Drug Action
Clozapine is a dopamine D1, dopamine D2, 5-HT2A, alpha1-adrenoceptor, and muscarinic-receptor antagonist.
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Drug reference
Clozapine is a dopamine D1, dopamine D2, 5-HT2A, alpha1-adrenoceptor, and muscarinic-receptor antagonist.
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Schizophrenia in patients unresponsive to, or intolerant of, conventional antipsychotic drugs ▶BY MOUTH ▶Adult 18–59 years: 12.5 mg 1–2 times a day for day 1, then 25–50 mg for day 2, then increased, if tolerated, in steps of 25–50 mg daily, dose to be increased gradually over 14–21 days, increased to up to 300 mg daily in divided doses, larger dose to be taken at night, up to 200 mg daily may be taken as a single dose at bedtime; increased in steps of 50–100 mg 1–2 times a week if required, it is preferable to increase once a week; usual dose 200–450 mg daily, max. 900 mg per day, if restarting after interval of more than 48 hours, 12.5 mg once or twice on first day (but may be feasible to increase more quickly than on initiation)—extreme caution if previous respiratory or cardiac arrest with initial dosing ▶Adult 60 years and over: 12.5 mg once daily for day 1, then increased to 25–37.5 mg for day 2, then increased, if tolerated, in steps of up to 25 mg daily, dose to be increased gradually over 14–21 days, increased to up to 300 mg daily in divided doses, larger dose at to be taken night, up to 200 mg daily may be taken as a single dose at bedtime; increased in steps of 50–100 mg 1–2 times a week if required, it is preferable to increase once a week; usual dose 200–450 mg daily, max. 900 mg per day, if restarting after interval of more than 48 hours, 12.5 mg once or twice on first day (but may be feasible to increase more quickly than on initiation)—extreme caution if previous respiratory or cardiac arrest with initial dosing Psychosis in Parkinson’s disease ▶BY MOUTH ▶Adult: 12.5 mg once daily, dose to be taken at bedtime, then increased in steps of 12.5 mg up to twice weekly, adjusted according to response; usual dose 25–37.5 mg once daily, dose to be taken at bedtime; increased in steps of 12.5 mg once weekly, this applies only in exceptional cases, increased if necessary up to 100 mg daily in 1–2 divided doses; Usual maximum 50 mg/24 hours
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Alcoholic and toxic psychoses. bone-marrow disorders. coma. drug intoxication. history of agranulocytosis. history of circulatory collapse. history of neutropenia. paralytic ileus. severe cardiac disorders (e.g. myocarditis). severe CNS depression. uncontrolled epilepsy
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Age over 60 years. prostatic hypertrophy. susceptibility to angle-closure glaucoma. taper off other antipsychotics before starting CAUTIONS, FURTHER INFORMATION ▶Agranulocytosis Neutropenia and potentially fatal agranulocytosis reported. Leucocyte and differential blood counts must be normal before starting; monitor counts every week for 18 weeks then at least every 2 weeks and if clozapine continued and blood count stable after 1 year at least every 4 weeks (and 4 weeks after discontinuation); if leucocyte count below 3000 /mm3 or if absolute neutrophil count below 1500 /mm3 discontinue permanently and refer to haematologist. Patients who have a low white blood cell count because of benign ethnic neutropenia may be started on clozapine with the agreement of a haematologist. Avoid drugs which depress leucopoiesis; patients should report immediately symptoms of infection, especially influenza-like illness. ▶Myocarditis and cardiomyopathy Fatal myocarditis (most commonly in first 2 months) and cardiomyopathy reported. . Perform physical examination and take full medical history before starting . Specialist examination required if cardiac abnormalities or history of heart disease found—clozapine initiated only in absence of severe heart disease and if benefit outweighs risk . Persistent tachycardia especially in first 2 months should prompt observation for other indicators for myocarditis or cardiomyopathy . If myocarditis or cardiomyopathy suspected clozapine should be stopped and patient evaluated urgently by cardiologist . Discontinue permanently in clozapine-induced myocarditis or cardiomyopathy ▶Intestinal obstruction Impairment of intestinal peristalsis, including constipation, intestinal obstruction, faecal impaction, and paralytic ileus, (including fatal cases) reported. Clozapine should be used with caution in patients receiving drugs that may cause constipation (e.g. antimuscarinic drugs) or in those with a history of colonic disease or lower abdominal surgery. It is essential that constipation is recognised and actively treated.
