Download Clozapine Guidelines - Southern Health NHS Foundation Trust

SH CP 114
Clozapine Guidelines
(including clozapine initiation both inpatient and community, long term
monitoring and treatment, actions following a red result and GP
reference guide)
Version: 2
Summary:
The UK product licence of Clozapine (Clozaril®) allows for
initiation as an inpatient or outpatient with intensive
community support.
Keywords (minimum of 5):
(To assist policy search engine)
Clozapine, Clozaril, initiation of clozapine, restarting
clozapine, blood tests, red results, smoking, clozapine GP
guide, treatment resistant schizophrenia
Target Audience:
All Mental Health Practitioners involved in clozapine use.
Next Review Date:
October 2018
Approved & Ratified by:
Medicines Management
Committee
Date issued:
October 2016
Author:
Stephen Bleakley: Deputy Chief Pharmacist
Rebecca Henry: Senior Clinical Pharmacist
Clozapine Clinic Lead Nurses
Sponsor:
Dr. Lesley Stevens, Medical Director
Date of meeting:
6th July 2016
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Clozapine Guidelines
Version: 2
October 2016
Version Control
Change Record
Date
Author
Version
September
2016
Rebecca
Henry
2
Page
Reason for Change
Policy Review
Reviewers/contributors
Name
Medicines Management Committee
Medicines Management Team
Medicines Management Committee
Position
Version Reviewed &
Date
Version 1, April 2014
Version 1, April 2014
V2 July 2016
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Clozapine Guidelines
Version: 2
October 2016
Contents
Page
1.
2.
3.
4.
5.
Summary of the Initiation of Clozapine
Criteria for Acceptance
Responsibilities of the consultant
Responsibilities of the care coordinator
Treatment Programme
Restarting Clozapine following an unplanned discontinuation
Further reading
4
5
5
6
7
9
9
Appendices
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Potential side effects
Clozapine initiation form
Baseline physical health monitoring
Clozapine physical monitoring sheet
Clozapine in the community contact monitoring sheet
Guidelines for the management of a red clozapine result
Smoking Cessation
Suggested GP letter
Shared care guideline
Clozapine initiation prescriptions
Clozapine outpatient prescriptions
Blood monitoring form
On-going physical health monitoring parameters
Clozapine clinic monitoring form
Information check list for patients on clozapine
Re-challenge to Clozapine following a red result
Changing Clozapine brands
Clozapine side effect rating scale (GASS-C)
Clozapine GP information leaflet
10
11
13
14
18
23
28
30
31
36
40
41
42
44
45
47
51
52
53
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SUMMARYOF THE INITIATION OF CLOZAPINE (for both in-patients and out-patients)
The MDT is in agreement that clozapine is appropriate and in the best interest of the patient

Give patient/carer appropriate information.
Obtain valid consent and record in patient’s records, or obtain second opinion.
Obtain new T2 or T3 if needed

Review current medication and medical conditions to ensure that it is appropriate to start clozapine. Record smoking status
.

Take initial blood tests (FBC). Complete baseline physical health monitoring (appendix 3).
Complete patient registration form and fax it to the Clozaril Patient Monitoring Service (CPMS) or Denzapine
Inform clozapine clinic, pharmacy department, GP, AMHT and the ward team as appropriate.
Write relevant clozapine-related care plans to include monitoring requirements and specific information regarding relevant
medical conditions.

Green blood result – clozapine can be started
If not seek advice from the CPMS/DMS and SHFT Pharmacist

Complete initiation forms and baseline monitoring (see appendix 2 and 3 ), send to AMHT with referral if appropriate.

(Start within 10 days of initial blood test)
Prescribe dose at 12.5mg daily, at night for inpatients and in the morning for community patients, and then follow the titration
chart (appendix 10).
Avoid increasing the dose when there is no medical cover (e.g. at weekends and bank holidays) Obtain supply of clozapine
from the pharmacy. Inform the nursing team of the titration schedule.

Day 1
Observations –see appendix 5 (pulse, temp, respiration and lying down and standing BP) three times, at baseline and ideally
at 2 and 6 hours post dose and for community patients, four contacts in all (the other contact may be by phone)

Day 2
Observations before the morning dose is given, ideally 2 and 6 hours post dose and for community patients an additional
phone contact.

Day 3 to 7
Repeat Blood test (weekly thereafter in line with local procedures) Include Trop T or I and C-reactive protein for the first
month.
Observations twice daily, before the morning dose and 6 hrs post dose and 3 contacts in all (1 phone contact)

Day 8 to 14
Observations once daily and community patients three contacts in all (2 phone contacts)

Day 14 Onwards
Daily observations to continue until there are no unacceptable side effects and the dose is stable

Stable dose
Inform clozapine clinic and community team if appropriate and CPMS if changing teams or consultant.
For ongoing monitoring see appendix 12 Full physical health check at 3 months, 6 months and then annually including RIO
physical health questionnaire. Ensure GP is aware of ongoing clozapine prescription, refer to GP brief reference guide.
Update care plan. Enter all results and communications in the electronic patient record.
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Guidelines for Initiating Patients on Clozapine
(including reinstating clozapine after non-compliance)
The UK product licence of Clozapine (Clozaril®) allows for initiation as an inpatient or outpatient with
intensive community support.
1.
Criteria for Acceptance
1.1
The patient is willing and able to accept the required level of physical health monitoring and attend
necessary appointments either as an inpatient or outpatient.
1.2
The patient must be willing and able to accept regular blood tests
1.3
The patient fulfils the standard licensed product criteria for receiving clozapine. The use of
clozapine outside of the product’s licence will be at the responsible clinician’s discretion and
should be documented in the medical notes.
1.4
Patients with medical co-morbidities may require increased monitoring to identify any change in
their condition and each patient should be considered on an individual basis. Proceed with
additional caution (i.e. slower dose titration and increased monitoring) in adolescent and elderly
patients. The results of a baseline tests and ECG should be recorded in the patient’s records. If
the patient has any complications the risks versus benefits needs to be considered and the
option, if they are in the community, to admit the patient for intensive monitoring be considered.
1.5
If the patient has a history of previous problems particularly respiratory, cardiac or seizures,
associated with clozapine initiation inpatient titration should be considered
1.6
Community patients should have a carer willing and able to monitor the patient particularly at
night and at weekends. Where there is no such carer the team may come to the conclusion
that involvement of the community team with their prior agreement, will suffice. Every effort,
however, needs to be made to acquire a suitable carer to ensure maximum safety. Record
details in the patient’s records.
2.
Responsibilities of the consultant
The patient’s responsible clinician must ensure:
2.1
That it is in the patient’s best interests to initiate clozapine. The decision to start the patient in the
community will need to be made by the team and agreement by all parties sought.
2.2
That they are satisfied that the patient has given valid consent to commencing treatment.
Consent is valid when




2.3
The patient has been given information about the treatment in a form that can be
understood including information about possible side effects, the likely consequences of not
having the proposed treatment and the pros and cons of any alternative treatment.
The patient has the capacity to make the decision about their treatment.
The patient has the freedom to make a choice.
An entry in the patient’s records confirming this has been carried out.
A doctor from the prescribing team is readily available to give advice to the community or inpatient
staff.
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2.4
Existing medication is reviewed and it is appropriate to start clozapine.
Some drugs will need to be discontinued (for example carbamazepine and antipsychotic depot
injections) before clozapine initiation.
2.5
The doctor must ensure the following are informed, and document





The patient’s G.P, supply GP with information on clozapine (see appendix 19 for the GP
reference guide), start date and emergency contact numbers, before initiation for community
patients and after discharge for inpatients.
All appropriate members of the mental health care team, including care co-ordinators.
AMH team if appropriate.
The appropriate supplying Pharmacy Dept.
The appropriate Clozapine Clinic Nurse/Clozapine nurse (if in post).
2.8
For community patients the responsibility remains with the community consultant. They may need
to negotiate/coordinate with the AMHT or inpatient consultant.
2.9
Ensuring the prescription chart is complete. This will be an in-patient drug chart or the community
clozapine chart (see appendix 11). Both will need regular review and re-writing in a timely
manner.
3.
Responsibilities of the care coordinator
3.1
When making the decision to proceed with clozapine initiation in the community or in-patient
wards the care coordinator or senior nurse in the team will identify staff competent to monitor the
patient’s physical health (see appendix 4). This includes blood pressure, temperature, pulse,
respiration and weight.
3.2
All nurse/practitioners involved must be familiar with:

Potential side effects of Clozapine and how these present.

