Clozapine clinic protocols

Contents

1 Introduction

Within the Doncaster, Rotherham and North Lincolnshire localities there are nurse led Clozapine clinics which provide a treatment and monitoring service to all patients who are prescribed Clozapine. In addition to this, colleagues in the clinics also undertake physical health screening with the patients who attend and provide health and wellbeing advice.

2 Purpose

The purpose of this protocol is to set out the minimum standards in relation to how the service is provided within the clinics and is to be read in conjunction with the trust’s safe and secure handling of medicines manual.

3 Scope

Whilst these protocols are specific to the colleagues who work within these clinics there is an expectation that other clinical colleagues, who in the course of their work may be involved in the care of patients receiving Clozapine treatment or attending the clinic, will have an awareness of the protocols.

4 Responsibilities, accountabilities and duties

4.1 Nurse lead for the Clozapine clinics

It is the responsibility of the nursing colleagues in charge of the clinics to:

• follow this protocol
• advise on baseline measurements that need to be done
• provide information on Clozapine to the patients who attend the clinic, including side effects, and how to manage them, and when to seek medical attention
• check patient details at each attendance
• monitoring physical health is the responsibility of the patient’s lead professional and will only be carried out by the clinic where the patient has no other lead professional. Monitoring is recorded within the patient’s record. Over and above monitoring for side effects, health monitoring will mainly entail using health screening tools, with referral to the appropriate service, for example, patients general practitioner (GP).  Good communication between the lead professional and Clozapine clinic is essential
• advise and monitor in respect of side effects from the medication and inform relevant medical colleagues (either primary or secondary care) of any concerns. For patients who do not have a care coordinator the clinic colleagues will inform, the responsible medical officer (RMO) or duty care worker, depending on who is most appropriate
• monitor patient’s mental state and inform the Lead Professional of any concerns
• undertake or participate in any required audit work
• provide local induction to any new colleagues in the clinic
• report any adverse events through the trust electronic incident reporting system
• identify any training needs
• attend any training which is provided to enable them to fulfil their duties within the clinic safely

4.2 Care coordinator

Care coordination remains the responsibility of the allocated care coordinator or lead professional.

The patients care coordinator will be responsible for:

• supporting the patient in their attendance at the clinic
• physical health monitoring
• following up any patients who do not attend their appointment
• highlight any concerns raised by the patient to the clinic

4.3 Consultant psychiatrist or lead professional

It is the responsibility of the consultant psychiatrist or lead professional to refer the patient to the Clozapine clinic and register them with the relevant Clozapine company.

If the clinic does not have a non-medical prescriber, they are also responsible for:

• prescribing the patients Clozapine
• informing clinic colleagues, pharmacy, and GP of any dose changes
• refer to primary care any concerns over the patient’s physical health

4.4 Supplying pharmacy

The supplying pharmacies are responsible for:

• informing the clinic colleagues of any problems in respect of the dispensing of Clozapine
• for patients currently under the clinic
  • will pre-dispense the Clozapine, with the clinic releasing the prescription on receipt of a green or amber result as per standard operating procedure (SOP)
• for inpatients:
  • will only dispense on receipt of green or amber result

5 Procedure or implementation

Background information and pre-clinic process.

5.1 When to consider Clozapine

Clozapine is an atypical antipsychotic which can be used to treat schizophrenia in patients where:

• there has been a poor response to two or more other antipsychotic medications, one of which should ideally have been atypical
• the patient has experienced severe side effects, or intolerance to either typical or atypical antipsychotic medication, which Clozapine is less likely to cause

Clozapine is known to be effective in the treatment of both positive symptoms such as auditory hallucinations, and negative symptoms such as a lack of motivation and poor social interaction.

5.2 Contra indications

The use of Clozapine is not recommended for a patient where any of the following are present:

• severe cardiac problems
• uncontrolled epilepsy
• history of previous hypersensitivity to Clozapine
• severe renal impairment
• active liver disease
• paralytic ileus, abdominal or gastrointestinal examination or history is recommended
• pregnancy
• history of neutropenia or agranulocytosis

5.3 Caution in prescribing

Caution is advised in the commencement of Clozapine in the following cases:

• hepatic impairment
• glaucoma
• renal impairment
• prostatic hypertrophy
• history of constipation and the co-prescribing of anticholinergic medication

5.4 Possible side effects

The most commonly reported side effects are sedation, increase in salivation, fluctuation in blood pressure, increased heart rate and increased body temperature, but these usually settle within four weeks of doses being stabilized, however; they may still need managing before this, for example, hyper salivation. Other reported side effects are constipation and weight gain both of which can be managed by a high fibre diet, and dietary advice.

For full details colleagues should refer to the most recent issue of the British National Formulary (BNF) (opens in new window).

5.4.1 Specific serious side effects

Agranulocytosis, acute intestinal obstruction and constipation, pyrexia, seizures, cardiovascular events, diabetes, and impaired glucose tolerance, for further information see the monitoring section.

5.5 Patient information

Please see appendix J chart for initiation on Clozapine.

Prior to the initiation of Clozapine treatment patients and, if appropriate, their carers must have a full discussion with the prescribing clinician about the risks and benefits of the proposed treatment. This discussion should also cover:

• common side effects
• requirement to attend for regular monitoring and the restrictions that this can impose on the patient
• the need to avoid alcohol, driving, and machine operation during the first few weeks of treatment commencing
• what to do if significant side effects occur
• the importance of not missing more than 48 hours of Clozapine

Patients will also be given the above information in writing.

For patients whose first language is not English arrangements will be made for the presence of an interpreter during any clinic appointments. Colleagues should refer to the trust’s interpreters policy (provision, access and use of, for patients, service users and carers).

5.6 Patient registration

Patients must be registered by the consultant team, using the Zaponex treatment access system (ZTAS) forms, available from the ZTAS website (opens in new window) the initial blood sample should be carried out by the treating team and the results sent to ZTAS.

The team will then contact the Clozapine clinic to arrange the first appointment, once titration is completed.

5.7 Consent

Due to the need for the patient to comply with the monitoring requirements through regular attendance at clinic, Clozapine is usually only prescribed once informed consent has been obtained. (colleagues should refer to the trust’s consent to care and treatment policy) However, in the case of a patient who lacks the capacity to consent but does not object, Clozapine can be administered under the Mental Capacity Act 2005 if it is deemed:

• necessary to save life, prevent deterioration or ensure an improvement in the patients physical or mental health
• in the best interest of the patient
• to be done so in accordance with the practice accepted at the time by a reasonable body of medical opinion skilled in that form of treatment
• following a best interests meeting
• assessments of capacity should be recorded on MCA1 forms and any best interest’s decision recorded on MCA2 in line with the MCA policy

5.8 Patients detained under the Mental Health Act 1983 who refuse to have blood samples taken for Clozapine monitoring

In the event that a patient detained under the Mental Health Act 1983 for treatment refuses to have their bloods taken for Clozapine monitoring the sample can be obtained under section 63 and then, if necessary, a section 58 certificate. However, the benefits of instigating treatment in this way must outweigh any possible adverse effects to the patient and minimal force is to be used to obtain the blood sample.

