SH CP 114 Clozapine Guideline

Transcription

1 SH CP 114 Clozapine Guidelines (including clozapine initiation both inpatient and community, long term monitoring and treatment, actions following a red result and GP reference guide) Summary: Keywords (minimum of 5): (To assist policy search engine) The UK product licence of Clozapine (Clozaril ) allows for initiation as an inpatient or outpatient with intensive community support. Clozapine, Clozaril, initiation of clozapine, restarting clozapine, blood tests, red results, smoking, clozapine GP guide, treatment resistant schizophrenia, constipation Target Audience: All Mental Health Practitioners involved in clozapine use. Next Review Date: October 2019 Approved & Ratified by: Medicines Management Committee Chair approval Date issued: December 2018 Date of meeting: 21 March December 2018 Author: Sponsor: Juliet Wells, Principal Pharmacist (AMH and LD) Dr. Karl Marlowe, Medical Director December

2 Version Control Change Record Date Author Versi on September 2016 March 2017 February 2018 February 2018 February 2018 February 2018 Page Reason for Change Rebecca Henry 2 Policy Review Rebecca 3 28 Insert Appendix 7, Guide to Interpretation of Clozapine Henry Plasma Levels. Add Norclozapine paragraph. Alex Weston 3 9 Added new information as point 4.16 about initiation of treatment in patients 60 years or older from Clozaril SPC Alex Weston 3 55 Removed GP information leaflet as formatting difficulties and incorrect advice. and problems reading due to font colour. Appendix 10 covers the pertinent points. Alex Weston 3 All Formatting reviewed throughout Alex Weston 3 8 Reviewed dose recommendations in line with Summary of Product Characteristics, Clozapine Handbook and Maudsley Prescribing Guidelines. Referenced. Moved from prescription initiation charts to section 4.6 Alex Weston 3 Through Replaced Novartis with Mylan as new owner of Clozaril out brand Alex Weston 3 4,8 Updated appendix numbers in flow diagram and text February 2018 February 2018 March 2018 March 2018 March 2018 April 2018 J Wells 4 Through out May 2018 August 2018 Alex Weston 3 37,38 Updated titration charts as per Maudsley guidelines as discussed with Vanessa Lawrence Alex Weston 3 Through Checked body of text to ensure appendix numbers still out correct Ed Horne 3 Through Added constipation poster as appendix 20 out Review of acceptance criteria, responsibilities, monitoring for community initiation patients and myocarditis risks and appendix 16 J Wells R Henry J Wells T Orchel R Ellenby 4 S5.3 p36 Appendix 9 Appendice s 1, 5.0 & Appendix 9 Removed valproate (see MHRA drug safety alerts 2017 and 18) and replaced with lamotrigine. Addition of HbA 1c throughout Constipation advice/porirura Protocol added to GP letter and throughout Review of GP letter. Addition of guidance of how to add to GP systems November J Wells Addition of by secondary care to Annual Review (SHFT 2018 holds the whole economy) 20/2/19 Update author details on front cover. Reviewers/contributors Name Position Version Reviewed & Date Medicines Management Committee Version 1, April 2014 Medicines Management Team Version 1, April 2014 Medicines Management Committee V2 July 2016 Medicines Management Committee V3 March 2018 Medicines Management Committee V3 May 2018 Medicines Management Committee V4 Nov 2018 December

3 Contents Page Summary of the Initiation of Clozapine 4 1. Criteria for Acceptance 5 2. Responsibilities of the consultant 6 3. Responsibilities of the care coordinator 7 4. Treatment Programme 8 5. Restarting Clozapine following an unplanned discontinuation 10 Further reading 11 Appendices 1 Potential side effects 12 2 Clozapine initiation checklist 13 3 Baseline physical health monitoring 15 4 Clozapine physical monitoring sheet 16 5 Clozapine in the community contact monitoring sheet 20 6 Guidelines for the management of a red clozapine result 23 7 Guide to Interpretation of Clozapine Plasma Levels Smoking Cessation effect on clozapine 30 9 Suggested GP letter Shared care guideline: information for the GP Clozapine initiation prescriptions Clozapine outpatient prescriptions Blood monitoring form On-going physical health monitoring parameters Clozapine clinic monitoring form Clozapine cardiac induced side effects flow chart Information check list for patients on clozapine Re-challenge to Clozapine following a red result Clozapine brand change procedure Clozapine side effect rating scale (GASS-C) Constipation poster 54 December

4 SUMMARYOF THE INITIATION OF CLOZAPINE (for both in-patients and out-patients) The patient meets the Acceptance Criteria for the initiation Give patient/carer appropriate information. Obtain valid consent and record in patient s records, or obtain second opinion. Obtain new T2 or T3 if needed Review current medication and smoking status for concurrent side-effects and drug interactions and medical conditions to ensure that it is appropriate to start clozapine resulting in which team initiates clozapine.. Take initial blood tests (FBC, Troponin I or T and CRP). Complete baseline physical health monitoring (appendix 3). Complete patient registration form and fax it to the Clozaril Patient Monitoring Service (CPMS) or Denzapine (DMS). Inform clozapine clinic, pharmacy department, GP, AMHT and the ward team as appropriate and complete risk assessment. Write relevant clozapine-related care plans to include monitoring requirements and specific information regarding relevant medical conditions. Green blood result clozapine can be started If not seek advice from the CPMS/DMS and SHFT Pharmacist Complete initiation forms and baseline monitoring (see appendix 2 and 3 ), send to AMHT with referral if appropriate. (Start within 10 days of initial blood test) Prescribe dose at 12.5mg daily, at night for inpatients and in the morning for community patients, and then follow the titration chart (appendix 11). Avoid increasing the dose when there is no medical cover (e.g. at weekends and bank holidays) Obtain supply of clozapine from the pharmacy. Inform the nursing team of the titration schedule. Day 1 Observations see appendix 4 and 5 (pulse, temp, respiration and lying down and standing BP) three times, at baseline and ideally at 2 and 6 hours post dose and for community patients, four contacts in all (the other contact may be by phone) Day 2 Observations before the morning dose is given, ideally 2 and 6 hours post dose and for community patients an additional phone contact. Day 3 to 7 Repeat Blood test (weekly thereafter in line with local procedures) Include Trop T or I and CRP for the first month. Observations twice daily, before the morning dose and 6 hrs post dose and 3 contacts in all (1 phone contact) Day 8 to 14 Observations once daily and community patients three contacts in all (2 phone contacts) Day 14 Onwards Daily observations to continue until there are no unacceptable side effects and the dose is stable Stable dose Inform clozapine clinic and CMHT if appropriate, and CPMS when changing teams or consultant. For ongoing monitoring see appendix 14 Full physical health check at 3 months, 6 months and then annually including RiO physical health questionnaire. Ensure GP is aware of ongoing clozapine prescription, refer to GP brief reference guide. Update care plan. Enter all results and communications in the electronic patient record. December

5 Guidelines for Initiating Patients on Clozapine (including reinstating clozapine after non-compliance) The UK product licence of Clozapine (Clozaril ) allows for initiation as an inpatient or outpatient with intensive community support. 1. Criteria for Acceptance 1.1 The patient is willing and able to accept the required level of physical health monitoring and attend necessary appointments either as an inpatient or outpatient, or enable staff contact e.g. through home visits to enable monitoring 1.2 The patient must accept regular blood tests. 1.3 The patient fulfils the standard licensed product criteria for receiving clozapine. The use of clozapine outside of the product s licence will be at the responsible clinician s discretion and should be documented in the medical notes. A standard letter should also be completed acknowledging the consultant s responsibility, and returned to the manufacturer i.e.mylan. 1.4 Patients with medical co-morbidities will require increased monitoring under AMHT until at a stable dose, to identify any change in their condition and each patient should be considered on an individual basis. This should be recorded in the patient s notes and Care Plan. Proceed with additional caution (i.e. slower dose titration and increased monitoring) in adolescent and elderly patients. The patient must also have their ability to self medicate a complex regimen assessed, including previous concordance history. If there are reasonable concerns and hence the patient s health may be at risk with non-concordance, then the decision not to proceed should be made by the team and documented. If there are concerns with the ability to manage the initiation regimen, then intensive support should be provided by AMHT, or as an inpatient.the outcome of this assessment should be documented along with the decision to proceed with clozapine therapy or not. The results of a baseline tests and ECG should be recorded in the patient s records. If the patient has any complications the risks versus benefits needs to be considered and, if they are in the community, to admit the patient for intensive monitoring be considered. If the risks of clozapine treastment are high, then the patient should not be accepted for clozapine treatment, and this outcome should be recorded in the patient s notes and the patient and carer informed. 1.5 If the patient has a history of previous problems particularly respiratory (including Obstructive Sleep Apnoea), cardiac or seizures, then inpatient titration must be considered. The outcome of this decision should be recorded in the patient s medical notes. 1.6 Community patients must have a carer willing and able to monitor the patient particularly at night and at weekends, on initiation. Where there is no such carer and the patient is alone then, review the appropriateness of community initiation and initiate as an inpatient or under AMHT until at a stable dose. Every effort, however, needs to be made to acquire a suitable carer to ensure maximum safety. Record details in the patient s records. December