The information that the patient will need about taking Clozapine (see
www.choiceandmedication.org.uk/southernhealth ).

The treatment programme.

The Clozaril Summary of Product Characteristics. The up to date version is available from
www.medicines.org.uk.

Physical health monitoring required while on clozapine and what to do if concerned about
any results.
3.3
It is the role of the nurse/practitioners to.

Monitor and report the development of any side effects.

Observe and report the patient’s progress and discuss management with the Consultant or
available physician. It may be helpful to refer to the document ‘Potential side effects ’
(Appendix 1).

Provide information and support to the patient and carers including patient information
leaflets.

Document all discussions and observations on the electronic patient record (RIO).
3.4
Nurse/practitioners should confirm information has been given and understood by the patient and
carer if appropriate. This is to include:

Common side effects and what to do if they occur

The importance of not travelling alone or driving for at least 2 weeks (due to a small but
known risk of collapse).
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





The signs of neutropenia including sustained temperature elevation with flu like symptoms
or a sore throat.
Why regular blood tests are essential.
Why you are taking regular observations.
Breaks in treatment. If stopped for longer than 48 hours the dose must build up again from
12.5mgs. See section 5.1 for further information. If more than 72 hours, blood tests will need
to go back to weekly for at least 6 weeks.
Provide the patient with the patient information leaflets.
The importance of informing anyone else treating him/her that they are on clozapine.
3.5
With community patients it is the role of nurse/practitioners to ensure that the patient and carer
know when and who to notify should problems arise both within normal working hours and
out of hours. If the patient decides to stop clozapine, the nurse must ensure that the patient
discusses this decision with the Consultant. To reduce the risk of rebound psychosis and
discontinuation symptoms the medication should be reduced slowly.
4.
Treatment Programme
4.1
When a decision is made to initiate clozapine, there must be a clear care plan written to ensure
close monitoring of any underlying medical conditions.
4.2
A time is set to take the initial blood test in order to register the patient with the Clozaril Patient
Monitoring Service (CPMS). Within ten days of the initial satisfactory blood test a date needs to
be set to start treatment. For community patients the start date of the treatment should ideally be
on a Monday (non-bank holiday weeks) to maximise the time available for professionals working
9-5, weekdays. Following the initial blood tests the patient should be registered with the CPMS.
4.3
Arrangements should be made for the blood tests to be taken at the Clozapine Clinic, by inpatient
staff or at the local medical hospital. For community patients the nurse/practitioner or care coordinator should ensure that someone accompanies the patient to these appointments initially.
4.4
On the third day of treatment a further blood test should be taken and the results sent/reported
back to the CPMS. Within a week of the second blood test a further blood test needs to be taken
4.5
The prescription should be written and sent (delivered or faxed) to pharmacy for supply.
Clozapine tablets cannot be supplied without a prescription and a green blood result.
After the initiation is complete and the patient discharged, from hospital or AMHT, an outpatient
prescription will be required, this is to be organised by the co-ordinating nurse or clozapine clinic.
4.6
The initial dose should be 12.5mgs, either given at a time to allow monitoring during working
day or taken last thing at night. If tolerated the dosage should be doubled. Thereafter dose
titration will need to be adjusted in accordance with the patient’s response to treatment. See
appendix 10 All medication given should be documented. Dose increases for outpatients
should not take place when there is no medical cover e.g. weekends and bank holidays, in
some areas.
4.7
During the first day observations (B.P lying down and standing, respiration, pulse and
temperature) should be undertaken as a baseline before the dose is given and then twice
daily, ideally two hours and six hours after the initial dose. There is no need to monitor the
patient after the night time doses. For community patients there should be at least 4 contacts three face-to-face during observations and at least one telephone contact ensuring contact is
distributed evenly throughout the day. Contacts should ascertain the patient’s general
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condition and report and document any side effects. If either the contacts or observations
indicate a cause for concern the team or on call doctor should be contacted to discuss
management. If there is a sustained rise (e.g. two successive measurements) in temperature
or other concerns about pulse, respiration, blood pressure or other side effects a report should
be made to the doctor. Observations should be documented on the track and trigger tool and
RIO.
4.8
On the second day, observations should be done three times - before the dose is given, then
two and six hours after the morning dose is given. For community patients there should be four
contacts in all.
4.9
For the remainder of the week observations should be made at twice a day, before the morning
dose is taken and ideally 6 hours after. For community patients four contacts should be made on
each day.
4.10
For the second week of treatment, three contacts should be made and observations made at
least once but ideally twice a day. After two weeks of treatment a medical review should take
place and future management decided. If there have been unacceptable side effects, or until the
dose is stable, the observations should remain daily – ideally two hours after the morning dose. It
may be appropriate for the patient to attend the clozapine clinic for weekly tests and for the
prescription to be made available to the patient in the usual way.
4.11
When the patient is on a stable dose the observations should be weekly for the first 18 weeks
then 3 monthly, full physical health check at 3 months, 6 months and then annually, including
RIO Physical Health questionnaire (see appendix 13).
4.12
Appendix 4 and 5 can be used as prompts and for data collection, but all observations must be
entered on RIO
4.13
The track and trigger tool should be used, and the results entered on RIO.
4.14
All forms should be available to all staff/teams involved in the patients care.
4.15
Clozapine titration for adolescents is slower than that recommended for adults to minimise
side effects and twice daily monitoring should continue until a therapeutic dose is reached. The
titration should pause when the dose is 150mg daily and a clozapine blood level taken.
Although side effects and monitoring of clozapine are generally the same in both adult and
adolescent populations there are some reports of a higher seizure risk in those under 16. EEG
monitoring (baseline and once the dose is stabilised) should be considered for any patient
under 16 receiving clozapine.
4.16
Clozapine is available as several different brands. In Southern Health we provide Clozaril tablets
and Denzapine 50mg/ml suspension. They presently require separate registration and monitoring.
See appendix 16 for procedures for changing brands.
4.17
Denzapine suspension must be shaken well for 90 seconds before administering and it can be
diluted with water. It should not be transferred from the manufacturer’s original container.
Pharmacy will supply whole containers for ward patient stock and if it is essential to supply smaller
quantities for a short term leave TTO pharmacy will supply an overage.
Clozapine and Denzapine are therapeutically equivalent but require different registration.
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5.
Restarting Clozapine following an Unplanned Discontinuation
Once clozapine has been discontinued the plasma level drops very quickly. Based on an average
half-life between 7 to 14 hours after 35-70 hours (5 times the half-life) there will be no detectable
clozapine left. Along with the rapid decline in plasma levels the tolerability to the side effects
rapidly declines. Patients who have had no clozapine for 48 hours (taken from the last dose
given) should be re-titrated from 12.5mg per day, as above. The speed of the titration depends on
the original acceptance and tolerability of clozapine, however it should be noted that a slow
titration is preferable to prevent adverse reactions. Hypotension, tachycardia, seizures and
drowsiness are particular risks when re-starting clozapine.
5.1
Novartis On/off treatment-assessment guidelines
The time off clozapine is taken from the last dose administered.
For clozapine patients on weekly white cell count monitoring
Monitoring
frequency
OFF clozapine
for less than 48
HRS
OFF > 48HRS
BUT < 7 DAYS
OFF for
7 DAYS OR
MORE
Weekly
No change to
blood monitoring
frequency.
Continue as
normal
No change to
monitoring
Re-titration dose
as per initial
titration.
Restart the 18
weeks of weekly
monitoring. Retitration dose as
for initial titration
For clozapine patients on fortnightly or 4 weekly white cell count monitoring
Monitoring
OFF <48 HRS
OFF > 48HRS
OFF 4 DAYS
frequency
BUT < 4 WHOLE OR MORE
DAYS
BUT< 28
WHOLE DAYS
Fortnightly and
4 weekly
No change to
monitoring
frequency.
Continue as
normal
No change to
monitoring
frequency
Re-titrate dose as
per initial titration.
TREATMENT
BREAK
Weekly for 6
weeks and then
back to previous
monitoring
frequency. Retitrate dose.
OFF
> 28 DAYS
Restart 18
weeks of weekly
monitoring. Retitrate dose.
Further reading
Bleakley S, Taylor D. Clozapine Handbook 1st Edition. Malta: Lloyd-Reinhold Communications
2013 (www.clozapine.co.uk)