5.9 Patient Appointments for clinic

5.9.1 Inpatients

If the person is an inpatient, contact colleagues on the relevant ward and arrange a time to take a local sample, This can then either be taken to the local Clozapine clinic who can analyse it using the PocHi machine, or can be sent to the local laboratory for testing, the results can then be emailed directly to ZTAS on info@ztas.co.uk, include the patient’s name, date of birth (DOB) and full blood count (this can be printed off ICE or Pathlinks).

5.9.2 Outpatients

If the person is an outpatient:

• contact them by phone and arrange a time for them to attend the clinic for a blood sample to be taken, if the appointment has not already been made at the previous one, which is the normal practice
• if clinic colleagues are not available to take the blood sample, a form for phlebotomy will be left for them to collect (convenient pick-up point to be arranged with the patient). The patient will be advised to attend the phlebotomy department at the local hospital at the earliest time possible
• an entry to this effect is to be made in the patient’s clinical record
• when the results are available the clinic colleagues will upload these to the ZTAS website (opens in new window)

5.10 Action to be taken if a patient fails to attend their appointment at the Clinic or is un contactable

5.10.1 Inpatients

In the event that an inpatient fails to keep their appointment the clinic colleagues are to contact ward colleagues and request that, if possible, the patient attends the clinic. In the event that the patient is not able to attend the clinic ward colleagues are to be instructed to obtain a sample which is to be brought to the clinic either for testing, or dispatch to the local laboratory.

5.10.2 Outpatients

In the event that an outpatient fails to attend their appointment clinic colleagues will:

• attempt to contact the patient by phone to make an alternative appointment for them to have their blood sampling done
• if the patient is not able to attend the clinic the care coordinator or lead professional must be contacted to facilitate a blood test as soon as possible
• in the event that no contact is made with the patient clinic colleagues are to try and establish contact either through the patient’s relative or carer or care coordinator or lead professional
• in the case of repeated non-attendance or difficulty in contacting the patient for a sample the following are to be informed:
  • patients consultant psychiatrist
  • the supplying pharmacy service
• depending upon the frequency of testing required for individual patients, an extra week, or 3 day supply of Clozapine may be authorised in order to facilitate continued Clozapine therapy. This is arranged with the local pharmacy supplier who will facilitate the delivery of medication to the patient’s home address, ward, or relevant community team
• if the patient’s medication has been delivered to clinic at the beginning of the week, then this may to be returned to pharmacy for re-dispensing in the appropriate numbers. (for example, patients or service users on 4 weekly monitoring will receive 3-weeks supply of Clozapine at their appointment the next week and will therefore require a 3-week appointment when they next attend)
• if a blood result is not received within 7 days of the due date a courtesy reminder will be emailed or tasked via SystmOne to their consultant psychiatrist. Further reminders will be sent each week. If there is no result after 28 days, the Clozapine company will modify the patient’s status to “interrupted” and the person will need to be re-registered

5.11 Monitoring requirements

For the first 18 weeks of treatment the patient will require weekly blood monitoring, this initially will be on the ward, and subsequently be at the clinic. At the appointment blood pressure, pulse, temperature, and weight monitoring will take place.

However, at 3 months the patient should be informed that some additional tests are to be carried out to monitor their physical health, if the patient is still an inpatient this will be done by the inpatient team, when discharged the team should inform the clinic when these are due. These will then be completed annually by their GP. These tests are:

• calculation of body mass index (BMI) using either the electronic scales (as outlined in the instruction manual) or by using a BMI calculator
• measuring of abdominal girth using a tape measure
• side effects questionnaire
• the following blood tests:
  • urea and electrolytes
  • lipids
  • liver function test
  • glucose
  • prolactin

To request these, tick the appropriate boxes in the biochemistry section, next to the glucose box write either random or fasting as appropriate. To order the prolactin serum test write ‘PRL’ under ‘other biochemistry requests’. The above tests will require a gold top bottle of blood be collected.

The Clozapine side effect questionnaire must be completed, along with a review of their mental health, and any issues addressed or referred to the appropriate professional.

ECGs’ are not routinely the responsibility of the Clozapine clinic, for inpatients they should be carried out and reviewed by the treating team. For community patients then the patients lead professional should organise them as agreed locally, and again reviewed by the treating team.

Once the results from the above tests arrive back at the Clozapine clinic, colleagues should contact the consultant psychiatrist or junior trainee in psychiatry for that patient and ask them to come and review the results and record the outcome in the patient’s record. Once this has been done the results are to be sent for filing. The medical team is responsible for any follow-up or actions required following the receipt of the results.

Clinic colleagues or the consultant secretary should then complete the GP Letter by adding the patients’ details and signing it to inform the GP that the 3 monthly interventions is complete, and they should now review the patient annually. Patient details and GP addresses are available in the patient’s contact details file.

For the next 34 weeks the patient will be required to attend clinic for blood tests every two weeks and once a month for their blood pressure, pulse, temperature, and weight monitoring to take place.

Subsequently their attendance is required every four weeks and at each appointment the patient’s blood pressure, pulse, temperature, and weight monitoring will take place.

Please see appendix C for initial monitoring for patients initiating or being titrated on Clozapine.

At all appointments there will be an assessment of the patient’s mental health both informally and through the use of available clinical assessment tools.

In addition, patients will have the opportunity to discuss any issues they may have in relation to their general physical health, social needs, and or employment or educational needs.

The monitoring of side effects will take place at each appointment with clinic colleagues completing the agreed side effects rating scale. If side effects are evident the severity of them is to be assessed and the need to increase the frequency of future monitoring is to be agreed with the patient.

The Clozapine side effect questionnaire should be completed on each visit, and where appropriate any issues addressed (appendix A).

During the monitoring of patients, particular attention should be paid to flu like symptoms such as sore throat and raised temperature, as these could be indicative of neutropenia. In the event that this is suspected contact is to be made with ZTAS for guidance.

In the event that any unusual adverse effects are noted practitioners should report these either using the yellow card found in the back of the British National Formulary (opens in new window) or online at Yellow Card (opens in new window)

5.11.1 Protocols for obtaining blood samples

Wherever possible the blood samples will be obtained in the Clozapine clinic. Clinic colleagues will follow consent procedures and make any adjustments that are deemed necessary for the patient’s comfort during the procedure.

5.11.1.1 Purpose, routine full blood count with differential

Frequency:

• weekly for 18/52, fortnightly till 52/52, four weekly thereafter

Where taken and tested:

• clinic PocHi or ZTAS local labs

Sent via:

• online or courier or local labs

5.11.1.2 Purpose, urgent FBC

Frequency:

• as required

Where taken and tested:

• PocHi or local lab

Sent via:

• online or transport

5.11.1.3 Purpose, serum level (trough)

Frequency:

• see below

Where taken and tested:

• clinic using Magna Laboratories

Sent via:

• Royal Mail

5.11.1.4 Purpose, other blood tests for monitoring, for example, lipids, prolactin

Frequency:

• baseline at 3 months then annually

Where taken and tested:

• clinic local labs

Sent via:

• transport

Withhold morning dose prior to blood collection if carrying out a serum level (not routine blood tests).

5.11.2 Point of care haematology (PocHi) Analyser is available

5.11.2.1 Patient procedure

Patient attends Clozapine clinic as per appointment and the clinic nurse will review the patient’s mental and physical state. A routine blood sample will be taken, and patient will be asked to stay until their blood results are available to enable medication to be issued following a ‘green’ blood result.