6 2. Responsibilities of the consultant The patient s responsible clinician must ensure: 2.1 The decision to start the patient in the community will need to be made by the team and agreement by all parties sought and the acceptance criteria met. 2.2 That they are satisfied that the patient has given valid consent to commencing treatment or if lack capacity that it is in their best interest Consent is valid when; The patient has been given information about the treatment in a form that can be understood, and is clearly explained, including information about possible side effects, physical monitoring, blood tests, on-going appointments/ home visits,concordance with the treatment regimen, and the likely consequences of not having the proposed treatment. The patient has been given information about alternative treatment options in a form that can be understood, and is clearly explained The patient has the capacity to make the decision about their treatment. The patient has the freedom to make a choice. An entry in the patient s records confirming this has been carried out. 2.3 A doctor from the prescribing team is readily available to give advice to the community, primary care or inpatient staff. 2.4 Existing medication and smoking status is reviewed, particularly for drug interactions and concurrent side-effects, and it is appropriate and safe to start clozapine. Some drugs will need to be discontinued (for example carbamazepine and antipsychotic depot injections) before clozapine initiation. Concurrent antipsychotic depot/long Acting Injections make treatment with clozapine off-licence use, as there are increased risks (see 1.3). 2.5 The doctor must ensure the following are informed, and document The patient s GP, supply GP with information on clozapine (see appendix 10 for the GP risk management/shared care guideline), start date and emergency contact numbers, before initiation for community patients and prior to discharge for inpatients. All appropriate members of the mental health care team, including care co-ordinators. 2.8 For community patients the responsibility remains with the community consultant. They may need to negotiate/coordinate with the AMHT or inpatient consultant. There should be regular specialist medical reviews (at least 6 to 12 monthly), particularly where there are changes in physical monitoring or deteriation in physical health. 2.9 Ensuring the prescription chart is complete, including a named care co-ordinator and contact details. This will be an inpatient drug chart or the community clozapine chart (see appendix 11). Both will need regular review and re-writing in a timely manner and communicating with all parties involved. 3. Responsibilities of the care coordinator 3.1 When making the decision to proceed with clozapine initiation in the community or inpatient wards the care coordinator or senior nurse in the team will identify staff competent to monitor the patient s physical health (see appendix 4). This includes blood pressure, temperature, pulse, respiration and December

7 weight. This is to be recorded on the paper work and track and trigger tool, as appropriate. If a non-qualified member of staff is completing the monitoring, then changes must be reported to a qualified member of staff. 3.2 All nurse/practitioners involved must be familiar with: Potential side effects of Clozapine and how these present. The information that the patient will need about taking Clozapine (see ). The treatment programme. The Clozaril Summary of Product Characteristics. The up to date version is available from Physical health monitoring required while on clozapine and what to do if concerned about any results. 3.3 It is the role of the nurse/practitioners to. Monitor and report the development of any side effects. Observe and report the patient s progress and discuss management with the Consultant or available physician where there are concerns and at regular specialist medical review. It may be helpful to refer to the document Potential side effects (Appendix 1). Provide information and support to the patient and carers including patient information leaflets. Document all discussions and observations on the electronic patient record (RIO) Maintain an appropriate Care Plan fo clozapine. Report and act on any concerns with obtaining physical monitoring, attendance for appointments/clozapine clinic and concordance issues. 3.4 Nurse/practitioners should confirm information has been given and understood by the patient and carer. This is to include: Common side effects, their symptoms and what to do if they occur To report constipation or change in bowel habit to healthcare professionals as a matter of urgency. The importance of not travelling alone or driving for at least 2 weeks (due to a small but known risk of collapse). Also to expect sedation which will effect their ability to drive and use machinery. The signs of neutropenia including sustained temperature elevation with flu like symptoms or a sore throat. Why regular blood tests are mandatory. To report feeling unwell and any symptoms of illness including fever, cough, chest pain, shortness of breath, diarrhea, increased salivation, increased pulse/tachycardia, nausea, vomiting, sore throat, myalgia, headache, sweatiness, and urinary discomfort or frequency change. Why regular observations are required. To give advice on weight management and diet. Consider both written and verbal. Smoking status; to record smoking status and to inform and seek advice from a member of their team if considering stopping/starting smoking and why (see Appendix 8). Breaks in treatment. If stopped for longer than 48 hours the dose must build up again from 12.5mgs. See section 5.1 for further information. If more than 72 hours, blood tests will need to go back to weekly for at least 6 weeks. Also advice why concordance with the reimen is required and to report any problems. Provide the patient and carer with the patient information leaflets. The importance of informing anyone else treating him/her that they are on clozapine. To provide the patient and carer with the name of their care co-ordinator, consultant and team and contact details. December

8 3.5 With community patients it is the role of nurse/practitioners to ensure that the patient and carer know when and who to notify should problems arise both within normal working hours and out of hours. 3.6 If the patient decides to stop clozapine, the nurse must ensure that the patient discusses this decision with the Consultant. To reduce the risk of rebound psychosis and discontinuation symptoms the medication should be reduced slowly. 4. Treatment Programme 4.1 When a decision is made to initiate clozapine, there must be a clear Care Plan written to ensure close monitoring of any underlying medical conditions. If the community team is unable to support the frequency of monitoring then clozapine should be started by inpatient initiation or with intensive support from AMHT. 4.2 A time is set to take the initial blood test in order to register the patient with the Clozaril Patient Monitoring Service (CPMS/ Mylan). Within ten days of the initial satisfactory blood test a date needs to be set to start treatment. For community patients the start date of the treatment should ideally be on a Monday (non-bank holiday weeks) to maximise the time available for professionals working 9-5, weekdays. Following the initial blood tests the patient should be registered with the CPMS. 4.3 Arrangements should be made for the blood tests to be taken at the Clozapine Clinic, by inpatient staff or at the local medical hospital. For community patients the nurse/practitioner or care coordinator should ensure that someone accompanies the patient to these appointments initially. Further, initial blood tests will require Troponin T or I and CRP also to be measured. 4.4 On the third day of treatment a further blood test should be taken and the results sent/reported back to the CPMS/ Mylan. Within a week of the second blood test a further blood test needs to be taken. 4.5 The prescription should be written and sent (delivered,faxed or by secure ) to the appropriate pharmacy for supply. Clozapine tablets cannot be supplied without a prescription and a green blood result. After the initiation is complete and the patient discharged from hospital or AMHT, an outpatient prescription will be required, this is to be organised by the co-ordinating nurse or clozapine clinic. 4.6 The initial dose should be 12.5mgs, either given at a time to allow monitoring during working day or taken last thing at night. If tolerated the dosage should be doubled. Thereafter dose titration will need to be adjusted in accordance with the patient s response to treatment. See appendix 11 All medication given should be documented. Dose increases for outpatients should not take place when there is no medical cover e.g. weekends and bank holidays, in some areas. For the effect of smoking on clozapine levels and dosage see Appendix 8 Target maintenance doses: Patients with drug-induced psychosis in Parkinson s Disease: mg 1. A dose of 50mg/day should only be exceeded in exceptional cases, a maximum of 100mg/day must never be exceeded 1 Patients over 60 years old with resistant schizophrenia: mg daily 2 Adult female non-smokers: 250mg daily 2 Adult male non-smokers: 350mg 2 Adult female smokers: 450mg 2 Adult male smokers: 550mg 2 December

9 References: 1. Summary of Product Characteristics (Clozaril). Accessed via (9/2/18) 2. Taylor D, Paton C, Kapur S. The Maudsley Prescribing Guidelines. 12 th edition. London: Informa Healthcare; Bleakley S, Taylor D. Clozapine Handbook 1 st Edition. Malta: Lloyd-Reinhold Communications 2013 ( 4.7 During the first day observations (BP and pulse lying down and standing, plus respiration and temperature) should be undertaken as a baseline before the dose is given and then twice daily, ideally two hours and six hours after the initial dose. There is no need to monitor the patient after the night time doses. For community patients there should be at least 4 contacts - three face-to-face during observations and at least one telephone contact ensuring contact is distributed evenly throughout the day. Contacts should ascertain the patient s general condition and report and document any side effects. If either the contacts or observations indicate a cause for concern the team or on call doctor should be contacted to discuss management. If there is a sustained rise (e.g. two successive measurements) in temperature or other concerns about pulse, respiration, blood pressure or other side effects a report should be made to the doctor. Observations should be documented on the track and trigger tool and RiO. 4.8 On the second day, observations should be done three times; before the dose is given, then two and six hours after the morning dose. However for community patients there should be four contacts in all. 4.9 For the remainder of the week observations should be made at twice a day; before the morning dose is taken and ideally 6 hours after. For community patients four contacts should be made on each day For the second week of treatment, three contacts should be made and observations made at least once but ideally twice a day. After two weeks of treatment a medical review should take place and future management decided. If there have been unacceptable side effects, or until the dose is stable, the observations should remain daily, ideally two hours after the morning dose. It may be appropriate for the patient to attend the clozapine clinic for weekly At all contacts with the patient the patient should be asked about illness and side-effects; feeling unwell and any symptoms of illness including fever, cough, chest pain, shortness of breath, diarrhea, constipation, increased salivation, increased pulse/tachycardia, nausea, vomiting, sore throat, myalgia, headache, sweatiness, and urinary discomfort or frequency change. Compliance with the treatment regimen and smoking status should also be checked. This should then be documented on RiO, the care plan checked, and concerns/changes raised with the team and responsible clinician When the patient is on a stable dose the observations should be weekly for the first 18 weeks then, full physical health check at 3 months, 6 months and then annually, including RiO Physical History and Monitoring Form (see appendix 14) Appendix 3 and 4 should be completed to demonstrate that monitoring has occurred and been documented on RiO, but all observations must be entered on RiO Physical History and Monitoring Form Abnormal results/concerns should be acted upon and consideration given to a specialist medical review. The Care Plan should be updated accordingly Annual Monitoring BP and P (sit and stand), temperature, respiratory rate, lipids (including cholesterol and triglycerides), weight, BMI, waist circumference, blood sugar/ HbA 1c. Then if clinically indicated December

