Procedure for the prescribing, administration and monitoring of … · 2019. 2. 27. · Procedure for the prescribing, administration and monitoring of clozapine (Med20) Review date:

Procedure for the prescribing, administration and monitoring of clozapine (Med20)

Review date: 20/10/2018 Version No: 4.0 Page 1 of 37


Document author Assured by

Sarah Jones (Locality Lead Pharmacist, BaNES)

and Terri Turner (Locality Lead Pharmacist, Swindon) AWP Medicines Optimisation Group

This document is version controlled. The master copy is on Ourspace.

Once printed, this document could become out of date.

Check Ourspace for the latest version.

This procedure forms part of the Medicines Policy P060

Version History

Version Date Revision description Editor Status

1.0 27/01/2010 Template for Procedural Documents CoSec Approved

1.1 03/01/2010 First draft SCJ Draft

1.2 31/03/2010 Comments received and incorporated from pharmacists and consultant psychiatrists

SCJ Draft

1.3 14/04/2010 To Quality and Effectiveness Management Group SCJ Draft

2.0 21/05/2010 Updated following comments from Quality and Effectiveness Management Group

SCJ Approved

2.1 05/01/2012 Minor changes following change of clozapine supplier SCJ Approved

2.2 09/5/2013 Updated to reflect the NEWS chart BS Draft

2.3 07/11/2013 Circulated to Medicines Management Group (MMG) for approval with inclusion of NEWS chart and pre/post administration monitoring guidance.

BS Draft

2.4 31/12/2013 Final revision from comments from *Medicines Optimisation Group on 20.12.13

BS Approved

3.0 26/02/2016 Revision of content (expanded to include community) and update of template

SCJ/TET Draft

3.1 11.04.16 Revision of content based on comments received – myocarditis monitoring, terminology, clarification of responsibilities, and clarification of real time monitoring system.

SCJ/TET Draft

3.2 08.06.16 Review of content by MDT review panels, SCJ/TET Draft

3.2 26.09.16 Review of content (particularly related to clozapine initiation in the community) by MDT Quality Forum.

SCJ/TET Draft



3.3 11.10.16 Update of format and review of content following comments of Quality Forum.

SCJ/TET Draft

3.4 13.10.16 Review by VM, SB and TT SCJ Draft

3.5 20.10.16 Approved by MOG pending minor amendments TET Final draft

4.0 04.01.17 Incorporation of final comments from MOG and publication SCJ Approved

4.1 29.11.17 Amendment to section 10 to reflect change from ‘clozapine discharge form’ to ‘clozapine transfer form’. Approved at MOG

SCJ Approved

Contributing authors / editors Val McElhinney (Acting Chief Pharmacist) Shirley Bickers (Deputy Chief Pharmacist)

Reviewed by/ comments received from Dr Adrian Vasko, Dr Alicuin Wilkie, Dr Clare Taylor, Dr Harvey Rees, Dr Prabhakaran Naveen, Sarah Harding (development nurse)

Attendees Quality Forum September 2016.

Attendees MDT panels at Jenner House July 2016

Trust Medicines Optimisation Group

Contents

Quick Start Guide to Clozapine .................................................................................................. 5

1. Introduction .......................................................................................................................... 6

2. Scope .................................................................................................................................... 6

3. Definitions ............................................................................................................................ 6

4. Roles and responsibilities ................................................................................................... 7

5. Key contact details .............................................................................................................. 9

6. Pre-initiation considerations ............................................................................................. 10

6.1 Informed consent to treatment .................................................................................................... 10

6.2 Pre-existing health problems......................................................................................................... 10

6.3 Pregnancy and breastfeeding ........................................................................................................ 10

6.4 Switching from other antipsychotics ............................................................................................. 11

6.5 Drug and other interactions with clozapine .................................................................................. 11

6.6 Baseline monitoring requirements ................................................................................................ 12

6.7 Setting for initiation ....................................................................................................................... 12

http://ourspace/Skills/MedicinesPharmacy/Medicines%20procedures/Med20.docx#_Toc499728414



6.8 Care planning ................................................................................................................................. 13

7. Clozapine initiation – information for all settings ............................................................ 14

7.1 Registering the service user with ZTAS.......................................................................................... 14

7.2 Prescribing the dose titration ........................................................................................................ 14

7.3 Ordering medication ...................................................................................................................... 14

7.4 Administration ............................................................................................................................... 14

7.5 Monitoring ..................................................................................................................................... 15

8. Clozapine initiation in community settings ...................................................................... 16

8.1 Suitability for community initiation ............................................................................................... 16

8.2 Preparation for community titration ............................................................................................. 16

8.3 Titration schedules ........................................................................................................................ 17

8.4 Monitoring schedules .................................................................................................................... 18

8.5 Administration of clozapine .......................................................................................................... 19

8.6 Managing acute problems ............................................................................................................. 19

8.7 Community initiation as part of a facilitated early discharge ....................................................... 19

9. Ongoing management of clozapine (inpatient and community) ..................................... 20

9.1 Target plasma levels and target doses .......................................................................................... 20

9.2 Monitoring in the longer term ....................................................................................................... 20

9.3 Management of side effects .......................................................................................................... 21

9.4 Clozapine and the risk of suicide ................................................................................................... 23

9.5 Team management of their service users taking clozapine .......................................................... 23

9.6 Access to the ZTAS monitoring system.......................................................................................... 24

10. Moving care settings ......................................................................................................... 24

10.1 Inpatient admission to an AWP ward ............................................................................................ 24

10.2 Admission to an acute hospital setting ......................................................................................... 25

10.3 Admission to a private mental health bed .................................................................................... 25

10.4 Transfer between wards ................................................................................................................ 25

10.5 Transfer between community teams ............................................................................................ 26

10.6 Discharge from inpatient care ....................................................................................................... 26

10.7 Out-of-area clozapine service users .............................................................................................. 27



11. Dealing with potential problems ....................................................................................... 27

11.1 Amber or red results ...................................................................................................................... 27

11.2 Re-challenge after a confirmed red blood result .......................................................................... 28

11.3 Platelet and eosinophil monitoring ............................................................................................... 28

11.4 Benign Ethnic Neutropenia ............................................................................................................ 28

11.5 Management of late or missing full blood count results .............................................................. 28

11.6 Missed doses ................................................................................................................................. 29

11.7 Smoking cessation and effect on clozapine levels......................................................................... 30

11.8 Travel ............................................................................................................................................. 31

11.9 Discontinuing clozapine ................................................................................................................. 31

12. References ......................................................................................................................... 32

13. Appendices and other supporting documents ................................................................ 33

13.1 Appendix – blood test parameters ................................................................................................ 34

13.2 Appendix – action on clozapine plasma levels .............................................................................. 35

13.3 Appendix – target dose of clozapine ............................................................................................. 36

13.4 Appendix – flow chart for monitoring for clozapine induced myocarditis .................................... 37



Service user

Ro

les

Risks

Mo

nit

ori

ng

Communication

A clear and specific care plan on RiO

Clear communication when care moves between settings including pharmacy

Pharmacy must be told of any alterations to a clozapine prescription

The AWP Clozapine Administration System to help information sharing about monitoring and dispensing

GPs must be told clozapine is being supplied by AWP and be advised of side-effects to be aware of

The clozapine monitoring service must be informed of changes to team, consultant, treatment breaks or the cessation of treatment

Full blood count monitoring is essential - without a valid, up-to-date blood result, medication cannot be supplied

Plasma levels of the drug may also be monitored (separate process)

Intensive monitoring of physical observations (e.g. BP, pulse and temp) is essential at the start of treatment

Myocarditis monitoring in the first 4 weeks of treatment

Ongoing monitoring of side-effects such as constipation and weight gain must be done

Regular physical health checks at least annually

There are risks of serious side effects including dangerously low blood counts

There are also other potentially serious side-effects such as cardiac problems or constipation

Risks are higher when treatment is started, it must be slowly titrated

Tolerance to clozapine wears off quickly, a treatment break of more than 48hrs means treatment must be re-titrated. This can cause problems for both physical and mental health

A high plasma level of clozapine increases the risk of side-effects

Drug interactions and changes in smoking habit can significantly alter clozapine levels

Responsibility for prescribing, supplying and monitoring clozapine rests with secondary care

The care coordinator manages communication between all people involved

The AWP pharmacy team supply medication and helps ensure blood count monitoring is being performed

The consultant retains overall responsibility for the prescription and monitoring of clozapine

The consultant must be registered with the relevant clozapine monitoring service

Prescribing may be delegated to other prescribers with the necessary competence

GP surgeries may agree to assist with blood sampling

Quick Start Guide to Clozapine



1. Introduction

This procedure explains how clozapine treatment should be initiated, continued and monitored for

service users on inpatient wards and in the community.

Clozapine was the first of the atypical antipsychotics to be developed and has been found to be the most effective antipsychotic drug for treatment-resistant schizophrenia (TRS), but its use has been limited because of the risk of serious side-effects.

In order to reduce the risk of these side-effects causing serious harm, The Medicine and Healthcare Products Regulatory Authority (MHRA) has placed restrictions on its prescribing and dispensing, including extensive monitoring. Clozapine is licensed for:

Treatment-resistant schizophrenia

‘Clozapine is indicated in treatment-resistant schizophrenic patients and in schizophrenia patients who have severe, untreatable neurological adverse reactions to other antipsychotic agents, including atypical antipsychotics.

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’

Psychosis during the course of Parkinson's disease

‘Clozapine is also indicated in psychotic disorders occurring during the course of Parkinson's disease, in cases where standard treatment has failed.’

Summary of Product Characteristics: Zaponex

2. Scope

This procedure applies to nursing, medical, pharmacy and support staff involved in providing care to service users taking clozapine on AWP inpatient units and in AWP community teams. This includes staff not directly employed by AWP, but contracted to provide services to the Trust.

It is beyond the scope of this procedure to cover all the clinical scenarios relevant to managing clozapine treatment. Some clinical issues are highlighted but this document should be used alongside other relevant literature (see references). If necessary seek advice from your locality pharmacist.

3. Definitions

Blood dyscrasias: A general term which is used to describe any abnormality in the blood cells or bone marrow cells. An example of a blood dyscrasia is agranulocytosis: a severe and dangerous lowered white blood cell count. It represents a severe lack of one major class of infection-fighting cells. Clozapine can rarely cause blood dyscrasias including agranulocytosis.

Care coordinator / navigator: the person in a community based team who is accountable for overseeing the care management of the service user.

