on managing hypersalivation.
- Glycopyrronium is rarely used for clozapine-induced hypersalivation as it does not feature in mental
health treatment algorithms.
Seizure
• Clozapine can rarely cause seizures, typically at doses above 500 mg daily.
• Antiepileptic drugs used for prophylaxis or treatment include valproate, topiramate or lamotrigine.

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CLOZAPINE: reducing the risk of harm

• Always report clozapine-associated seizures on a Yellow Card.

Drug interactions
Commonly used antibiotics which are safer to co-prescribe, and antibiotics to avoid, are listed below.
This is not an exhaustive list.

CARE: It is essential to ensure that an antibiotic is not prescribed for an indication caused by an underlying
neutropenia; consider a routine FBC when prescribing antibiotics.
Antibiotics SAFE to prescribe Antibiotics to AVOID because they Antibiotics to AVOID because they
include can cause neutropenia include increase or decrease serum
clozapine concentrations include
Azithromycin Dapsone Erythromycin
Clarithromycin (Caution: QT Isoniazid Quinolones
prolongation) Metronidazole Rifampicin
Fusidic acid eye drops Nitrofurantoin
Penicillins Quinolones
Tetracyclines Rifampicin
Sulphonamides
Trimethoprim

Other drugs to use with CAUTION include Other drugs to AVOID include
Mirtazapine due to neutropenia risk and weight gain Carbamazepine
Topical and ocular chloramphenicol due to neutropenia Chemotherapy and cytotoxic agents
risk Carbimazole
SSRIs including fluoxetine, paroxetine, and fluvoxamine Chloramphenicol (non-eye-drop formulations)
due to increased and toxic serum clozapine
Depot antipsychotics
concentrations

• If the use of an interacting drug is unavoidable, please inform the CMHT urgently.
• Contact the CMHT urgently if your service user receives a diagnosis of cancer that will require
chemotherapy; the oncologist must liaise urgently with the consultant psychiatrist and mental health
pharmacist.

Non-Drug Interactions
Smoking: clinically significant
• Inhaled tobacco smoke (not nicotine replacement therapy or e -cigarettes) can significantly reduce clozapine
plasma concentrations and can lead to loss of efficacy.
• Stopping smoking can significantly increase clozapine plasma concentrations and can quickly lead to toxicity.

• Therefore, refer to the CMHT before the service user quits or cuts down smoking (including switching to
e-cigarettes). The CMHT can then modify the clozapine dose and arrange for the appropriate monitoring.
- This is especially important during acute in-patient stays where smoking is (temporarily) reduced or
stopped.

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CLOZAPINE: reducing the risk of harm

Caffeine
• Caffeine may interact with clozapine and can increase plasma clozapine concentrations; a corresponding
decrease in clozapine serum concentrations can occur after even a short caffeine -free period
• Advise service users to maintain a stable caffeine intake. Inform the CMHT of any changes
• Caffeine is found in coffee, tea, cola drinks, chocolate, and energy drinks such as Red Bull®,
Monster Energy®, etc.

Contact details for the community mental health teams

Cheshire and Wirral Partnership
Stein centre (where both CMHT’s are based in Wirral) 0300 3033157
Upton Lea 01244 397451
Cherrybank 0151 4888434
Vale House 01606 555103
Jocelyn Solly Resource Centre 01625 505600
Delamere Resource Centre 01270 655200

Mersey Care
If you are unsure which team the patient falls under then please contact the CCTT via email for further advice
Community Clozapine Titration Team (CCTT) [email protected]

Key Contacts and Clozapine Clinic / Health & Wellbeing Clinic Details
Clozapine Patient Monitoring Service (CPMS) 0845 769 8269 – have the patient’s details & CPMS
number ready
Denzapine Monitoring Service (DMS) 0333 200 4141 – have the patient’s details & DMS
number ready
Community Clozapine Titration Team (CCTT) [email protected]
Medicines Management Department (Maghull) Mersey Care, Hollins Park Pharmacy – 01925 629200
Dispensary – 0151 250 6061 / 6028 Hollins Park Hospital (1st Floor), Hollins Park, Winwick
Clozapine Dispensary – 0151 250 6169 Lane, Warrington
Medicines Information – 0151 250 6011
Medicines Management Building, Maghull Health Park,
Maghull, Liverpool

For all clozapine queries out of hours

Emergency Duty Pharmacist (via the Trust switchboard) 0151 473 0303
Emergency Medical Advice (via the Trust switchboard) 0151 473 0303
Crisis Resolution Home Treatment Team (24hrs) (via the Trust switchboard) 0151 473 0303

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Site Blood Test Clinic Location Day of Clinic Contact Number of Clinic
Knowsley Yew Trees, Capper Grove, Huyton Mon Knowsley Recovery Team
0151 290 4999
St Helens Harry Blackman House Tues, Wed & Thurs St Helens Recovery Team
01744 736708
Warrington Masefield Suite Hollins Park Tues, Wed & Thurs 01925 664826
Halton Runcorn Brooker Centre Tuesday 01928 753968
Widnes St John’s Unit Thursday 0151 422 6801
Sefton Clock View Hospital 2a Oak House Park, Mon, Tues & Wed 0151 330 7275
L9 1EP
North Liverpool Broadoak Unit Thomas Drive, L14 3PJ Mon, Tues & Wed 0151 250 5078
Southport Hartley Hospital 1b Curzon Road, PR8 6PL Mon and Tuesday 01704383086

Service user information about clozapine

• www.choiceandmedication.org/cheshire-and-wirral
• www.choiceandmedication.org/merseycare
• www.choiceandmedication.org/lancashirecaretrust

Prescribing information for clozapine

• Clozapine: https://www.medicines.org.uk/emc/search?q=clozapine
• Clozaril SPC: https://www.medicines.org.uk/emc/product/4411
• Denzapine SPC: https://www.medicines.org.uk/emc/product/6087/smpc
• Zaponex SPC: https://www.medicines.org.uk/emc/product/7715/smpc
• BNF: https://bnf.nice.org.uk/drug/clozapine.html

Contact details for clozapine manufacturers

• Clozaril Connect, Viatris’ portal,: https://www.clozaril.co.uk/ has professionals and service user resources
Tel: 0845 - 769 8269
• Denzapine’s portal: https://www.denzapine.co.uk/ Tel: 0333 - 200 4141
• Zaponex portal: https://www.zaponex.co.uk/ Tel: 0207 - 365 58 42

Bibliography
1. MHRA Drug Safety Update (October 2017). Clozapine: reminder of potentially fatal risk of intestinal obstruction,
faecal impaction, and paralytic ileus. [Accessed 3rd November 2020]
2. MHRA Drug Safety Update (August 2020). Clozapine and other antipsychotics: monitoring blood concentrations
for toxicity. [Accessed 02 February 2023]

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