10 Troponin I/T, CRP, ECG, EEG (<= 16 yo) and clozapine/norclozapine levels. Check for side effects including constipation, sedation and hypersalivation. This is by secondary care Clozapine titration for adolescents: is slower than that recommended for adults to minimise side effects and twice daily monitoring should continue until a therapeutic dose is reached. The titration should pause when the dose is 150mg daily and a clozapine blood level taken. Although side effects and monitoring of clozapine are generally the same in both adult and adolescent populations there are some reports of a higher seizure risk in those under 16. EEG monitoring (baseline and once the dose is stabilised) should be considered for any patient under 16 receiving clozapine Clozapine titration for patients 60 years of age and older: initiation is recommended at a particularly low dose (12.5mg given once on the first day) with subsequent dose increments restricted to 25mg/day Support for community initiation patient: this should be reviewed regularly as per care plan to ensure the required contacts are being made, and that there are no concerns with blood tests, physical monitoring and concordance with the regimen. If there are concerns the patient should be medically reviewed, consideration to the remaining initiation occurring as an inpatient should happen. This should be documented on RiO Clozapine is available as several different brands. In Southern Health we provide Clozaril tablets and Denzapine 50mg/ml suspension. They presently require separate registration and monitoring. See appendix 16 for procedures for changing brands Denzapine suspension must be shaken well for 90 seconds before administering and it can be diluted with water. It should not be transferred from the manufacturer s original container. Pharmacy will supply whole containers for ward patient stock and if it is essential to supply smaller quantities for a short term leave TTO pharmacy will supply an overage. Clozapine and Denzapine are therapeutically equivalent but require different registration. 5. Restarting Clozapine following an Unplanned Discontinuation Once clozapine has been discontinued the plasma level drops very quickly. Based on an average half-life between 7 to 14 hours after hours (5 times the half-life) there will be no detectable clozapine left. Along with the rapid decline in plasma levels the tolerability to the side effects rapidly declines. Patients who have had no clozapine for 48 hours (taken from the last dose given) should be re-titrated from 12.5mg per day, as above. The speed of the titration depends on the original acceptance and tolerability of clozapine, however it should be noted that a slow titration is preferable to prevent adverse reactions. Hypotension, tachycardia, seizures and drowsiness are particular risks when re-starting clozapine. 5.1 Mylan (Clozaril ) On/off treatment-assessment guidelines The time off clozapine is taken from the last dose administered. For clozapine patients on weekly white cell count monitoring Monitoring frequency Weekly OFF clozapine for less than 48 HRS No change to blood monitoring frequency. Continue as normal OFF > 48HRS BUT < 7 DAYS No change to monitoring Re-titration dose as per initial titration. OFF for 7 DAYS OR MORE Restart the 18 weeks of weekly monitoring. Retitration dose as for initial titration December

11 For clozapine patients on fortnightly or 4 weekly white cell count monitoring Monitoring OFF <48 HRS frequency OFF > 48HRS BUT < 4 WHOLE DAYS OFF 4 DAYS OR MORE BUT< 28 WHOLE DAYS OFF > 28 DAYS Fortnightly and 4 weekly No change to monitoring frequency. Continue as normal No change to monitoring frequency Re-titrate dose as per initial titration. TREATMENT BREAK Weekly for 6 weeks and then back to previous monitoring frequency. Retitrate dose. Restart 18 weeks of weekly monitoring. Retitrate dose. Further reading Bleakley S, Taylor D. Clozapine Handbook 1 st Edition. Malta: Lloyd-Reinhold Communications 2013 ( December

12 Appendix 1: Potential side effects This list is not exhaustive. More information can be obtained from the Clozaril Patient Monitoring Service or clozapine handbook. Seek advice if you are unsure. Be cautious when prescribing other medicines with similar side effects to clozapine. Constipation Usually persists, adjust diet, high fibre and adequate fluid. Give a bulk-forming and stimulant laxative if needed. Ensure adequate fluid intake. Constipation should not be ignored, it can be rapidly fatal. Review other medications which may cause constipation. Consider the using the Porirua Protocol (CNS Drugs Jan;31(1): doi: /s y. The Porirua Protocol in the Treatment of Clozapine-Induced Gastrointestinal Hypomotility and Constipation: A Pre- and Post-Treatment Study. Every-Palmer S et al) and sallowed=y Tachycardia Very common in early stages of treatment, but usually benign. Tachycardia, if persistent at rest and associated with fever, hypotension or chest pain, may indicate myocarditis. Signs and symptoms of myocarditis or cardiomyopathy include persistent tachycardia at rest, palpitations, arrhythmias, chest pain and other signs and symptoms of heart failure (e.g. unexplained fatigue, dyspnoea, tachypnoea), or symptoms that mimic myocardial infarction. Refer to a cardiologist urgently. Clozapine should be stopped if tachycardia occurs in the context of chest pain, heart failure or raised Trop I or T or CRP. Pyrexia Temperature above 38 o C is often normal in the first three weeks of treatment. However, a blood sample should be taken to exclude agranulocytosis and exclude causes of infection. Paracetamol may be beneficial. Beware myocarditis and neuroleptic malignant syndrome. Seizures Drowsiness Hypersalivation Hypotension Weight gain Cholesterol check Diabetes check Blood disorders Especially with rapid dose titration and high clozapine levels/ doses. Stop clozapine for 24 hours. Restart at half the original dose. Consider adding sodium valproate or lamotrigine. Refer for EEG and neurological examination if appropriate. May be more common in those under 16 years old. This is usually within the first four weeks, but may persist. Can be managed by giving more of the dose at bedtime and increasing the dose more slowly. Appears early on in the treatment, may persist and may be worse at night. If troublesome consult doctor/pharmacist. Hyoscine hydrobromide is usually an effective treatment either as the tablets (Kwells mcg at night or in divided doses) sucked or chewed or patches (1.5mg every 72 hours). An alternative pirenzepine mg at night or in divided doses (unlicensed). Usually occurs in the first four weeks. Instruct patient to stand slowly; support stockings may be of use. Split the dose, with a larger proportion at bedtime, slow the titration or reduce the dose Can be significant. Give advice about exercise and diet. Refer to dietician. It s easier to minimise weight gain over the first few months than try to lose it afterwards. Full lipid profile including triglycerides, ideally fasting, after 1, 3 and 6 months, and then every 6 months. Treat if necessary. Plasma glucose, ideally fasting, after 1, 3 and 6 months, and then every 6 months. Consider checking HbA 1c also. Treat if necessary. Reduction in white blood cells occurs in 3% of people exposed to clozapine. More common in the first year of clozapine treatment. The white blood cell count monitoring is a mandatory requirement of prescribing and supplying clozapine. December

13 Appendix 2: Clozapine initiation checklist File in secondary notes Patient details Name Date of birth / / Address Hosp/ NHS No. Tel No. Consultant GP name: Tel no: Care coordinator Tel no: Care-coordinator or named nurse Baseline physical health monitor is complete (appendix 4) Patient information leaflet given (see and advice (see section 3) For community patients a carer has agreed to be involved in the programme For community patients document the Name and contact no. of team doctor who will be available throughout treatment programme. CPMS Reg no Date of first blood test (must be within 10 days prior to start date). Hospital Pharmacy informed Clozapine Clinic informed, if applicable A Care Plan is in place. This should include reference to appropriate appendices for intiation and/or monitoring in this document. Smoking status is recorded (see Appendix 8) Dietary advice given (to prevent weight gain and constipation) Sign, date and give details as required Name: Contact no: Name: Contact no: CPMS No: Doctor Patient fulfils standard criteria for receiving clozapine ( see section 1). Sign, date and give details as required Patient has had a review of medical co-morbidities including history of epilepsy, cardiovascular, constipation, renal and hepatic disorder. Risk versus benefits considered Baseline ECG, Troponin I/T and CRP checked. Please specify. Patient has no history of other medical problems associated with clozapine. Please specify December