Clozapine monitoring service: a national registry for service users taking clozapine. The service holds and reviews the platelet, white cell and neutrophil counts for each service user and issues warnings if blood results fall too low. One monitoring service is run by each of the companies that manufacture and market clozapine. The service used within AWP is the Zaponex Treatment Access System (ZTAS).

Clozapine pharmacist: a pharmacist named on the Zaponex Treatment Access System (ZTAS) as having responsibility for a group of clozapine patients (alongside their named consultant). In AWP this would usually be the Locality Lead Pharmacist for each area.

https://www.medicines.org.uk/emc/medicine/30938



Community initiation: this means initiation in a place other than a hospital ward. This may include the service user’s home, supported accommodation, respite house, care home, day care/hospital facilities, friends’ or families’ homes.

Community team: for example a Recovery team, Early Intervention team, forensic team or variation of these. This is the team that usually is responsible for the care of the service user while they are in the community.

Facilitator: the person overseeing the process of initiation in the community. This person should be aware of all pertinent information in order to be in a position to make decisions about the needs of the individual service user. This role is concerned with the practicalities of the initiation process. The facilitator, depending on their clinical background, may be in a position to make some clinical decisions if agreed with the responsible clinician.

Full blood count (FBC): a panel of blood tests that examine different parts of the blood such as white blood cells, red blood cells, haemoglobin and platelets. ZTAS employs a ‘traffic light' classification system for results, which applies to WBC and neutrophil counts. Full details can be found in appendix 14.1

Intensive Service: also known as crisis or home treatment services - a team that provide a 24 hour service to help people access support in a mental health crisis situation and as an alternative to hospital admission. These teams provide ‘wrap around care’ in addition to the care provided by community teams and may facilitate early discharge from hospital wards.

Summary of Product Characteristics (SPC): a technical document giving detailed information about a medicine, and its approved uses in the UK. It is checked and approved by the UK or European government agencies which license medicines.

Treatment resistant schizophrenia (TRS): schizophrenia which fails to respond to two antipsychotics (one of which should be an atypical) taken at adequate doses for an adequate duration of time.

Zaponex: the brand of clozapine that is currently used with in AWP. Two other brands are available: Clozaril and Denzapine. Service users transferring from an area using a different brand will need to be changed to Zaponex (contact your locality pharmacist for advice).

4. Roles and responsibilities

All AWP staff involved with the use of medicines, must be aware of this procedure.

Consultants

Consultants who oversee the care of service users taking clozapine must be registered with the monitoring service (ZTAS). Before initiating clozapine for a service user, the consultant must assess the service user’s eligibility to receive clozapine and then register them or ensure that they are registered with the ZTAS monitoring service and ensure all the appropriate baseline monitoring is completed. They have responsibility for deciding on an appropriate initiation regimen. They retain overall responsibility for their service users prescribed clozapine, ensuring the required monitoring is carried out and the prescription is reviewed regularly.

They are also responsible for directly communicating with and agreeing the precise arrangements for handover to another registered consultant when the service user moves care settings as per the Trust ‘red top internal safety alert’ November 2015.

If a service user taking clozapine has a red blood result, the consultant retains ultimate responsibility to ensure that their clozapine is stopped and their mental and physical health is intensively monitored.

http://ourspace/StaffServices/PtoT/RiskCompliance/Safety%20Alerts/INT-2015-0014%20Clozapine%20Prescribing.doc



Other medical staff and prescribers

The prescribing and monitoring of clozapine may be delegated to other competent medical staff or non-medical prescribers. Any prescriber should ensure they only prescribe clozapine to service users who are registered with ZTAS. They may also take responsibility for the day-to-day monitoring of the service user’s physical and mental health (including taking blood samples). The registered consultant retains ultimate responsibility for the service user and for ensuring any prescriber working with them is aware of this procedure.

Nursing staff

Nursing staff are responsible for carrying out much of the required monitoring of service users taking clozapine. They must also be sure that any service user they administer clozapine to has a valid blood result and that in line with their code of practice they are aware of the side effects, usual doses and cautions of using clozapine.

They are responsible for flagging up any concerns about the physical and mental health of a service user to the consultant or on call/team doctor.

Pharmacy staff

Pharmacy staff must only dispense clozapine to a service user registered with ZTAS to receive clozapine and who has a valid blood result. Although pharmacy staff can support medical and nursing staff in ensuring that appropriate monitoring (in particular FBC monitoring) is carried out (e.g. issuing reminders when blood tests are due). The final responsibility however remains with the clinical team and in the community the care coordinator/ recovery navigator.

Pharmacy staff will be expected to assist in the process of stopping clozapine if a red blood result occurs (e.g. removing medication from a ward, not issuing further supplies). There is a small team at the Calne Dispensary with particular responsibility for dispensing clozapine. Locality Lead Pharmacists play a key role in supporting consultants and teams in the prescribing and monitoring of clozapine in their area.

Ward or team managers

Those in charge of wards and teams are responsible for ensuring that their staff follow this procedure, especially new starters and locum staff. Managers should have a mechanism (for example through clinical supervision) to make sure their staff have an understanding of how clozapine is prescribed and monitored appropriate to their role and case load. This includes the allocation of an appropriate care coordinator for service users taking clozapine.

They should have a mechanism in place to maintain real-time oversight of all service users prescribed clozapine within their team and the arrangements in place for monitoring and medication supply.

If a team is asked to take on an extended role in relation to clozapine (for example supporting community initiation), then the manager must be assured that the team has the capacity and competence to do this.

Care coordinators/ key workers/ recovery navigators

Care coordinators are responsible for ensuring the continuity of the provision of clozapine treatment and blood tests across boundaries of care and also while the service user is under the care of a long term community based mental health team. The care coordinator must ensure that clozapine treatment features in the service users care plan along with information on blood sampling frequency and location, how the service user receives their clozapine supplies and what the dose and formulation of the clozapine is.

They are responsible for the coordinating the communication between all other professionals involved in the care of the service user including consultants, GPs and the clozapine team at the Calne Dispensary.



5. Key contact details

Zaponex Treatment Access System

0207 365 5842

www.ztas.co.uk

Includes an out-of-hours on-call service after 5pm

AWP Calne dispensary clozapine desk

01225 675476 Monday to Friday 9am to 5pm

AWP on-call pharmacist 01249 468045 Out-of-hours service

Magna Laboratories (clozapine plasma level laboratory)

01989 763 333 Monday to Friday 9am to 5pm (out-of-hours call the Zaponex Treatment Access System above)

AWP Pharmacy Team Contact details can all be accessed on Ourspace

http://www.ztas.co.uk/

http://ourspace/Skills/MedicinesPharmacy/Pages/PharmacyServices%20and%20contact%20details.aspx



6. Pre-initiation considerations

6.1 Informed consent to treatment

The following questions need to be considered:

Does the service user have capacity to consent to treatment?

Does the service user consent to treatment? How has this been documented?

Is clozapine treatment authorised on their T2/T3/CTO11/CTO12 (section 58) treatment plan (if applicable)? The statement ‘including clozapine’ does not now have to be specified on consent to treatment forms, only that an antipsychotic has been authorised.

Will they consent to regular blood tests? Will consent fluctuate?

Is there support from their carer/family (where applicable)?

All service users considering commencing clozapine treatment should have access to written information about the issues involved. If possible they should be offered a one-to-one discussion with a locality pharmacist. An AWP leaflet about clozapine is available (copies can be printed from Ourspace here)

Further information about clozapine for service users and carers can be found at www.choiceandmedication.org.uk/awp. This website offers information in several languages and formats and the latest version should always be printed off and given to the service user.

Enforcement of blood testing is controversial but is considered legal under section 63 of the Mental Health Act; however least restrictive practice should always be used. If the service user does not consent to blood tests the multi-disciplinary should think carefully about long term adherence and alternative treatment should be considered. The advice of a lead Approved Mental Health Professional (AMHP) and other senior clinicians should be sought if any enforcement of treatment may occur.

6.2 Pre-existing health problems

The service user’s physical health will have an impact on whether and how clozapine can be safely initiated. In general, the more complex the person’s physical health condition, the more cautious the initiation of clozapine should be.

There are specific risks such as pre-existing cardiac disease or diabetes that need consideration. Advice from your locality pharmacist, the service user’s GP and other professionals/specialists involved in their care should be sought.

Contra indications include - clozapine-induced myocarditis or cardiomyopathy, uncontrolled epilepsy. See SPC for full list

6.3 Pregnancy and breastfeeding

Advice from a specialist mental health or medicines information pharmacist should always be sought, when considering the choice of medication in pregnancy or breastfeeding. Close liaison with the midwifery and obstetric teams involved is also required.

Consent Physical health

Other medication

Baseline monitoring

Setting Care plan

http://ourspace/ClientServices/PatientInformation/Approved%20Patient%20Information/Clozapine%20Leaflet.pdf

http://www.choiceandmedication.org.uk/awp

http://www.medicines.org.uk/emc/medicine/30938#CONTRAINDICATIONS



6.4 Switching from other antipsychotics

Depending on clinical circumstances, a cross titration from the service user’s current oral antipsychotic treatment may be indicated. Otherwise a gradual withdrawal of other antipsychotics should be planned prior to commencing clozapine (this is the approach recommended by the manufacturer in the SPC). Consider possible drug interactions between clozapine and the service user’s other medication (see section on Interactions). Speak to your locality pharmacist for further advice.

Depots and long acting injections must be stopped before clozapine is introduced because of the risks of myelosuppression. Discuss issues related to individual long acting injections (for example wash out periods) with the relevant locality pharmacist

When swapping from an antipsychotic that may elevate prolactin levels in a female service user, ensure where appropriate, that contraception is considered. Clozapine is unlikely to raise prolactin levels, and so the chances of pregnancy may be increased unless effective contraception is used.

6.5 Drug and other interactions with clozapine

Clozapine can interact with many other medicines and with some other substances. Care should be taken when altering other medication for a service user taking clozapine. Consult a specialist mental health pharmacist for advice on specific cases if necessary.

