Pharmacological Therapy Policy Practice Guidance Note ...…2020/09/05 · Treatment resistant schizophrenia (TRS) Severe untreatable neurological adverse reactions to other antipsychotic

Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust PPT-PGN-05 Safe Prescribing of Clozapine – V03- Iss 5 Sep 2020 Part of NTW(C)38 – Pharmacological Therapy Policy

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Pharmacological Therapy Policy Practice Guidance Note

Safe Prescribing of Clozapine – V03-Dr

Version issued

Issue 1 – Apr 2019 Issue 2 – Sep 2019 Issue 3 – Nov 2020 Issue 4 – Apr 2020 Issue 5 – Sep 2020

Planned review

April 2022 PPT-PGN-05 Part of CNTW(C)38 Pharmacological Therapies Policy

Author/Designation Peter Clarke, Lead Pharmacist – South Locality

Responsible Officer / Designation

Tim Donaldson, Trust Chief Pharmacist

Contents

Section Description Page No

1 Introduction 3

2 Clozapine initiation 5

3 Clozapine maintenance and transfer of care 8

3.1 Therapeutic drug monitoring of clozapine plasma levels 9

4 Complications 10

4.1 Blood monitoring issues 10

4.2 Concordance issues 10

4.3 Discontinuation 10

4.4 Side effects 11

4.5 Smoking 13

4.6 Out of hours / transfer issues 13

Appendices, listed separate to Practice Guidance Note

Document No Description

Appendix 1 Monitoring requirements for adult patients prescribed clozapine

Appendix 2 Clozapine titration/retitration prescription


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Appendix 3 Clozapine initiation monitoring

Appendix 4 Clozapine clinic referral form

Appendix 5 Contact details

Appendix 6 Shared care agreement & GP letter template

Appendix 7 Clozapine clinic standard work

Appendix 8 Guide to interpretation of clozapine plasma levels

Appendix 9 RED result protocol

Appendix 10 AMBER result protocol

Appendix 11 Overdue blood results

Appendix 12 Denzapine re-challenge process

Appendix 13 Treatment break protocol

Appendix 14 Retitration by the CRHT

Appendix 15 Clozapine related constipation

Appendix 16 Clozapine related hypersalivation

Appendix 17 Clozapine related tachycardia

Appendix 18 Clozapine and smoking


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1 Introduction 1.1 This document outlines the process to safely initiate and maintain clozapine in

patients within CNTW services. 1.2 Clozapine is an atypical antipsychotic and is licensed for1:

Treatment resistant schizophrenia (TRS)

Severe untreatable neurological adverse reactions to other antipsychotic drugs

Psychotic disorders in Parkinson’s Disease 1.3 Clozapine is recommended by National Institute for Health and Care Excellence

(NICE) as a treatment option in TRS2,3. 1.4 To comply with the Product Licence1 of clozapine in the UK, regular monitoring of

white cell count (WCC) and a differential is mandatory. The frequency of this is weekly for the first 18 weeks, fortnightly until 1 year of clear results (as stated by the monitoring service), then 4-weekly thereafter for the total duration of treatment (and 4 weeks after stopping clozapine).

1.5 Prior to commencement on clozapine, all patients must be fully registered with the

Denzapine Monitoring Service (DMS) and have a valid blood test. DMS must be informed of all subsequent, relevant changes relating to the patient (e.g. prescriber, location, physical illness).

1.6 Any patients transferred from outside CNTW services who are registered with another

clozapine monitoring service must be re-registered with DMS. 1.7 Other indications are deemed as off license, and must be discussed with the multi-

disciplinary team (MDT) and DMS. Refer to section 9 of the Prescribing Medicines policy (UHM-PGN-02) for further guidance on off license prescribing.