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Appendix 1: Potential side effects
This list is not exhaustive. More information can be obtained from the Clozaril Patient Monitoring
Service or clozapine handbook. Seek advice if you are unsure. Be cautious when prescribing
other medicines with similar side effects to clozapine.
Constipation
Tachycardia
Pyrexia
Seizures
Drowsiness
Hypersalivation
Hypotension
Weight gain
Cholesterol check
Diabetes check
Blood disorders
Usually persists, adjust diet, high fibre and adequate fluid. Give a bulk-forming and stimulant
laxative if needed. Ensure adequate fluid intake. Constipation should not be ignored, it can
be rapidly fatal. Review other medications which may cause constipation.
Very common in early stages of treatment, but usually benign. Tachycardia, if persistent at
rest and associated with fever, hypotension or chest pain, may indicate myocarditis. 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.
Refer to a cardiologist urgently. Clozapine should be stopped if tachycardia occurs in the
context of chest pain, heart failure or raised Trop I or T or CRP.
Temperature above 38 degrees C is often normal in the first three weeks of treatment.
However, a blood sample should be taken to exclude agranulocytosis and exclude causes of
infection. Paracetamol may be beneficial. Beware myocarditis and neuroleptic malignant
syndrome.
Especially with rapid dose titration and high clozapine levels/ doses. Stop clozapine for 24
hours. Restart at half the original dose. Consider adding sodium valproate or lamotrigine.
Refer for EEG and neurological examination if appropriate. May be more common in those
under 16 years old.
This is usually within the first four weeks, but may persist. Can be managed by giving more
of the dose at bedtime and increasing the dose more slowly.
Appears early on in the treatment, may persist and may be worse at night. If troublesome
consult doctor/pharmacist. Hyoscine hydrobromide is usually an effective treatment either as
the tablets (Kwells 300-900mcg at night or in divided doses) sucked or chewed or patches
(1.5mg every 72 hours). An alternative pirenzepine 50-150mg at night or in divided doses
(unlicensed).
Usually occurs in the first four weeks. Instruct patient to stand slowly; support stockings may
be of use. Split the dose, with a larger proportion at bedtime, slow the titration or reduce the
dose
Can significant. Give advice about exercise and diet. Refer to dietician. It’s easier to
minimise weight gain over the first few months than try to lose it afterwards.
Full lipid profile including triglycerides, ideally fasting, after 1, 3 and 6 months, and then every
6 months. Treat if necessary.
Plasma glucose, ideally fasting, after 1, 3 and 6 months, and then every 6 months. Treat if
necessary.
Reduction in white blood cells occurs in 3% of people exposed to clozapine. More common in
the first year of clozapine treatment. The white blood cell count monitoring is a mandatory
requirement of prescribing and supplying clozapine.
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Appendix 2: Clozapine initiation checklist
File in secondary notes
Patient details
Name
Address
Consultant
GP name:
Care coordinator
Date of birth
/
Hosp/ NHS No.
Tel No.
/
Tel no:
Tel no:
Care-coordinator or named nurse
Sign, date and give details as required
Baseline physical health monitor is complete
(appendix 4)
Patient
information
leaflet
given
(see
www.choiceandmedication.org/southernhealth)
For community patients a carer has agreed to be Name:
involved in the programme
Contact no:
For community patients document the Name and Name:
contact no. of team doctor who will be available Contact no:
throughout treatment programme.
CPMS Reg no
CPMS No:
Date of first blood test (must be within 10 days prior to
start date).
Hospital Pharmacy informed
Clozapine clinic nurse informed, if applicable
Doctor
Sign, date and give details as required
Patient fulfils standard criteria for receiving clozapine.
Patient has had a review of medical co-morbidities
including history of epilepsy, cardiovascular, renal and
hepatic disorder. Risk vs benefits considered
Baseline ECG performed. Please specify.
Patient has no history of other medical problems
associated with clozapine. Please specify
Medication reviewed
Does the patient have a history of any adverse
reactions to antipsychotics? Please specify.
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Has consent or SOAD authorization been obtained
and documented?
Entry in records made with regard to patient
consenting to treatment
Complete baseline physical health monitoring
(appendix 3)
Write prescription and obtain medication from hospital
pharmacy. Do not increase dose over the weekend if
there is no medical cover.
Dates of planned consultant appointments during
titration, if known
Inform patient to consult with their psychiatrist before
driving and that DVLA will need to be informed.
GP informed of clozapine initiation and ongoing
prescribing. Have they been sent a copy of the GP
clozapine guidelines?
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Appendix 3 Baseline physical health monitoring
To be completed pre Clozapine, no more than one month prior to initiation,
(reproduced with permission from Clozapine Handbook 1st edition, 2013).
File in secondary file
Monitoring parameters
Sign /
date
Blood Pressure (lying down and standing)
Pulse
Temperature
Respiratory rate
Urea and electrolytes (including eGFR)
Full blood count (WBCs, Neutrophils, Eosinophils)
ECG
Blood lipids, ideally a fasting sample (full lipid profile including triglycerides)
Troponin T or I (depending on what is available at the local lab)
C-reactive protein
Weight (including BMI, and abdominal circumference)
Plasma glucose (fasting sample ideally)
Liver Function Tests (ALT, AST, bilirubin, albumin, prothrombin) Fasting sample ideally.
EEG (Under 16s only)
Investigate potential problems with prescribed, purchased or herbal medication, illicit drugs and
alcohol.
Record current smoking status, caffeine intake, lifestyle and diet.
Investigate for any previous history of blood disorders, seizures, DVTs, PEs, cardiac, bowel or
bladder dysfunction, glaucoma, OCD and liver or renal impairment.
Record physical health information on electronic record.
Signed By Doctor or Nurse
Date
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Appendix 4: Clozapine Physical Monitoring Sheet (to be kept with medication chart). The track and trigger tool may be used
in place of the monitoring sheet but the frequency of monitoring should be the same.
Patients name
CPMS no:
Clozapine start date
Baseline observations
Temp:
Pulse:
Hospital/NHS No.
time:
date:
BP (standing):
Wt…………… Height............BMI………
BP standing / lying:
Respiration:
During initiation: Omit if temperature >38.5’C, postural drop >30mmHg or pulse > +/- 15% baseline, and inform the
Doctor.
Observations
Day (use the
morning
dose where
possible)
Date
Time
Temp
Pulse
Respiratory Lying
rate
BP
(normal
rate 12-18
breaths per
minute)
Standing
Other side effects,
BP
particularly flu like
symptoms,
hypersalivation,
palpitations, chest
pain, constipation
Outcome if Dr
informed
Sign
1
Before dose
2hrs post, if
awake
6hrs post, if
awake
2
Before dose
2hrsafter
dose
6hrs after
dose
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Day (use the
morning
dose where
possible)
Date
Time
Temp
Pulse
Respiratory Lying
rate
BP
(normal
rate 12-18
breaths per
minute)
Standing
Other side effects,
BP
particularly flu like
symptoms,
hypersalivation,
palpitations, chest
pain, constipation
Outcome if Dr
informed
Sign
3
Before dose
6hrs after
dose
4
Before dose
6hrs after
dose
5
Before dose
6hrs after
dose
6
Before dose
6hrs after
dose
7
Before dose
6hrs after
dose
8
9
10
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Day (use the
morning
dose where
possible)
Date
Time
Temp
Pulse
Respiratory Lying
rate
BP
(normal
rate 12-18
breaths per
minute)
Standing
Other side effects,
BP
particularly flu like
symptoms,
hypersalivation,
palpitations, chest
pain, constipation
Outcome if Dr
informed
Sign
11
12
13
14
15
16
17
18
19
20
21
22
23
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Day (use the
morning
dose where
possible)
Date
Time
Temp
Pulse
Respiratory Lying
rate
BP
(normal
rate 12-18
breaths per
minute)
Standing
Other side effects,
BP
particularly flu like
symptoms,
hypersalivation,
palpitations, chest
pain, constipation
Outcome if Dr
informed
Sign
24
25
26
27
28
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Appendix 5: Clozapine in the Community Contact Monitoring Sheet (to be kept with medication chart)
Patients name
CPMS no:
Clozapine start date
Baseline observations
Temp:
Pulse:
Contacts
Day
1
Date
Hospital/NHS No.
time:
date:
BP (standing):
Time
Wt…………… Height............BMI………
BP (lying):
Respiration:
Contacted by
Method
Outcome
2
3
4
5
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Day
Date
Time
Contacted by
Method
Outcome
6
7
8
9
10
11
12
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Day
Date
Time
Contacted by
Method
Outcome
13
14
15
16
17
18
19
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Day
Date
Time
Contacted by
Method
Outcome
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21
22
23
24
25
26
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Day
Date
Time
Contacted by
Method
Outcome
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Appendix 6: Guidelines for the management of a red clozapine result.
1) Background information:
The CPMS categorise blood results according to the following colour-coded
system:
Colour alert
WBC count x 109/L
Neutrophil count x
109/L
Green
> 3.5
> 2.0
Amber
3.0 – 3.5
1.5 – 2.0
Red
<3.0
<1.5
If a patient has an amber blood result, a full blood count must be performed twice
weekly until the blood count stabilizes in this range or increases.
2) Management of a Red Alert:
If a patient’s WBC is less than 3.0 x 109 /L and/or the neutrophil count is
less than 1.5 x 109/L, this is known as a red alert and the following action
must be taken:







STOP CLOZAPINE TREATMENT IMMEDIATELY.
Check the patient for any signs of infection (refer to details below) and
contact the CPMS as soon as possible.
Make arrangements to undertake confirmatory blood counts on the 2 days
following the date of the red alert sample. If either of these follow up blood
counts is in the red alert range then red alert status is taken to be
confirmed.
If the red alert is confirmed, THE PATIENT MUST NOT RESTART
CLOZAPINE TREAMENT.
Full blood counts with differential white cell counts must be performed
DAILY whilst the blood counts remain in the RED range, and the patient
must be observed closely for infection (e.g. sore throat, fever). The results
should be reported to the CPMS as soon as they are available.
If antipsychotic medication is considered essential, use agents with low
potential to cause neutropenia and avoid depot preparations.
Review all other medication. Consider stopping those agents with
potential to adversely affect neutrophil counts. If necessary, introduce a
more appropriate alternative.
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If a patient’s neutrophil count falls to less than 1.0 x 109/L or the WBC falls
to less than 2.0 x109 /L OR if the patient develops a fever, please observe
the following additional recommendations:
It is extremely important to contact a specialist haematologist, or failing this,
a general medical physician, regarding the most appropriate treatment for the
patient. This will probably involve transferring the patient to a ward with facilities
for the care of neutropenic patients.
If unable to contact the hospital
haematologist immediately, please refer to the guidelines below:




Check the patient’s temperature, blood pressure and pulse FOUR hourly.
Nurse patient in a single room, taking care to wash hands before and after
contact with the patient, wear aprons etc.
Avoid salads, yoghurt, unpeeled fruit, paté or soft cheese in the patient’s
diet. Give sterilised milk, water or canned drinks. Remove flowers from
the patient’s room.
Give patient an antibacterial and antifungal mouthwash prophylactically
(eg. chlorhexidine 10mls QDS and nystatin suspension 1ml QDS )
Granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage
colony stimulating factors have been used in the management of clozapine
induced agranulocytosis although this is not a licensed indication. The cost of
such drugs if used will be reimbursed by CPMS.
Effect of sudden discontinuation of clozapine:
When a patient has a red alert it is essential to stop clozapine immediately. This
sudden cessation of treatment can lead to physical and mental withdrawal effects
which may occur within 2 – 3 days and usually within the first 2 weeks. Patients
may experience a rapid deterioration in their mental state with rebound
psychosis. In addition, abrupt withdrawal of clozapine has been associated with
symptoms such as nausea, vomiting, diarrhoea, headache, restlessness,
agitation and sweating and it has been suggested that these are a result of
cholinergic rebound since clozapine has strong anticholinergic action.
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SOUTHERN HEALTH NHS FOUNDATION TRUST
GUIDELINES FOR THE MANAGEMENT OF A RED CLOZAPINE RESULT
LOCAL PRACTICAL ACTION
A pharmacist is available at CPMS 24 hours a day, for the provision of patient
specific pharmaceutical advice.
o Telephone number 9am – 5pm Monday to Friday: 0845 7698269 option 2
o Out of hours service: 01276 692504
1.
ACTION
Ensure the patient’s consultant, care coordinator and the
clozapine clinic staff are aware of the red result and
management implications as soon as possible and discuss
and determine an individual care plan on RIO for
monitoring bloods mental and physical health and review
of medication. For out-patients, inform the patient’s GP.
2.
Ensure that all involved are aware of contact details and
are in receipt of these guidelines.
3.
Care coordinator to ensure that adequate systems are in
place so that the:
3.1
Patient does not receive any more clozapine until advised
that this can be reintroduced by the CPMS. If the patient
is off clozapine for more than 48 hours, this will need
to be retitrated.
3.2
Patient is monitored for mental state (possibility of rebound
psychosis following abrupt clozapine withdrawal).
3.3
Patient is monitored for any physical health problems
including temperature as they will be less able to combat
these due to the low white cell count.
3.4
ACTION
Arrangements are in place for daily full blood count tests
which will need to be analysed as soon as possible and the
results phoned through to the CPMS. Doctor on call
should do bloods if out of hours There will need to be at
least 2 days worth of daily follow up blood tests; these will
continue until advised by the CPMS that they are no longer
required (at least 2 consecutive non red results).
SIGNATURE
DATE
SIGNATURE
DATE
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3.5
The team responsible for care over a weekend has
available the patient’s full notes, including up to date risk
assessment, details of current medication, a description of
the patient and emergency contact details (eg next of kin),
on-call services at group homes.
3.6
In order to facilitate all of the above, for patients for whom
admission is not appropriate or necessary and where
follow-up is needed over the weekend, is likely to be the
most appropriate course of action. This team will then
need to liaise with the on-call duty doctor to ensure the
daily blood tests occur at a suitable time and venue on
each day.
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Appendix 7: Smoking Cessation – Effect on Clozapine
Summary.
Smoking increases the clearance of clozapine thus smokers will often require more
clozapine than non-smokers. Stopping smoking can dangerously increase clozapine
levels. During smoking cessation the clozapine dose will need reducing.
Background.
The hydrocarbons in tobacco smoke induce the production or activity of various liver
enzymes, in particular cytochrome CYP1A2, an enzyme associated with the metabolism of
several psychotropic drugs including clozapine. Therefore, in response to smoking
cessation it is possible that the metabolism of these drugs will decrease and plasma levels
will rise. This is particularly the case for clozapine where it is possible that plasma levels
may be elevated to toxicity.
Note – CYP1A2 activity is affected by hydrocarbons and not by nicotine. Therefore
nicotine replacement therapy (NRT) will not alliterate the clozapine vs smoking interaction.
When stopping smoking while receiving clozapine, clozapine levels may rise by as much
as 50-70%.
For clozapine:
1. Review preadmission (outpatient) serum clozapine levels (if available) and order a new
baseline serum clozapine level as soon as practicable. (Note – no ‘call-out’ is required,
as dose reduction need not be immediate. Arrange bloods in normal ‘office hours’).
2. Review side-effects history and, if possible, check against the serum clozapine levels
at which they occurred.
3. Assess the risk of toxicity (i.e. if level exceeds 1000mcg/l) by using the non-smoking
serum clozapine level using the formula below if appropriate :
Serum clozapine (Non-smoker) = [1.5 x Serum clozapine (Smoker) ] + 50
eg. smoking level of 500mcg/l gives a non-smoking level of 800mcg/l
nb. The formula is considered to give a suitably accurate result in approximately 80% of cases.
However, in patients with higher smoking clozapine levels or doses, (eg. above 700mcg/l or
above 700mg daily), the CYP1A2 enzyme may have been saturated resulting in much higher
rates of metabolism. Greatly increased levels may then occur in these patients when they stop
smoking and the formula may be wildly inaccurate.
4. Set a target (non-smoking) serum clozapine level, taking into consideration the patient’s
current condition and clinical response to current dose / level. If indicated, adjust the clozapine
dose accordingly. (Note – if compliance has been poor prior to admission, the baseline level
may be artificially low. This should be taken into consideration).
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eg.
Smoker admitted on clozapine 600mg daily and serum level found to be 480mcg/l. Compliant
with medication but clinically unwell on this dose and considered to need a higher level.
Estimated serum level on cessation of smoking is (1.5 x 480) + 50 = 770mcg/l. If clinician
considers that a target serum level of 770mcg/l is appropriate then no adjustment of dose
may be necessary. However, if it is felt that the target level should be in the region of
600mcg/l, then the patient’s dose may need reducing to 350mg or 375mg daily.
5. Necessary reductions in daily dose should be made at a rate of approximately 10% per
day.
6. Monitor serum clozapine level at day 3 and then weekly (until stabilised to target
level). Also, pre-discharge level (unless done in previous 48 hours).
7. Monitor for adverse effects – bearing in mind that some may take as long as 2 to 3
weeks after adjustment of dose to become apparent.
8. On discharge or leave, reassess patient’s likelihood to recommence smoking and the
potential reduction in serum clozapine level in response. If this occurs it is likely that the
clozapine dose will have to be increased.
9. Post-discharge, monitor serum clozapine level once each week, (or fortnightly if total
dose change was less than 20%), until stable.
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Appendix 8: Suggested GP letter
Add team address
Dear Dr.....
Re: patient’s name
Address
DOB.
The above patient is prescribed clozapine at ...
mg/day and is under the care of Dr...
(consultant psychiatrist) based at ………………..,.. Clozapine prescribing and supply is
retained by secondary care mental health services but we would recommend you add an
alert to the patient’s primary care file as clozapine can have profound effects on physical
health.
A full white blood cell count is currently taken at ………………….every…………week(s)
A full physical health check is carried out at………………………every….. months.
Clozapine can present risks to physical health and requires close monitoring. Side effects
include constipation, blood disorders, tachycardia, sedation, hypersalivation, hypotension,
cholesterol changes, diabetes and weight gain (please see the clozapine risk management
guidelines for further information). We would be grateful if you would share any concerns
you have about the patient’s physical health with our team. In addition clozapine has many
important drug interactions (e.g. stopping or starting smoking, antidepressants, drugs
which can affect white blood cells, other antipsychotics etc).
If the patient reports any of the following symptoms, please contact our team or the
Clozaril Patient Monitoring Service on 0845 7698269 immediately as further blood tests/
monitoring may be required.