Some medicines increase the risk of blood dyscrasias such as agranulocytosis and as such are contraindicated with clozapine. If clozapine is to be considered with any of the following medicines, specialist advice must be sought in advance of treatment, initially from the Locality Lead Pharmacist. High risk medicines include (but are not limited to):

• Carbamazepine

• Carbimazole

• Long acting antipsychotic injections

• Sulphonamide antibiotics e.g. co-trimoxazole

• Cytotoxic or immunosuppressive agents such as methotrexate

• Cancer chemotherapy

Some medicines and other substances can significantly alter clozapine plasma levels, resulting in either toxicity or sub-therapeutic effect. For example:

• Hydrocarbons in cigarette smoke: smoking tobacco appears to decrease clozapine levels and clozapine toxicity may occur due to increased levels on smoking cessation. Therefore extreme care is needed if a service user taking clozapine changes their smoking habits. Dose adjustment may be needed to avoid toxicity (see relevant section below)

• Some SSRIs such as fluoxetine and paroxetine can raise clozapine plasma levels. Fluvoxamine can raise plasma levels profoundly; the combined use of the two drugs presents a significant clinical risk and should not be prescribed.

• High caffeine intake can increase clozapine plasma levels by up to 47%.

• Some antibiotics may increase clozapine levels e.g. erythromycin and ciprofloxacin and some authors suggest that clozapine levels may be increased by bacterial infections independently of antibiotic treatment.

Other pharmacodynamic interactions may also occur for example:

• Concomitant use of clozapine with drugs known to prolong the QT interval may increase the risk of ventricular arrhythmias e.g. tricyclic antidepressants, citalopram/escitalopram certain anti-arrhythmic medicines.



• Combining clozapine with other drugs or substances known to result in sedation (e.g. benzodiazepines or opioid analgesics particularly when given parenterally or alcohol) can lead to a profound sedative effect

• Medication known to reduce seizure thresholds (for example tricyclic antidepressants or other antipsychotics) when given with clozapine can lower the threshold enough to induce seizures.

• Medication which increases the risk of constipation such as anticholinergics or opioid analgesics.

6.6 Baseline monitoring requirements

A comprehensive physical health check is required before commencing clozapine, including:

• Full blood count

• Liver function tests

• Urea and electrolytes (U&Es)

• Glucose

• Lipid profile

• Troponin and C-Reactive protein

• ECG

• Weight, body mass index (BMI) and waist circumference

• Blood pressure

• Temperature

• Pulse

• Pulse oximetry if indicated

The initiating consultant must also be familiar with the service user’s previous medical history and the contraindications to clozapine treatment given in the SPC for example: uncontrolled epilepsy or severe renal or cardiac disorders.

A slower than usual titration may be advised because of physical co-morbidities or additional monitoring may be appropriate. The locality pharmacist can provide advice on this. Any risks of clozapine treatment which result from pre-existing physical co-morbidities should be clearly documented in the service user’s care plan and any risk management strategies outlined.

6.7 Setting for initiation

The decision to initiate or re-titrate clozapine in an inpatient setting or in the community is a complex one. There should be a dialogue between the service user’s community consultant and the consultant for the inpatient unit and the intensive team to determine the most appropriate initiation setting. This will depend on the physical health and mental state of the service user, the availability of an inpatient bed, the resources available to the relevant community team(s) and the wishes of the service user.

Community initiation or re-titration should not be carried out unless the teams involved have the correct equipment, staffing levels and skills to carry out the physical health observations required.

The following table sets out the factors which indicate community titration may be lower or higher risk.

For a full discussion of community initiation refer to the relevant section.

https://www.medicines.org.uk/emc/medicine/30938



Lower risk of problems: community initiation desirable

Higher risk of problems: community initiation may be possible

Community initiation inadvisable:

No cross tapering of other oral antipsychotics

No physical health co-morbidities or none that would affect clozapine initiation

Supportive family or carer able to stay with the service user throughout the titration

Cross tapering of other oral antipsychotic

On other medication where caution is advised

Physical health co-morbidity advised as a caution

Alcohol or drug use that is at a level where the service user is still able to engage in the process

Parkinson’s disease

Off-license initiation due to indication or co-prescribed medication.

History of seizures uncontrolled by medication

History of significant cardiac problems

History of Neuroleptic Malignant Syndrome

Service user living alone with no access to support during titration

Chaotic lifestyle that precludes daily monitoring or where the service will not allow access for monitoring

Significant substance misuse, including alcohol

Pregnancy

Where capacity to consent to treatment is lacking

Co-prescribed medication suggesting caution Co-morbidities suggesting caution

Benzodiazepines, alcohol, opiates

Lithium

Paroxetine, fluoxetine, tricyclic antidepressants

Anti-arrhythmics, quinine,

Depots (even when stopped before initiation)

Anti-hypertensives

Medicines with hypotensive, anticholinergic or sedative side effects

Diabetes

Heart disease

Dual diagnosis

Respiratory depression

6.8 Care planning

The service user’s care plan should state they are being initiated on clozapine and should include:

• Frequency of monitoring (including blood tests and physical observations)

• Who is carrying out the monitoring

• Who should be alerted if any monitoring parameters go out of range

• The planned dose titration

• The sampling location for blood tests and where the blood results are processed

• What processes are in place should the service user not attend for a blood test

• How the service user will obtain their supply of clozapine (for example collection from team base, or delivery by a member of staff)

• Who is responsible for prescribing the clozapine



The ‘alerts’ function on RiO must also state that a service user takes clozapine

7. Clozapine initiation – information for all settings

7.1 Registering the service user with ZTAS

The service user must be registered with ZTAS before the supplying pharmacy can dispense clozapine and treatment can commence. Registration forms can be found at www.ztas.co.uk > download forms> patient data form. Routinely the registered consultant should sign the service user registration form. It should ideally be checked by a pharmacist before being faxed to ZTAS.

Treatment must be commenced within 10 days of the baseline blood test; another blood test is required within this 10 day period.

If clozapine is to be used for an indication other than those specified in the SPC, then the ‘off-license’ part of the registration form needs to be completed by the consultant registering the service user. This will need to be submitted and accepted by the clozapine monitoring service before commencement.

The pharmacy team can check to confirm when the registration process has been completed by ZTAS. Initiation of treatment cannot begin until the service user is registered.

7.2 Prescribing the dose titration

The dose must be gradually titrated when clozapine is initiated. Initiation charts for inpatient and community use can be found on the clozapine page on Ourspace. The speed of titration will depend on the treatment setting, and the service user’s physical health. A blank titration chart is available for individualised regimens.

The titration chart must be completed and signed by the prescriber, then kept alongside the current medicine chart. Clozapine should also be written up on the main chart: “Clozapine - see titration chart”

7.3 Ordering medication

Once prescribed, both charts can then be sent to pharmacy for supply or the local pharmacy team can place the order if they are available. They will usually supply up to one week of clozapine.

7.4 Administration

Clozapine should be administered in the same manner as any other oral medicine (see Med 01 Procedure for administration of medicines). It is available as a tablet (25mg or 100mg strength) or as an unlicensed liquid. Tablets may be halved when necessary to administer the prescribed dose. The bottle of liquid must be shaken thoroughly before administration.

If the liquid is to be used (or in the short term, if tablets are going to be crushed) to aid administration, then the prescriber must authorise this as both the liquid and crushing the tablets represent use of the medication outside of the license.

Registraion Prescribing Ordering Administration Monitoring


http://www.ztas.co.uk/pdf/WT%20PATIENT%20DATA%20FORM%20A%20-%20V03.pdf

http://ourspace/Skills/MedicinesPharmacy/Pages/Clozapine.aspx

http://ourspace/Skills/MedicinesPharmacy/Clozapine%20documents/Clozapine%20titration%20chart%20BLANK.doc

http://ourspace/Skills/MedicinesPharmacy/Medicines%20procedures/Med01.doc




7.5 Monitoring

The full blood count (FBC) must be monitored weekly for service users initially started on clozapine. For the first 4 weeks, blood tests to measure troponin and CRP should be conducted alongside the FBC wherever possible. For full details of the FBC parameters and blood test classifications see appendix 14.1

The specific schedules for monitoring in inpatient and community settings are summarised in the linked documents.

Any staff undertaking the physical health checks of a service user commencing clozapine must have undergone the appropriate training including the AWP National Early Warning Score (NEWS) workbook and a face-to face physical health observation training workshop.

Other more general physical health monitoring should include being alert for the following issues:

Flu-like symptoms

Particular attention should be paid to flu-like complaints such as fever or sore throat, which may be indicative of neutropenia. An extra FBC should be arranged.

Myocarditis

Clozapine is associated with an increased risk of myocarditis which has, in rare cases, been fatal. The increased risk of myocarditis is greatest in the first two months of treatment. Measuring CRP and troponin levels at baseline and weekly for the first four weeks can be helpful (see flow chart).

Myocarditis or cardiomyopathy should be suspected in patients who experience persistent tachycardia at rest, especially in the first two months of treatment, and/or palpitations, arrhythmias, chest pain, diarrhoea, vomiting, dysuria and other signs and symptoms of heart failure (e.g. unexplained fatigue, dyspnoea, tachypnoea) or symptoms that mimic myocardial infarction.

If myocarditis or cardiomyopathy is suspected, clozapine treatment should be promptly stopped and the patient immediately referred to a cardiologist. Where cardiology referral is made, blood tests for troponin and C-reactive protein (CRP) levels should be performed to guide management. Service users who develop clozapine-induced myocarditis or cardiomyopathy should not be re-exposed to clozapine (see also the section on the management of side-effects)

Diabetes

Cases of diabetes have developed within one month of starting clozapine. Death from ketoacidosis has been reported. Symptoms suggestive of diabetes should be investigated. Plasma glucose should be checked after one, six and twelve months of treatment, and routinely every 12 months thereafter. Approximately one third of people started on clozapine will develop diabetes within 5 years.

Constipation

Constipation may be severe and fatalities due to bowel obstruction or ischaemia have been reported. The multidisciplinary team must enquire about constipation specifically, when asking the service user about side-effects. Regular long-term laxatives may be needed. Problems are most likely in the first four months of treatment.

Symptoms that warrant urgent medical attention are: abdominal distension, abdominal pain, vomiting, overflow diarrhoea, absent bowel sounds and symptoms of sepsis. If these occur clozapine should be withheld along with other anticholinergic medication until the service user has been medically assessed.