1.8 RiO Clozapine documentation should be completed by all teams managing patients prescribed clozapine. These are available at: Service Specific Files > Physical Treatment > Clozapine Documentation and include:

Clozapine Pre-Treatment Checklist


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Clozapine Clinic Record New

Side Effect Monitoring Record

Clozapine Initiation Care Plan and Monitoring Record

Clozapine Maintenance Care Plan

1.9 Patients should be given information and education regarding:

Mandatory monitoring (its significance and consequences)

Onset of action and expected benefits

Side effects and how to combat these (The side effect monitoring record in the clozapine treatment pack and on RiO can be used as an aide memoire to support this discussion)

Missed doses

Clinic attendance

Timing of plasma levels

The effect of smoking

This discussion must be clearly documented in the clinical record 1.10 Clozapine can be initiated safely as an inpatient or in a community setting – see

section 2 for initiation guidance.


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2 Clozapine initiation

Decision to prescribe after considering the following: diagnosis, drug history, oral compliance, swallowing difficulties, comorbidities, client/family views, concurrent (interacting) drugs and whether a SOAD is needed (Prescriber)

On RiO, see Service Specific Files> Physical Treatment> Clozapine Documentation:

Complete Pre-Treatment Checklist including baseline bloods, ECG,

CK and physical examination by SHO/screening for faecal impaction:

(Prescriber, Nurse)

Register patient with Denzapine Monitoring Service (DMS)

(Prescriber)

Prescriber must also be registered DMS (Prescriber)

Complete Initiation Care Plan and Monitoring record on RiO

(Nurse)

Complete Side Effect Monitoring Record (at baseline / titration)

(Prescriber/Nurse/Pharmacy)

Patient Clozapine counselling, including discussion around side

effects and monitoring requirements (Pharmacy/Prescriber)

Complete core documentation care plan (Nurse)

For patients being re-initiated – see section 3 Troubleshooting

Inpatient Initiation


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Prescribe clozapine titration (Prescriber)

Ensure DMS is updated with blood results (Prescriber)

A valid blood result (<10 days old) is required before commencing treatment

Send valid order including titration prescription (appendix 2) to NTW

Solutions Pharmacy (Pharmacy/Nurse)

Dispense and supply appropriate quantities of clozapine on receipt of

valid DMS green blood result (Dispensing Pharmacy)

Throughout titration, physical health observations (pulse, blood

pressure, temperature) must be completed on the Clozapine Initiation

Care Plan and Monitoring Record on RiO – see also appendix 1

(Nurse)

Ensure patient has enough supplies of medication and taking into

account any weekends, bank holidays (Nurse/Pharmacy)

Community Initiation

Decision to prescribe after considering the following: diagnosis, drug history, oral compliance, swallowing difficulties, comorbidities, client/family views, concurrent (interacting) drugs and whether hospital admission is required. Ideally discussed with an NTW pharmacist based in community services (Prescriber) Complete Pre-Treatment Checklist including baseline bloods, ECG, CK

and physical examination by SHO/faecal impaction screening:

(Doctor/Prescriber/Nurse/Pharmacy)

Register patient with Denzapine Monitoring Service (DMS) (Prescriber)

Prescriber must also be registered with DMS (Prescriber)

Clozapine patient counselling including information around side effects

and explanation of monitoring requirements (Prescriber/Pharmacy)

Contact relevant blood collection centre to request routine blood

monitoring before initiation within 10 days of starting. Complete referral

form (Nurse/Pharmacy)

Contact relevant CRHT to discuss involvement over weekends if

applicable – medication supplies, physical observations, or bloods

(Prescriber/Pharmacy)

Complete core documentation care plan (Nurse)

Complete a clozapine care plan with details of arrangements,

monitoring, and physical health monitoring thresholds to report back to

designated available medic (Nurse)

For patients being re-initiated, notify relevant blood collection clinic or

GP surgery, DMS, NTW Solutions Pharmacy, Community Treatment

Team, and community Consultant Psychiatrist (Nurse/Pharmacy)

Prescribe clozapine titration on outpatient prescription and on titration chart (appendix 2). Ensure DMS is updated with blood results. Send prescription and escalation chart to NTW Solutions Pharmacy. Ensure arrangements already in place for supply to patient (Prescriber)

The initial blood result MUST be no more than 10 days old on the day the patient starts treatment

