Guideline for the In-patient initiation of Clozaril (Clozapine) within CWPT

Guideline for the In-patient initiation of Clozaril (Clozapine) within CWPT Version: 1 Author: Ambreena Asghar Designation: Pharmacist Responsible Director: Sharon Binyon Approved By: Drugs and Therapeutics MH Committee Approval Date: 12 th November 2015 Review Date: November 2017 Trust Board Strategic Drugs & Therapeutic Committee 1 of 13

Contents 1. BACKGROUND.... 3 2. THE ROLE OF THE CLOZARIL PATIENT MONITORING SERVICE (CPMS)... 3 3. CONSIDERATIONS BEFORE STARTING:... 4 4. BLOODS ON INITIATION AND DURING TREATMENT... 5 5. PRE-TREATMENT MONITORING... 5 6. DOSING OF CLOZARIL... 5 7. SIDE EFFECTS AND DOSING:... 9 8. MISSED DOSES:... 10 9. THE SUPPLY OF CLOZARIL TO CWPT PATIENTS TRANSFERRED TO OTHER NHS TRUSTS.... 10 10. FURTHER ADVICE TO GIVE TO PATIENTS ON DISCHARGE.... 11 11. DISCHARGE PROCESS FOR PATIENTS ON CLOZAPINE... 11 12. APPENDIX 1... 13 2 of 13

1. Background. Following the European harmonisation of the Clozaril Summary of Product Characteristics (SmPC), there is no longer a mandatory regulatory requirement for inpatient initiation of Clozaril (clozapine). However, in-patient initiation is still recommended in patients who are not suitable for outpatient initiation due to individual patient complexities see later. Aim. The overall aim of this guideline is to ensure that: prescribing, monitoring and supply of Clozaril treatment occurs in a timely, safe and appropriate manner for those patients where Clozaril is deemed appropriate (with due regard to licensed indications). Suitable patients. Patients should be considered for in-patient initiation in view of their current symptomatology and safety risk such as those with diabetes or a history of cardiac disease, seizures, or neuroleptic malignant syndrome (NMS) as well as elderly patients who may be more susceptible to some side effects and require a slower dose titration. In patient initiation is also advised in those patients who are receiving potent sedatives or benzodiazepines or who are at risk of severe relapse during a switchover of antipsychotics. 2. The Role of the Clozaril Patient Monitoring Service (CPMS) The CPMS is a 24 hours a day, 7 days a week service which aims to optimise the safety of all patients receiving Clozaril in the UK. The main role of the CPMS is haematological monitoring of patients taking Clozaril. All patients as well as the responsible doctor must be registered with the CPMS prior to starting Clozaril. (Please note that there are various brands of clozapine and this trust uses the Clozaril brand. If an out of area patient is admitted into the trust who is stable on another brand of clozapine then this guideline will not apply and advice must be sought form the CWPT medicines management department.) Registering Patients with CPMS If the responsible doctor (consultant) is already registered with CPMS and the ward is ready to start a patient on Clozaril, then the consultant must go to the CPMS website (www.clozaril.co.uk) and select Forms to download a registration form or call the CPMS on 0845 769 8269 for further instructions. 3 of 13

3. Considerations Before Starting: Each case should be considered on an individual basis. Patients should consent to Clozapine treatment and blood tests and be aware of and agree to the necessity for future outpatient clinic attendance/home visits. If patients do not consent then consider appropriate treatment under the Mental Health Act. Patients should be provided with information about Clozapine see choice and medication website or contact Medicines Management or CPMS for other sources of clozapine patient information Of particular importance are: - Realistic expectations for recovery including timeframe. - Recognition of adverse reactions to Clozapine and what to do if they occur. - Importance of adherence A full medical history of particular interest are a history of cardiovascular problems (including ECG), epilepsy, diabetes or haematological disorders Concomitant medications look for possible interactions e.g. bone marrow suppressants, benzodiazepines, anticholinergics, antihypertensive, alcohol, CNS depressants, highly protein bound drugs, phenytoin, lithium, depot antipsychotics. Consideration should be given as to how the switch will take place from other antipsychotics. Particular care should be taken to avoid complex dose titration and to consider potential drug interactions with other prescribed medications and additive side effects of antipsychotics during cross taper. ECG monitoring is prudent when clozapine is co-prescribed with other drugs known to affect QT interval. An appropriate physical examination including BMI, pulse, temperature, and blood pressure. The patient will require an initial full blood count and any other required baseline and on-going blood monitoring should be undertaken. Please refer to CWPT Antipsychotic Monitoring Guidance. Undertake Psychiatric baseline measurements (i.e. HoNOS) wherever possible in order to act as a baseline against which to measure progress. Arrangements should be in place for the first full blood count on treatment (this is usually on day 3 of treatment) and on-going full blood counts. Arrangements for communication of the blood result to the relevant Pharmacy should be in place if necessary. If a patient becomes non-compliant then the duty doctor must be informed immediately. In patients in whom the interval since the last dose of Clozaril exceeds 4 of 13