Seizures

The risk of seizure is dose (and plasma level) related. A prophylactic anticonvulsant (not carbamazepine) may be considered when the dose is above 500mg/day or the plasma level exceeds 0.6mg/L.

http://ourspace/Skills/MedicinesPharmacy/Clozapine%20documents/Inpatient%20Pre%20and%20Post%20Clozapine%20Administration%20Monitoring%20Guidance.docx

http://ourspace/Skills/MedicinesPharmacy/Clozapine%20documents/Community%20Pre%20and%20Post%20Clozapine%20Administration%20Monitoring%20Guidance.docx

http://ourspace/Skills/Nursing/Documents/NEWS%20Workbook.docx

http://ourspace/Skills/Nursing/Documents/NEWS%20Workbook.docx



Risk of DVT/PE

There is a risk with all antipsychotics of precipitating deep vein thrombosis or pulmonary embolism. Any symptoms should prompt medical examination.

8. Clozapine initiation in community settings

8.1 Suitability for community initiation

The service user must be willing to engage. They must consent to the treatment and the monitoring, including on-going blood tests and agree to either attending daily appointments or allowing daily monitoring in their home

There should be a carer, family member, friend or member of staff in supported accommodation that should be able to be nearby to the service user at night so that help can be raised if the person experiences severe side effects that require immediate attention.

The service user should not have a significant or unmanaged substance misuse problem that may affect clozapine initiation in the community. The sedative effects of alcohol or opiates in particular need consideration.

Co-morbidities that indicate caution include: unstable cardiovascular disease, Parkinson's disease, epilepsy or high risk of seizures, liver dysfunction, increased risk of blood or immune disorders or vulnerability to infection.

Previous adverse reactions to clozapine (particularly a previous red result) or other antipsychotics e.g. neuroleptic malignant syndrome (or NMS) usually means community initiation is not suitable. Older adults and pregnant women are also at increased risk of side-effects.

8.2 Preparation for community titration

The care coordinator should arrange a review with the service user’s consultant to ascertain that the service user meets the criteria for community initiation / re-titration and that any risk factors are identified and addressed.

The decision to start the process for community initiation of clozapine resides with the service user’s allocated community consultant. Other staff or teams may later identify factors that make

Engagement

Support at home

No active substance misuse

Physical health stable

Low risk of adverse reactions



inpatient initiation necessary or desirable and decisions should be made in collaboration with all teams involved and clearly documented.

All the relevant factors outlined in the sections on pre-treatment considerations and initiation above must be addressed.

The care coordinator along with the community team manager or senior practitioner should determine the level of help required from the Intensive Service. It is suggested that there is one member of staff (the facilitator) within the community team, that will be aware of observation results, blood sample arrangements and the progress of the service user.

Best practice is that the Intensive Service and the service user’s usual community team work together during the titration. A schedule of visits and who will carry out each dose administration and monitoring should be developed and agreed by both teams for each individual’s initiation.

The care coordinator should contact the Intensive Service and ask if and when the (re)titration can take place. In some areas there may be a waiting time, due to the time commitment for the intensive monitoring required. It is suggested that the Intensive Service generally undertake one initiation at a time.

If a faster re-titration is needed for a service user that has only missed a few doses then the community team may be able to do the re-titration themselves, however the Intensive Service must still be informed, in case of any concerns or questions arising out of hours.

The care coordinator should check that the core assessment, care plan and the risk assessment are current, complete and valid. They should then inform any other team involved in the (re)titration so that they can view the documents electronically and agree to support the (re)titration and monitoring proposed.

The care coordinator should ensure that an up to date list of all current medication that the service user takes is uploaded on RiO; this includes medication prescribed by the GP, medication supplied by mental health teams, other specialists and any over the counter medication.

The community team consultant and care coordinator must propose a titration and monitoring schedule for the service user. These must be discussed with the Intensive Service consultant and agreed by both teams.

8.3 Titration schedules

The recommended community titration has dose increases occurring at night, to minimise the impact of side-effects such as dizziness or drowsiness as the service user will be in bed. Post dose observations depending on the risks identified are generally not conducted at night so a service user’s sleep is not interrupted.

Teams may devise a bespoke titration in consultation with the locality pharmacist. This may be needed to address particular service user or team characteristics, but should never compromise the safety of the service user.

It is suggested that the dose is split to twice a day to minimise side effects. If a once daily dose must be used, then the titration may need to be conducted more slowly to minimise side effects. The alternative is to titrate using a twice daily dose and once the target dose is reached the dose is moved gradually to once a day by reducing one dose and increasing the next dose until the whole dose is taken once a day. Note the SPC does not recommend once daily dosing where the total daily dose exceeds 200mg.

Service users with Parkinson’s disease may be initiated in the community, but staff should be aware of the sensitivity of this type of service user to antipsychotics and a slow titration starting at 6.25mg should be carried out. Subsequent increases in dose should not exceed 12.5mg per day, with a maximum of two dose increases in a week, with a target dose of no more than 37.5mg for the initial titration and then pause to assess clinical effect. This will be a ‘bespoke’ initiation and designed around the service user. Staff should be given extra advice from the responsible consultant on what to monitor and a more intensive monitoring schedule should be considered.

http://ourspace/Skills/MedicinesPharmacy/Clozapine%20documents/Clozapine%20titration%20chart%20standard%20community%20tablets.docx


http://www.medicines.org.uk/emc/medicine/30938#CONTRAINDICATIONS



8.4 Monitoring schedules

The table below sets out when different levels of observation and monitoring should be used in the community. This information is also summarised here.

Level 1 monitoring Level 2 monitoring Level 3 monitoring:

only to be considered when there is considerable clinical experience and resource

Type of service user

No serious comorbidity Diabetes, cardiovascular disease above simple hypertension, elderly, people with Parkinson’s disease

Epilepsy that is well controlled where inpatient admission is not an option. Several co-morbidities present.

Day 1 monitoring requirements

Pre dose and then 2, 4 and 6 hours after the dose

Pre dose and then at 2, 4 and 6 hours after the dose

Pre dose and then at 2, 4 and 6 hours after the dose, consider monitoring on healthcare premises

Day 2 onwards Pre dose and again 2-6 hours after morning dose throughout the titration on all days where there is a dose increase

As level 1 with addition of extra pre-dose observations before evening dose for first week

As level 1 with addition of observations pre evening dose on all days where there is a dose increase for the duration of the titration

A note of all record of monitoring should be made on RiO as soon as possible after they are taken so that all involved can access the results. If monitoring is done and the member of staff has not got immediate access to RiO, the results should be telephoned back to a colleague. The person taking the readings should record on RiO as soon as possible.

If it is safe to do so, the monitoring equipment, recording sheets and medication could be left with the service user. If shared records and equipment cannot be left with the service user then arrangements need to be made for each team visiting to have access to these.

Communication and responsibilities during community initiation

Thorough preparation, a clear understanding of everyone’s role and ongoing communication are vital to the success of a community initiation of clozapine.

The care coordinator should agree with the Intensive Service each team’s role and responsibilities during the titration and this should be clearly documented in a care plan. The care coordinator should maintain contact with the Intensive Service and the service user throughout the titration.

The responsibility for prescribing and practical management of the titration and decisions around medical treatment and monitoring will reside with the Intensive Service consultant. The consultant may delegate these tasks to other appropriate members of the team, though they retain accountability. There should be liaison between consultants as to which consultant should be registered with ZTAS.

Liaison with the relevant dispensary and locality pharmacist is also important. Medication may be arranged to be delivered to an inpatient ward, home treatment team or the community team whichever is most suitable. The general procedures relating to storage and transport of medication in community teams must be followed.






8.5 Administration of clozapine

Where possible the service user should self-administer their medication, and staff may support and encourage this. To be classed as self-administration, the service user must be able to manage all parts of the process themselves including selecting the dose (including counting the number of tablets or measuring out the liquid).

Not all service users will be able to perform this role independently. If clozapine is being administered (rather than self-administration being observed) then this is a nursing role and the procedure for administering medication must be followed.

8.6 Managing acute problems

The Intensive service will have initial responsibility for managing any difficulties which arise during the titration. These can often be addressed by slowing the rate of titration and/or prescribing medication to manage side-effects.

If more serious physical health problems occur then the Intensive service should arrange a physical health review via the GP or out-of-hours care appropriate to the seriousness of the issue (including the local Emergency Department if necessary).

If a titration has to be slowed or stopped and this precipitates a mental health crisis, this should be assessed by the Intensive Service in the usual way and an inpatient bed sought if necessary.

8.7 Community initiation as part of a facilitated early discharge

Service users initiated on clozapine as inpatients may be discharged to the community before their titration is complete, if there is sufficient support from the Intensive service. The recommendation is that service users complete a full week of their clozapine titration on a ward, before being considered for discharge. Whilst a service user is still having their clozapine dose titrated up in the community, daily visits from the Intensive team would be considered necessary with observations (temperature, blood pressure and heart rate) being checked as per the appropriate monitoring level; depending on the risk assessment. Before discharging a service user still titrating clozapine, it is important to establish:

That the Intensive Service are able to facilitate visits to supervise administration of medication, monitor the service user and whether the community team are able to provide support with visits

When the next blood test is due

Where the blood samples will be taken and by whom

Who will review and act upon all blood results including CRP and troponin

How many days of clozapine are being supplied on discharge

If the titration schedule will need to be changed

Who will continue prescribing clozapine. A prescription must be written and sent to pharmacy on the appropriate chart. The prescription is available to the team supplying the medication to record doses given.

A clozapine discharge form should be completed and sent with the order for medication to the pharmacy


http://ourspace/Skills/MedicinesPharmacy/Clozapine%20documents/Clozapine%20discharge%20form.pdf



9. Ongoing management of clozapine (inpatient and community)

9.1 Target plasma levels and target doses

After the initial titration of clozapine is complete, the dose may still need adjustment. The dose of clozapine producing clinical effect without intolerable side-effects varies considerably between service users. To guide what dose to aim for when initiating clozapine, the gender and smoking status of the service user should be taken into consideration. The weight and age of the person are also likely to have an effect. A model, taking these factors in to account can be used to determine a target dose likely to give an efficacious, non-toxic plasma level (see appendix). These target doses cannot be used as a substitute for individual plasma level monitoring.

Plasma level testing is separate from the FBC monitoring required to allow clozapine treatment to continue. Plasma levels cannot be performed by local laboratories, samples must be sent to Magna Laboratories using a pre-addressed kit.

Samples should be taken at the trough point (i.e.11-14 hours post the previous dose, usually before the morning dose is taken) and the drug will take three to five days to reach steady state after a dose change.

In broad terms, response is thought to be most likely within a plasma level range of 0.35-0.6 milligrams/L. Side effects are much more likely at levels above 0.6 milligrams/L and measures such as seizure prophylaxis need to be considered at this point. If you need further advice on interpreting a plasma level result, contact Magna Laboratories by telephone on: 01989 763 333 or contact a local specialist pharmacist to discuss appropriate action.