Dispense and supply appropriate quantities of clozapine on receipt of

valid green DMS blood result (Dispensing Pharmacy)

Throughout titration, physical health observations (pulse, blood pressure,

and temperature) must be completed on the Clozapine Initiation Care

Plan and Monitoring Record on RiO – see also appendix 1 (Nurse)

Ensure there is a local procedure in place for highlighting any abnormal

readings to a designated medic for nursing staff to report to

(Prescriber/Nurse)


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2.2 Clozapine dose titration

Clozapine should be initiated using the CNTW ‘Clozapine Titration/Re-titration

Prescription’ (see appendix 2) which is available from the Pharmacy Admin

Team. They can be contacted at [email protected] or 0191

2456606.

Intensive physical health monitoring is required initially (see appendix 1 and

Clozapine Initiation Care Plan and Monitoring Record on RiO). For patients

in the community, locally agreed arrangements should be put in place to

ensure this is carried out safely. See appendix 3 for practical guidance on

initiation monitoring.

Only clozapine labelled with the relevant patient’s name can be administered

to that patient. Out of hours, the on-call pharmacist should be contacted if

labelled medication unavailable (see section 4).

Should any dose–dependent side effects e.g. hypotension become

problematic during titration, a slower dose increase should be considered by

the prescriber. The CNTW ‘Clozapine Titration/Re-titration Prescription’ can

be used to facilitate an unambiguous dose modification.

In older patients, it is recommended to prescribe lower doses of clozapine and

titrate more slowly, starting at 12.5mg daily with maximum increments of 25mg

daily1.

In Parkinson’s disease psychosis there is evidence for very low clozapine

doses, starting at 6.25mg-12.5mg daily and increasing by no more than

12.5mg per day with a target of 25-37.5mg daily at maintenance. Doses of

50mg daily should not normally be exceeded, except in exceptional

circumstances. The maximum licensed dose is 100mg daily1,4.

mailto:[email protected]


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3 Clozapine maintenance and transfer The following chart demonstrates the process for patients who have been stabilised on treatment.

Physical health monitoring to be completed as per appendix 1 (nurse/ prescriber)

Baseline clozapine plasma level one week after dose stabilised see section 3.1 (prescriber)

On RiO, see service specific files>physical treatment>clozapine documentation: Ensure Clozapine Clinic Record New is completed for each intervention/blood monitoring episode (prescriber/nurse) Clozapine Maintenance Care Plan to be completed 3 months post initiation and annually (prescriber/nurse)

Complications– e.g. retitration, red result, side effects – see section 4

Clozapine clinic referral form (appendix 4) to be completed: -Contact community treatment team (CTT) to inform of pending discharge in order to arrange OP prescription to be sent to NTW Solutions Pharmacy (prescriber/nurse) -Contact relevant clozapine clinic to arrange appointment details (prescriber/nurse/pharmacy) see appendix 5 for contact details for each clinic. -Contact DMS (see appendix 5) to update clinic/prescriber/pharmacy details (nurse/pharmacy/clinic team) -Arrange discharge medication with ward pharmacy team (prescriber/nurse) -Forward completed referral form to clozapine clinic and scan onto RiO (prescriber/nurse/pharmacy) -Inform patient/CTT of clinic appointment details (prescriber/nurse)

If patient is unable to access a clozapine clinic, arrangements should be made with the CTT for provision of blood sampling and monitoring. In exceptional circumstances a shared care agreement may be required (see appendix 6).

