North nottinghamshire

Clozapine
Information Sheet for GPs
Please consult the manufacturers Summary of Product Characteristics (SPC)1 for further information Clozapine is a RED drug, prescribed, monitored and supplied by Nottinghamshire Healthcare NHS Trust. However, familiarity with the contents of this document will serve to protect patients treated with clozapine from adverse events associated with its use. IMPORTANT POINTS
Ensure that clozapine is added to the GP electronic patient’s medication list
File this document prominently in the patient’s GP notes Add patient to the mental health register Urgent full blood count if signs of infection inc. sore throat & flu symptoms Do not restart if there has been a break of >48hr between doses Stopping smoking can increase clozapine levels, be alert to smoking status Be alert to constipation, it can lead to clozapine toxicity and bowel perforation DRUG INTERACTIONS
Clozapine is contraindicated with other medicines with a substantial potential to depress bone marrow function (e.g. carbamazepine, oxcarbazepine, penicillamine, chloramphenicol (not topical), any chemotherapy regimen, depot antipsychotics). other medicines with sedative effects, including alcohol other medicines with anticholinergic effects other medicines with hypotensive effects or those known to prolong the QTc interval, phenytoin – may decrease clozapine plasma levels CP4501A2 inducers such as omeprazole, may lead to decreased clozapine levels CP4501A2 inhibitors such as fluvoxamine, ketoconazole, erythromycin, clarithromycin and ciprofloxacin, may lead to increased clozapine levels. CP4502D6 inhibitors such as fluoxetine, paroxetine and venlafaxine, may increase clozapine levels. Sertraline may do to a lesser extent. This is not an exhaustive list. Please see BNF and SPC1 for further information. SMOKING AND CAFFEINE
Smoking cessation can increase clozapine plasma levels by up to 72% (cigarette smoke is an inducer of the CP4501A2 system). If your patient wants to quit/cut down smoking, inform the psychiatric team. A dose reduction may be appropriate when stopping smoking. Side-effects of clozapine should be reviewed regularly during the period of cutting down. Patient Advice Leaflet available. Plasma clozapine levels are increased by caffeine intake and decreased by 50% following a 5 day caffeine-free period. Advise patient to maintain a stable caffeine intake and inform psychiatric team of any changes. REVIEW DATE: July 2014 DATE APPROVED BY THE NOTTINGHAMSHIRE APC: July 2012 Author: John Lawton (Pharmacy, NHCT)
Background
Licensed Indications1
Clozapine has been shown to be the drug treatment of choice in treatment-resistant
schizophrenia2. Response rates are reported to be 30% at 6 weeks and 60% at one year. The
average maintenance dose is around 400mg/day, though it is licensed up to 900mg/day. Some
patients will experience adverse effects at doses much less than 400mg/day. In non-
responders, clozapine is sometimes augmented with a second antipsychotic e.g. sulpiride.
Approximately 1-2% of patients on clozapine may develop neutropenia leading to
agranulocytosis. Regular full blood counts (FBC) are conducted for all patients taking clozapine,
co-ordinated by a centralised monitoring service. The Zaponex® brand of clozapine is prescribed
by Nottinghamshire Healthcare NHS Trust co-ordinated by the Zaponex Treatment Access
System (ZTAS). Each patient will have their own unique ZTAS Patient Identification Number.
There are other brands of clozapine with similar patient monitoring systems (e.g. Clozaril,
Clozaril Patient Monitoring Service (CPMS) and Denzapine, Denzapine Patient Monitoring
Service (DPMS)). It is important to ensure patients do not switch between different brands of
clozapine to ensure patient safety.

Dose Initiation and Breaks in Treatment
Clozapine will always be initiated by a psychiatrist under close supervision either as an in-patient
or as an out-patient with close support from the Home Treatment Team. Many of the adverse
effects of clozapine are dose-dependent and associated with speed of titration. It is started at a
low dose (12.5mg once a day) and increased slowly. Doses above 200mg/day are generally
given in two divided doses with the larger portion at bedtime.
Tolerance to the sedative and hypotensive effects is rapidly lost. If the patient has not taken
clozapine for longer than 48 hours you should advise that the usual dose must not be resumed.
The psychiatrist must be contacted urgently as the dose must be re-titrated from 12.5mg/day.
Please report any concerns regarding non-adherence with treatment to the psychiatrist.

When and How to Discontinue Treatment
Discontinuation will usually be managed by secondary care. Gradual discontinuation over at
least 1-2 weeks is recommended to avoid the risk of acute withdrawal syndromes or rapid
relapse. If the patient stops the medication without medical advice please refer immediately to
secondary care.