Levels above 1 milligrams /L should be acted on urgently. Magna labs will usually contact the named pharmacist and registered pharmacy by telephone to inform them of such a result. The pharmacist receiving the information will ensure that the team involved are contacted so that this can be discussed with the consultant and action taken.

9.2 Monitoring in the longer term

The FBC must be monitored weekly for service users initially started on clozapine. If there are no problems with their blood results, after 18 weeks, monitoring can be reduced to fortnightly. If blood results remain stable for the remainder of the year, monitoring can be reduced to once every four weeks. ZTAS will advise when a service user’s monitoring frequency has changed.

FBC tests are carried out at local hospital laboratories, using a barcode system to allow the result to be automatically uploaded to the ZTAS database. Bar code labels are ordered for individual service users via www.ztas.co.uk > download forms > label request form.

ZTAS employs a ‘traffic light' classification system for results, which applies to the white blood cell and neutrophil counts. Full details of the thresholds for red, amber and green results can be found in the relevant appendix.

Additional physical health checks are recommended:

1 month 3 months 6 months 12 months

Weight/BMI/waist circumference

BP and pulse

ECG

Plasma glucose / HbA1c and lipids

LFTs


http://www.ztas.co.uk/pdf/Magna_Label_Request_Form.pdf



1 month 3 months 6 months 12 months

Prolactin

U&Es, CPK, TFTs

Staff involved in monitoring the service user should also remain aware of risks such as constipation and myocarditis as outlined in the acute monitoring section above. More detail is also given in the section on managing side effects below.

All patients on clozapine should as an absolute minimum, be offered a full annual physical health check. At this check and other consultations service users should also be asked about extra pyramidal and other side effects, smoking status, alcohol and illicit drug use and offered appropriate interventions and advice.

9.3 Management of side effects

In order to monitor the side-effect burden of clozapine, teams may wish to use the Glasgow Antipsychotic Side-effect Scale (GASS) or its recently developed clozapine specific variant: GASS-C. The original GASS scale is freely available (along with instructions on its use) on RiO (‘specialist assessments’ section from service users home page and then click on ‘rating scales’) or from http://www.reach4resource.co.uk/glasgow-antipsychotic

The management of side effects of clozapine may need the prescription of other medication. Physical side effects such as constipation are common with clozapine, where possible the prescribing of medication for such physical side effects may be managed by the GP and the GP should be given information on clozapine, what warning flags to be aware of and when to seek advice.

Management of other side effects, such as hypersalivation, involves ‘off label’ (outside of the licensed indications) use of a medicine. Whilst the GP may be invited to take on the prescription of these medicines, the off-label indication may mean they are unwilling to prescribe. In which case prescribing should remain with AWP and medication prescribed on the same prescription chart as the clozapine. For unlicensed medications such as pirenzapine the prescribing must remain with AWP. In both cases the AWP procedure on the use of unlicensed and off-label medication should be followed.

Sudden onset of side effects may suggest erratic adherence, therefore the service user should be reviewed. Myoclonus has been identified as a warning sign of seizures and the service user may also present as agitated, jittery or over sedated.

Side effect Time frame Management strategies during titrations

Management strategies once dose stable

Pyrexia Benign hyperthermia can occur early in treatment especially in the first 3-4 weeks

If temperature is above 38.5oC perform a white cell count and withhold clozapine until the results are known. An anti-pyretic such as paracetamol may be given until cause is known. Consider NMS or myocarditis

If temperature is above 38.5oC perform a white cell count and withhold clozapine until the results are known. An anti-pyretic such as paracetamol may be given until cause is known. Consider NMS or myocarditis

Drowsiness / sedation

Usually within the first 4 weeks but may last longer

Slow down titration, move to give lower dose in the morning once titration is complete

Give lower dose in mornings, check plasma levels.

http://www.reach4resource.co.uk/glasgow-antipsychotic

http://ourspace/Skills/MedicinesPharmacy/Medicines%20procedures/Med10.docx

http://ourspace/Skills/MedicinesPharmacy/Medicines%20procedures/Med10.docx





Hypersalivation Appears early in treatment (1-4 weeks)

Clozapine dose increases may need to be adjusted and increase slowly. Prop up pillows at night and use towel to cover pillow If severe, administer small dose of anticholinergic

Prop up pillows at night and use towel to cover pillow If severe, consider treatment with cholinergic or other medication (see hypersalivation treatment options document on trust website)

Tachycardia Early in treatment but can persist throughout. Often dose related

This side effect is mainly troublesome if combined with high temp as it could indicate infection however other potentially serious causes of tachycardia must be excluded such as pulmonary embolism or myocarditis. Use low starting dose and only increase very gradually. Monitor pulse at least daily. If >120bmp or >30bpm above baseline ECG and daily blood samples to test troponin and CRP should be taken and analysed if clinically indicated. Consider cardiology referral. See flow chart

Use lowest possible maintenance dose. Review caffeine intake and suggest relaxation techniques. If persists and is benign try beta-blocker (such as atenolol or bisoprolol which do not act centrally) providing there are no medical contraindications

Constipation Anytime during treatment but more common in first 4 months and often continues

Adjust diet; ensure fluid intake adequate. Give a stool softener or macragol laxative. Senna can be used This side effect should never be ignored. Bulk-forming laxatives and lactulose are not suitable for acute management

Adjust diet; ensure fluid intake adequate. Give a stool softener or macragol laxative. Senna can be used. This side effect may be fatal and should never be ignored.

Nausea/ vomiting May occur early in treatment

Reduce the dose and increase more slowly. If severe give an anti-emetic (avoid prochlorperazine or metoclopramide if had EPSEs in past). Consider myocarditis as a potential cause.

Reduce the dose and increase more slowly. If severe give an anti-emetic. (avoid prochlorperazine or metoclopramide if had EPSEs in past).

Hypotension First 4 weeks Seek medical advice if there is a drop in systolic blood pressure of >30 mmHg. Consider myocarditis as a potential cause. Give advice on standing slowly. Slow down titration rate.

Seek medical advice if there is a drop in systolic blood pressure of >30 mmHg. Give advice on standing slowly.





Marked weight gain

Anytime during treatment weight gain may be more in first year of treatment

Exercise. Monitor weight. Dietary counselling before and during treatment.

Exercise. Monitor weight. Dietary counselling before and during treatment.

Seizures Can occur at anytime. Dose dependent. Incidence rises at doses >500mg daily

Use lowest effective dose and avoid rapid dose increases. If a seizure occurs, withhold clozapine for 24hrs, then resume at 50% of dose. Consider anticonvulsant therapy (not carbamazepine).

Use lowest effective dose and avoid rapid dose increases. If a seizure occurs, withhold clozapine for 24hrs, then resume at 50% of dose. Consider anticonvulsant therapy (not carbamazepine).

Hypertension May happen during initial treatment

Lifestyle assessment advice, e.g. Reduce caffeine/sodium/nicotine intake

Lifestyle assessment advice, e.g. Reduce caffeine/sodium/nicotine intake

Nocturnal enuresis

When treatment first started

Adjust dose, consider desmopressin nasal spray considering the risk of hypernatremia.

Adjust dose, consider desmopressin nasal spray considering the risk of hypernatremia.

Not passing urine Anytime Urgent medical referral Urgent medical referral

Flu like symptoms / sore throat

More likely in early treatment

Arrange to check White Blood Cell count via local path lab. Consider myocarditis.

Arrange to check White Blood Cell count via local path lab.

Breathing difficulties / chest pain / leg swelling

Anytime Consider pulmonary embolism / Deep vein thrombosis. Follow local protocol for suspected DVT/PE.

Consider pulmonary embolism / Deep vein thrombosis. Follow local protocol for suspected DVT/PE.

9.4 Clozapine and the risk of suicide

Service users are more likely to commit suicide within the first few weeks or months after a hospital discharge. It has been hypothesised that an improvement in psychotic symptoms can lead to a better awareness of life circumstance, and a corresponding increase in despair. This then appears to potentially increase the risk for suicide on discharge. This is not a clozapine specific effect but the risk should be considered in the context of commencing clozapine. Good quality psychosocial interventions can help mitigate this effect.

Conversely, in the medium to long term, there is a significant amount of evidence that clozapine treatment is a protective factor in preventing suicide. For example, the InterSePT study (International Suicide Prevention Trial) showed treatment with clozapine reduced serious suicide attempts and hospitalizations to prevent suicide, by 26% when compared to olanzapine over 2 years. The US FDA includes suicidal behaviour in schizophrenia as an indication for clozapine treatment.

9.5 Team management of their service users taking clozapine

Each community mental health team / recovery team must have an internal real-time monitoring system for identifying and discussing the current dispensing, monitoring and prescribing status of all service users on the team’s caseload who are receiving clozapine treatment as written in the Trust red top internal safety alert November 2015. In most teams this takes the form of a regularly updated spreadsheet.

http://ourspace/StaffServices/PtoT/RiskCompliance/Safety%20Alerts/INT-2015-0014%20Clozapine%20Prescribing.doc



In late 2016, the Trust’s bespoke Clozapine Administration System will be rolled out to community teams, allowing them access to the records which pharmacy hold on all service users taking clozapine, including blood monitoring frequency, blood result status, when medication was last dispensed and where it was delivered to.

Teams should make sure that a service user’s GP is aware that they are prescribed clozapine, and that it is recorded in the GP’s electronic notes system for example as a ‘hospital only’ repeat prescription. Locality pharmacists can support the implementation of this requirement.

9.6 Access to the ZTAS monitoring system

Staff involved in looking after service users taking clozapine can apply to have access to the ZTAS monitoring website in order to check validity of blood tests and also when blood tests are next due. An application form can be printed from the ZTAS website www.ztas.co.uk > download forms > proxy data form. This will need to be completed by the staff member and counter signed by the local clozapine pharmacist (usually the Locality Lead Pharmacist); once this is complete it must be faxed to ZTAS.

ZTAS will then process the request and send a user name and password in the post or via email to the individual staff member; this may take several weeks for the request to be processed. Access can only be granted to individuals, not teams or generic users.

Each year ZTAS will supply the named clozapine pharmacist with a list of current authorised users for the pharmacist to check. The pharmacist must confirm which users still need access and ask for removal of those staff members no longer working in the locality or who no longer require access.