48 hours, treatment should be re-initiated with 12.5 mg once or twice on the first day and the dose re-titrated. Pharmacy must be informed as soon as possible after the Clozapine is initiated. 4. Bloods On Initiation and During Treatment Ensure there is a mechanism in place in order for bloods to be taken and analysed and for the results to be transferred onto the CPMS system. There are some units within the trust where they have access to on-site analysis of bloods by the use of a pocchi machine and the results automatically download onto the CPMS website - see local guideline for further information (Clozapine - Avenue Clinic SOP Jan 2010) If the bloods are sent to an external unit for analysis for example a local acute trust then the results of the blood tests must be faxed or phoned through to CPMS for them to enter the results onto the system. Without this the pharmacy will be unable to dispense clozapine for the patient. 5. Pre-treatment Monitoring The patient will require an initial full blood count and any other required baseline and on-going blood monitoring should be undertaken. Please refer to CWPT Antipsychotic Monitoring Guidance Patients must have a normal pre-treatment white blood cell (WBC) count and absolute neutrophil count (ANC) (WBC >3.5 x 109/L, neutrophil count >2.0 x 109/L). It is also very important to establish that the patient has not previously experienced an adverse haematological reaction to clozapine that necessitated its discontinuation. Patients who have low WBC counts because of benign ethnic neutropenia (BEN) - please refer the Clozaril and Benign Ethnic Neutropenia fact sheet which is available from the CPMS website. Those with abnormal cardiac findings or a history of cardiac illness should be referred to a specialist for other examinations that might include an ECG, and then only treated if the expected benefits clearly outweigh the risks. For full information on listed contraindications and special warnings and precautions, please refer to the Summary of Product Characteristics for Clozaril. 6. Dosing of Clozaril Age Restrictions when prescribing. The SPC for Clozaril states the following: 5 of 13

Paediatric population No paediatric studies have been performed. The safety and efficacy of Clozaril in children and adolescents under the age of 16 years have not yet been established. It should not be used in this group until further data become available. Patients 60 years of age and older Initiation of treatment is recommended at a particularly low dose (12.5 mg given once on the first day), with subsequent dose increments restricted to 25 mg/day. Treatment-resistant schizophrenic patients- adult dosage. Starting therapy 12.5 mg once or twice on the first day, followed by 25 mg once or twice on the second day. If well tolerated, the daily dose may then be increased slowly in increments of 25 to 50 mg in order to achieve a dose level of up to 300 mg/day within 2 to 3 weeks. Thereafter, if required, the daily dose may be further increased in increments of 50 to 100 mg at half-weekly or, preferably, weekly intervals. NB: Speed of titration should be patient specific and is based on a number of factors including patient tolerability, patient age, significant medical history, significant abnormal findings in observations, level of support available etc. It may be appropriate to start at a lower dose and use a slower titration or it may be appropriate to alter titration schedule once clozapine has been started. Suggested Titration regimen (adopted from the CPMS Website) (adults) Day Morning dose(mg) Evening dose (mg) Total Daily Dose (mg) 1 12.5 12.5 2 12.5 12.5 25 3 12.5 25 37.5 4 25 25 50 5 25 50 75 6 25 75 100 7 25 75 100 8 50 75 125 9 50 100 150 10 50 100 150 11 50 125 175 12 100 100 200 13 100 125 225 14 100 150 250 15 100 175 275 16-21 100 200 300 22-24 100 250 350 25-28 100 300 400 * 6 of 13