5.11.2.1 Doncaster, Rotherham, and North Lincolnshire

Follow the standard operating procedure (SOP) for the PocHi machine in appendices F, G and H.

For full details colleagues are to refer to the internal quality control procedure for the point of care analyser contained within appendices F, G and H.

5.11.3 Procedures if a PocHi is not available

Note, blood samples must be obtained by an accredited phlebotomist.

Doncaster, Rotherham, and North Lincolnshire:

• if necessary, 2 to 3 days medication can be given to the patient whilst waiting for the blood result. Once a green result is obtained the rest of the medication can be sent

5.11.4 Protocol for obtaining a blood sample for local analysis

Note, blood samples must be obtained by an accredited phlebotomist.

This protocol should only be used if:

• for any reason a sample could not to be obtained at the Clozapine clinic
• a sample has been contaminated or lost
• a request has been made for a further sample
• the patient did not attend clinic

To obtain a blood sample for local analysis colleagues must complete a biochemistry, haematology and immunology form with the following:

• tick full blood count and underneath write ‘with differential’
• in the clinical details box write ‘patient on Clozapine’
• ensure all the fields are completed:
  • surname
  • forename
  • NHS hospital number
  • DOB
  • tick male or female
  • tick NHS
  • consultant (RMO)
  • relevant team, ward, or Clozapine clinic
  • sample type, v blood and sign the form

If clinic colleagues (or other phlebotomy trained colleagues) are not available, the patient will to be asked to take the completed form and attend their GP or local walk-in centre. In an emergency they may also be able to go to the phlebotomy department at the local general hospital.

If colleagues are available a sample should be obtained using a red top Monovette bottle or a lavender top bottle, whichever is used for EDTA, in your area (check expiry date) following local phlebotomy protocols.

The sample should then be taken to the laboratory at the local general hospital either by a staff colleague or hospital transport.

Swallownest Court only, place the sample in the drug fridge. If the sample is ready before 11am it will be taken by hospital transport. If after 11am the sample should be taken to the laboratory at Rotherham General Hospital by a member of staff.

Please note, if a sample is infected it should be labelled accordingly and carried in additional packaging following Trust protocols.

If the sample has been done by the ward, then it is their responsibility to fax the results to ZTAS, if however, it is a community patient then the Clozapine clinic colleagues will input the results. Alternatively, the sample can be sent to the clinic to be run through the PocHi machine.

Clinic colleagues are to retrieve the blood results and enter them onto the ZTAS system manually in order for medication to be dispensed. If clinic colleagues are unavailable the results are to be obtained from PAS or ICE system and emailed to ZTAS, info@ztas.co.uk, as soon as possible, alternatively ZTAS can be called with the result.

5.11.5 Procedure for obtaining serum Clozapine levels

• ZTAS guidance Clozapine metabolism and plasma level monitoring (opens in new window)

5.11.5.1 Frequency

• Change in caffeine consumption.
• A patient stops smoking or switches to an e-cigarette.
• Concomitant medicines may interact to increase blood Clozapine levels.
• A patient has pneumonia or other serious infection. See section on fever or pyrexia (see 5.11.8). Plasma levels may increase, requiring dose reduction.
• Poor (reduced) Clozapine metabolism is suspected.
• Toxicity is suspected.
• One week post dose stabilisation.
• Annually.
• For checking compliance.

5.11.5.2 Where

• Either by prior arrangement with the Clozapine clinic.
• Inpatients on the ward by ward colleagues if the clinic is off site.
• Alternatively, it may be required at the acute hospital trust. The acute hospital can then contact the clinic to arrange collection of the sampling kit; this can be done via the hospital liaison team.
• The request should normally be made by the Consultant or key worker.
• The request should be clearly marked in the Clozapine clinic diary once received.
• The patient must be aware of the need for a serum sample and informed not to take their morning dose of Clozapine otherwise the serum level cannot be taken. Clinic colleagues are to contact the ward (if appropriate) to ensure the morning dose of Clozapine is omitted.
• Prior to taking the sample, check with the patient that they have not taken their morning dose of Clozapine.
• For patients where it has been taken on the ward, the paperwork and containers can be accessed via the Clozapine clinic.
• If they have taken their Clozapine the test must be re-scheduled for a later date.
• For a serum sample a separate sample is required (2 samples if routine monitoring is being done at the same time), and a separate Clozapine serum assay request should be sent, using the Magna Laboratory paperwork.
• Please ensure that labels are placed on the request form and the blood bottle is sent. For inpatients who may not have the stickers enter the ZTAS pin and patient details
• The sample should be posted using Royal Mail.
• The results may take 3 to 7 days and will be emailed directly to the Consultant Psychiatrist. Alternatively, the blood results are uploaded to a web-based service and can be accessed through this mechanism. To do this the viewer must be registered with Magna laboratories:
  • Phone: 01989 763333
  • Email: info@magnalabs.co.uk

Acute hospitals will need to contact the hospital liaison team to access both the equipment, and to liaise with the consultant or clinic to access the results.

5.11.5.3 Results

It is the responsibility of the consultant to follow-up and act on the blood results, where abnormal results are found Magna will contact the consultant concerned.

Normal Range:

• Clozapine, 0.35 to 0.6mg/l

For advice on how to interpret the levels please contact either trust pharmacy or Clozapine clinic if necessary.

5.11.6 Protocol for red blood results

On receiving a RED result clinic colleagues must:

5.11.6.1 Doncaster, Rotherham, and North Lincolnshire

• Do not retest the result. ZTAS will not allow two results for one patient on the same day. Only obtain a new sample to send that day if the first one appears clotted, and then still send it locally.
• B. If colleagues are unavailable to utilise PocHi, then an urgent ‘fast-track’ local sample should be sent to the local lab and results retrieved and emailed to ZTAS as soon as possible. Stop Clozapine immediately.
• The initial sample should be sent to the local laboratories for testing, to check of any issues with the PocHi machine. Once the local sample results are received by ZTAS then colleagues should contact ZTAS for guidance regarding any further action required.
• Upon receipt of a red result ZTAS will generate an alert or warning to the patient’s psychiatrist and Clozapine pharmacist. Other appropriate healthcare providers are also to be contacted by phone.
• Contact the psychiatrist, care coordinator and, or the ward as appropriate and inform them that the patient is to stop Clozapine immediately. Whilst there is a significant risk of relapse at this time, patients should not take other antipsychotics (however haloperidol can be used, if necessary, as discussed with RMO).
• Ask the patient to return to the Clozapine Clinic for a further blood test within 24 hours (this may require liaison with Crisis team in order that procedure may be followed, for example, out of hours, weekends, or bank holidays). They should bring all Clozapine with them, if possible, to be kept in secure storage until the blood results are satisfactory. This can be carried out on the ward if an inpatient or being admitted.
• The responsible clinician or their nominated deputy should be informed immediately. They may wish to arrange for an assessment of the patient’s mental state and may request the patient to remain in hospital to be assessed.
• If there is a secondary infection, or when the neutrophil count decreases below 1.0×10⁹/L, the psychiatrist should contact a haematologist in the hospital or at ZTAS to discuss the appropriate treatment regime.
• Any local samples taken should be ‘fast-tracked’ and colleagues trained to enter results onto the ZTAS system should do so as soon as possible. If they  are unavailable (evenings, weekends, or bank holidays) the on-call doctor can phone or email the results through to ZTAS and feedback the result to the appropriate colleagues.
• If the patient has only one red result, they may be able to re-start Clozapine. However, this cannot occur until there have been 2 separate green results on 2 consecutive days. If amber results occur at any point daily testing is to be continued and the Clozapine withheld. This may mean that the patient needs to be re-titrated if the delay is more than 48 hours; the RMO will decide how quickly this can be done.
• If the patient has 2 red results, they are ‘non-re-challengeable’  which means they will no longer be able to take any brand of Clozapine. Once a green result has occurred the patient will have stopped Clozapine. However, further weekly testing will be required for a period of 4 weeks to ensure blood results remain stable.
• At this point daily testing should occur until 1 green result is found, consideration should be made for weekends, especially if the PocHi system is not available, testing at the local labs, marked urgent, and results emailed to ZTAS, this will depend on local circumstances.
• Monitor for any signs of infection or flu like symptoms.
• Identify other medication which may be contributing to the red result, and review.
• Check temperature, blood pressure and pulse once daily.
• Instruct the patient to check their own temperature if feeling unwell or warm.
• Instruct the patient to report any symptoms of illness, for example, sore throat, flu like symptoms, immediately.
• If they have 2 consecutive temperatures above 38^oC to contact A and E or 111 or 999 as there is a risk of sepsis.
• Any decision to restart after having a non-re-challengeable status must be done in consultation with ZTAS, it would be an unlicenced use of Clozapine.