Patient to attend clozapine clinic (or CTT) for mandatory monitoring -see clozapine clinic standard work (appendix 7) for process and recording requirements. (nursing/pharmacy clinic staff)

Physical health monitoring to be completed as per appendix 1 (nurse/ prescriber)

Community

maintenance

Discharge

preparation

Inpatient

maintenance

Plasma levels minimum annually (see section 3.1). (nurse/ prescriber)


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3.1 Therapeutic Drug Monitoring of Clozapine Plasma Levels 3.1.1 Clozapine plasma levels are useful for optimising therapy as support to the clinical

monitoring (response and adverse effects) of patients prescribed clozapine. Plasma levels should be checked and recorded at the following points:

Baseline – 7 days after target dose reached

Annually

3.1.2 In addition, as per the MHRA drug safety update8 relating to clozapine toxicity,

clozapine plasma levels should always be checked in the following circumstances:

Prescribed medicines which may interact and increase blood clozapine

levels

Patient stops/reduces smoking or switches to e-cigarettes

Suspected toxicity / overdose

Suspected poor metaboliser

Patient has pneumonia or other serious infection

3.1.3 It is also advisable to check levels in the following scenarios:

Clozapine dose change (minimum 7 days after change)

Poor compliance suspected

Poor response to treatment (after >3 months)

Increase in smoking

Suspected rapid metaboliser

Prescribed medicines which may interact and lower blood clozapine levels

3.1.4 Plasma Assay forms can be accessed from Analytical Services International (ASI) -

see appendix 5. The forms should be sent to ASI as instructed on the form. 3.1.5 Trough blood sample to be taken 10-12 (minimum 6) hours post dose (usually in the

morning before a dose is taken). 3.1.6 See appendix 8 for a guide to plasma level interpretation and clinical response. For

further advice, contact ASI (see appendix 5).

Complications– e.g. retitration, red result, side effects – see section 4

Annual review by prescriber (prescriber)


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3.1.7 Plasma level requests and results should be documented on RiO progress notes with a clear rationale.

3.1.8 Abnormal clozapine plasma level results should be acknowledged by clinicians on

RiO, along with documenting clear actions to be taken in response. 4 Complications 4.1 Blood monitoring issues

4.1.1 In the event of a RED result, the prescriber and ward/team are contacted by DMS

directly. Clozapine should be stopped immediately; the patient should be assessed

for any signs of infection. The relevant clozapine monitoring service must be

contacted for guidance on the management of red results. (See Appendix 9).

4.1.2 In the event of an AMBER result, arrange a retest and contact DMS. (See Appendix

10)

4.1.3 If blood monitoring becomes overdue (e.g. because patient does not attend clinic

appointment), the prescriber is responsible for ensuring alternative arrangements are

made for monitoring. A supply of clozapine can still be made for a short period (see

appendix 11). Once clozapine becomes prohibited a further supply will not be made

until a valid blood result is received.

4.1.4 If a prescriber wishes to recommence clozapine in a patient with a previous

discontinuation due to RED result (rechallenge), the process outlined in appendix 12

must be followed.

4.2 Concordance issues

4.2.1 If a dose or doses of clozapine are omitted, it can be safely continued at the patient’s

normal dose. However if there has been a break of more than 48 hours, the clozapine

will need to be retitrated. Depending on the length of the break, this may also affect

monitoring frequency and potentially require re-registration. Please see Appendix 13

for the treatment break protocol.

4.2.2 If retitration is required please follow the process outlined in the initiation section of

this document (section 2). Please see appendix 14 if CRHT involvement is required

in the retitration process.


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4.3 Discontinuation

4.3.1 Clozapine should usually be prescribed and monitored for at least one year in order to establish its effectiveness as a long term treatment.

4.3.2 If the decision is made to discontinue clozapine for anything other than a

haematological reason, the dose should be reduced as slowly as possible. This should take into account any clinical risk factors, the mental state of the patient and alternative treatment plan.

4.4 Side effects 4.4.1 Side effects and tolerability to treatment should be reviewed at each review and

following dose changes. More frequent monitoring of side effects may be indicated where the clinical significance of the side effect warrants this. A summary of the yearly review should be recorded in the patient’s clinical records and communicated to the GP.

4.4.2 Constipation

Severe constipation is a potentially life threatening complication of clozapine that can lead to intestinal obstruction, faecal impaction, paralytic ileus and ultimately death. To minimise the risk of serious constipation prescribers should:

Educate patients about the risk of constipation and provide written information on dietary management (this should be documented)

Be particularly vigilant for constipation in patients who are prescribed concomitant medicines with anticholinergic activity (e.g. hyoscine, tricyclic antidepressants, drugs for bladder instability)

Exercise caution in patients aged 60 years and older and patients with a history of colonic disease or lower bowel surgery.