Each locality pharmacist should check their clozapine service users details on ZTAS at least once a year to ensure that registered consultants and treatment locations are still current.

10. Moving care settings

10.1 Inpatient admission to an AWP ward

Ensuring that their medication is continued as intended on admission and discharge is important for all service users. The restrictions on the supply of clozapine, and the risks associated with unintended dose changes or cessation, make it particularly important that the processes are managed smoothly for service users taking this medication.

If a service user already taking clozapine is admitted to an inpatient unit, the admitting doctor must take care to establish who supplies the clozapine, whether the service user has been compliant with their medication at the prescribed dose, and whether they have a valid blood result. The service user should be asked to bring their clozapine in to hospital with them so treatment can continue without interruption.

If there is any doubt as to whether a service user taking clozapine has a valid blood result, contact your locality pharmacist for advice (or the on-call pharmacist out-of-hours)

If it becomes clear that the service user has not been taking their clozapine as prescribed for more than 48 hours, and the decision is taken to recommence treatment, then a re-titration regimen must be prescribed. Additional blood sampling may be required (see the section on Missed doses)

Each inpatient unit has access to an emergency supply of clozapine which can only be accessed following confirmation from a member of pharmacy staff. Out of hours authorisation must be sought from the pharmacist on call.


http://www.ztas.co.uk/pdf/WT%20PROXY%20CARE%20DATA%20FORM%20F%20-%20V02.pdf



10.2 Admission to an acute hospital setting

If a member of the mental health team becomes aware that a service user taking clozapine has been admitted to an acute hospital for physical health treatment, it is important to make sure that the healthcare team there are aware of the importance of clozapine treatment and associated monitoring. It is also helpful to ensure that they are aware of the various risks to physical health that are associated with clozapine.

Because clozapine is prescribed by secondary mental health services, it can be missed by the acute hospital’s medicines reconciliation process. In addition, healthcare staff in a general setting may be unfamiliar with clozapine, its monitoring requirements and adverse effect profile, so good communication from the mental health team is vital.

The acute hospital pharmacy may not be registered to supply clozapine, so arrangements to have a supply delivered from the AWP pharmacy in Calne may be necessary. The AWP pharmacy team can assist with this. Out of hours supply can be facilitated by the AWP pharmacist on call.

Most acute hospitals do not administer medication from compliance aids brought in by service users, thus even if the service user does take their compliance aid in with them, a boxed supply will be need to be obtained from pharmacy.

10.3 Admission to a private mental health bed

Ensuring that their medication is continued as intended on admission and discharge is important for all service users. The restrictions on the supply of clozapine, and the risks associated with unintended dose changes or cessation, make it particularly important that the processes are managed smoothly for service users taking this medication

Where possible the service user’s own supply of clozapine should be sent with them. If this is not possible, liaise with the private ward to determine their arrangements for accessing clozapine in such a situation.

Information on the service user’s registration with the ZTAS monitoring service, when the next blood test is due and when the blood validity runs out must be communicated to the receiving ward. The pharmacy team can access this information and provide it if the clinical team do not know. Out of hours the on call pharmacist can be contacted to access the information.

The receiving private ward will need to register the service user with their respective clozapine monitoring service. A service user can only be registered with one monitoring service at a time, so their registration with ZTAS, the AWP pharmacist and AWP consultant will cease. The reverse will need to happen when the service user transfers back to AWP. The change in registration process takes 24-48 hours.

10.4 Transfer between wards

Any patient on clozapine being transferred to another inpatient bed (either within or outside the Trust) should have their clozapine medication sent with them to the receiving ward. An AWP clozapine transfer form must be completed with as much information as possible, and sent to the receiving ward.

If a patient is being admitted to an AWP inpatient ward from an external ward, whoever is coordinating the transfer should make a specific request for the clozapine medication to be transferred with the patient along with written details of their clozapine monitoring service, their blood test frequency and the date and result of the most recent full blood count.

A new or updated registration form to register the service user will need to be completed and faxed to ZTAS. Refer to the registration section in this document.

The receiving AWP ward should alert their local pharmacy team that a service user on clozapine has been admitted. The locality pharmacist should coordinate the transfer between the clozapine

http://ourspace/Skills/MedicinesPharmacy/Clozapine%20documents/Clozapine%20Transfer%20Form.docx



monitoring services, which can take 24-28 hours. The AWP pharmacy cannot supply additional clozapine until this transfer is complete unless the emergency protocols between the clozapine monitoring services have been instigated and a supply has been authorised by ZTAS.

10.5 Transfer between community teams

An AWP clozapine transfer form must be completed, and sent to the receiving team. It should also be copied to the AWP dispensing pharmacy when the new community prescription is sent from the receiving community team.

An updated registration form to confirm any changes to consultant, team base and pharmacy will need to be completed and faxed to ZTAS. Refer to the registration section in this document.

10.6 Discharge from inpatient care

It is essential that at discharge clozapine patients and their carers are informed of:

• Why clozapine has been prescribed, the importance of continuing treatment and the need for blood tests.

• When the next blood test is due (and the ongoing frequency)

• Where the blood samples will be taken

• How many days of clozapine are being supplied on discharge

• Who will continue prescribing clozapine (clozapine can only be prescribed in secondary care services, and cannot be transferred to the GP)

• How the service user will obtain their next supply of medication. Clozapine must be dispensed by the AWP dispensary in Calne but there may be local arrangements for delivery

All discharge planning must include a representative from the relevant community team (usually the care coordinator). The local pharmacist and/or pharmacy technician must also be involved in the discharge planning for any service user taking clozapine, and if possible should attend the discharge CPA.

Discharge arrangements relating to future blood sampling and clozapine supplies should be documented in the care plan and a Clozapine Transfer Form must be completed. A copy of this must be sent to the dispensary with the request for discharge medication.

The ward team must communicate the discharge arrangements to the clozapine team in Calne and let them know when they will need to start dispensing and ensure an AWP community prescription is written and faxed to the Calne dispensary.

The details held by ZTAS should be updated to reflect the new community team and consultant.

It should be clearly communicated to the GP that clozapine has been prescribed, and the responsibility for ongoing prescriptions will remain with AWP. It is helpful if the GP surgery can indicate that clozapine is prescribed on their electronic records for example as a ‘hospital only’ drug. Primary care may also be involved in ongoing arrangements for FBC testing and monitoring for side-effects. In particular, make sure the GP is aware of the risk of haematological and gastrointestinal side-effects and the potential seriousness of these. A guide to clozapine for primary care staff is available here.

Service users initiated on clozapine as inpatients may be discharged to the community before their titration is complete, if there is sufficient support from the local Intensive Service, see the relevant section.

Service users on a stable dose may not need daily visits and monitoring unless there is a particular cause for concern.



http://ourspace/Skills/MedicinesPharmacy/Clozapine%20documents/Clozapine%20a%20guide%20for%20primary%20care.docx



All service users discharged on clozapine should be given written information about the treatment (see relevant section above) and a copy of their clozapine transfer form. Alert cards are available from Zaponex and can be given if requested.

10.7 Out-of-area clozapine service users

Occasionally a service user from another area may arrive in the AWP catchment and require access to clozapine. Such people will not be registered with our ZTAS system and thus AWP will not have access to their monitoring information or prescription. Either the locality pharmacist, the pharmacy team at Calne pharmacy or the on call pharmacist must be contacted for advice.

Where time allows, the service user should obtain a supply from their usual pharmacy. In an emergency, in order to avoid a greater than 48 hours break in treatment, pharmacy (including the on-call pharmacist) can liaise with the monitoring service that the service user is registered with, and see if it is possible to do an emergency supply. Emergency blood tests may need to be arranged and a prescriber will be required to write a prescription on an AWP approved prescription chart for the doses to be supplied.

11. Dealing with potential problems

11.1 Amber or red results

Monitoring following the reintroduction of clozapine in 1990 demonstrated a cumulative incidence of agranulocytosis at 0.8% within a study period of almost five years. The incidence of both agranulocytosis and neutropenia is highest between 6 weeks and 18 weeks after starting clozapine treatment. It is generally believed that the risks of agranulocytosis and neutropenia are not dose related.

ZTAS routinely monitors blood results. Abnormalities in these parameters, (i.e. when outside agreed ZTAS ranges) are considered haematological adverse events. In case of amber, red or an ‘Out of Range’ result, or any other information received by ZTAS that indicates an adverse event, the healthcare provider will be requested by ZTAS to complete an adverse event report. A request will be sent in the post or via fax to the registered consultant of the service user.

Communications such as emails and faxes from the ZTAS monitoring service should never be ignored; if they are sent to a team no longer involved in the care of the service user, they must be passed onto the new team providing care with a request to contact ZTAS to inform them of the change in arrangements.

Where an amber result is obtained, the pharmacy can only supply up to one week of medication. The pharmacy will inform the care coordinator or duty worker of the team concerned. They will also telephone the consultant or their administrator and will email the consultant. Blood monitoring will be required twice a week until a green or red result is obtained.

If a red result occurs clozapine should be stopped immediately. Pharmacy cannot supply medication and will inform the relevant locality pharmacist, care coordinator (or duty worker) and consultant (or their administrator). Immediate arrangements should be made by the team to conduct daily blood tests until a green result is obtained. The results should be communicated to ZTAS as soon as possible. The service user should be monitored for signs of fever, sore throat or other signs of infection.

If the second blood result is also red, this is considered a “confirmed red result” and the service user will no longer be able to receive clozapine treatment. Daily blood tests are required until they are in the green range and thereafter weekly blood tests are required for a further 4 weeks.

If the second result is amber or green and there have been no anomalous blood results in the previous three months, treatment can be restarted after a further amber or green result. ZTAS should be contacted for individual advice. The way in which this is carried out will depend on the number of doses missed (see the section on Missed doses)



If a service users white cell count drops below 2 x109 /L or the neutrophil count is less than 1 x109 /L then extra precautions should be taken and the advice of a haematologist or a doctor experienced in dealing with neutropenia should be sought. Consult your local specialist pharmacist for advice should alternative pharmacological treatment be required.

If a service user shows persistently low blood counts which appear benign but cannot otherwise be explained, there are various approaches which can be taken. Benign ethnic neutropenia should be considered (see below). There are also approaches to attempt to increase blood counts. These all carry some degree of risk and should not be undertaken without a multidisciplinary discussion (including advice from the relevant locality lead pharmacist).