5.11.7 protocol for amber blood results

If an amber result is received the clinic colleagues must:

• re-test blood sample locally to confirm it is not an error. If a second amber result is obtained, then advise them to return in 48 hours (or as soon after this as possible) for further testing. Advise pharmacy that the patient is amber and will therefore require only one week’s supply of medication
• where no PocHi machine is available contact the patient to arrange a second blood test within 48 hours
• after the follow-up test, if the result is green, then patient is supplied the remaining 3-weeks of medication following liaison with pharmacy and requested to attend for their regular routine appointment. If the result remains amber, then the patient is required to attend twice weekly testing and supplied with weekly medication until a green result is obtained
• the patient should be informed to watch for further signs of infection and contact the clinic or their consultant psychiatrist or lead professional if they occur. They can go home once the blood test has been taken. Twice weekly blood tests will continue until signs of infection have abated
• bloods should be monitored twice a week until blood results return to the green classification, this may mean only one further test is required following an amber if the follow-up blood result is green. However, if there are signs of infection then testing should continue twice weekly until the symptoms have abated
• the patient can continue to take Clozapine but must have a further blood test taken; this may mean arranging a taxi or contacting their care coordinator to bring the patient to clinic as soon as possible for a local sample to be taken
• the patient should be informed to watch for signs of infection and contact the clinic or their consultant psychiatrist or lead professional should they occur. They can go home once the blood has been taken
• it is also advised to increase monitoring to twice weekly if there are symptoms of infection, even if the samples are normal, until the symptoms have abated. This is also advised if there is a ‘single drop’ or ‘downward trend’ in the white blood count greater than 3×10/L this is indicated by a downwards arrow against the blood result on the ZTAS monitoring screen

If unsure of the above, contact ZTAS for advice.

5.11.8 Monitoring for specific serious side effects

5.11.8.1 Agranulocytosis

• ZTAS guidance on agranulocytosis and neutropenia (opens in new window)

Routine blood monitoring will identify sub-clinical cases. Particular attention must be paid to flu like symptoms such as sore throat and raised temperature that may be indicative of neutropenia. ZTAS currently provides guidance about procedures to be followed in the event of neutropenia or agranulocytosis developing.

5.11.8.2 Acute intestinal obstruction and constipation

• ZTAS guidance constipation (opens in new window)
• Clozapine exerts anticholinergic activities, which may produce undesirable effects to patients on this treatment. Its anticholinergic properties may cause varying degrees of impairment or slowing of intestinal peristalsis ranging from constipation to intestinal obstruction, faecal impaction and paralytic ileus that may be fatal. Acute obstruction is a medical emergency. Symptoms include abdominal distension, pain, and vomiting.
• Particular care is necessary in clients who are receiving concomitant medications known to cause constipation: especially those with anticholinergic properties such as other antipsychotics, antidepressants, and antiparkinsonian treatment. Clients who have a history of colonic disease or a history of lower abdominal surgery should be carefully monitored as this may exacerbate the risk of constipation.

5.11.8.3 Pyrexia (fever)

• ZTAS guidance fever (opens in new window)
• Mild hypothermia occurs in approximately 5% of patients, typically early in treatment and is usually not significant, however; a medical examination and full blood count should be performed as soon as possible. If the body temperature exceeds 38.50^oc, Clozapine should be stopped until the temperature drops. ZTAS (or equivalent) should be contacted, and their advice followed.
• Levels may increase due to the P450 inhibitory effect of fever or inflammation, see section on plasma level monitoring (5.11.5) requiring dose reduction.

5.11.8.4 Seizures

• ZTAS guidance seizures (opens in new window)

Clozapine may lower the seizure threshold; this is a dose or dose increased related effect.

Should a seizure occur, withhold Clozapine for one day, restart at a lower dose. Those needing doses of Clozapine that cause seizures may be prescribed sodium valproate at doses between 1000 to 2000mg per day, use of modified release preparation may aid compliance as it can be given once daily and may be better tolerated. MHRA guidance on the use of valproate in women of childbearing potential must be followed. MHRA valproate guidance (opens in new window). Plasma levels may be useful as a rough guide to dosing, aim for 0.35 to 0.6mg/l, although some may require higher levels.

5.11.8.5 Cardiovascular events

• ZTAS guidance myocarditis and cardiomyopathy (opens in new window)
• Clozapine may increase the risk of pulmonary embolism and sudden death.
• Clozapine has been associated with cardiomyopathy and myocarditis. The risk of myocarditis is highest during the first two months of treatment. Cardiac complications should be suspected if clients experience persistent tachycardia at rest, palpitations, chest pain or heart failure develops. In these cases, Clozapine should be promptly stopped, and the client referred to a cardiologist by their psychiatrist. Such clients should never be re-exposed to Clozapine.
• The risk of orthostatic hypotension can be minimised by slowly tapering the dose and spreading doses through the day.

5.11.8.6 Diabetes and impaired glucose tolerance

• ZTAS guidance metabolic side effects (opens in new window)
• Clozapine has been strongly linked to hyperglycaemia, impaired glucose tolerance and diabetic ketoacidosis.
• As many as a third of patients may develop diabetes after 5 years of treatment.
• Most cases of diabetes are noted in the first 6 months of treatment, and some occur within one month.
• Death from ketoacidosis has also been reported.
• Diabetes associated with Clozapine is not necessarily linked to obesity or to a family history of diabetes.
• Patients should be referred to primary care to manage this.

5.11.9 Procedure for reporting and managing identified side effects

5.11.9.1 Managing constipation

• ZTAS guidance constipation (opens in new window)
• A gastrointestinal history and, or abdominal examination is recommended in all patients prior to starting Clozapine. If there is a pre-existing problem this should be adequately treated prior to initiation. Other concomitant medication should be assessed and where possible discontinued, for example, procyclidine, opiates and so on. Suitable advice should be given to the patient around appropriate diet, exercise and mobility and not ignoring the urge to poo.
• Utilising the Clozapine side effect questionnaire, the patient should be asked about any changes in bowel habits, as a rule of thumb if someone passing motions less than every 3 days, then the GP should be contacted to prescribe appropriate laxatives. A copy of the ZTAS managing constipation can be sent for further guidance. If this is persistent, they should be reviewed by the psychiatrist to review the ongoing dose.

