The licensed indications for the use of Clozapine are:- Treatment resistant schizophrenia.

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1 1. Introduction Future Directions CIC will support the use of the antipsychotic Clozapine in all appropriate cases. The purpose of this procedure is to set out the standards for Clinicians, Pharmacists, nursing staff and other health care professionals involved in the prescribing, administration and monitoring of Clozapine. Future Directions CIC supports a spectrum of individuals with complex needs and associated conditions, e.g. learning disability, challenging behaviour, mental illness, offending behaviours. It is important that Future Directions CIC are able to support service users with chronic physical conditions; therefore it is especially important to be aware and be able to monitor them closely for side effects of Clozapine. 2. Standards For Prescribing 2.1. Indications The licensed indications for the use of Clozapine are:- Treatment resistant schizophrenia. Service users who have severe, untreatable neurological adverse reactions to other antipsychotics including an atypical antipsychotic. Psychotic disorders occurring during the course of Parkinson s disease when standard treatment has failed Prescribing NB: Its use is recommended when other antipsychotic drugs have proved ineffective or not tolerable. Trials of a minimum of two antipsychotics in adequate dosage, one of which should be an atypical, each for a minimum of six weeks should be completed before Clozapine is tried. The initiation of Clozapine is restricted to Physicians registered with the Clozaril Patient Monitoring Service or equivalent. Nominated Pharmacists and service users must also be registered. For ongoing prescribing, Clozapine must be prescribed by the individual s Consultant Psychiatrist or a designated Psychiatrist who has a regular commitment to a Clozapine Clinic Consent 1

2 In the case of adult service users, Clozapine treatment is usually given after informed consent has been obtained. Prior to the commencement of therapy, agreement must be reached with the service user to comply with the treatment/blood monitoring regime as clinically indicated. Where the service user does not have the capacity to consent to treatment, but does not object, Clozapine can be given under common law (refer to Mental Capacity Act 2005) if it is:- Necessary to save life or prevent deterioration or ensure an improvement in the service user s physical or mental health. In accordance with the practice at the time by a reasonable body of medical opinion skilled in that form of treatment. In the best interest of the service user. Consideration must be given to whether the service user will comply with the blood testing regime. Blood tests are part of the treatment and can be taken from the service user without capacity who does not object to the procedure if it is in their best interests and has been agreed by the Multi Disciplinary Team. NB: Staff should support service users to look at ways that they can comply with blood tests and look at desensitisation programs. Examples of work undertaken to aid compliance: Smaller Needles Same clinician at every appointment Regular visits to environment and talked through process in story/pictorial format. 3. Service User Information Prior to initiation, the service user must have a full discussion with the prescribing Clinician regarding the risks and benefits of Clozapine treatment and the need for lifestyle changes, e.g. avoidance of alcohol and activities such as driving or operating machinery especially during the initial weeks of treatment. The range of common side effects and potential medical complications should be discussed. An entry should be made by the support staff in the service user s records that this information has been given, how it has been given and how it was received. The current Clozaril summary of product characteristics SPC (Novartis) contains a comprehensive list of cautions and contraindications and this should be available in all Clozapine Clinics, and to prescribing Physicians and Clinicians involved in the care of service user on Clozapine. Service users should be supplied with an Alert Card that is provided with the initial Clozapine pack. All service users will be given the Patient Handbook, currently supplied by the Clozaril Patient Monitoring Service, or equivalent, which describes the reasons 2

3 for regular blood tests and other helpful information. This will be issued at the service user s first Clozapine Monitoring Clinic (CMC) appointment. Leaflets, videos and other educational material are available, via the CMC, to assist in providing information about schizophrenia and its treatment. The information will include the need for regular attendance at clinics. If the service user has little or no English and the member of staff does not speak their language, they should be offered the opportunity of discussing their treatment through an interpreter. 4. Initiation and Monitoring of Clozapine Treatment A full description of the protocol for community initiation is given in the Summary of Product Characteristics for Clozaril. This includes the recommended regime for dosage titration. Staff are required to familiarise themselves fully with these guidelines. Relevant medical conditions and special precautions should be considered by the prescribed Clinician. Contraindicated medications should be discontinued prior to initiation of Clozapine therapy, and other antipsychotics cross-tapered with caution. Prescribing Clinicians may decide to titrate doses more slowly depending on the service user s needs and presentation. Routine Baseline Assessment Full medical and psychiatric history Physical Examination: weight, pulse and blood pressure Blood Tests: full blood counts, different white cell count, random glucose, HbA 1c Electrocardiogram, if thought appropriate by the Clinician Routine Follow Up Monitoring Blood Tests: Full blood count and differential white cell count at weekly, fortnightly or monthly intervals as appropriate. The Maudsley Guidelines recommended plasma glucose at 1 month, HbA 1c at baseline and thereafter at 3 monthly intervals 3. An oral glucose tolerance test should be performed if HbA 1c or plasma glucose is raised. Side effects should be regularly monitored. The NICE Clinical Guideline number 82 for schizophrenia recommends that the service user attends their GP for a regular physical examination. 3