14 Medication reviewed Does the patient have a history of any adverse reactions to antipsychotics? Please specify. Has consent or SOAD authorisation been obtained and documented? Entry in records made with regard to patient consenting to treatment Complete baseline physical health monitoring (appendix 3) Write prescription and obtain medication from hospital pharmacy. Do not increase dose over the weekend if there is no medical cover. Dates of planned consultant appointments during titration, if known Inform patient to consult with their psychiatrist before driving and that DVLA will need to be informed. GP informed of clozapine initiation and ongoing prescribing. Have they been sent a copy of the GP clozapine guidelines? December

15 Appendix 3 Baseline physical health monitoring To be completed pre Clozapine, no more than one month prior to initiation, (reproduced with permission from Clozapine Handbook 1 st edition, 2013). File in secondary file Monitoring parameters Sign / Blood Pressure (lying down and standing) Pulse Temperature Respiratory rate Urea and electrolytes (including egfr) Full blood count (WBCs, Neutrophils, Eosinophils) ECG Blood lipids, ideally a fasting sample (full lipid profile including triglycerides) Troponin T or I (depending on what is available at the local lab) C-reactive protein CRP Echocardiography if suspected underlying heart disease Weight (including BMI, and abdominal circumference) Plasma glucose (fasting sample ideally), HbA 1C Liver Function Tests (ALT, AST, bilirubin, albumin, prothrombin) Fasting sample ideally. EEG (Under 16 year olds only) Investigate potential problems with prescribed, purchased or herbal medication, illicit drugs, and alcohol. Assess ability to self medicate. Record current smoking status (see Appendix 8), caffeine intake, lifestyle and diet. Investigate for any previous history of blood disorders, seizures, DVTs, PEs, cardiac, bowel or bladder dysfunction, glaucoma, OCD and liver or renal impairment. date Record physical health information on electronic record. Signed By Doctor or Nurse December

16 Appendix 4: Clozapine Physical Monitoring Sheet (to be kept with medication chart). The track and trigger tool may be used in place of the monitoring sheet but the frequency of monitoring should be the same. Patients name CPMS no: Hospital/NHS No. Clozapine start date Baseline observations time: date: Wt Height...BMI Temp: Pulse: BP (standing): BP standing / lying: Respiration: During initiation: Omit if temperature >38.5 C, postural drop >30mmHg or pulse > +/- 15% baseline, and inform the Doctor. Observations Day (use the morning dose where possible) 1 Before dose 2hrs post, if awake 6hrs post, if awake 2 Before dose 2hrsafter dose 6hrs after dose Date Time Temp Pulse Respiratory rate (normal rate breaths per minute) Lying BP Standing BP Other side effects, particularly flu-like symptoms, hypersalivation, palpitations, chest pain, constipation, GASS-C Outcome if Dr informed Sign December

17 Day (use the morning dose where possible) 3 Before dose 6hrs after dose 4 Before dose 6hrs after dose 5 Before dose 6hrs after dose 6 Before dose 6hrs after dose 7 Before dose 6hrs after dose 8 Date Time Temp Pulse Respiratory rate (normal rate breaths per minute) Lying BP Standing BP Other side effects, particularly flu-like symptoms, hypersalivation, palpitations, chest pain, constipation, GASS-C Outcome if Dr informed Sign 9 10 December

18 Day (use the morning dose where possible) 11 Date Time Temp Pulse Respiratory rate (normal rate breaths per minute) Lying BP Standing BP Other side effects, particularly flu-like symptoms, hypersalivation, palpitations, chest pain, constipation, GASS-C Outcome if Dr informed Sign December

19 Day (use the morning dose where possible) 24 Date Time Temp Pulse Respiratory rate (normal rate breaths per minute) Lying BP Standing BP Other side effects, particularly flu-like symptoms, hypersalivation, palpitations, chest pain, constipation, GASS-C Outcome if Dr informed Sign December

20 Appendix 5: Clozapine in the Community Contact Monitoring Sheet (to be kept with medication chart) Patients name CPMS no: Hospital/NHS No. Clozapine start date Baseline observations time: date: Wt Height...BMI Temp: Pulse: BP (standing): BP (lying): Respiration: Contacts Day Date Time Contacted by Method Outcome December

21 Day Date Time Contacted by Method Outcome December

22 Day Date Time Contacted by Method Outcome December

23 Appendix 6: Guidelines for the Management of a Red Clozapine Result. 1) Background information: The CPMS categorise blood results according to the following colour-coded system: Colour alert WBC count x 10 9 /L Neutrophil count x 10 9 /L Green > 3.5 > 2.0 Amber Red <3.0 <1.5 If a patient has an amber blood result, a full blood count must be performed twice weekly until the blood count stabilises in this range or increases. 2) Management of a Red Alert: If a patient s WBC is less than 3.0 x 10 9 /L and/or the neutrophil count is less than 1.5 x 10 9 /L, this is known as a red alert and the following action must be taken: STOP CLOZAPINE TREATMENT IMMEDIATELY. Check the patient for any signs of infection (refer to details below) and contact the CPMS as soon as possible. Make arrangements to undertake confirmatory blood counts on the 2 days following the date of the red alert sample. If either of these follow up blood counts is in the red alert range then red alert status is taken to be confirmed. If the red alert is confirmed, THE PATIENT MUST NOT RESTART CLOZAPINE TREAMENT. Full blood counts with differential white cell counts must be performed DAILY whilst the blood counts remain in the RED range, and the patient must be observed closely for infection (e.g. sore throat, fever). The results should be reported to the CPMS as soon as they are available. If antipsychotic medication is considered essential, use agents with low potential to cause neutropenia and avoid depot preparations. Review all other medication. Consider stopping those agents with potential to adversely affect neutrophil counts. If necessary, introduce a more appropriate alternative. If a patient s neutrophil count falls to less than 1.0 x 10 9 /L or the WBC falls to less than 2.0 x10 9 /L OR if the patient develops a fever, please observe the following additional recommendations: It is extremely important to contact a specialist haematologist, or failing this, a general medical physician, regarding the most appropriate treatment for the patient. This will probably involve transferring the patient to a ward with facilities for the care of neutropenic patients. If unable to contact the hospital haematologist immediately, please refer to the guidelines below: Check the patient s temperature, blood pressure and pulse FOUR hourly. December

24 Nurse patient in a single room, taking care to wash hands before and after contact with the patient, wear aprons etc. Avoid salads, yoghurt, unpeeled fruit, paté or soft cheese in the patient s diet. Give sterilised milk, water or canned drinks. Remove flowers from the patient s room. Give patient an antibacterial and antifungal mouthwash prophylactically (eg. chlorhexidine 10mls QDS and nystatin suspension 1ml QDS ) Granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony stimulating factors have been used in the management of clozapine induced agranulocytosis although this is not a licensed indication. The cost of such drugs if used will be reimbursed by CPMS. Effect of sudden discontinuation of clozapine: When a patient has a red alert it is essential to stop clozapine immediately. This sudden cessation of treatment can lead to physical and mental withdrawal effects which may occur within 2 3 days and usually within the first 2 weeks. Patients may experience a rapid deterioration in their mental state with rebound psychosis. In addition, abrupt withdrawal of clozapine has been associated with symptoms such as nausea, vomiting, diarrhoea, headache, restlessness, agitation and sweating and it has been suggested that these are a result of cholinergic rebound since clozapine has strong anticholinergic action. December

25 SOUTHERN HEALTH NHS FOUNDATION TRUST GUIDELINES FOR THE MANAGEMENT OF A RED CLOZAPINE RESULT LOCAL PRACTICAL ACTION A pharmacist is available at CPMS 24 hours a day, for the provision of patient specific pharmaceutical advice. o Telephone number 9am 5pm Monday to Friday: option 2 o Out of hours service: ACTION SIGNATURE DATE 1. Ensure the patient s consultant, care coordinator and the clozapine clinic staff are aware of the red result and management implications as soon as possible and discuss and determine an individual care plan on RIO for monitoring bloods mental and physical health and review of medication. For out-patients, inform the patient s GP. 2. Ensure that all involved are aware of contact details and are in receipt of these guidelines. 3. Care coordinator to ensure that adequate systems are in place so that the: 3.1 Patient does not receive any more clozapine until advised that this can be reintroduced by the CPMS. If the patient is off clozapine for more than 48 hours, this will need to be retitrated. 3.2 Patient is monitored for mental state (possibility of rebound psychosis following abrupt clozapine withdrawal). 3.3 Patient is monitored for any physical health problems including temperature as they will be less able to combat these due to the low white cell count. ACTION SIGNATURE DATE 3.4 Arrangements are in place for daily full blood count tests which will need to be analysed as soon as possible and the results phoned through to the CPMS. Doctor on call should do bloods if out of hours There will need to be at least 2 days worth of daily follow up blood tests; these will continue until advised by the CPMS that they are no longer required (at least 2 consecutive non red results). December