Be aware of the warning signs indicative of severe constipation:

• abdominal pain
• abdominal dilation
• vomiting

The use of a stool diary could be considered, especially in the first 4 months of treatment.

If constipation does occur a full assessment should be made to assess the role of Clozapine in this and to rule out other causes. A three-step approach should be taken:

1. lifestyle changes, fluid intake, dietary fibre, exercise and toileting routine
2. stimulant laxatives
3. osmotic laxatives
4. pro-kinetic drugs

Severe constipation needs to be managed but generally does not warrant discontinuation, however; in cases of intestinal obstruction, faecal impaction or paralytic ileus it should be stopped immediately, and the patient referred urgently to a specialist for treatment.

If blockage or paralytic ileus has occurred then patients should be reviewed with respect to restarting it, and where alternative options are available these would be preferred. In instances where this is not possible it is important that the constipation has fully resolved first, and the patient re-titrated slowly and monitored carefully.

5.11.9.2 General considerations

• If side effects are reported or noted consideration should be made for a more in depth physical examination following consultation with the prescriber.
• Enter information in the patient record along with details of whom you have informed, and what advice has been given.
• Inform the treating team, including the consultant, by email and where urgent by phone as well. Advise them to read the entry in the patient’s clinical record and act accordingly.
• If non-urgent ask the team or consultant to inform the patients GP regarding any advice or follow-up that might be necessary
• If urgent contact the GP directly, ideally emailing them the SystmOne entry or asking admin support to make it into a letter if less urgent.
• Follow-up any issues during the next clinic visit to ensure action has been taken.

5.12 Clozapine supply

5.12.1 Doncaster, Rotherham, and North Lincolnshire

• Follow the SOP for taking blood and setting up the PocHi machine (appendices F, G and H).
• When access has been gained to patient detail screen minimise it and log onto SystmOne.
• NEQAS monthly QC results should be filed.
• Get out the patient file from the filing cabinets for the correct clinic week.
• The pharmacy order is in the light blue transport boxes. Break the seals to open and inside each box is a single delivery receipt that has patient identifying labels on it for all of the medication in that box. Check that each patient’s medication is present and tick on the clinic log sheet to confirm arrival. Repeat with each box and then place the medication alphabetically into the drug cupboard. Keep the clinic log sheets next to the clinic computer so that the medication given, and date boxes can be completed each time a green ZTAS patient result is seen in clinic in the following week.
• When the blood is tested on the PocHi machine normally the patient’s name will appear highlighted in green to indicate a ‘green’ result. It also states whether the patient has 2 or 4 weekly blood tests and the date of the last test (which should always be that days date).

Note, if there are several patients with the same surname check carefully to see you are looking at the correct patients result.

• Give the patient their medication and complete the clinic log sheet.
• Complete the Clozapine questionnaire template on SystmOne.
• “(Patients name) attended the Clozapine clinic at (today). PocHi issued a green result, and he or she was given 1, 2 or 4 weeks’ supply of his or her medication”. You will also enter a brief statement regarding their mental state and any problems which need addressing. Remember to save the entry. Remember to sign the Clozapine clinic log sheet to say you have supplied the medication to the patients.
• Put the ZTAS patient information folders back in the filing cabinet and lock it.
• Lock the fridge, the drug cupboard any clinical cupboards that are open and return the keys to allocated key cupboard.
• Lock the clinic door and switch off the light.
• Email the drug receipt and issue forms to Lloyds pharmacy, once all service users have been seen and medication been issued, include any did not attend (DNA) patients:
  • Rotherham clinic, Lloyds pharmacy email: mhtbarnsleyinterchange@nhs.net
  • Doncaster clinic, Lloyds pharmacy email: mhtbarnsleyinterchange@nhs.net
  • Scunthorpe clinic, Lloyds pharmacy email: mhtbarnsleyinterchange@nhs.net

5.12.2 Rotherham

The Rotherham clinic is held at Ferham Clinic which opens at 9:00am, with the clinic starting at 9:30am weekday mornings, and the medication is delivered at 3pm on a Friday afternoon. The key for the drug cupboard is kept in the key cupboard in reception and held by qualified nursing colleagues and pharmacy colleagues only.  A spare key for the cupboard is held by the recovery team manager if needed. The key to the treatment room is kept in reception in the key cupboard.

5.12.3 Doncaster

The Doncaster Clinic is held at Bungalow 4 and the medication is delivered at 8:30am on a Thursday morning. The key for the drug cupboard is kept in the key cupboard in reception and held by qualified nursing colleagues and pharmacy colleagues only. The main clinic door is accessed via a keypad lock. The code for which is available from the Opal Centre reception if required. A spare treatment room key is also available from the Opal Centre reception.

5.12.4 North Lincolnshire

The clinic in North Lincolnshire is held at the Ironstone Centre, and the medication is delivered on Friday. The key for the drug cupboard is in a locked key cabinet in a locked room. The spare key is in the locked key cupboard.

5.13 Ordering and receipt of Clozapine

Lloyds pharmacy for Doncaster, Rotherham and North Lincolnshire services (see SOP appendix C, D and E).

Prescriptions are requested by Lloyds pharmacy to the relevant patient’s community team or inpatient ward. The frequency is dependent on how the patient is currently being managed or how long the last repeat prescription was requested for.

The prescriptions are emailed to the Lloyds pharmacy using the email addresses stated above, and the originals are sent via the Lloyds drivers either in the Lloyds pouch or blue pharmacy boxes.

Yellow copies of the prescription are to be filed in the patient’s notes.

On receipt of the medication colleagues are to check that the medication has been received for the patients who are on the list. Once this has been confirmed the ‘received by’ section on the delivery sheet is to be signed. All medication is then to be locked away in the drug cupboard. The key for which is held in the key cupboard in reception.

5.13.1 Ordering Clozapine out of hours (for example, if admitted to a general hospital)

Patients admitted to an acute hospital should have a supply of their own Clozapine with them. The ward should be advised to contact the local Clozapine clinic to inform them of their admission. Where they exist the mental health liaison service should be contacted who will be able to facilitate further supplies and will be able to access their clinical record and inform the ward when further blood tests are due.  Where possible, if the patient has not brought in their supply, a carer should be asked to bring it in.  If the patient has a valid blood test, then the nominated Lloyds pharmacy may be able to supply, if they have a prescription.

5.14 Protocol for patients who are going on holiday whilst on Clozapine

Patients are able to take a holiday for a maximum of two weeks if established on fortnightly monitoring or four weeks if established on four weekly monitoring.  If the holiday period does not exceed the normal sampling time this protocol does not need to be instigated.

5.14.1 Holidays in the UK

• The patient should discuss the dates of the holiday with the clinic colleagues so that they can ensure a sample is not required during the holiday period and there is adequate time to collect medication prior to departure. This may require the routine appointment being adjusted to one or two weeks early (depending on frequency of monitoring and holiday dates). The pharmacy supplier should also be informed, and the prescription adjusted accordingly. For example, if a patient attends one week early and is four weekly monitoring, they will have a week of medication left from the last prescription, so a three-week prescription can be given and an appointment four weeks from the last appointment.
• In the event that a patient is planning to be away for more than four weeks clinic colleagues should liaise with the relevant company to arrange for sampling and medication delivery in the locality of the holiday destination.