Breathlessness
Flu like symptoms
Any symptoms that may mimic heart problems
Tachycardia
Should you have any questions or concerns with this patient or their Clozapine
prescription, do not hesitate to contact either Dr......... or …………………….Community
Treatment Team.
Yours sincerely
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Appendix 9: Shared care guidelines: Information for the GP
Clozapine Risk Management Guidelines for
Primary and Secondary Care
Name of patient treated under this guideline:
This shared care guideline has been produced to support prescribing and monitoring of
patients between secondary and primary care, and provides an information resource to
support clinicians providing care to the patient. It does not replace discussion about
sharing care on an individual patient basis.
This guideline was prepared using information available at the time of preparation, but
users should always refer to the manufacturer’s current edition of the Summary of Product
Characteristics (SPC or “data sheet”) available at www.medicines.org.uk
1.0 Status of Clozapine
Clozapine (Clozaril®) is a red drug. This means that treatment will be initiated and retained
by secondary care. However, because of the extensive adverse reactions, interactions and
monitoring of clozapine it is essential for all GPs to be fully aware which of their patients
are receiving clozapine and the relevant prescribing issues.
2.0 Indications and Dose
Clozapine is indicated for treatment-resistant schizophrenia and in schizophrenia patients who
have severe, untreatable neurological adverse reactions to other antipsychotic agents.
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 is also indicated in psychotic disorders occurring during the course of Parkinson's
disease, in cases where standard treatment has failed.
3.0 Referral Criteria
Not applicable. Clozapine will only be initiated in secondary care.
4.0 Patient Selection
Not applicable. Clozapine will only be initiated in secondary care
5.0 Safety Issues
Clozapine (Clozaril®) is a very effective atypical antipsychotic used when other treatment
strategies have failed. Approximately 3% of patients treated with clozapine will develop
neutropenia (around 1% will progress to agranulocytosis) which makes them vulnerable to
serious infections. Detection of neutropenia is achieved by regular haematological
monitoring, through the Clozaril Patient Monitoring Service (CPMS).
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All patients receiving clozapine must be registered with the CPMS and monitored for the
complete duration of therapy. In the event of an abnormal blood result the CPMS will
contact the psychiatric team immediately to request an additional blood sample if
necessary.
The patient, and if appropriate their carer, should regularly be reminded to remain vigilant
for any signs of infection, e.g. fever or sore throat, which may indicate the presence of
neutropenia. While it is unlikely that such symptoms are related to the development of
clozapine-induced neutropenia, an immediate full blood count (WBC and neutrophil counts
are required) will be necessary to exclude the possibility. Patients should be advised to
contact their GP, or hospital team, if they experience signs of infection. If neutropenia is
confirmed the patient must immediately be referred to the consultant for continued
monitoring, haematological referral if required and management of the patient’s psychiatric
condition. All clozapine supplies will be removed and withheld in the event of
agranulocytosis.
It has also been suggested that clozapine is associated with rare reports of myocarditis
and cardiomyopathy. Myocarditis seems to occur within 6-8 weeks of starting clozapine
while cardiomyopathy may occur later (median 9 months). The risk of myocarditis is
estimated to be around 1%. Patients should be monitored for symptoms such as
tachycardia, fever, flu-like symptoms, fatigue, dyspnoea and chest pains. Any signs of
heart failure should provoke the immediate discontinuation of clozapine. Successful rechallenge is possible with specialist advice.
5.1 Contra-indications (see BNF or SPC)
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.
• 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.
• Clozaril 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.
5.2 Cautions (see BNF or SPC)
See general guidance or common adverse effects.
5.3 Common Side Effects (See BNF or SPC)
Clozapine is associated with a number of adverse effects, some of which are listed below.
For a complete list please refer to the BNF or www.medicines.org.uk
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ADRs
Time course
Potential treatments
Sedation
Usually 4 weeks
Give a larger dose in the
evening
Hypersalivation
May persist
Hyoscine Hydrobromide
300mcgs nocte
(occasionally up to
900mcgs / day)
Constipation (which
may lead to impaction
and perforation)
Usually persists
↑ fibre, laxatives
Tachycardia
Worse first 4 weeks
Stop or Slow down
titration If persists refer to
cardiologist
Hypotension
First 4 weeks
Reduce or slow titration
Hypertension
First 4 weeks, sometimes
longer
As per hypertension
guidelines
Weight gain
First year
Dietary counselling
Nocturnal enuresis
Any time
Avoid fluids at bedtime,
altering the timing of
doses may help,
Emerging diabetes
Any time
As per diabetic guidelines
Seizures / myoclonic
jerks
Any time
Dose / dose increase
related, withhold
clozapine for 24hours,
introduce at a lower dose,
consider valproate
Management in the community is generally possible for most adverse effects by referral
to/discussion with secondary care prescribers; however those requiring immediate referral
to hospital include:
Neutropenia/agranulocytosis, persistent tachycardia, persistent or troublesome nocturnal
enuresis, chest pain, shortness of breath, severe drowsiness, seizures, severe
constipation or any other serious event.
5.4 Drug Interactions (see BNF or SPC)
All drugs which have the potential to cause neutropenia (e.g. carbamazepine,
cephalosporins, quinolones, trimethoprim, cytotoxics and long acting depot antipsychotics)
should be avoided. Clozapine is metabolised by many liver enzymes so drugs which may
alter these enzymes can either increase toxicity or increase the risk of relapse of
symptoms.
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Drugs which
avoided
should
be
Drugs which may be used with
caution (extra monitoring for
clozapine
adverse
reactions
required)
Carbamazepine
Fluoxetine
Fluvoxamine
Paroxetine
Erythromycin
Sertraline
Rifampicin
Warfarin (increased INR possible)
Ciprofloxacin
Antihypertensives
Lithium
Other drugs which cause constipation
This list is not exhaustive please refer to the BNF or www.medicines.org.uk
Smoking cessation interaction
Clients who smoke usually require a higher dose than non-smokers due to the effects
cigarette smoke has on clozapine levels. When giving up smoking clozapine levels can
increase by as much as 50%, thus the dose of clozapine will need reducing. Nicotine
replacement therapy does not negate this interaction. Refer to specialist advice when a
clozapine client wishes to give up smoking.
6.0 Role of Secondary Care Team
(a) To assess the suitability of the patient for clozapine and counsel patient and carer
about implications of diagnosis and treatment.
(b) To carry out initial and on-going physical health monitoring. The GP may be asked to
conduct and interpret some of the physical health tests depending on local arrangement,
however the responsibility for ensuring monitoring is complete rests with the secondary
care team.
(c) To give the patient the appropriate drug information leaflets.
(d) To explain the possible side effects of the medication to the patient.
(e) To emphasise the need for continued compliance and the need for regular blood tests.
(f) To initiate treatment, arrange for the clozapine community card to be prescribed and
arrange ongoing supplies of clozapine through hospital pharmacy.
(g) To write to the GP informing them of the ongoing prescribing, monitoring and supply of
clozapine. This shared care guideline should be included in this correspondence.
(h) To keep the GP informed of any changes in doses, mental state or prescribing status of
clozapine.
(i) To keep the GP informed of any physical tests performed and on-going physical health
concerns regarding clozapine.
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7.0 Role of GP
(a) To ensure clozapine is recorded in the GP records
(b) To notify the psychiatric team of any changes in mental state, physical state, any
suspected adverse drug reactions or changes in non-clozapine medication.
(c) To ensure all relevant staff within the practice are aware of the shared care
guidelines and the concerns surrounding clozapine
(d) To consider the precautions, interactions and adverse reactions of
clozapine when co-prescribing for patients receiving clozapine.
(e) To notify the psychiatric team when the client wishes to give up smoking and smoking
cessation advice is given.
8.0 Responsibilities of the patient / carer
a) To monitor mental state and report and deterioration in symptoms
b) Assist with adherence or discuss with the GP or secondary care team concerns with
adherence.
c) Report any side effects or physical health concerns
9.0 Cessation of treatment
Clozapine often represents the client’s best hope of recovery from enduring and treatment
resistant schizophrenia. Cessation of treatment should be avoided except in life
threatening conditions which are linked to clozapine use. Any patient wishing to
discontinue treatment should be referred back to secondary care services.
Patients who have had no clozapine for 48 hours (taken from the last dose given) should be
retitrated at 12.5mg per day, as above. The speed of the titration depends on the original
acceptance and tolerability of clozapine, however it should be noted that a slower titration is
preferable to prevent adverse reactions. Hypotension, tachycardia and seizures are particular
risks when re-starting clozapine.
Further reading
Bleakley S, Taylor D. Clozapine Handbook: Lloyd-Reinhold Communications LLP.
Warwickshire 2013.
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Appendix 10a: Clozapine Outpatient initiation prescription
(Please note this is suggested as a guide only: slower titrations may be required in the
elderly, adolescents, those with a medical co-morbidity or those with a previous poor
tolerability to clozapine)
Surname:
Consultant:
First name(s):
CMHT:
Date of birth:
NHS number:
Address:
Service User contact telephone numbers:
Allergies / previous serious
adverse drug reactions:
Mental Health Act
Section:
Date T2/T3 due:
T2/T3 copy attached:
Date Day Clozapine
to
po
start
Mane
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
12.5mg
12.5mg
12.5mg
25mg
25mg
25mg
25mg
50mg
50mg
50mg
50mg
100mg
100mg
100mg
100mg
100mg
100mg
100mg
100mg
100mg
100mg
100mg
100mg
100mg
100mg
100mg
Given
Sign and
date
Clozapine Given
po
Sign and
Nocte
date
12.5mg
25mg
25mg
50mg
50mg
50mg
50mg
75mg
100mg
125mg
100mg
100mg
100mg
150mg
200mg
200mg
200mg
200mg
200mg
200mg
250mg
250mg
250mg
300mg
300mg
Yes / No (circle))
Dr.
Total
Signature daily
and date Dose
mgs
12.5
25
37.5
50
75
75
75
100
125
150
175
200
200
200
250
300
300
300
300
300
300
350
350
350
400
400
Pharm
screen
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27
28
100mg
100mg
300mg
300mg
400
400
Avoid dose increases at the weekend or bank holidays if no routine medical cover is
available,
Target maintenance doses:

Patients with drug-induced psychosis in Parkinson’s Disease:37.5mg

Adult female non-smokers / elderly patients with resistant-schizophrenia: 250mg

Adult male non-smokers: 350mg

Adult female smokers / resistant childhood-onset schizophrenia: 450mg

Adult male smokers: 550mg
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Appendix 10b: Clozapine Inpatient initiation prescription
(Please note this is suggested as a guide only: slower titrations may be required in the
elderly, adolescents, those with a medical co-morbidity or a previous poor tolerability to
clozapine)
Add a reference to this on the main drug chart e.g. CLOZAPINE – see separate titration
chart
Surname:
Consultant:
First name(s):
CMHT:
Date of birth:
NHS number:
Address:
Service User contact telephone numbers:
Allergies / previous serious
adverse drug reactions:
Mental Health Act
Section:
Date T2/T3 due:
T2/T3 copy attached:
Date Day Clozapine
to
po
start
Mane
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
12.5mg
12.5mg
25mg
25mg
50mg
50mg
50mg
50mg
100mg
100mg
100mg
100mg
100mg
100mg
100mg
100mg
Given
Sign and
date
Clozapine Given
po
Sign and
Nocte
date
12.5mg
12.5mg
25mg
25mg
50mg
50mg
75mg
100mg
125mg
100mg
150mg
200mg
200mg
200mg
250mg
250mg
300mg
Yes / No (circle))
Dr.
Total
Signature daily
and date Dose
mgs
12.5
25
37.5
50
75
100
125
150
175
200
250
300
300
300
350
350
400
Pharm
screen
Avoid dose increases at the weekend or bank holidays if no routine medical cover is
available,
Target maintenance doses:

Patients with drug-induced psychosis in Parkinson’s Disease:37.5mg
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
Adult female non-smokers / elderly patients with resistant-schizophrenia: 250mg

Adult male non-smokers: 350mg

Adult female smokers / resistant childhood-onset schizophrenia: 450mg

Adult male smokers: 550mg
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Appendix 11: Clozapine Outpatient Prescription
Name:
Date of birth:
/
/
.
Address:
Hospital Number:
CPMS No.:
Care co-ordinator:
Medicine and Form
Tel:
Dose
Allergies/ intolerances:
Consultant:
Frequency/
Time
A Clozapine
Maximum
supply
(subject to
blood tests)
Please circle
MDS Yes/ No (please circle)
Weekly
Fortnightly
Monthly
Other medication to be supplied: (only in exceptional circumstances)
B
C
D
E
F
G
H
Repeat supplies
Items (please code)
Maximum
supply
Review date
.
Clinic:
.
Doctor’s signature
Date
Pharmacist
screen
Doctor’s signature
Date
Pharmacist
screen
Please tick
1 month
3 months
6 months
Review date
Repeat one
Repeat two
Repeat three
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Appendix 12: Blood Monitoring Form
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Appendix 13: On-going physical health monitoring parameters
Parameter
Blood Pressure (lying
down and standing)
Pulse
Temperature
Respiratory rate
1st month only
Frequently in the
first month
Frequently in the
first month
Frequently in the
first month
Frequently in the
first month
At 3 months
√
At 6 months
√
Yearly
√
√
√
√
√
√
√
Repeat if clinically indicated
√
Urea and electrolytes
(including eGFR)
Full blood count
(WBCs, Neutrophils,
Eosinophils)
Troponin T or I
(depending on local
availability)
C-reactive protein
ECG
Blood lipids (full lipid
profile including
triglycerides), Fasting
sample ideally.
Weight (including BMI,
and abdominal
circumference)
√
As per National / company guidelines
Weekly in the first
month
Repeat if clinically indicated
Weekly in the first
month
Repeat if clinically indicated
√
√
√
√
Repeat if clinically indicated
√
√
√
√
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Plasma glucose
(fasting sample
ideally)
Liver Function Tests
(ALT, AST, bilirubin,
albumin, prothrombin)
√
√
√
√
√
√
√
√
Monitor for
hypersalivation
Monitor for
constipation
Monitor for sedation
EEG (Under 16s only)
√
√
√
√
√
√
√
√
√
√
√
Repeat if clinically indicated
√
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Appendix 14: Clozapine Clinic Monitoring Form
Patient name
DOB
NHS no
Address
CMPS no
Clozapine commenced
Pick up point
Known Allergies
Phone Number
Mobile Number
MHA Status
Smoker
Date
Dose
BP
Weight
BMI
Pulse
GP/Surgery
GP Phone no
Registered Clinician
Care coordinator
Height
Comments/Checks
Contact
Contact no
Signed
Physical
Checks
Baseline
Current Frequency
1/12
3/12
6/12
Yearly
Glucose*
Lipids
U+E
LFT
ECG
Rethink
Clz level
Requirements in first year of treatment
At One Month: Pulse, BP, BMI, Glucose, Clozapine level
At Three and Six Months: Pulse, BP, BMI, Glucose, Lipids, U+E, LFT,
ECG and Rethink
At 12 Months: Pulse, BP, BMI, Glucose, Lipids, U+E, LFT, ECG,
Rethink Questionnaire Form. Clozapine level if clinically indicated.
Requirements after one year of treatment.
Monthly: Pulse, BP, BMI,
Yearly: Pulse, BP, BMI, Glucose, Lipids, U+E, LFT and ECG, Rethink
Questionnaire Form. Clozapine level if clinically indicated.
*Fasting Glucose if possible or repeat fasting if random glucose outside
normal range
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Appendix 15: Information check list for patients on clozapine
The following information must be given to the patient when commencing clozapine
and reinforced when arranging the persons discharge or transfer to another team.
Any member of the MDT can complete this form but it is the care coordinators
responsibility to ensure it is completed.
Initiation of clozapine / review appointments
Signature of
healthcare
professional
Date
The indication for clozapine has been explained
including who will review treatment.
The reasons for clozapine physical health
monitoring has been explained.
The common side effects have been explained
and actions to take should they occur (see
appendix 1).
Explain the signs and symptoms of an infection
and what to do should they occur.
Discuss the importance of regular blood tests and
what may happen if they miss their blood test.
The reason for a slow titration of clozapine has
been explained.
Explain to the patient who will take the physical
health checks and how often they will be visited
at home (if applicable).
Discuss why it is important to continue clozapine
and what to do if they miss a dose, especially if
they miss more than 48 hours of doses.
Explain the importance of informing other
healthcare professionals (GP, Dentist or
Pharmacist) that you are on clozapine.
Who to contact in an emergency both with hours
and out of hours.
Give dietary and lifestyle advice. Add advice on
alcohol consumption (ideally avoid or no more
than 2-3 units per day).
Explain how smoking can affect clozapine levels
and the importance of letting the team know if you
are intending to stop or cut down smoking (if
applicable).
Give written appropriate advice (see
www.choiceandmedication.org/southernhealth)
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On discharge or transfer to another team
Advise when and how the patient will receive
ongoing clozapine supplies and the required
blood tests.
Give dosing advice and allow time for questions.
Reinforce the information given above.
Ensure the GP is aware of the clozapine (see
appendix 8). Send the GP a copy of the shared
care risk management guidelines (see appendix
9).
To be completed by the patient:
I understand the risks and benefits of taking clozapine. I confirm that I have had the
chance to discuss and understand the information that I have been given.
Signed……………………………………………………. Date…………………
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Appendix 16: Protocol* for First Re-Exposure to Clozapine after a Blood Dyscrasia
Requiring Discontinuation
Clozapine prescribing is strictly controlled by the Summary of Product Characteristics (SPCs)
requiring regular blood monitoring throughout treatment. The SPCs state that clozapine prescribing
is contra-indicated in someone with a history of clozapine-induced agranulocytosis, and once
therapy has been discontinued for haematological reasons, patients must not be re-exposed to
clozapine.
Reuse of clozapine after a “red” result is thus unlicensed. All manufacturers have a form that allows
re-exposure but it is the Consultant’s “decision and clinical responsibility alone” and includes the
disclaimer that “I waive any rights I or the hospital may have against” the suppliers.
Clozapine can be a life-changing therapy and re-exposure to clozapine can both improve mental
state and not necessarily lead on to a second dyscrasia.
Incidence of recurrence on first rechallenge
A review of 53 patients rechallenged with clozapine after a leucopenia or neutropenia, showed 38%
had a further dyscrasia and in most it was more severe, longer-lasting and occurred more quickly. Of
the 53, 55% were rechallenged successfully and remained in treatment1. A second dyscrasia
incidence peaks at 5.5 weeks (range up to 150 days). A recent review has stated that “Uncertainty
over the likely cause of blood dyscrasia in people taking clozapine, coupled with uncertainty over the
mechanism by which clozapine causes both neutropenia and agranulocytosis, makes any attempt to
restart clozapine a high-risk venture requiring the utmost caution.”2
Protocol for re-exposure following a previous dyscrasia
A protocol is a detailed plan that must be followed for a course of medical treatment. This is a
protocol*. The Trust will not support anyone acting outside this protocol. This is in recognition that the
mechanism for clozapine-induced neutropenia or agranulocytosis is unknown, nor the extraneous
factors involved, and so extreme caution must be exercised if re-exposing someone to clozapine after
a dyscrasia.
In exceptional circumstances, the Trust supports re-exposure to clozapine after agranulocytosis as
follows:
The Consultant must obtain in writing:
1. A second opinion supporting the need for clozapine
2. Advice from a haematologist regarding the dyscrasia and its likely relationship with clozapine,
possible other causes and any other relevant factors and a care plan put in place
3. Advice from the relevant senior specialist clinical pharmacist
4. Informed consent from the patient, including the risks (1 in 3 chance of a repeat dyscrasia) and
benefits, assuring that the patient is able to retain this information. The person's capacity to
consent should be considered and documented. If patient lacks capacity the Mental Capacity Act
should be followed.
 This should be in collaboration with any relatives or an advocate. However, since in law no one
person can give consent for another, it should be made clear he or she will be advising
relatives/advocates but that they cannot consent.
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If clozapine is re-prescribed:
1. Minimise the potential from contributing drugs e.g. any that might have been implicated in the
original dyscrasia, any other drugs associated with blood dyscrasias.
2. Increase blood monitoring frequency and alertness, and document clear actions to be taken. The
minimum should be:
 Twice weekly for the first ten weeks, then weekly to 18 weeks, then fortnightly to one year
plus TWO samples before re-starting to establish an adequate baseline
 This should be more frequent (eg 3 times a week) should 3 falls in a row occur or if there is
any suspicion of a dyscrasia developing
 A slightly slower dose escalation should be considered, although there is little evidence as to
whether this reduces the risk or not.
3. Clear action plan made in the notes and copied to pharmacy should a dyscrasia recur:




Emergency contacts 24/7 (patient, carer, RMO, pharmacy) haematologist
Discontinuing therapy plan
Replacement therapies or management options
The patient must be an inpatient.
4. Service user educated about the relevance of any physical changes, particularly fever, sore
throat or other signs or symptoms of infection, and to whom these must be reported and
information leaflet given.
Second rechallenge to clozapine
Personal communication with Novartis CPMS (Feb 2011)

3 patients have been rechallenged with clozapine for the second time. 1 is still continuing with
green blood results

It was difficult to identify the patients on clozapine and GCSF. It appears that 6 patients are
continuing with green results due to GCSF. It is not clear if these patients have had one or two
clozapine rechallenges.

No deaths have occurred.
No information available from manufacturers of generic clozapine .
References
1. Rechallenge with clozapine following leucopenia or neutropenia during previous therapy. Dunk, Annan
and Andrews, Br J Psychiatry 2006;188:255-63.
2. Restarting clozapine after neutropenia: evaluating the possibilities and practicalities.
Whiskey and Taylor, CNS Drugs 2007;21:25-35.
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Checklist for clozapine re-challenge
The following checklist should be completed, retained in the notes and a copy sent to pharmacy.
The re-supply of clozapine will not occur unless all of the below has been completed and approved
in pharmacy and this form is signed and dated.
Action
Has a written report been obtained from a
second opinion supporting the need for
clozapine re-challenge?
Yes/No *
YES/NO
Notes
This must/should be a Consultant
Psychiatrist from the same speciality and
not a member of another profession (as
in ‘second opinion’ under MHA).
Name:
Has advice been sought from a consultant
haematologist regarding the dyscrasia, other
causes and relevant factors and a written
report obtained?
YES/NO
Please state name of haematologist
and date of contact:
Has the advice been documented and
incorporated into care plan for dyscrasia.?
YES/NO
Include emergency contact names and
numbers (including out of hours )
Advice from specialist clinical pharmacist has
been sought and received
YES/NO
Clinical Pharmacists should review notes
and enter any relevant comments in
them. eg confounding factors for
dyscrasias
Name of Pharmacist:
Written, informed consent obtained, discussion
to include
 Risk of repeat dyscrasia (1 in 3
 Assessment as to capacity to consent
considered and documented.
OR
 MHA commissioners contacted
Discussion with relatives and carers or
advocate as to the nature of the treatment and
relative risks
Discussion and understanding of the
commitment to increased blood test frequency
YES/NO
If unable to consent, MHA commissioners
should be contacted.
Should include written information to the
service user about what physical changes
to report, particularly fever, sore throat or
other signs or symptoms of infection
YES/NO
Cannot consent for patient. They can
only advise (see note above)
YES/NO
Twice weekly for 10 weeks
Weekly from weeks 11 to 18 (inclusive)
Fortnightly to week 52 (inclusive)
Then monthly ongoing
Should 3 falls in WBC occur then
frequency of testing should increase to 3
times per week at minimum.
See attached “Action plan after reoccurrence of blood dyscrasia after
clozapine re-challenge.”
Clear direction in notes for increased blood
YES/NO
test monitoring if falls in WBC counts occur
three times in a row
Action plan completed with input from the
YES/NO
haematologist and placed in notes and
pharmacy should a dyscrasia occur
* If answering “no” to any of these questions refer to pharmacy.
Consultant’s Name and
Signature.
Dated:
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Action plan should there be a re-occurrence of blood dyscrasia after clozapine re-challenge
This form should be retained in the notes and a copy sent to pharmacy.
Emergency Contacts:
Doctor to complete details.
Patient
Carer/
nearest
relative
RMO (within
hours)
Pharmacy
(within
hours)
Out of
Hours
phone (if
applicable
)
Name:
Address:
Post Code
Home
Phone No.
Mobile
Phone No.
Discontinuation Advice:
Replacement therapy and management options should blood dyscrasia recur.
Consultant Psychiatrist signature:
Consultant Haematologist signature:
Date:
Date:
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Appendix 17: Clozapine Brand Change Procedure
Please note a patient cannot be registered on two databases at the same time.
Clozaril (Novartis) to Denzapine (Genus)
1. Consultant to complete a brand transfer form, obtained from Medicines management
team or Denzapine/Genus website.
2. Ward to fax completed form to Genus on 03332004142
3. Once the form has been received Genus will contact Novartis to transfer the patient and
information onto the new system.
4. Pharmacy will check the website and supply the new medication.
Denzapine (Genus) to Clozaril (Novartis)
1. HCP (nurse, Doctor or medicines management team) to contact Novartis to request a
patient be transferred.
2. Please supply patient name, DOB, ward and consultant details, including fax/email
address.
3. Novartis will fax/email a form for the consultant to complete.
4. Once completed fax/email form to Novartis on 08457698541.
5. Novartis will contact Genus to transfer the patient and information onto the new system.
6. Pharmacy will check the website and supply the new medication.
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Appendix 18: Clozapine side effect rating scale (GASS-C)
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Appendix 19
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