26 3.5 The team responsible for care over a weekend has available the patient s full notes, including up to date risk assessment, details of current medication, a description of the patient and emergency contact details (eg next of kin), on-call services at group homes. 3.6 In order to facilitate all of the above, for patients for whom admission is not appropriate or necessary and where follow-up is needed over the weekend, is likely to be the most appropriate course of action. This team will then need to liaise with the on-call duty doctor to ensure the daily blood tests occur at a suitable time and venue on each day. December

27 December

28 Appendix 7: Guide to Interpretation of Clozapine Plasma Levels Reference: Northumberland, Tyne and Wear NHS Foundation Trust Appendix 2 Guide to Interpretation of Clozapine Plasma Levels Part of PPT-PGN-04 Therapeutic Drug Monitoring of Clozapine Plasma Levels V02 Issue 1 Sep 12 Trough clozapine (mg/l) <0.01 not detected < 0.35 Clinical response Any Good Comment Clozapine is unlikely to have been taken for at least a week before sampling except perhaps in the very early stages of dose escalation (dose 100mg/day or less). Consider repeating assay at 6 months, then annually unless response deteriorates or side-effects become troublesome Poor/ incomplete If poor adherence is suspected, consider psychoeducation or supervised administration. Please note if a suspension of crushed clozapine tablets is prepared care must be taken to ensure that the bottle is shaken well before administering the suspension to the patient. Review patient and repeat assay after adherence intervention. Consider cautious dose increase (especial caution if dose already 450 mg/d or above due to increased risk of sideeffects, in particular seizures). Monitor mental state and sideeffects. Review patient again and repeat assay after at least 1 week on new dose. Good Consider repeating assay at 6 months, then annually unless response deteriorates or side-effects are troublesome. If sideeffects are persistent/serious consider cautious dose reduction (e.g. 25 mg/d in week 1, further 25 mg/d in week 2, etc.), but bear in mind possible loss of response. Poor/ incomplete If clozapine treatment has continued at least 3-6 months at current dose, consider psychosocial intervention. Augmentation with other psychoactive drugs to be of benefit, although this is not recommended in the SPC. It is important any such attempts should be carefully considered with respect to side-effects (including the risk of neutropenia) and possible interactions. Clozapine should not be used with drugs known to have a substantial potential for causing agranulocytosis Good no clinical features of toxicity Poor/ incomplete/ reduced and/or clinical features of toxicity Review. Consider a cautious dose reduction (e.g. 25 mg/d in week 1, further 25 mg/d in week 2, etc.), but balance against risk of diminishing the response to clozapine. Consider using an anticonvulsant (not carbamazepine) as prophylaxis against seizures, if dose reduction thought inadvisable. Monitor mental state. Repeat assay after at least 1 week on a new dose, otherwise 3-monthly. Cautious dose reduction (see above) to bring plasma clozapine below 0.6 mg/l. Monitor mental state. Repeat assay after at least 1 week on a new dose. December

29 Trough clozapine (mg/l) Clinical response Comment & above Good no clinical features of toxicity Poor, incomplete or reduced and/ or clinical features of toxicity Good no clinical features of toxicity Poor, incomplete or reduced and/or clinical features of toxicity Review. Consider a cautious dose reduction (e.g. 25 mg/d in week 1, further 25 mg/d in week 2, etc.) to bring plasma clozapine below 1.0 and possibly below 0.6 mg/l, but balance against risk of diminishing the response to clozapine. Consider using anticonvulsant prophylaxis (not carbamazepine). Monitor mental state. Repeat assay after at least 1 week on a new dose, otherwise 3-monthly. Plasma clozapine may continue to rise in the short term even after the dose has been reduced. Cautious dose reduction (see above) to bring plasma clozapine below 1.0 and possibly below 0.6 mg/l. Monitor mental state. Repeat assay after at least 1 week on a new dose. Plasma clozapine may continue to rise in the short term even after the dose has been reduced. Urgent review. Consider cautious dose reduction (e.g. 25 mg/d in week 1, further 25 mg/d in week 2, etc.) to bring plasma clozapine below 1.0 mg/l, and possibly below 0.6 mg/l. Consider anticonvulsant prophylaxis (not carbamazepine). Monitor mental state. Repeat assay after at least 1 week on a new dose. Plasma clozapine may continue to rise in the short term even after the dose has been reduced. Urgent review. If patient is in the community, consider admitting for observation. Withhold Clozaril for 24 h and re-start at 75 % of last dose, thereafter reduce dose slowly (e.g. 25 mg/d in week 1, further 25 mg/d in week 2, etc.) to bring plasma clozapine below 1.0 mg/l, and possibly below 0.6 mg/l. Consider anticonvulsant prophylaxis (not carbamazepine). Monitor mental state. Repeat assay after at least 1 week on a new dose. Plasma clozapine may continue to rise in the short term even after the dose has been reduced. Norclozapine is one of the main metabolites of clozapine. It has a longer half-life than clozapine so less effected by daily fluctuations and not dependent on a trough sampling time. Mean clozapine to norclozapine levels and ratios Reference: Bleakley S, Taylor D. Clozapine Handbook. 1 st Ed. Lloyd-Reinhold Communications LLP, Dorsington, UK) Clozapine level Median clozapine to norclozapine Norclozapine level ratio <350mcg/L 1.25 <280mcg/L mcg/L mcg/L mcg/L mcg/L >1000mcg/L 2.08 >481mcg/L December

30 Appendix 8: Smoking Cessation Effect on Clozapine Summary. Smoking increases the clearance of clozapine thus smokers will often require more clozapine than non-smokers. Stopping smoking can dangerously increase clozapine levels. During smoking cessation the clozapine dose will need reducing. Background. The hydrocarbons in tobacco smoke induce the production or activity of various liver enzymes, in particular cytochrome CYP1A2, an enzyme associated with the metabolism of several psychotropic drugs including clozapine. Therefore, in response to smoking cessation it is possible that the metabolism of these drugs will decrease and plasma levels will rise. This is particularly the case for clozapine where it is possible that plasma levels may be elevated to toxicity. Note CYP1A2 activity is affected by hydrocarbons and not by nicotine. Therefore nicotine replacement therapy (NRT) will not alliterate the clozapine vs smoking interaction. When stopping smoking while receiving clozapine, clozapine levels may rise by as much as 50-70%. For clozapine: 1. Review preadmission (outpatient) serum clozapine levels (if available) and order a new baseline serum clozapine level as soon as practicable. (Note no call-out is required, as dose reduction need not be immediate. Arrange bloods in normal office hours ). 2. Review side-effects history and, if possible, check against the serum clozapine levels at which they occurred. 3. Assess the risk of toxicity (i.e. if level exceeds 1000mcg/l) by using the non-smoking serum clozapine level using the formula below if appropriate : Serum clozapine (Non-smoker) = [1.5 x Serum clozapine (Smoker) ] + 50 eg. smoking level of 500mcg/l gives a non-smoking level of 800mcg/l nb. The formula is considered to give a suitably accurate result in approximately 80% of cases. However, in patients with higher smoking clozapine levels or doses, (eg. above 700mcg/l or above 700mg daily), the CYP1A2 enzyme may have been saturated resulting in much higher rates of metabolism. Greatly increased levels may then occur in these patients when they stop smoking and the formula may be wildly inaccurate. 4. Set a target (non-smoking) serum clozapine level, taking into consideration the patient s current condition and clinical response to current dose / level. If indicated, adjust the clozapine dose accordingly. (Note if compliance has been poor prior to admission, the baseline level may be artificially low. This should be taken into consideration). eg. Smoker admitted on clozapine 600mg daily and serum level found to be 480mcg/l. Compliant with medication but clinically unwell on this dose and considered to need a higher level. Estimated serum level on cessation of smoking is (1.5 x 480) + 50 = 770mcg/l. If clinician considers that a target serum level of 770mcg/l is appropriate then no adjustment of dose may be necessary. December

31 However, if it is felt that the target level should be in the region of 600mcg/l, then the patient s dose may need reducing to 350mg or 375mg daily. 5. Necessary reductions in daily dose should be made at a rate of approximately 10% per day. 6. Monitor serum clozapine level at day 3 and then weekly (until stabilised to target level). Also, pre-discharge level (unless done in previous 48 hours). 7. Monitor for adverse effects bearing in mind that some may take as long as 2 to 3 weeks after adjustment of dose to become apparent. 8. On discharge or leave, reassess patient s likelihood to recommence smoking and the potential reduction in serum clozapine level in response. If this occurs it is likely that the clozapine dose will have to be increased. 9. Post-discharge, monitor serum clozapine level once each week, (or fortnightly if total dose change was less than 20%), until stable. December