Consider prophylactic laxative treatment when starting clozapine in patients with a history of constipation or bowel obstruction.

Monitor for signs and symptoms related to reduced bowel movements, including nausea, vomiting, bloating, abdominal pain or difficulty passing wind.


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If the patient is constipated, clozapine should not be initiated until this has been resolved

Use lowest effective dose of clozapine

Monitor bowel movements daily for the first 4 weeks then weekly thereafter at each clinic appointment or blood sampling.

If there is a change in bowel habits or the patient has had fewer than

three bowel movements per week an abdominal examination should

be carried out

Intervene actively when patients report constipation, ensuring that an

effective laxative regimen is prescribed promptly (e.g. senna &

docusate sodium or a polyethylene glycol-based osmotic laxative) and

that the effectiveness of this treatment is monitored closely thereafter

Refer urgently all patients who present with symptoms indicating a

potentially life-threatening gastrointestinal complication (e.g.

abdominal pain with nausea in the context of constipation), in whom

clozapine should be temporarily discontinued

Please refer to appendix 15 and the Bowel Care policy (PPT-PGN-16) for further information.

4.4.3 Tachycardia – please see appendix 17

4.4.4 Hypersalivation – please see appendix 16

4.4.5 Hypotension

Hypotension is listed as a potential adverse effect of clozapine which is most likely

during the first 4 weeks of treatment.

In the first instance patients should be advised to take time when standing up and

encouraged to increase their fluid intake to 2 litres a day.

Slowing down the rate of dose increase or a small reduction in dose could be

considered.

If hypotension persists or is severe, medical review is required.

4.4.6 Pneumonia and other infections

A robust approach should be made to ensure that Clozapine patients presenting with

symptoms of infection are monitored closely to minimise risks associated with

Clozapine toxicity. Clozapine levels should be checked and urgent consideration


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given by the treating clinician to reducing the Clozapine dose until the patient is fully

recovered.

An increased risk of pneumonia should be assumed for all patients taking Clozapine

for any length of time and regardless of age. Early medical intervention should be

considered where there is any doubt about the severity or type of chest infection when

reported or observed.

At each consultation, a patient receiving Clozapine must be reminded to contact the

treatment team immediately if any kind of infection begins to develop. Particular

attention should be paid to flu-like complaints such as fever or sore throat, persistent

cough and to other evidence of infection.

Many of our patients have co-morbidities such as COPD and diabetes and would

therefore fit the criteria to have influenza and pneumococcal vaccination. Clinical staff

should strongly encourage these are received.

As clozapine metabolism may be inhibited by respiratory infections, serious

respiratory infection may contribute to additional side effects thereby exacerbating

the risk of hyper salivation, sedation, aspiration and arrhythmia.

During episodes of respiratory infection or illness, there is also a likelihood that

patients may reduce smoking habits. Therefore please refer to 4.5 below.

4.5 Smoking

Patients intending to stop/start smoking, or change their smoking habit should seek advice from the clozapine clinic staff/prescriber, who will formulate a plan, to ensure their ongoing safety. Please see appendix 18 for further advice.

4.6 Out of hours / transfer issues 4.6.1 Out of area admission to CNTW ward

Contact clozapine monitoring service to confirm monitoring frequency and when

blood test is next due.

If monitored by DMS, the details should be updated and a supply can then be made

if needed.

If monitored by a different service, complete a transfer form from DMS website and

return completed form by fax.

Once received DMS will contact the previous monitoring service to transfer the

patient and information onto the DMS system.

Supply of medication made if necessary once DMS system has been updated.

4.6.2 Patient transfer /admission to acute hospital

CNTW is responsible for the supply of clozapine to local acute hospitals.


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When transferred from a CNTW inpatient setting, a copy of the inpatient

prescription chart and a clozapine supply should be sent with the patient.