*Thereafter, if required, the daily dose may be further increased in increments of 50 to 100mg at half weekly or, preferably weekly intervals up to the maximum dose of 900mg per day according to response. All contact with the patient by the healthcare professional should be documented. The first dose may be taken at bedtime - see below for changes in observation & monitoring. A healthcare professional must check the pulse, temperature and standing and lying BP at the appropriate intervals as detailed below. All monitoring must be recorded using the trust observation forms. Utilise a flexible dosage titration Don t increase the dose of Clozapine at the weekend or on bank holidays. Enquiry should be made daily into the occurrence of adverse reactions. A doctor should see the patient regularly. The doctor should assess the patient s general condition and progress, assessing any adverse reactions to Clozapine, adjusting the titration rate, managing anti-psychotic medication cross-titration, reassuring the patient. At regular intervals psychiatric measurements should be performed and suicidality assessed in order to monitor progress. Patient must be advised to contact nursing staff immediately in case of adverse effects. Ideally the start date should allow patient tolerability to be assessed prior to the weekend. Consideration should be given as to when the first full blood count on treatment (this is usually on day 3 of treatment) will be taken as well as further weekly full blood counts. Ensure the appropriate amount of Clozapine is available for the patient. Arrangements for this should be discussed with the trust supplying pharmacy. Observations & Monitoring Day 1 Day 2 Day 3 Day 4-7 Pulse, temperature and standing and lying blood pressure should be taken before giving the clozapine. After this dose pulse, temperature and standing and lying blood pressure should be repeated after 3 hours and 6 hours BUT this may not be necessary if this first dose is given immediately before retiring to bed this must be a medical decision and the patient MUST be observed by healthcare staff overnight. A healthcare professional takes the patient s pulse, temperature and standing and lying BP before the patient takes the morning and evening dose Clozapine dose and then at 3 and 6 hours after the morning dose only. A healthcare professional takes the patient s pulse, temperature and standing and lying BP before the patient takes the morning and evening Clozapine dose and then at 3 and 6 hours after the morning dose only. The patient s first full blood count must take place on this day and sent for analysis A healthcare professional takes the patient s pulse, temperature and standing and lying BP before the morning and evening Clozapine dose and then 6 hours after the morning dose only. 7 of 13

The level of observations may be reduced to once daily in week 2 at the discretion of the treating clinician. This decision should be patient specific as it is dependent on a number of factors such as speed of titration, tolerability, significant medical history etc. Please note that the next blood test must take 7 days after the first ideally day 10 and then continue on the same day each week for 18 weeks after which it can be reduced to once every 2 weeks please see Summary of Product Characteristics for further information. The focus of nursing observation during the initial seventy-two (72) hour period is to monitor for hypotension, excessive drowsiness, tachycardia and hyperthermia. The most likely time for this to occur is during the first six hours after receiving the initial dose. It is crucial that the client be closely observed throughout this initial six-hour period and following any subsequent increase in dosage. Should the client experience any of the above: Initiate first aid measures, and seek medical advice Record vital signs; pulse, respiration, temperature and blood pressure. Contact medical staff to discuss management. (Particularly if temperature is >than 38 c, pulse >100bpm, postural drop >30mmHg, clear over-sedation, intolerable adverse effects or flu-like symptoms). If out of hours, contact the duty doctor for advice In most patients, antipsychotic efficacy can be expected with 200 to 450mg/day given in divided doses. The total daily dose may be divided unevenly, with the larger portion at bedtime. To obtain full therapeutic benefit, a few patients may require larger doses, in which case judicious increments (i.e., not exceeding 100mg) are permissible up to 900mg/day. The possibility of increased adverse reactions (in particular seizures) occurring at doses over 450mg/day must be borne in mind. After achieving maximum therapeutic benefit, many patients can be maintained effectively on lower doses. Careful downward titration is therefore recommended. Treatment should be maintained for at least 6 months. If the daily dose does not exceed 200mg, once daily administration in the evening may be appropriate. Switching from a previous antipsychotic therapy to Clozaril. It is generally recommended that Clozaril should not be used in combination with other antipsychotics. When Clozaril therapy is to be initiated in a patient undergoing oral antipsychotic therapy, it is recommended that the other antipsychotic should first be discontinued by tapering the dosage downwards however, cross tapering of antipsychotics will increase the risks of adverse effects and this will be at the discretion of the responsible consultant. Psychotic disorders occurring during the course of Parkinson's disease, in cases where standard treatment has failed. The starting dose must not exceed 12.5 mg/day, taken in the evening. Subsequent dose increases must be by 12.5 mg increments, with a maximum of two increments a week up to a maximum of 50 mg, a dose that cannot be reached until the end of the second week. Patients with Parkinson s disease require much lower doses; please refer to the Summary 8 of 13