32 Appendix 9: Suggested GP letter December

33 December

34 Appendix 10: Shared care guidelines: Information for the GP Clozapine Risk Management Guidelines for Primary and Secondary Care Name of patient treated under this guideline (PID): This shared care guideline has been produced to support prescribing and monitoring of patients between secondary and primary care, and provides an information resource to support clinicians providing care to the patient. It does not replace discussion about sharing care on an individual patient basis. This guideline was prepared using information available at the time of preparation, but users should always refer to the manufacturer s current edition of the Summary of Product Characteristics (SPC or data sheet ) available at Status of Clozapine Clozapine (Clozaril ) is a red drug. This means that treatment will be initiated and retained by secondary care. However, because of the extensive adverse reactions, interactions and monitoring of clozapine it is essential for all GPs to be fully aware which of their patients are receiving clozapine and the relevant prescribing issues. 2.0 Indications and Dose Clozapine is indicated for treatment-resistant schizophrenia and in schizophrenia patients who have severe, untreatable neurological adverse reactions to other antipsychotic agents. Treatment resistance is defined as a lack of satisfactory clinical improvement despite the use of adequate doses of at least two different antipsychotic agents, including an atypical antipsychotic agent, prescribed for adequate duration. Clozapine is also indicated in psychotic disorders occurring during the course of Parkinson's disease, in cases where standard treatment has failed. 3.0 Referral Criteria Not applicable. Clozapine will only be initiated in secondary care. 4.0 Patient Selection Not applicable. Clozapine will only be initiated in secondary care December

35 5.0 Safety Issues Clozapine (Clozaril ) is a effective atypical antipsychotic used when other treatment strategies have failed. Approximately 3% of patients treated with clozapine will develop neutropenia (around 1% will progress to agranulocytosis) which makes them vulnerable to serious infections. Detection of neutropenia is achieved by regular haematological monitoring, through the Clozaril Patient Monitoring Service (CPMS). All patients receiving clozapine must be registered with the CPMS and monitored for the complete duration of therapy. In the event of an abnormal blood result the CPMS will contact the psychiatric team immediately to request an additional blood sample if necessary. The patient, and if appropriate their carer, should regularly be reminded to remain vigilant for any signs of infection, e.g. fever or sore throat, which may indicate the presence of neutropenia. While it is unlikely that such symptoms are related to the development of clozapine-induced neutropenia, an immediate full blood count (WBC and neutrophil counts are required) will be necessary to exclude the possibility. Patients should be advised to contact their GP, or hospital team, if they experience signs of infection. If neutropenia is confirmed the patient must immediately be referred to the consultant for continued monitoring, haematological referral if required and management of the patient s psychiatric condition. All clozapine supplies will be removed and withheld in the event of agranulocytosis. It has also been suggested that clozapine is associated with rare reports of myocarditis and cardiomyopathy. Myocarditis seems to occur within 6-8 weeks of starting clozapine while cardiomyopathy may occur later (median 9 months). The risk of myocarditis is estimated to be around 1%. Patients should be monitored for symptoms such as tachycardia, fever, flu-like symptoms, fatigue, dyspnoea and chest pains. Any signs of heart failure should provoke the immediate discontinuation of clozapine. Successful re-challenge is possible with specialist advice. Constipation and gastrointestinal hypomotility is common (14 60% of users), underinvestigated and associated with rare, but fatal consequences. There are now more deaths with clozapine from gastrointestinal adverse reactions than from blood disorders in the UK. Bowel habits most be regularly monitored, actively questioned for with open questions, advice given on diet, fluid intake, exercise and laxatives considered. Consider the Poirua Protocol e=1&isallowed=y ( There should be a low thresh-hold for treatment and investigation. Bleakley S, Taylor D. Clozapine Handbook 1 st Edition. Malta: Lloyd-Reinhold Communications 2013 ( See also MHRA alert Contra-indications (see current BNF or SPC) Hypersensitivity to the active substance or to any of the excipients. Patients unable to undergo regular blood tests. History of toxic or idiosyncratic granulocytopenia/agranulocytosis (with the exception of granulocytopenia/agranulocytosis from previous chemotherapy). History of Clozaril induced agranulocytosis. Impaired bone marrow function. Uncontrolled epilepsy. Alcoholic and other toxic psychoses, drug intoxication, comatose conditions. Circulatory collapse and/or CNS depression of any cause. Severe renal or cardiac disorders (e.g. myocarditis). December

36 Active liver disease associated with nausea, anorexia or jaundice; progressive liver disease, hepatic failure. Paralytic ileus. Clozaril treatment must not be started concurrently with substances known to have a substantial potential for causing agranulocytosis; concomitant use of depot/ long-acting injection antipsychotics is to be discouraged (listed under contra-indications in the SPC). 5.2 Cautions (see BNF or SPC) See general guidance or common adverse effects. 5.3 Common Side Effects (See BNF or SPC) Clozapine is associated with a number of adverse effects, some of which are listed below. For a complete list please refer to the BNF or Consider using GASS C and documenting reults on RiO ADRs Time course Potential treatments Sedation Usually 4 weeks Give a larger dose in the evening Hypersalivation May persist Hyoscine Hydrobromide 300mcgs nocte (occasionally up to 900mcgs / day) Constipation (which may lead to impaction and perforation) Usually persists Increase fibre, consider long-term laxatives. Consider the Porirua Protocol. Tachycardia Worse first 4 weeks Stop or Slow down titration If persists refer to cardiologist Hypotension First 4 weeks Reduce or slow titration Hypertension First 4 weeks, sometimes longer As per hypertension guidelines Weight gain First year Dietary counselling Nocturnal enuresis Any time Avoid fluids at bedtime, altering the timing of doses may help, Emerging diabetes Any time As per diabetic guidelines Seizures / myoclonic jerks Any time Dose / dose increase related, withhold clozapine for 24hours, introduce at a lower dose, consider lamotrigine. Take clozapine/ norclozapine levels. December

37 Management in the community is generally possible for most adverse effects by referral to/discussion with secondary care prescribers; however those requiring immediate referral to hospital include: Neutropenia/agranulocytosis, persistent tachycardia, persistent or troublesome nocturnal enuresis, chest pain, shortness of breath, severe drowsiness, seizures, severe constipation or any other serious event. 5.4 Drug Interactions (see BNF or SPC) All drugs which have the potential to cause neutropenia (e.g. carbamazepine, cephalosporins, quinolones, trimethoprim, cytotoxics and long acting depot antipsychotics) should be avoided. Clozapine is metabolised by many liver enzymes so drugs which may alter these enzymes can either increase toxicity or increase the risk of relapse of symptoms. Drugs which should be avoided Carbamazepine Fluvoxamine Erythromycin Rifampicin Ciprofloxacin Drugs which may be used with caution (extra monitoring for clozapine adverse reactions required) Fluoxetine Paroxetine Sertraline Warfarin (increased INR possible) Antihypertensives Lithium Other drugs which cause constipation This list is not exhaustive please refer to the current BNF or Smoking cessation interaction Patients who smoke usually require a higher dose than non-smokers due to the effects cigarette smoke has on clozapine levels. When giving up smoking clozapine levels can increase by as much as 50%, thus the dose of clozapine will need reducing. Nicotine replacement therapy does not negate this interaction. Refer to specialist advice when a clozapine patient wishes to give up smoking. 6.0 Role of Secondary Care Team (a) To assess the suitability of the patient for clozapine and counsel patient and carer about implications of diagnosis and treatment. (b) To carry out initial and on-going physical health monitoring. The GP may be asked to conduct and interpret some of the physical health tests depending on local arrangement, however the responsibility for ensuring monitoring is complete rests with the secondary care team. (c) To give the patient the appropriate drug information leaflets. (d) To explain the possible side effects of the medication to the patient. (e) To emphasise the need for continued compliance and the need for regular blood tests. (f) To initiate treatment, arrange for the clozapine community card to be prescribed and arrange ongoing supplies of clozapine through hospital pharmacy. (g) To write to the GP (see Appendix 9) informing them of the ongoing prescribing, monitoring and supply of clozapine. This shared care guideline should be included in correspondence. December

38 (h) To keep the GP informed of any changes in doses, mental state or prescribing status of clozapine. (i) To keep the GP informed of any physical tests performed and on-going physical health concerns regarding clozapine. 7.0 Role of GP (a) To ensure clozapine is recorded in the GP records (see second page of the GP letter). (b) To notify the psychiatric team of any changes in mental state, physical state, any suspected adverse drug reactions or changes in non-clozapine medication. (c) To ensure all relevant staff within the practice are aware of the shared care guidelines and the concerns surrounding clozapine (d) To consider the precautions, interactions and adverse reactions ofclozapine when coprescribing for clozapine patients. (e) To notify the psychiatric team when the patient wishes to give up smoking and smoking cessation advice is given. 8.0 Responsibilities of the patient / carer a) To monitor mental state and report and deterioration in symptoms b) Assist with adherence or discuss with the GP or secondary care team concerns with adherence. c) Report any side effects or physical health concerns 9.0 Cessation of treatment Clozapine often represents the patient s best hope of recovery from enduring and treatment resistant schizophrenia. Cessation of treatment should be avoided except in life threatening conditions which are linked to clozapine use. Any patient wishing to discontinue treatment should be referred back to secondary care services. Patients who have had no clozapine for 48 hours (taken from the last dose given) should be retitrated at 12.5mg per day, as above. The speed of the titration depends on the original acceptance and tolerability of clozapine, however it should be noted that a slower titration is preferable to prevent adverse reactions. Hypotension, tachycardia and seizures are particular risks when re-starting clozapine. Further reading Bleakley S, Taylor D. Clozapine Handbook: Lloyd-Reinhold Communications LLP. Warwickshire December