11.2 Re-challenge after a confirmed red blood result

In general terms, service users who have had a confirmed red result whilst taking clozapine cannot receive clozapine again. There are instances where a clozapine re-challenge may be appropriate with advice from a haematologist and a mental health specialist pharmacist.

Re-challenge with clozapine after a confirmed neutropenia/agranulocytosis is off-license treatment. It is usually considered when a service user has failed to respond to any alternative treatment and their clinical presentation poses a significant risk to themselves and/or others.

Before restarting clozapine in a service user who has previously experienced neutropenia/agranulocytosis, an extensive risk/benefit analysis should be made. In this analysis the likelihood that the first neutropenia/agranulocytosis was a true and typical clozapine-induced dyscrasia should be determined.

A thorough care-plan must be drawn up by the multidisciplinary team including the locality lead pharmacist. ZTAS must be informed. Twice weekly FBC monitoring for the first 12 weeks is usually recommended.

11.3 Platelet and eosinophil monitoring

Monitoring of eosinophil counts was introduced in 2012. Although its reliability as a predictor is unknown, high eosinophil counts may be of significance for predicting myocarditis; eosinophilia is co-reported in 14% of patients with myocarditis.

In the event of eosinophilia (high eosinophils - above 3.0 x 109/L) or thrombocytopenia (low platelets – below 50 x 109/L), discontinuation of clozapine is recommended. Clozapine therapy should be restarted only after the eosinophil count has fallen below 1.0 x 109/L or the platelet count is above 50 x 109/L.

ZTAS has a warning system in place for eosinophil or platelet counts: the result will be marked as ‘Out of Range’ and the consultant, the clozapine pharmacist and the dispensary will be informed via fax. This communication provides relevant treatment and monitoring advice.

11.4 Benign Ethnic Neutropenia

Benign Ethnic Neutropenia (BEN) occurs in 25-50% of people of African descent, for whom the standard classification system of FBC results may be inappropriate. In order to monitor a patient according to BEN reference ranges, confirmation of the BEN diagnosis is required from a consultant haematologist. Further information and the ZTAS form: “Confirmation of Benign Ethnic Neutropenia Monitoring Criteria Approval” can be downloaded from ZTAS by registered users. The form must be signed by both the consultant psychiatrist and a consultant haematologist. Please seek assistance from your locality pharmacist if this is appropriate for one of your service users.

11.5 Management of late or missing full blood count results

It is the responsibility of the clinical team caring for the service user to ensure that blood tests are carried out according to the ZTAS monitoring schedule. Pharmacy staff do not routinely alert



teams when blood results are not received as expected. ZTAS will fax the team the service user is registered with when blood results are not received at the time required, according to the monitoring schedule. Information on such faxes should be followed up with the care coordinator to ensure that a blood test is planned and taken.

11.6 Missed doses

It is important that service users taking clozapine, take it regularly without gaps in treatment. Once clozapine doses have been missed the plasma levels drop rapidly, and tolerance to treatment is quite quickly reduced. The half-life of clozapine is 7-14 hours, therefore after 35-70 hours there will be no detectable clozapine left in the blood.

If a dose is missed, do not attempt to make up for the missing dose by giving more. If the treatment break is less than 48 hours, treatment can be continued at the previously prescribed dose.

If a service user has clozapine omitted for more than 48 hours they must have the medication reintroduced gradually (these titrations can usually be done more quickly than initial titrations - speak to your local pharmacist for advice).

For service users re-titrating back to their previous dose after missing more than 48 hours of clozapine, a bespoke titration should be used and blank titration charts are available to facilitate this.

48-72 hours of missed doses: The Maudsley Prescribing Guidelines suggest restarting at half the previous total daily dose on day one and split this into 2 divided doses, then give 75% of the total daily dose on day 2 as split doses. If tolerated give the normal dose schedule on day 3.

However, this is a quick re-titration; factors such as the tablet strengths available, tolerance to initial titration, and the mental and physical health of the service user should be considered. A slower titration is less likely to cause side effects.

72 hours – 1 week of missed doses: begin with 12.5mg or 25mg on day 1 and titrate according to how the service user is tolerating it. Conduct the titration over at least 4 days. Blood monitoring frequency will change; see below.

More than one week of missed doses: re-titrate as if a new titration, over at least two weeks. For service users being re-titrated in the community, a bespoke titration over at least two weeks may be conducted depending on risk, duration of treatment and tolerability.

The dispensary at Calne and ZTAS need to be informed of any treatment breaks. This should be done by the care coordinator or prescriber. The locality pharmacist should also be contacted.

The frequency of blood tests may need to be adjusted when restarting a service user on clozapine, depending on where they were on the monitoring frequency cycle, and the length of time elapsed since the last dose taken. ZTAS will advise on the required frequency of blood test as set out in the table below:

Previous monitoring frequency

Length of treatment break New monitoring frequency

Weekly < 3 days Continue 18 weeks period



Previous monitoring frequency

Length of treatment break New monitoring frequency

Weekly > 3 days but >1 week Weekly, continuing the 18 weeks period; patient must have at least 6 weeks of weekly monitoring prior to a decrease of the monitoring frequency to fortnightly

Weekly > 1 week Weekly, restart 18 weeks period

Fortnightly < 3 days Fortnightly, continue

Fortnightly > 3 days but < 4 weeks Weekly monitoring for 6 weeks, then continue Fortnightly

Fortnightly > 4 weeks Weekly, restart 18 weeks period

4-Weekly < 3 days 4-Weekly, continue

4-Weekly > 3 days but < 4 weeks Weekly monitoring for 6 weeks, then continue 4-Weekly

4-Weekly > 4 weeks Weekly, restart 18 weeks period, after 18 weeks, then switch to 4-Weekly

For service users still on titration, if even one dose is missed, seek advice from the prescribing doctor: the titration may need to be adjusted to avoid unintended large increases in dose.

11.7 Smoking cessation and effect on clozapine levels

Tobacco smoke interacts with clozapine. The interaction is not caused by nicotine, but by components of the smoke (polycyclic aromatic hydrocarbons). Therefore the interactions discussed here do not apply to nicotine replacement therapy or to vaporised nicotine use.

The majority of interactions are as a result of tobacco smoke inducing cytochrome P450 enzymes in the liver (primarily CYP1A2). This process speeds up the metabolism and clearance of some medicines including clozapine.

In order to have the desired therapeutic effect, smokers may need higher doses of clozapine compared to non-smokers. Conversely, if a smoker abstains from tobacco then clozapine requires a dose reduction to prevent unintended toxicity.

It has been suggested that smoking 7 to 12 cigarettes daily is enough to result in maximum induction of the relevant drug metabolising enzymes.

A patient on a stable dose of clozapine who stops smoking might experience a 50% increase in clozapine concentrations within 2 to 4 weeks of ceasing to use tobacco.

It has also been estimated that if a service user taking clozapine starts to smoke, a dose increase of up to 50% might eventually be needed (although this should be done cautiously).

It has been suggested that when smoking cessation is planned with a person taking clozapine, the following strategy should be applied:



• Take a clozapine plasma level before changing smoking habit

• On stopping smoking, reduce the clozapine dose gradually over a week by about 25%

• Repeat the clozapine plasma level one week after stopping tobacco and act according to the level (although anticipate that further dose reductions will probably be needed).

All these recommendations are based on approximations, and in many cases smoking cessation will be incomplete or a quit attempt may not be immediately successful. There is no formula as to exactly how clozapine doses should be adjusted in these different scenarios. The key is to remain aware of the interaction and that ongoing dose adjustment may be needed. Use plasma level monitoring, assessment of the individual’s mental health and side effect burden to guide to dose adjustment.

11.8 Travel

If a service user taking clozapine has plans to travel abroad or to an area of the UK outside of the AWP catchment area, particularly if this may be for a period beyond the validity of their blood result, forward planning is essential to make sure safe treatment can be continued. It is possible to make arrangements to continue blood monitoring in a local medical facility.

The service user (and carer if applicable) should be fully briefed on the course of action to be taken should a viral or bacterial infection develop and the service user must be able to contact their consultant in case of emergency.

ZTAS can provide a standard holiday letter in one of 14 different languages which can be completed by the service user’s care coordinator prior to travel.

In every case the arrangements for blood tests and the supply of medication must be discussed with the pharmacy team a minimum of six weeks in advance of travel. Arrangements to transmit the results of blood tests securely must be made so that these can be uploaded to the ZTAS monitoring service.

11.9 Discontinuing clozapine

In most circumstances if clozapine is being discontinued, it should be done gradually over at least two to four weeks (often longer). Websites such as http://www.choiceandmedication.org/awp/pages/printableleaflets/ and http://www.comingoff.com/plan.php may help promote discussion with the service user on an appropriate time frame over which to discontinue.

If an abrupt discontinuation is necessary (for example due to a red blood result) the service user must be closely observed for relapsing psychosis (the rebound psychosis following clozapine discontinuation can be severe and rapid in onset). A comprehensive care plan must be put in place. Seek specialist advice on other treatment options. The physical health of the service user should also be closely monitored. Symptoms of clozapine discontinuation include cholinergic rebound (sweating, headache, diarrhoea, vomiting).

If clozapine has been discontinued due to a red blood result, (see relevant section), consideration must be given to the service user’s vulnerability to infection.

Before a planned cessation of clozapine is undertaken, careful consideration of the reasons and of the future treatment options must be undertaken, preferably within the multidisciplinary team and with the input of the service user and carers (if applicable).

Reasons for considering discontinuation should be discussed, as other actions may be appropriate, for example finding better ways to manage side-effects or treating other co-morbidities more effectively.