of Product Characteristics. The total daily amount should preferably be given as a single dose in the evening. Patients aged 60 years and older. Initiation of treatment is recommended at a particularly low dose (12.5 mg given once on the first day), with subsequent dose increments restricted to 25 mg/day. 7. Side Effects and Dosing: Like all antipsychotics, Clozaril can cause a range of side-effects which are often dosedependent and can be more troublesome at the beginning of treatment. Cautious titration and a divided dosage schedule are necessary to minimise the risks of hypotension, seizure and sedation. The dose should be built up over 3-4 weeks. Increases in dose should be considered against side-effects. The aim is to maintain the patient on the lowest effective dose and hence minimise side-effects. N.B. Clozaril-induced neutropenia / agranulocytosis are not dose-related. Management of Adverse Effects or Potential Problems. This list is not exhaustive. More information can be obtained from the Clozaril Patient Monitoring Service or from the Medicines Management team. Seek advice if you are unsure. Pyrexia: Seizures: Tachycardia Drowsiness Hypersalivation: Hypotension Hypertension: Nausea/vomiting Temperature above 38 C is often normal in the first three weeks of treatment and may not be related to blood dyscrasias. However, blood sample should be taken to exclude agranulocytosis and exclude causes of infection. The rate of dose titration may need to be reduced. Paracetamol may be beneficial. Be aware of the risk of myocarditis. Especially with doses in excess of 600 mg. Stop clozapine for 24 hours. Restart at reduced dose. Consider sodium valproate as prophylaxis. Refer for EEG and neurological examination. May persist throughout treatment. Reduce dose and consider ECG. Consider risk of myocarditis. This is usually within the first four weeks. Can be managed by giving more of the dose at bedtime and increasing the dose more slowly. Appears early in treatment. If troublesome consult doctor/pharmacist. Hyoscine hydrobromide (Kwells) is often an effective treatment. Please see trust guide on alternatives if hyoscine is unavailable. Occurs in the first four weeks. Instruct patient to stand slowly, split the dose, with a larger proportion at bedtime or reduce the dose. Usually occurs in the first 4 weeks. Monitor closely and increase dose as slowly as is necessary Reduce dose. An anti-emetic may be of use avoid 9 of 13

prochlorperazine and metoclopramide if previous EPSE. Constipation Adjust diet. Give stool softener. Ensure adequate fluid intake. Constipation should not be ignored. Service user should be regularly prompted about constipation. Weight gain Can be up to 2 stones (13kg). Give advice about exercise and diet. It s easier to minimise weight gain over the first few months than try to lose it afterwards. Neutropenia/agranulocytosis More common in first 18 weeks but may occur at any time. Patients should be advised to report any evidence of infection, cold, fever, sore throat or flu like symptoms. If neutropenia/agranulocytosis is suspected, Clozapine should be stopped immediately. Risk of suicide Improvements in mental state and insight can also lead to an increased risk of suicide. Use risk assessment and direct questioning to access suicidality. Nocturnal enuresis May occur at any time. Avoid fluids before bedtime. May resolve spontaneously or may persist for months or years. 8. Missed doses: If a dose is missed, the next dose should be taken at the normal time; do not attempt to make up for the missed dose by giving more If Clozaril is omitted for more than 48hrs: It is important to restart gradually from 12.5mg once or twice on the first day and inform CPMS. The patient s psychiatrist / prescriber should be informed as psychotic episodes may start to return before the patient s therapeutic dose can be reached In patients who tolerate the initial doses of Clozaril well, it may be possible to re-titrate the remaining dose more quickly Patients who have been on Clozaril for more than 18 weeks and have missed treatment for more than 3 days but less than 4 weeks require extra weekly monitoring for 6 weeks. If no haematological abnormality occurs, monitoring at intervals not exceeding 4 weeks may be resumed. Patients who have missed over 4 weeks of treatment require weekly monitoring for 18 weeks and the dose needs to be re-titrated. Please contact the CPMS for details. 9. The Supply of Clozaril to CWPT Patients Transferred to Other NHS Trusts. The arrangement for supply of Clozaril to these patients should be managed on a case by case basis ensuring communication with all necessary parties at all times. 10 of 13