39 Appendix 11a: Clozapine Outpatient initiation prescription (only years old) (Suggested guide only: note that much faster titrations can be undertaken in many patients where tolerability allows) Surname: Consultant: First name(s): Date of birth: Address: CMHT: NHS number: Service User contact telephone numbers: Allergies / previous serious adverse drug reactions: Mental Health Act Section: Date T2/T3 due: T2/T3 copy attached: Yes / No (circle)) Date to start Day Clozapine po Mane (mg) Given Sign and date Clozapine po Nocte (mg) Given Sign and date Dr. Signature and date Total daily Dose mgs Pharm screen 1: Mon : Tues : Wed : Thur : Fri : Sat : Sun : Mon : Tues : Wed : Thur : Fri : Sat : Sun : Mon : Tues : Wed : Thur : Fri : Sat : Sun : Mon : Tues : Wed : Thur : Fri : Sat : Sun For target maintenance doses, see section 4.6. Ref: Maudsley Prescribing Guidelines 12 th Ed. December

40 Appendix 11b: Clozapine Inpatient initiation prescription (only years old) (Suggested guide only: slower titrations will be required in the elderly (>60 years), adolescents, those with a medical co-morbidity or a previous poor tolerability to clozapine) Add a reference to this on the main drug chart e.g. CLOZAPINE see separate titration chart Surname: Consultant: First name(s): Date of birth: Address: CMHT: NHS number: Service User contact telephone numbers: Allergies / previous serious adverse drug reactions: Mental Health Act Section: Date T2/T3 due: Date to start Day Clozapine po Mane Given Sign and date T2/T3 copy attached: Clozapine po Nocte Given Sign and date Yes / No (circle)) Dr. Signature and date Total daily Dose mgs mg mg 12.5mg mg 25mg mg 25mg mg 50mg mg 50mg mg 50mg mg 75mg mg 75mg mg 100mg mg 100mg mg 125mg mg 125mg mg 150mg mg 150mg mg 150mg mg 150mg mg 200mg mg 200mg mg 200mg mg 200mg mg 200mg mg 200mg mg 200mg mg 200mg mg 200mg mg 200mg mg 250mg 450 For target maintenance doses, see section 4.6. Ref: Maudsley Prescribing Guidelines 12 th Ed. Pharm screen December

41 Appendix 12: Clozapine Outpatient Prescription Name: Date of birth: / /. Address: Hospital Number: CPMS No.: Allergies/ intolerances:. Care co-ordinator: Tel: Consultant: Clinic:. Medicine and Form Dose Frequency/ Time A Clozapine Maximum supply (subject to blood tests) Please circle MDS Yes/ No (please circle) Weekly Fortnightly Monthly Other medication to be supplied: (only in exceptional circumstances) B C D E F G H Review date Doctor s signature Date Pharmacist screen Please tick 1 month 3 months 6 months Repeat supplies Items (please code) Maximum supply Repeat one Repeat two Repeat three Review date Doctor s signature Date Pharmacist screen December

42 Appendix 13: Blood Monitoring Form December

43 Appendix 14: On-going physical health monitoring parameters Parameter 1 st month only At 3 months At 6 months Yearly Blood Pressure (lying down Frequently in the first and standing) month Pulse Frequently in the first month Temperature Frequently in the first month Respiratory rate Urea and electrolytes (including egfr) Full blood count (WBCs, Neutrophils, Eosinophils) Frequently in the first month Repeat if clinically indicated December As per National / company guidelines Troponin T or I (depending Weekly in the first month Repeat if clinically indicated on local availability) C-reactive protein Weekly in the first month Repeat if clinically indicated ECG Blood lipids (full lipid profile including triglycerides), Fasting sample ideally. Weight (including BMI, and abdominal circumference) Plasma glucose (fasting sample ideally) and/or HbA 1c Liver Function Tests (ALT, AST, bilirubin, albumin, prothrombin) Repeat if clinically indicated Monitor for hypersalivation Actively monitor for constipation Monitor for sedation EEG (Under 16s only) Repeat if clinically indicated

44 Appendix 15: Clozapine Clinic Monitoring Form Patient name CMPS no GP/Surgery DOB Clozapine commenced GP Phone no NHS no Pick up point Registered CPMS Clinician Address Known Allergies Care coordinator Phone Number MHA Status Contact Mobile Number Smoker Height Contact no Date Dose BP Weight BMI Pulse Comments/Checks Signed Physical Checks Baseline Current Frequency 1/12 3/12 6/12 Yearly Glucose*/ HbA 1c Lipids U+Es LFT ECG Rethink Cloz level Requirements in first year of treatment At One Month: Pulse, BP, BMI, Glucose/HbA 1c, Clozapine level At Three and Six Months: Pulse, BP, BMI, Glucose/HbA 1c, Lipids, U+Es, LFT, ECG and Rethink At 12 Months: Pulse, BP, BMI, Glucose/HbA 1c, Lipids, U+Es, LFT, ECG, Rethink Questionnaire Form. Clozapine level if clinically indicated. Requirements after one year of treatment. Monthly: Pulse, BP, BMI, Yearly: Pulse, BP, BMI, Glucose/HbA 1c, Lipids, U+Es, LFT and ECG, Rethink Questionnaire Form. Clozapine/Norclozapine levels if clinically indicated/change of smoking status *Fasting Glucose if possible or repeat fasting if random glucose outside normal range December

45 Appendix 16: Clozapine Cardiac induced Side Effects A flowchart to aid the screening, monitoring and management of cardiac side effects, such tachycardia and myocarditis in all patients on clozapine. Patient starting or restarting clozapine Cardiac Baseline Monitoring ( + see Appendix 4) Sitting and standing BP and Pulse Temperature, respiratory rate CRP Troponin I or T ECG (see SH CP 204 ECG Policy) + echocardiography, if suspected underlying cardiac disease If meets acceptance criteria start clozapine initiation (community or inpatient) and baseline tests acceptable If does NOT meet acceptance criteria and/or baseline tests NOTacceptable. Send for medical review and consider inpatient or AMHT initiation if still suitable for clozapine treatment Increased monitoring requirement hence AMHT supported initiation or admission to inpatient unit STOP Physical monitoring BP, P, T, RR as per schedule (see Appendices 3, 4, 5, & 14 as appropriate) Once every week for the first 4 weeks and at 8 weeks if retitrating CRP Troponin I ot T Ask patients at each contact and advise patient/carer; To report feeling unwell and any symptoms of illness, including; fever, cough, chest pain, shortness of breath, diarrhoea, vomiting, nausea, sore throat, myalgia, headache, sweatiness, dizziness and urinary discomfort and frequency. Check concordance Check smoking status If the Patient develops: Signs or Symptoms of unidentified illness (see above) OR, HR > 120 bpm or increased by > 30 bpm (repeat ECG) OR, CRP mg/L Troponin elevation > lab normal level OR, rises 20% above baseline value OR, CRP > 100 mg/l Continue clozapine with increased monitoring Consider slowing down titration if symptomatic Check Troponin and CRP daily and monitor for developing illness If Troponin > normal lab levels seek urgent cardiology advice and perform urgent echocardiogram If features do not normalize within 4 weeks, arrange echocardiogram and refer to cardiology STOP clozapine Perform urgent echocardiogram Urgent referral to cardiology Use of beta blockers Can exacerbate postural hypotension Do not use routinely If symptoms of palpitations significant, consider small doses December

46 Appendix 17: Information Checklist for Patients on Clozapine The following information must be given to the patient when commencing clozapine and reinforced when arranging the persons discharge or transfer to another team. Any member of the MDT can complete this form but it is the care coordinators responsibility to ensure it is completed. Initiation of clozapine / review appointments The indication for clozapine has been explained including who will review treatment. The reasons for clozapine physical health monitoring has been explained. The common side effects have been explained and actions to take should they occur (see appendix 1), in particular cardiac side-effects Sedation driving/handling machinery warning given Explain the signs and symptoms of an infection and what to do should they occur. Constipation advice to promptly contact the team Discuss the importance of regular blood tests and what may happen if they miss their blood test. The reason for a slow titration of clozapine has been explained. Explain to the patient who will take the physical health checks and how often they will be visited at home (if applicable). Discuss why it is important to continue clozapine and what to do if they miss a dose, especially if they miss more than 48 hours of doses. Explain the importance of informing other healthcare professionals (GP, Dentist or Pharmacist) that you are on clozapine. Who to contact in an emergency both with hours and out of hours. Give dietary and lifestyle advice. Add advice on alcohol consumption (ideally avoid or no more than 2-3 units per day). Signature of healthcare professional Date December