4 Clozapine Levels Clozapine levels can be checked. Levels should be checked as and when clinically indicated, e.g. Symptoms suggesting excessive side effects. Lack of clinical response. Following stabilisation when a reduction of dose is being considered. Clozapine metabolism may be altered, e.g. a drug interaction. 5. Risk Management 5.1. Concurrent Prescription with Drugs Known to have a Substantial Potential for Causing Agranulocytosis History of toxic or idiosyncratic granulocytopenia/agranulocytosis (with the exception of granulocytopenia/agranulocytosis from previous chemotherapy). History of Clozapine induced agranulocytosis. Impaired bone marrow function. Hypersensitivity to the active substance or to any of the inactive ingredients. 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. Active liver disease associated with nausea, anorexia or jaundice, progressive liver disease, hepatic failure. History or paralytic ileus Special Precaution to the Use of Clozapine Refer to the SPC for a full list of special precautions 4. Clozapine is excreted in breast milk; mothers receiving Clozapine should not breast-feed. In women of child bearing potential a return to normal menstruation may occur as a result of switching from other antipsychotics to Clozapine. 4

5 Adequate contraceptive measures must therefore be advised in women of child bearing age. Use in the elderly requires a particularly low dose at initiation of treatment, and the dose titrated up more slowly as the elderly are more susceptible to side effects. In practice, when using Clozapine in people with learning disability, consideration should be given to any underlying medical condition which may affect their tolerability to Clozapine Drug Interactions Some antipsychotic drugs may increase the risk of sudden cardiac death by causing QTc interval prolongation. All depot antipsychotics, sertindole, primozide, and thioridazine should be stopped before Clozapine is started. Drugs such as depot antipsychotics and carbamazepine that can increase the risk of agranulocytosis are contraindicated with Clozapine. A change in smoking habits and some prescribed drugs (e.g. Selective Serotonin Reuptake Inhibitors SSSRIs) can affect metabolism of Clozapine and thereby alter Clozapine levels. Care must be taken to avoid substances including alcohol that increase the sedating effects of Clozapine. Service users known to abuse alcohol should not be prescribed Clozapine. It may be appropriate to test blood alcohol levels if there is doubt about alcohol abuse Serious Adverse Events Any drug may produce unwanted or unexpected adverse reactions. Detection and recording of these is important. All adverse reactions should be reported to the service user s Doctor, Pharmacists and Nurses who should report adverse reactions to the Medicines and Healthcare Products Regulatory Agency (MHRA) Agranulocytosis Routine blood monitoring will identify sub-clinical cases. Particular attention must be paid to flu like symptoms such as sore throat which may be indicative of neutropenia. The Clozapine Monitoring Service currently provides guidance about procedures to be followed in the event of neutropenia or agranulocytosis developing Pyrexia 5