10. Further Advice to give to patients on Discharge. Alcohol and Clozapine It is recommended that people taking clozapine should not drink alcohol. This is because both antipsychotics and alcohol can cause drowsiness. If the two are taken together, severe drowsiness can result. This can lead to falls and accidents. As well as this, drinking alcohol may make psychosis worse. However, once people are used to taking medication, then very small amounts of alcohol may not be harmful. Advise patients to discuss any concerns they may have with their doctor, pharmacist or nurse. Smoking and Clozapine There is now an official ban of smoking within the trust. This may be important if patients are heavy smokers in the community and are unable to smoke when they are hospitalized. Generally, smoking increases the breakdown of clozapine in the body so when a patient stops smoking the levels of clozapine can rise - please contact the medicines management office or your ward pharmacist for specific advice. The patient s smoking history must be highlighted to the responsible consultant and appropriate advice given to the patient on the interaction between smoking and clozapine levels. It must be stressed to the patient on the importance of smoking abstinence when on leave as smoking could possible reduce the blood levels of clozapine and consequently increase the risk of relapse. If patients feel that smoking abstinence will be a problem then they must be referred to the smoking cessation nurse on the ward. Abrupt Withdrawal of Clozapine. Patients must be advised that they must never stop taking clozapine without discussing with the prescriber, even if they feel better. They must be advised that if they stop taking clozapine, their original symptoms will return. Most people need to be on clozapine for quite a long time, sometimes years. It is now trust policy that all clozapine patients must have a psychiatric review by a psychiatrist on a minimum of a 6 monthly basis see Clozapine prescribing standards Approved March 2015. Patients should always discuss any plans they have to reduce or stop any of their prescribed medicines with their psychiatrist / prescriber. Patient Information Leaflets: Patients, family members/carers should be provided with information about Clozapine this can be done by utilizing patient information leaflets (PIL). See most up to date PIL on the electronic medicines compendium as well as the choice and medication website or contact the medicines management team for further advice. 11. Discharge Process for Patients on Clozapine Please refer to Appendix 1 for flow chart summarizing the process to be followed when discharging such a patient. 11 of 13

References Guidance for the Out Patient Initiation of Clozapine, CWPT NHS Trust, Version 4, July 2014 Psychtropic Drug Directory, Stephen Bazire, 2014 In patient Initiation of Clozaril, February 2015, Clozaril Patient Monitoring Service South Staffordshire and Shropshire Healthcare NHS Foundation Trust Policy for Clozapine Treatment, October 2013 Summary of product Characteristics, Clozaril, 2015. 12 of 13

12. Appendix 1 Out Patient Prescriptions for On Going Clozaril Supply by CWPT Following Discharge from In Patient Services. A number of incidents have occurred whereby; following discharge from an in-patient unit, a prescription has not been provided to Lloyds Pharmacy for on-going supply of Clozaril. To ensure a prescription is available at Lloyds Pharmacy to enable on-going supply of Clozaril, please follow the process below. Service user prescribed Clozaril to be discharged from an inpatient unit within CWPT and all dispensing is to remain via Lloyds Pharmacy Discharge prescription written for an appropriate treatment length (28 days). Ensure that the discharge destination and key worker are complete. In-patient team to fax a copy of the discharge prescription to the community team/community consultant and request that a clozapine out-patient prescription is supplied to Lloyds pharmacy to allow on-going supply Community team/consultant to supply an out-patient prescription to Lloyds Pharmacy within 72 hours to allow on-going supply of medication 13 of 13