5.14.2 Holidays outside the UK

For any patients who are planning to take a holiday outside the UK the following should have occurred prior to the holiday:

• the responsible clinician will have assessed the likely effect of the trip on the patient’s health
• emergency contact between the Clozapine clinic and the patient is to be agreed
• patient has a satisfactory blood result prior to leaving the country. If necessary, a sample should be taken and analysed locally just prior to departure and placed on the ZTAS system by pharmacy or clinic colleagues

No more than 14 days (or 28 days for 4 weekly monitoring) supply of Clozapine should be taken on holiday with the patient.

Patients are unable to take holidays exceeding their monitoring schedule as the clinic is unable to organise supplies beyond this.

Patients and carers should be aware of the procedure to follow if the patient develops an infection. If an infection does develop an emergency white blood count with differential should be performed immediately and the results transmitted urgently to the patient’s consultant.

If an emergency occurs and you are unsure of any contact details in any destination, contact ZTAS for advice.

In an emergency, if a patient cannot return in time to have a sample or collect medication:

• inform pharmacy immediately.
• discuss with responsible clinician or lead professional
• this may involve liaising with a hospital at the holiday destination to obtain a blood sample; this should be emailed to the pharmacy
• pharmacy may be able to liaise with the hospital at the destination to dispense a supply of Clozapine (depending on which company they obtain their supply from)
• if this is not possible clinic colleagues should discuss with responsible clinician or lead professional, care coordinator, and family or carers to see if arrangements can be made to deliver a supply

5.15 Minimum clinic checks

As a minimum the following checks should be carried out on the first Clozapine clinic of every month:

• that there are adequate supplies of paperwork if supplies are low photocopy
• that there are adequate supplies of consumables such as blood bottles, needles, needle holders, rigid transporters, absorbent material, plastic bags, envelopes, and request forms. If there are not enough for a further 5 clinics order more using the consumables request form (which is emailed to Magna Laboratories, info@magnalabs.co.uk). Blood bottles and needles for use in the PocHi machine should be ordered via the usual route
• that there are supplies of other equipment, for example, gloves, cotton wool, plasters, and sharps container. If supplies are low an order is to be put in
• a review of the sampling frequency of all the patients by looking on the appropriate site, contact ZTAS by phone if confirmation is needed
• the scales are calibrated annually professionally and should be adjusted to ensure they are level by the clinic
• the record form for the health and safety checklist should be completed and signed, and any comments placed in the appropriate box. Any further issues, which cannot be dealt with immediately, should be written in the communications book and a check made that they have been resolved

5.16 Transfer of patients between Clozapine clinics (to another pharmacy supplier)

To transfer a patient:

• ensure the transferring consultant is aware of the need for planning and the time it may take
• the transfer can only proceed if a consultant psychiatrist has accepted responsibility in the new area. It is the responsibility of the receiving consultant to register or complete change of consultant forms
• the details for the Clozapine clinic in that area and which company the area uses to purchase and monitor Clozapine are to be obtained and when the next blood test is due
• if a different company is used to purchase and monitor Clozapine the patient will need registering by the new consultant
• once the details of the new Clozapine clinic have been received a photocopy of the patient’s record is to be forwarded to the new clinic along with a copy of the standard letter
• if the new area also uses ZTAS do not send them the patient stickers as they are bar-coded to send the results to the current consultant not the new one
• ensure there is time for the patient to find and attend the new Clozapine clinic before they run out of medication, and that they and the new clinic are aware of their appointment date and time
• inform pharmacy of the transfer dates

To receive a transfer:

• if a referral is received without a standard letter, if time allows, send a copy for completion, or phone if referral has been made at short notice.
• check which company the patient was registered with in their last area, if it isn’t the same company as the clinic referred ask the new consultant to complete a patient information form and email it to them as soon as possible (registration may take 24 hours).
• if it is the same company, they will request an email from the new consultant stating the date they took over care and all the patient’s details, this should.
• also include the new pharmacy and Clozapine clinic addresses and contact details.
• once registered on the local database, order new labels by emailing the request to the relevant company.
• contact pharmacy and make sure they are aware of the new patient.
• book the patient an appointment at Clozapine clinic and commence the routine monitoring (please note if they have been monitored on a different day in the other area, they must be seen on the clinic the day before that date. For continuity of care, it is important that samples are sent early rather than late)

5.17 Re-initiation of Clozapine

5.17.1 Following non-compliance

In patients in whom the interval since the last dose of Clozapine exceeds 48 hours, treatment should be re-initiated with 12.5mg given once or twice on the first day. If this dose is well tolerated, it may be feasible to titrate the dose to the therapeutic level more quickly than is recommended for initial treatment. However, in any patient who has previously experienced respiratory or cardiac arrest with initial dosing but was then able to be successfully titrated to a therapeutic dose, re-titration should be carried out with extreme caution.

5.17.1.1 Monitoring frequency, weekly

Time off Clozapine less than or equal to 48 hours:

• no change to monitoring frequency

Time off Clozapine greater than 48 hours but less than 7:

• no change to monitoring frequency. Re-titration dose as per initial titration

Time off Clozapine greater than 7 days:

• restart at 18 weeks of weekly monitoring. Re-titration dose as per initial titration

5.17.1.2 Monitoring frequency, fortnightly and monthly

Time off Clozapine less than or equal to 48 hours:

• no change to monitoring frequency

Time off Clozapine greater than 48 hours but less than 3 days (72 hours):

• no change to monitoring frequency. Re-titration dose as per initial titration

Time off Clozapine greater than 3 days (72 hours) but less than 28 days:

• treatment breaks weekly for 6 weeks and then return to previous monitoring frequency

Time off Clozapine greater than 28 days:

• restart 18 weeks of monitoring weekly monitoring

ZTAS must be contacted in the event of treatment break, and they will confirm the changes to monitoring requirements.

Please see appendix D for the monitoring requirement when patients are being re-titrated on Clozapine and the suggested dose titration schedule.

Please see appendix J re-titration on Clozapine guidance.

5.17.2 Following red blood result

Consideration of re-initiation of Clozapine is only appropriate in specific circumstances. The risks and benefits of re-challenge of Clozapine therapy need to be considered by the whole multi-disciplinary team (MDT). Neutropenia during Clozapine therapy needs to be assessed for the likelihood of being directly attributable to Clozapine and not from any other cause, such as concomitant myelosuppressive drugs such (for example, carbamazepine) and underlying physical conditions (for example, benign ethnic neutropenia). Determination if neutropenia is due to Clozapine or another cause cannot be made with certainty. Risk factors for true Clozapine induced neutropenia are a low baseline white blood count, Afro-Caribbean ethnicity and young age. True Clozapine induced neutropenia usually develops early in treatment, for example, in the first 18 weeks decreasing rapidly over 1 to 2 weeks, with a slow return to normal levels.

The final decision for rechallenge of Clozapine therapy must be made between the chief pharmacist and the named consultant psychiatrist in consultation with ZTAS and should be initiated on a named-patient basis with completion and filing in the patient’s notes of a new consent form as in such circumstances use will be ‘off licence’. The patient and family or carers where appropriate must have a fully documented discussion with the clinician regarding the risks associated with a rechallenge of Clozapine.