6 5.7. Seizures Mild hyperthermia occurs in approximately 5% of patients, typically early in treatment and is usually not significant. If a service user develops pyrexia and a flu like illness, a medical examination and full blood count should be performed as soon as possible. If the body temperature exceeds 38.5ºC, Clozapine should be suspended until the temperature drops. The Clozaril Monitoring Service (or equivalent) must be contacted and their advice followed. In the presence of a high fever, the possibility of neuroleptic malignant syndrome (NMS) must be considered. Clozapine lowers the seizure threshold and service users may develop a seizure disorder especially on high doses of Clozapine. The minimum effective dosage should be prescribed. Those service usrs needing doses of Clozapine that causes them seizures may be concomitantly prescribed an anticonvulsant that is not associated with bone marrow suppression Cardiovascular Events Clozapine treated service users may have an increased risk of pulmonary embolism and sudden death. Clozapine has been associated with cardiomyopathy and fatal myocarditis. The risk of myocarditis is highest during the first two months of treatment. Cardiac complications should be suspected if service users experience persistent tachycardia at rest, palpitations chest pain or heart failure develops. In these cases Clozapine should be promptly stopped, and the service user referred to a Cardiologist by their Psychiatrist. Such service users should never be re-exposed to Clozapine. The risk of orthostatic hypotension can be minimised by slowly tapering the dose and spreading doses through the day Acute Intestinal Obstruction Due to slowing of intestinal peristalsis, Clozapine can cause constipation, obstruction and paralytic ileus which may be fatal. Acute obstruction is a medical emergency. Symptoms include abdominal distension, pain and vomiting. When suspected, the medical team must be alerted and a surgical referral initiated if appropriate 6

7 Drugs which have anti-cholinergic side effects should be avoided as these may exacerbate the obstruction by slowing peristalsis Diabetes and Impaired Glucose Tolerance Clozapine has been strongly linked to hyperglycaemia, impaired glucose tolerance and diabetic ketoacidosis. Up to one third of Clozapine treated service users develop diabetes after five years of treatment, the majority of these within the first six months. Carers and staff treating service users with Clozapine should be alert for symptoms of diabetes and HbA 1c and blood glucose (where indicated) routinely monitored Common Side Effects These include hyper salivation, dizziness, fast heart rate, weight gain, jerking, seizures/fits, urinary problems, sweating, dry mouth, nausea, visual disturbances and sedation. Obessional symptoms and sexual dysfunction may occur. These should be screened for at routine clinic visits and advice on management given and liaison with the medical team if necessary. To avoid constipation, a high fibre diet is recommended and bulk forming laxatives and/or stimulants may be used. Other constipating medication should be avoided. Weight gain must be monitored and dietary advice made available to service users by supporting staff teams in conjunction and supported by local services e.g. GP, Dietician Communication Close liaison must exist between the Clozapine prescriber, dispensing Pharmacy, General Practitioner and the service user. Anyone suspecting non-compliance with Clozapine should notify the prescriber and appropriate action taken to follow this up with the service user. For Clozapine related issues, staff should contact in the first instance the prescribing Clinician or the individuals GP where appropriate and notify the On Call Manager. Where staff are unable to contact the prescribing Clinician or the individual service users GP, then advice should be sought from NHS Direct/NHS Walk In Centre, On Call GP or Accident and Emergency. 6. Training and Awareness Staff involved with service users undertaking treatment with Clozapine should be familiar with this procedure. 7. Legislation, Supporting Policies and Guidelines Human Rights Act 1998 Mental Capacity Act

8 Medicines Procedure Procedure to be reviewed 3 yearly subject to yearly audit. 8. Monitoring Minimum Requirement to be Monitored/ Audited All staff working with individual service users who undertaking treatment with Clozapine will be familiar with this procedure Process for Monitoring e.g. Audit Appraisal and PDP/ Supervision Responsible Individual/ Group/ Committee Team Leader/ Network Manager Frequency of Monitoring and/or Audit Annual Team Leader/ Network Manager. Team Leader/ Network Manager Responsible Individual/ Group/ Committee for Development of Action Plan Team Leader/ Network Manager Responsible Individual/ Group/ Committee for Monitoring of Action Plan Team Leader/ Network Manager Compliance with the procedure Via Health promotion objectives Network Managers 3 yearly Community Governance Meeting Community Governance Meeting Community Management Team 9. References and Associated Documentation Core Interventions in the Treatment and Management of Schizophrenia in Primary and Secondary Care. National Institute for Clinical Excellence, December Childhood-Onset Schizophrenia. A Double-blinded Clozapine-haloperidol Comparison. Kumra S, et. al., Archives of General Psychiatry. 53(12)109007, 1996 December Core Interventions in the Treatment and Management of Schizophrenia in Primary and Secondary Care. National Institute for Clinical Excellence, December 2002 Guidance Note Summary of Product Characteristics Clozaril, Novartis Pharmaceuticals UK Ltd, December The Maudsley Prescribing Guidelines 2003 British National Formulary 8