Monitoring
All patients receiving clozapine will have their white cells, neutrophils and platelets checked by
the Mental Health Trust each week, fortnight or month depending on the specification of ZTAS.
In some cases the GP practice may agree to take the routine blood tests if this is more
acceptable for the patient and there has been prior discussion and agreement with the Mental
Health Trust.
REVIEW DATE: July 2014 DATE APPROVED BY THE NOTTINGHAMSHIRE APC: July 2012 Author: John Lawton (Pharmacy, NHCT) General Monitoring Requirements
Ask about compliance and side effects at every consultation. All patients should be offered an annual physical health check (more often if clinically indicated). Particular attention should be given to: Lifestyle factors
smoking, alcohol, substance misuse, diet, exercise, sexual health, contraceptive advice Cardiovascular risk factors
Endocrine disorders
Other side-effects
such as weight gain (monitor BMI), sexual dysfunction, lethargy Schedule for Physical Monitoring5
Initial Health Check &
Annual Health Check
First Year
(frequency may increase if clinically Thyroid Function
Liver Function
Renal Function
Full Blood Count
Blood Plasma Glucose
Weight / Height (B.M.I.)
Lipid Profile
Blood Pressure
Prolactin
hyperprolactinaemia, then after 6 months) Please review and copy the results to the psychiatrist and GP. SIDE EFFECTS
VERY COMMON (>1/10)
Advise on diet, fluid, exercise and offer laxatives if necessary. Constipation can lead to clozapine toxicity so must always be addressed and actively treated. Inform psychiatrist. Patient Advice Leaflet available. May be treated with hyoscine hydrobromide (Kwells). NB. Off-label use. Manipulation of dosage times may alleviate daytime sedation i.e. a majority of the dose at night. Dose may be too high. Do not drive/operate machinery. Inform psychiatrist Dose may have been increased too quickly or dose is too high. COMMON (>1/100, <1/10)
Advise symptomatic relief. May be a sign of dose being too high. May be a sign of the dose being too high. Consider informing psychiatrist. Careful supervision is indicated in the presence of narrow-angle glaucoma. Do not drive/operate machinery. REVIEW DATE: July 2014 DATE APPROVED BY THE NOTTINGHAMSHIRE APC: July 2012 Author: John Lawton (Pharmacy, NHCT) Consult psychiatrist and urologist. Noctural incontinence may respond to dose reduction or taking the night-time dose earlier in the evening. Acute retention may need emergency catheterisation/hospital admission. Dose may have been increased too quickly or dose is too high. Encourage a healthy balanced diet, regular exercise. Monitor and refer to dietician or Consultant if appropriate. More common with higher doses of clozapine. Inform psychiatrist If patient reports symptoms of infection (e.g. flu-like symptoms, sore throat, high temperature) an urgent full blood count is indicated. Inform psychiatrist immediately. Clozapine to be discontinued if White Cell Count <3.5x109/L or Neutrophil Count <2.0x109/L. Check Full Blood Count. Reduce rate of dose titration. Not usually related to blood dyscrasias but beware myocarditis (see below). If eosinophil count rises above 3.0x109/l inform psychiatrist. UNCOMMON (>1/1000, <1/100)
If patient report symptoms of infection (e.g, flu-like symptoms, sore throat, high temperature) an urgent full blood count is indicated. Inform psychiatrist immediately. Clozapine to be discontinued if WCC<3.5x109/L or ANC<2.0x109/L. Hyperthermia, muscle rigidity, autonomic instability, altered consciousness, raised CPK. Discontinue ALL antipsychotic(s). If suspected immediate referral to a hospital is required. RARE/VERY RARE (<1/1000)
If suspected clozapine should be stopped and patient referred to cardiologist immediately. Suspect in patients who have persistent tachycardia at rest, palpitations, arrhythmias, chest pain, and other signs/symptoms of heart failure or symptoms that mimic Myocardial Infarction. Flu-like symptoms may also be present. Inform psychiatrist.
Precautions
-
Pregnancy and breast-feeding – refer to consultant Hyperglycaemia – Appropriate clinical monitoring is advisable in diabetic patients and in patients with risk factors for developing diabetes mellitus. Epilepsy – As with other antipsychotics caution is recommended when treating patients with a history of seizures as convulsive threshold may be lowered. Prostatic enlargement / narrow-angle glaucoma - due to anticholinergic properties of clozapine careful supervision is required in these conditions Antipsychotic use maybe associated with an increased risk of venous thromboembolic events (VTE), all possible risk factors for VTE should be identified before and during antipsychotic treatment and preventative measures undertaken3 This is not an exhaustive list. Please see BNF / e-BNF and SPC1 for further information. REVIEW DATE: July 2014 DATE APPROVED BY THE NOTTINGHAMSHIRE APC: July 2012 Author: John Lawton (Pharmacy, NHCT)
References


Useful Contacts

Bassetlaw District General Hospital 01909 - 502467 Sherwood Forest Hospitals NHS Trust 01623 – 622151 Ext. 3415 or 3179

Author
John Lawton, Clinical Pharmacy Services Manager, Nottinghamshire Healthcare NHS Trust
Date of Writing: June 2012
Based on work by Derbyshire Mental Health Services NHS Trust
REVIEW DATE: July 2014 DATE APPROVED BY THE NOTTINGHAMSHIRE APC: July 2012 Author: John Lawton (Pharmacy, NHCT)

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