Please see appendix E for the monitoring requirement when patients are being re-titrated on Clozapine and the suggested dose titration schedule.

Please see appendix J chart for re-titration on Clozapine.

5.18 Planned discontinuation of Clozapine

• As with all antipsychotic medication, discontinuation from Clozapine should, if possible, occur gradually. This should take a period of 1 to 2 weeks.
• The patient should be carefully monitored for signs and symptoms of psychosis during this time.
• The consultant should email a letter to ZTAS explaining the dates and reason for discontinuation.
• Monitoring should continue for a further 4 weeks at the established frequency from the day the last dose was taken.
• Sudden withdrawal from Clozapine may give rise to physical symptoms such as confusion, sweating, restlessness, nausea, dyskinesia, headache, insomnia, and vomiting. If necessary, treatment with an anticholinergic agent may be helpful.

5.19 Smoking and Clozapine

Please see the trust leaflet regarding Clozapine and smoking (opens in new window). This leaflet should be talked through with the patients.

5.19.1 Stopping smoking

If a patient wishes to stop smoking the procedure for obtaining serum Clozapine levels from section 5.11.5 should be followed, and the Clozapine doses should be subsequently adjusted accordingly.

5.19.2 Starting smoking

Serum Clozapine levels should be monitored, and Clozapine doses subsequently adjusted to ensure the plasma level does not become sub-therapeutic.

Unless clinically indicated the levels should be checked 2 to 4 weeks post change in status

5.20 Record keeping

All patients attending the trust Clozapine clinics will have a care plan in place, and an entry will be made following each clinic attendance.

Following each clinic appointment, the Clozapine clinic template must be completed on SystmOne.

The record should include.

• brief mental state
• record of any assessments carried out
• results of side effects questionnaire, and where aberrant results are detected what has been done about them
• this can be found as a questionnaire on SystmOne
• what has been supplied
• date of next appointment

5.21 Communication with primary care

A letter should be sent to the patient’s GP, requesting them to update their records, including the summary care record on (with a note to say dispensed elsewhere):

• initiation of Clozapine
• discontinuation of Clozapine
• annually following the physical health check
• three monthly

Any request to help manage side effects such as constipation, where ZTAS information leaflets are available, these can be sent with the letter (you must be logged on the ZTAS website (opens in new window) to access them).

6 Training implications

The Clozapine clinic leads will be responsible for coordinating any Clozapine related training which is required by clinical colleagues working within either the community or inpatient services.

All colleagues working in the Clozapine clinical are responsible for keeping their own training up to-date and informing their service manager of any identified training needs.

In regard to this protocol clinical colleagues will be made aware of it in the following ways:

• the reissue of the protocol will be included in the trusts monthly team talk
• discussion at team or ward meetings
• a copy of the protocol will be available on the trust website

7 Monitoring arrangements

7.1 Compliance with the side effects monitoring requirements

• How: Clinical records audit.
• Who by: Clinic leads.
• Reported to: Service manager and care group director.
• Frequency: Annual.

7.2 Patient satisfaction with the service delivered by the clinics

• How: Patient satisfaction with the service delivered by the clinics.
• Who by:  Patient satisfaction survey. Instigation and outcome of any complaints received in respect of the clinics, and review of action plans.
• Reported to: Clinic leads.
• Frequency: Annual.

7.3 Any emerging themes from incidents reported through on the electronic IR1 system

• How: Review of any IR1s submitted in respect of the Clozapine clinics.
• Who by: Service manager.
• Reported to: The local clinical governance group, and medicines management.
• Frequency: Ongoing as incidents are reported.

8 Equality impact assessment screening

To access the equality impact assessment for this policy, please email rdash.equalityanddiversity@nhs.net to request the document.

8.1 Privacy, dignity and respect

The NHS Constitution states that all patients should feel that their privacy and dignity are respected while they are in hospital. High Quality Care for All (2008), Lord Darzi’s review of the NHS, identifies the need to organise care around the individual, ‘not just clinically but in terms of dignity and respect’.

As a consequence the trust is required to articulate its intent to deliver care with privacy and dignity that treats all service users with respect. Therefore, all procedural documents will be considered, if relevant, to reflect the requirement to treat everyone with privacy, dignity and respect, (when appropriate this should also include how same sex accommodation is provided).

8.1.1 How this will be met

There are no additional requirements in relation to privacy, dignity, and respect

8.2 Mental Capacity Act

Central to any aspect of care delivered to adults and young people aged 16 years or over will be the consideration of the individuals’ capacity to participate in the decision-making process. Consequently, no intervention should be carried out without either the individual’s informed consent, or the powers included in a legal framework, or by order of the court.

Therefore, the trust is required to make sure that all staff working with individuals who use our service are familiar with the provisions within the Mental Capacity Act (2005). For this reason all procedural documents will be considered, if relevant to reflect the provisions of the Mental Capacity Act (2005) to ensure that the rights of individual are protected and they are supported to make their own decisions where possible and that any decisions made on their behalf when they lack capacity are made in their best interests and least restrictive of their rights and freedoms.

8.2.1 How this will be met

All individuals involved in the implementation of this policy should do so in accordance with the guiding principles of the Mental Capacity Act (2005) (section 1).

9 Links to any other associated documents

• Consent to care and treatment policy
• Interpreters policy (provision, access and use of, for patients, service users and carers)
• Safe and secure handling of medicines manual
• MCA Mental Capacity Act 2005 policy
• Incident management policy
• Infection prevention and control manual

10 References

• Zaponex treatment access system (accessed 12 March 2024) (opens in new window).
• Clozapine and other antipsychotics, monitoring blood concentrations for toxicity (accessed 12 March 2024) (opens in new window).

11 Appendices

11.1 Appendix A Clozapine clinic side effects questionnaire and monitoring

• Appendix A Clozapine clinic side effects questionnaire and monitoring (staff access only) (opens in new window)

11.2 Appendix B NEWS2

•  Appendix B NEWS2 (staff access only) (opens in new window)

11.3 Appendix C Clozapine inpatient initiation

• Appendix C Clozapine inpatient initiation (staff access only) (opens in new window)

11.4 Appendix D Re-titration of Clozapine guideline (inpatients only)

• Appendix D Re-titration of Clozapine guideline (inpatients only) (staff access only) (opens in new window)

11.5 Appendix E Clozapine initiation monitoring

• Appendix E Clozapine initiation monitoring (staff access only) (opens in new window)

11.6 Appendix F Point of care haematology (PocHi) standard operating procedure (Doncaster)

• Appendix F Point of care haematology (PocHi) standard operating procedure (Doncaster)

11.7 Appendix G Point of care haematology (PocHi) standard operating procedure (Rotherham)

• Appendix G Point of care haematology (PocHi) standard operating procedure (Rotherham)

11.8 Appendix H Point of care haematology (PocHi) standard operating procedure (North Lincolnshire)

• Appendix H Point of care haematology (PocHi) standard operating procedure (North Lincolnshire)

11.9 Appendix I Common Clozapine drug interactions

• Appendix I Common Clozapine drug interactions (staff access only) (opens in new window)

11.10 Appendix J Initiating or re-titrating inpatients on Clozapine ward pack

• Appendix J Initiating or re-titrating inpatients on Clozapine ward pack (staff access only) (opens in new window)

11.11 Appendix K Use of intramuscular Clozapine

11.11.1 Introduction

The use of clozapine in the management of treatment resistant schizophrenia is widely held to be the gold standard of treatment. Due to the nature of the condition it is often difficult to establish a therapeutic relationship with the patient during the acute phase of their illness which makes it difficult to establish medication adherence. Clozapine has historically only been available in oral forms: Clozaril® tablets, Denzapine® suspension and tablets and Zaponex® tablets which has limited the options available to clinicians when selecting a treatment approach for those patients who are unwilling or unable to take medication orally.