Whenever a service user discontinues clozapine, ZTAS and the local dispensing pharmacy must be informed. Continued blood monitoring will be advised for a period of four weeks at the service user’s usual frequency of blood tests.

http://www.choiceandmedication.org/awp/pages/printableleaflets/

http://www.comingoff.com/plan.php



12. References

Baxter K, Preston CL (eds), Stockley’s Drug Interactions. [online] London: Pharmaceutical Press http://www.medicinescomplete.com / (date of access 09/12/2015)

Hynes C et al (2015) Glasgow Antipsychotic Side-effects Scale for Clozapine - Development and validation of a clozapine-specific side-effects scale. Schizophrenia Research Vol 168(1-2) pp 505–513

Kasckow J, Felmet K and Zisook S (2011) Managing Suicide Risk in Patients with Schizophrenia CNS Drugs Vol 25(2) pp129-143

Leyland Delta. Summary of Product Characteristics for Zaponex accessed via www.ztas.co.uk (date of access 09/12/2015)

Leyland Delta. ZTAS Online Treatment Manual (2015) and associated fact-sheets accessed via www.ztas.co.uk [only accessible to registered users] (date of access 09/12/2015)

Miller J, Fitchet A, Hakim N. Screening and monitoring for clozapine induced tachycardia and myocardititis. Greater Manchester West Mental Health NHS Trust

Novartis. Clozaril prescribing information. Available from http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/019758s054lbl.pdf (date of access 11th April 2016)

Ronaldson K, Fitzgeral P, Yalor A, Topliss D, NcNeil J.(2011) A new monitoring protocol for clozapine-induced myocarditis based on an analysis of 75 cases and 94 controls. Australian and New Zealand Journal of Psychiatry. 45: 458-465 DOI: 10.3109/00048674.2011.572852

Rostami-Hodjegan, A. Amin AM, Spencer EP, et al (2004). Influence of dose, cigarette smoking, age, sex and metabolic activity on plasma clozapine concentrations: a predictive model and nomograms to aid clozapine dose adjustment and to assess compliance in individual patients. J Clin Psychopharmacol 24 (1), 70-78

Taylor D, Bleakley S. The clozapine handbook. (2014). Dorsington : Lloyd-Reinhold Communications

Taylor D, Paton C, Kapur S. (2015) The Maudsley Prescribing Guidelines in psychiatry. 12th edition Oxford :Informa Healthcare

Waddell L and Taylor MJ (2008) A new self-rating scale for detecting atypical or second-generation antipsychotic side effects. Psychopharmacol Vol 22(3): 238-243.

Van Beelen A J, Jollie-Helthuis M (2015) Zaponex fact sheet Myocarditis and Cardiomyopathy. Information sheet, ZTAS monitoring service

http://www.medicinescomplete.com/



http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/019758s054lbl.pdf



13. Appendices and other supporting documents

This document includes a set of appendices to support the main text.

Addiction documents such as titration charts and monitoring schedules can be found in the Clozapine document library on Ourspace. Links to these documents are also included throughout the text of the procedure, and in a summary list below.

Clozapine: a guide for primary care

Observations for inpatient clozapine initiation

Observations for community clozapine initiation

Inpatient standard clozapine tablet titration chart

Inpatient standard clozapine liquid titration chart

Inpatient slow clozapine liquid titration chart

Inpatient slow clozapine tablets titration chart

Community standard clozapine tablets titration chart

Clozapine titration prescription chart blank

Clozapine Transfer Form

http://ourspace/Skills/MedicinesPharmacy/Clozapine%20documents/Clozapine%20a%20guide%20for%20primary%20care.docx

http://ourspace/Skills/MedicinesPharmacy/Clozapine%20documents/Inpatient%20Pre%20and%20Post%20Clozapine%20Administration%20Monitoring%20Guidance.docx


http://ourspace/Skills/MedicinesPharmacy/Clozapine%20documents/Clozapine%20titration%20chart%20standard%20inpatient%20tablets.docx

http://ourspace/Skills/MedicinesPharmacy/Clozapine%20documents/Clozapine%20titration%20chart%20standard%20inpatient%20liquid.docx

http://ourspace/Skills/MedicinesPharmacy/Clozapine%20documents/Clozapine%20titration%20chart%20slow%20inpatient%20liquid.docx

http://ourspace/Skills/MedicinesPharmacy/Clozapine%20documents/Clozapine%20titration%20chart%20slow%20inpatient%20tablets.docx

http://ourspace/Skills/MedicinesPharmacy/Clozapine%20documents/Clozapine%20titration%20chart%20standard%20community%20tablets.docx





13.1 Appendix – blood test parameters

The full blood count (FBC) must be monitored weekly for service users initially started on clozapine. If there are no problems with their blood results, after 18 weeks, monitoring can be reduced to fortnightly. If blood results remain stable for the remainder of the year, monitoring can be reduced to once every four weeks. ZTAS will advise when a service user’s monitoring frequency has changed.

FBC tests are carried out at local hospital laboratories, using a barcode system to allow the result to be automatically uploaded to the ZTAS database. ZTAS employs a ‘traffic light' classification system for results, which applies to the white blood cell and neutrophil counts.

ZTAS has a warning system in place for eosinophil and platelet counts: abnormal results will be marked as ‘Out of Range’ and the consultant, the clozapine pharmacist and the dispensary will be informed via fax which provides relevant treatment and monitoring advice.

Reference values for new patients or those post-treatment break

Red Amber Amber (intermediate) Green

White cell count <3.0 x10

9/L

and/or Neutrophils <1.5 x10

9/L

White cell count

3.0 and <3.5 x109/L

and/or Neutrophils

1.5 and <2.0 x109/L

White cell count

3.5 and <4.0 x109/L

and/or Neutrophils

2.0 and <2.5 x109/L

WBC 4.0 x109/L

Neutrophils 2.5 x10

9/L

The blood result is not valid to initiate clozapine.

Repeat FBC

Investigate the cause of the abnormal blood result. Urgent medical review

The blood result is not valid to initiate treatment.

Additional blood sampling is required. Treatment may only be initiated on a green or intermediate amber result.

Treatment may be initiated at the consultant’s discretion.

Additional blood sampling is advised to ensure blood counts are not dropping.

Treatment may be initiated. Repeat FBCs according to standard schedule

Reference values for routine blood results

Red Amber Green

White cell count <3.0 x109/L

or Neutrophils <1.5 x109/L

White cell count 3.0 and <3.5 x10

9/L

or Neutrophils 1.5 and >2.0 x10

9/L

WBC 3.5 x109/L

Neutrophils 2.0 x109/L

Stop clozapine immediately

Repeat FBC

Urgent medical review

Continue with caution

Repeat FBCs twice a week until green or red result

Continue treatment

Repeat FBCs according to standard schedule



13.2 Appendix – action on clozapine plasma levels

Trough Clozapine plasma level (micrograms / L)

Clinical Response

Comment

<10 micrograms / L or not detected Any Clozapine unlikely to have been taken

for at least a week unless in the very early stages of initiation.

<350 micrograms / L Good Continue current dose, repeat levels

annually or sooner if response deteriorates, or adverse reactions become troublesome

Poor or incomplete

If poor adherence is suspected, consider education, supervised consumption, reminder cards, compliance aids or using crushed tablets. If no improvement, consider a cautious dose increase, monitoring response and tolerability. Repeat level after 1 week at new dose.

350 – 600 micrograms / L

(Target range for good clinical response vs minimal toxic effects)

Good Continue current dose, review regularly for continuing response and tolerability. Consider repeating levels annually

Poor or incomplete

If clozapine has continued for at least 3 to 6 months and still incomplete response, consider augmentation with another suitable psychotropic.

601 – 999 micrograms /L Good with no features of toxicity

Consider a cautious dose reduction, weighing against response, risk and tolerability. If considered essential to maintain at current dose, consider using a prophylactic anticonvulsant to protect against seizures (usually lamotrigine or valproate). Monitor closely for tolerability and response

Poor, incomplete or features of toxicity

Consider a cautious dose reduction, weighing against response, risk and tolerability. Repeat levels once stabilized on new dose. Consider augmentation with another antipsychotic if clozapine has been taken for at least 3-6 months.

>1000 micrograms /L

(upper limit not well defined)

Any Review urgently. Consider a dose reduction to bring levels down below 1000 micrograms /L and ideally below 600 micrograms/L, weighing against risk, response and tolerability. If clinical signs of toxicity (severe sedation, delirium, falls, seizures) consider withholding clozapine for 24 hours and re introducing at a lower dose. Consider initiating an anticonvulsant to protect against seizures. Repeat levels once the lower dose is stabilized.



13.3 Appendix – target dose of clozapine

The final target dose of clozapine varies considerably between service users. To guide what dose to aim for when initiating clozapine the gender and smoking status of the service user should be taken into consideration. The weight and age of the person will also have a bearing

As a starting point the target doses below give a low probability of a plasma level above 1mg/L (approximately 5% or less). The probability of a low plasma level (below 0.35mg/L)is somewhat higher at 50%. In other words, individual doses may still need increasing even after this target dose has been reached, but the chance of inadvertently reaching a toxic plasma level from the suggested dose is low. The information is based on a predictive model published in 2004. This is obviously not a substitute for individual plasma level monitoring.

Demographic Baseline dose

Male smoker 425mg/day

Male non-smoker 250mg/day

Female smoker 325mg/day

Female non-smoker 225mg/day

Weight can affect the expected plasma concentration by around 5% for every 10 kilograms over 80Kg.

Weight Male smoker Male non-smoker

Female smoker

Female non-smoker

60Kg -50mg -50mg -25mg -25mg

80Kg As baseline As baseline As baseline As baseline

100Kg +75mg +50mg +50mg As baseline

Age increases the expected plasma concentration by about 4% for every 5 years over the age of 40 years, therefore people may need lower does as they get older.

Age Male smoker Male non-smoker

Female smoker

Female non-smoker

20 +100mg +50mg +100mg +25mg

40 As baseline As baseline As baseline As baseline

60 -50mg -25mg -25mg -25mg

This is a rough guide only and clinicians should be guided by their clinical judgement and the individual situation.



13.4 Appendix – flow chart for monitoring for clozapine induced myocarditis

This flow chart should be used for all service users commencing clozapine regardless of the setting (inpatient or outpatient).

Daily during titration - monitor - blood pressure, heart rate, respiration rate, temperature according to schedule. Ask service user / carers to report any symptoms such as fever, cough, chest pain, shortness of breath, diarrhoea, nausea, vomiting, myalgia, sweating

Pause titration and carry on current dose or reduce dose slightly. Check CRP and troponin daily until back in normal range or until develops values that warrant referral to Cardiology. If troponin rises above normal lab range or 20% above baseline for troponin T or 33% above baseline for troponin I arrange echocardiogram and seek advice from Cardiology

Troponin > 2xUNL

CRP > 100mg/L

Stop clozapine. Consult a cardiologist; arrange echocardiogram.

CRP=C-reactive protein

FBC= full blood count

ECG - electrocardiogram

Continue with clozapine

No signs or symptoms and blood tests all in

normal range

Signs or symptoms of unidentified illness or Heart rate >120bpm or ↑ by >30bpm or CRP 50-100mg/L

Baseline - before start clozapine troponin CRP ECG FBC

On days 7, 14, 21 and 28 FBC troponin

CRP