47 Explain how smoking can affect clozapine levels and the importance of letting the team know if you are intending to stop or cut down smoking (if applicable). Give written appropriate advice (see On discharge or transfer to another team Advise when and how the patient will receive ongoing clozapine supplies and the required blood tests. Give dosing advice and allow time for questions. Reinforce the information given above. Ensure the GP is aware of the clozapine (see appendix 8). Send the GP a copy of the shared care risk management guidelines (see appendix 9). To be completed by the patient: I understand the risks and benefits of taking clozapine. I confirm that I have had the chance to discuss and understand the information that I have been given. Signed. Date December

48 Appendix 18: Protocol* for First Re-Exposure to Clozapine after a Blood Dyscrasia Requiring Discontinuation Clozapine prescribing is strictly controlled by the Summary of Product Characteristics (SPCs) requiring regular blood monitoring throughout treatment. The SPCs state that clozapine prescribing is contra-indicated in someone with a history of clozapine-induced agranulocytosis, and once therapy has been discontinued for haematological reasons, patients must not be re-exposed to clozapine. Reuse of clozapine after a red result is thus unlicensed. All manufacturers have a form that allows re-exposure but it is the Consultant s decision and clinical responsibility alone and includes the disclaimer that I waive any rights I or the hospital may have against the suppliers. Clozapine can be a life-changing therapy and re-exposure to clozapine can both improve mental state and not necessarily lead on to a second dyscrasia. Incidence of recurrence on first rechallenge A review of 53 patients rechallenged with clozapine after a leucopenia or neutropenia, showed 38% had a further dyscrasia and in most it was more severe, longer-lasting and occurred more quickly. Of the 53, 55% were rechallenged successfully and remained in treatment 1. A second dyscrasia incidence peaks at 5.5 weeks (range up to 150 days). A recent review has stated that Uncertainty over the likely cause of blood dyscrasia in people taking clozapine, coupled with uncertainty over the mechanism by which clozapine causes both neutropenia and agranulocytosis, makes any attempt to restart clozapine a high-risk venture requiring the utmost caution. 2 Protocol for re-exposure following a previous dyscrasia A protocol is a detailed plan that must be followed for a course of medical treatment. This is a protocol*. The Trust will not support anyone acting outside this protocol. This is in recognition that the mechanism for clozapine-induced neutropenia or agranulocytosis is unknown, nor the extraneous factors involved, and so extreme caution must be exercised if re-exposing someone to clozapine after a dyscrasia. In exceptional circumstances, the Trust supports re-exposure to clozapine after agranulocytosis as follows: The Consultant must obtain in writing: 1. A second opinion supporting the need for clozapine 2. Advice from a haematologist regarding the dyscrasia and its likely relationship with clozapine, possible other causes and any other relevant factors and a care plan put in place 3. Advice from the relevant senior specialist clinical pharmacist 4. Informed consent from the patient, including the risks (1 in 3 chance of a repeat dyscrasia) and benefits, assuring that the patient is able to retain this information. The person's capacity to consent should be considered and documented. If patient lacks capacity the Mental Capacity Act should be followed. December

49 This should be in collaboration with any relatives or an advocate. However, since in law no one person can give consent for another, it should be made clear he or she will be advising relatives/advocates but that they cannot consent. If clozapine is re-prescribed: 1. Minimise the potential from contributing drugs e.g. any that might have been implicated in the original dyscrasia, any other drugs associated with blood dyscrasias. 2. Increase blood monitoring frequency and alertness, and document clear actions to be taken. The minimum should be: Twice weekly for the first ten weeks, then weekly to 18 weeks, then fortnightly to one year plus TWO samples before re-starting to establish an adequate baseline This should be more frequent (eg 3 times a week) should 3 falls in a row occur or if there is any suspicion of a dyscrasia developing A slightly slower dose escalation should be considered, although there is little evidence as to whether this reduces the risk or not. 3. Clear action plan made in the notes and copied to pharmacy should a dyscrasia recur: Emergency contacts 24/7 (patient, carer, RMO, pharmacy) haematologist Discontinuing therapy plan Replacement therapies or management options The patient must be an inpatient. 4. Service user educated about the relevance of any physical changes, particularly fever, sore throat or other signs or symptoms of infection, and to whom these must be reported and information leaflet given. Second rechallenge to clozapine Personal communication with Mylan/CPMS (Feb 2011) 3 patients have been rechallenged with clozapine for the second time. 1 is still continuing with green blood results It was difficult to identify the patients on clozapine and GCSF. It appears that 6 patients are continuing with green results due to GCSF. It is not clear if these patients have had one or two clozapine rechallenges. No deaths have occurred. No information available from manufacturers of generic clozapine. References 1. Rechallenge with clozapine following leucopenia or neutropenia during previous therapy. Dunk, Annan and Andrews, Br J Psychiatry 2006;188: Restarting clozapine after neutropenia: evaluating the possibilities and practicalities. Whiskey and Taylor, CNS Drugs 2007;21: December

50 Checklist for clozapine re-challenge The following checklist should be completed, retained in the notes and a copy sent to pharmacy. The re-supply of clozapine will not occur unless all of the below has been completed and approved in pharmacy and this form is signed and dated. Action Yes/No * Notes Has a written report been obtained from a second opinion supporting the need for clozapine re-challenge? YES/NO This must/should be a Consultant Psychiatrist from the same speciality and not a member of another profession (as in second opinion under MHA). Name: Has advice been sought from a consultant haematologist regarding the dyscrasia, other causes and relevant factors and a written report obtained? Has the advice been documented and incorporated into care plan for dyscrasia.? Advice from specialist clinical pharmacist has been sought and received YES/NO YES/NO YES/NO Please state name of haematologist and date of contact: Include emergency contact names and numbers (including out of hours ) Clinical Pharmacists should review notes and enter any relevant comments in them. eg confounding factors for dyscrasias Name of Pharmacist: Written, informed consent obtained, discussion to include Risk of repeat dyscrasia (1 in 3 Assessment as to capacity to consent considered and documented. OR MHA commissioners contacted Discussion with relatives and carers or advocate as to the nature of the treatment and relative risks Discussion and understanding of the commitment to increased blood test frequency Clear direction in notes for increased blood test monitoring if falls in WBC counts occur three times in a row Action plan completed with input from the haematologist and placed in notes and pharmacy should a dyscrasia occur YES/NO YES/NO YES/NO YES/NO YES/NO * If answering no to any of these questions refer to pharmacy. Consultant s Name and Signature. Dated: If unable to consent, MHA commissioners should be contacted. Should include written information to the service user about what physical changes to report, particularly fever, sore throat or other signs or symptoms of infection Cannot consent for patient. They can only advise (see note above) Twice weekly for 10 weeks Weekly from weeks 11 to 18 (inclusive) Fortnightly to week 52 (inclusive) Then monthly ongoing Should 3 falls in WBC occur then frequency of testing should increase to 3 times per week at minimum. See attached Action plan after reoccurrence of blood dyscrasia after clozapine re-challenge. December

51 Action plan should there be a re-occurrence of blood dyscrasia after clozapine rechallenge This form should be retained in the notes and a copy sent to pharmacy. Emergency Contacts: Doctor to complete details. Name: Patient Carer/ nearest relative RMO (within hours) Pharmacy (within hours) Out of Hours phone (if applicable) Address: Post Code Home Phone No. Mobile Phone No. Discontinuation Advice: Replacement therapy and management options should blood dyscrasia recur. Consultant Psychiatrist signature: Consultant Haematologist signature: Date: Date: December

52 Appendix 19: Clozapine Brand Change Procedure Please note a patient cannot be registered on two databases at the same time. Clozaril (Mylan) to Denzapine (Genus) 1. Consultant to complete a brand transfer form, obtained from Medicines management team or Denzapine/Genus website. 2. Ward to fax completed form to Genus on Once the form has been received Genus will contact Mylan to transfer the patient and information onto the new system. 4. Pharmacy will check the website and supply the new medication. Denzapine (Genus) to Clozaril (Mylan) 1. HCP (nurse, Doctor or medicines management team) to contact Mylan to request a patient be transferred. 2. Please supply patient name, DOB, ward and consultant details, including fax/ address. 3. Mylan will fax/ a form for the consultant to complete. 4. Once completed fax/ form to Mylan on Mylan will contact Genus to transfer the patient and information onto the new system. 6. Pharmacy will check the website and supply the new medication. December

53 Appendix 20: Clozapine side effect rating scale (GASS-C) See: December

54 Appendix 21: Constipation poster Struggling to go? Let us know! We want to know about a change in your bowel habits. Constipation may be caused by medicines like clozapine, procyclidine and amitriptyline. December