Clozapine intramuscular injection (IM) (25mg/ml) is an unlicenced product which can be imported from the Netherlands. It is manufactured by Brocacef Hospital Pharmacy and imported into the UK via Durbin PLC. This represents an alternative treatment option for those patients where a UK licenced product is not acceptable or appropriate.

There are important differences in the pharmacokinetics of clozapine when administered via the IM route compared to the oral route; due to these the dosing of the intramuscular and oral forms are not bioequivalent. Care is needed when prescribing and administering the product to ensure the correct dose is selected.

The primary aim of using clozapine injection is a short term intervention to initiate clozapine for inpatients who refuse medication, with a view to convert to oral clozapine as soon as possible.

11.11.2 Purpose and scope

The aim of this document is:

• to outline the trust position on the use of this unlicenced product
• to provide clinical guidance that will allow safe and effective use of the product where it has been approved for use

11.11.3 Principles

11.11.3.1 Patient selection

Clozapine IM is approved for use where the following criteria are met and are clearly documented as part of the patients’ clinical record:

• the patient meets the criteria for clozapine treatment as set out in the trust policy, and is registered with a clozapine monitoring service
• the administration of clozapine via the oral route has been attempted and it has not been possible to establish or maintain the patient on treatment using this route, covert administration and the use of alternate forms of clozapine have been considered and are not appropriate
• the barriers to the use of oral clozapine are characterized and are expected to be temporary and to resolve with the administration of clozapine
• alternate non-clozapine treatment options have been considered and are clinically inappropriate and the need for clozapine IM has been agreed by the MDT including a pharmacist
• previous response

Clozapine IM is not approved for use where:

• the patient is likely to have an ongoing impairment of their ability to accept oral treatment after their mental state has improved
• the patient has previously received this treatment and has experienced an adverse event to this formulation

Clozapine IM is only approved for use under this policy for a maximum duration of treatment of 2 weeks.

If clozapine IM is to be used during the maintenance phase to prevent re-titration, there is no requirement to switch the patient to ZTAS (for example, the patient is to remain with the monitoring agency with whom they are currently registered with). Colleagues must however be confident with compliance to oral clozapine up to the point the IM formulation is needed.

11.11.3.2 Trust approval process

Applications for clozapine intramuscular should be through the following route:

• write to the chief pharmacist or care group medical director outlining the rationale and request, this must be by the consultant under whose care the patient is to be registered

All applications for use will be reported to the trust medicines management committee.

Where use is approved the chief pharmacist will detail:

• date of approval
• length of time for which it has been approved (for example, titration and during maintenance to avoid re-titration)
• any additional requirements above those specified in this document
• if approval is required before the next meeting of MMC, approval must be sought from the Care group medical director and chief pharmacist (or their immediate deputies)
• patients should have shown a previous response to clozapine

11.11.3.3 Patient registration

All patients treated with clozapine require registration with a UK clozapine monitoring service; the manufacturers of the unlicenced product do not provide this service. Patients requiring this treatment from titration should be registered with the Zaponex treatment access system (ZTAS) one week before commencing treatment. Liquid options should be considered first.

At the point of registration, it is the responsibility of the consultant psychiatrist to contact the monitoring service to advise them of the use of the unlicenced form of medication, the consultant is responsible for documenting the use of an unlicenced and ensuring the patient or significant others are aware of this.

An unlicenced form should be completed and sent to the supplying pharmacy

11.11.3.4 Patient monitoring

All patients should have their baseline, titration, and ongoing monitoring completed as set out in this policy.

In addition all patients receiving a clozapine IM injection should be monitored post-injection as set out in the rapid tranquillisation policy.

11.11.3.5 Prescribing and administration of clozapine intramuscular injection

Clozapine IM should only be prescribed as a short term intervention to manage either:

• initiation of clozapine treatment
• an acute deterioration in a patient who is normally maintained on oral clozapine in order to prevent a re-titration (only where the patient has previously experienced a significant relapse in this situation)

Clozapine IM is not considered suitable as part of an ongoing care plan for managing intermittent refusals.

As clozapine IM is an unlicenced medicine in the UK, all aspects of section 17 of the medicines code must be followed including completion of the appropriate forms and a documented discussion with the patient and or representative(s).

When prescribing clozapine IM for titration, the following must be in place:

• a care plan to offer oral first and only administer IM if this is refused
• a care plan describing the physical health monitoring and blood sampling arrangements. This should include guidance if monitoring is unable to be performed in accordance with the clozapine policy
• prescription for both the oral and IM forms (see appendix B). Clozapine should be prescribed on the main drug chart and annotated “see separate clozapine titration chart”
• a plan for weekly review of the administration of the intramuscular form
• specified aims of treatment

The dose of Clozapine when prescribed by the IM route should be 50% of that when prescribed by the oral route due to the differences in bioavailability.

When prescribing clozapine IM during maintenance to prevent re-titration, the following must be in place:

• a care plan to offer oral first, to consider the use of a flexible dosing strategies, whereby the administration window is extended to optimise opportunities to administer orally, and to only administer IM if this fails
• a care plan describing the physical health monitoring and blood sampling arrangements. This should include guidance if monitoring is unable to be performed in accordance with the clozapine policy (liaison with the local MAV team may be necessary)
• a care plan describing the point at which clozapine IM will be administered (for example, at the 3rd refused dose for patients on a twice daily regime), the dose that will be administered arrangements for prescribing this dose and plans for medical review in the event of further refusals

Please note that colleagues must be confident that the patient has been compliant with oral clozapine beforehand.

Administration of Clozapine IM should follow standard approaches for the administration of medication by the IM route. Consideration should be given to the following:

• the maximum volume that can be injected into each site is 4ml (100mg). Doses greater than 100mg should be administered into two sites
• any unused injection should be discarded as per section 12 of the medicines code
• the injection is administered into the gluteal muscle and is painful, and there is a risk of local irritation

Where is it required to give this injection under restraint standard approaches should be considered, and advice sought from the local MAV team where standard approaches are unsuitable.

Clozapine IM should not be administered within 1 hour of Lorazepam IM.

11.11.4 Suggested titration schedule

11.11.4.1 Note daily dosing

IM dose is 50% of oral dose (Clozapine):

Note, the bioavailability of oral and IM is different.

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Document control

• Version: 5.
• Unique reference number: 105.
• Approved by: Clinical policy review and approval group.
• Date approved: 5 March 2024.
• Name of originator or author: Senior pharmacist on behalf of medicines management committee.
• Name of responsible individual: Chief pharmacist, medicines management committee.
• Date issued: 3 April 2024.
• Review date: 30 April 2027.
• Target audience: Clinical colleagues working in the mental health and learning.

Page last reviewed: December 11, 2024
Next review due: December 11, 2025

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