When directly admitted from a community setting, the acute hospital should be

advised to attempt to obtain the patient’s own supply in the first instance.

If re-titrating, the clozapine titration/re-titration prescription (appendix 2) should be

completed by the prescriber and sent to the relevant CNTW pharmacy site as well

as a copy to the acute hospital for reference.

Ongoing supply of clozapine from CNTW pharmacy obtained by acute hospital ward

staff through liaison with CNTW pharmacy department.

4.6.3 Out of hours

When clozapine is newly started or a patient is admitted out of hours, the CNTW EDC pharmacist should be contacted via switchboard before obtaining a supply to ensure the patient is appropriately registered and has a valid blood result.

References

1. Summary of Product Characteristics (SPC) Denzapine 100mg tablets.

https://www.medicines.org.uk/emc/product/6120/smpc Accessed 24/01/19

2. National Institute for Health and Care Excellence (NICE). Psychosis and

schizophrenia in adults: treatment and management (CG178). Last updated

February 2014. Accessed at: https://www.nice.org.uk/guidance/CG178

3. National Institute for Health and Care Excellence (NICE). Psychosis with Co-

Existing Substance Misuse (CG120). Last updated March 2011. Accessed at

https://www.nice.org.uk/guidance/CG120

4. Taylor, David, Barnes, Thomas E., Young, Allan. The Maudsley Prescribing

Guidelines in Psychiatry. 13th Edition. 2018. pp 592

5. Medicines and Healthcare products Regulatory Agency Drug Safety Update

(26th October 2017). Clozapine: reminder of potentially fatal risk of intestinal

obstruction, faecal impaction, and paralytic ileus https://www.gov.uk/drug-

https://www.medicines.org.uk/emc/product/6120/smpc



https://www.gov.uk/drug-safety-update/clozapine-reminder-of-potentially-fatal-risk-of-intestinal-obstruction-faecal-impaction-and-paralytic-ileus


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safety-update/clozapine-reminder-of-potentially-fatal-risk-of-intestinal-

obstruction-faecal-impaction-and-paralytic-ileus.Accessed 30/01/20

6. US Food and Drug Administration (28th January 2020). Clozaril, Fazaclo ODT,

Versacloz (clozapine): Drug Safety Communication - FDA Strengthens Warning

That Untreated Constipation Can Lead to Serious Bowel Problems

https://www.fda.gov/safety/medical-product-safety-information/clozaril-fazaclo-

odt-versacloz-clozapine-drug-safety-communication-fda-strengthens-warning-

untreated. Accessed 30/01/20

7. Jose De Leon, Emilio J Sanz, Carlos De las Cuevas, Data From the World

Health Organization’s Pharmacovigilance Database Supports the Prominent

Role of Pneumonia in Mortality Associated With Clozapine Adverse Drug

Reactions, Schizophrenia Bulletin, Volume 46, Issue 1, January 2020, Pages

1–3, https://doi.org/10.1093/schbul/sbz093

8. Medicines and Healthcare products Regulatory Agency Drug Safety Update (26th

August 2020). Clozapine and other antipsychotics: monitoring blood concentrations

for toxicity. Accessed at https://www.gov.uk/drug-safety-update/clozapine-and-

other-antipsychotics-monitoring-blood-concentrations-for-toxicity on 02/09/20



https://www.fda.gov/safety/medical-product-safety-information/clozaril-fazaclo-odt-versacloz-clozapine-drug-safety-communication-fda-strengthens-warning-untreated.%20Accessed%2030/01/20



https://doi.org/10.1093/schbul/sbz093

https://www.gov.uk/drug-safety-update/clozapine-and-other-antipsychotics-monitoring-blood-concentrations-for-toxicity

https://www.gov.uk/drug-safety-update/clozapine-and-other-antipsychotics-monitoring-blood-concentrations-for-toxicity

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Pharmacological Therapy Policy Practice Guidance Note ...…2020/09/05 · Treatment resistant schizophrenia (TRS) Severe untreatable neurological adverse reactions to other antipsychotic