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Clozapine has been used for psychosis in Parkinson’s disease in children aged 16 years and over.
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MHRA/CHM ADVICE: CLOZAPINE: REMINDER OF POTENTIALLY FATAL RISK OF INTESTINAL OBSTRUCTION, FAECAL IMPACTION, AND PARALYTIC ILEUS (OCTOBER 2017) Clozapine has been associated with varying degrees of impairment of intestinal peristalsis—see Cautions and Contra-indications for further information. Patients and their carers should be advised to seek immediate medical advice before taking the next dose of clozapine if constipation develops.
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→Appendix 1: clozapine
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▶Common or very common Appetite decreased. eosinophilia . fatigue. fever. headache. hypertension. leucocytosis. muscle complaints. nausea. oral disorders. postural hypotension (dose-related). speech impairment. sweating abnormal. syncope. temperature regulation disorders. urinary disorders. vision blurred ▶Uncommon Fall ▶Rare or very rare Anaemia. cardiac arrest. cardiac inflammation. cardiomyopathy. circulatory collapse. confusion. delirium. diabetes mellitus. dyslipidaemia. dysphagia. gastrointestinal disorders. glucose tolerance impaired. hepatic disorders. hyperglycaemia. increased risk of infection. intestinal obstruction (including fatal cases). ketoacidosis. nephritis tubulointerstitial. obsessive-compulsive disorder. pancreatitis. pericardial effusion. respiratory disorders. restlessness. sexual dysfunction. skin reactions. sleep apnoea. Nervous system thrombocytopenia. thrombocytosis ▶Frequency not known Angina pectoris. angioedema. chest pain. cholinergic syndrome. diarrhoea. gastrointestinal discomfort. hypersensitivity vasculitis. mitral valve incompetence. muscle weakness. myocardial infarction. nasal congestion. palpitations. polyserositis. pseudophaeochromocytoma. renal failure. rhabdomyolysis. sepsis. systemic lupus erythematosus (SLE) SIDE-EFFECTS, FURTHER INFORMATION Hypersalivation associated with clozapine therapy can be treated with hyoscine hydrobromide [unlicensed indication], provided that the patient is not at particular risk from the additive antimuscarinic side-effects of hyoscine and clozapine.
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Use with caution.
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Avoid.
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Manufacturer advises caution— monitor liver function (discontinue if liver enzymes are greater than 3 times the upper limit of normal or jaundice occurs); avoid in symptomatic or progressive impairment and in hepatic failure.
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Avoid in severe impairment.
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▶Monitor leucocyte and differential blood counts. Clozapine requires differential white blood cell monitoring weekly for 18 weeks, then fortnightly for up to one year, and then monthly as part of the clozapine patient monitoring service. ▶Close medical supervision during initiation (risk of collapse because of hypotension and convulsions). ▶Blood lipids and weight should be measured at baseline, at 3 months (weight should be measured at frequent intervals during the first 3 months), and then yearly with antipsychotics. Patients taking clozapine require more frequent monitoring of these parameters: every 3 months for the first year, then yearly. ▶Fasting blood glucose should be measured at baseline, at 4–6 months, and then yearly. Patients taking clozapine should have fasting blood glucose tested at baseline, after one months’ treatment, then every 4–6 months. ▶Patient, prescriber, and supplying pharmacist must be registered with the appropriate Patient Monitoring Service—it takes several days to do this.
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Shake oral suspension well for 90 seconds when dispensing or if visibly settled and stand for 24 hours before use; otherwise shake well for 10 seconds before use. May be diluted with water. Orodispersible tablets should be placed on the tongue, allowed to dissolve and swallowed.
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There can be variation in the licensing of different medicines containing the same drug. Forms available from special-order manufacturers include: oral suspension, oral solution Tablet CAUTIONARY AND ADVISORY LABELS 2, 10 ▶Clozaril (Mylan) Nervous system Clozapine 25 mg Clozaril 25mg tablets | 28 tablet P £3.02 (Hospital only) | 84 tablet P £8.40 DT = £16.64 (Hospital only) | 100 tablet P £10.00 (Hospital only) Clozapine 100 mg Clozaril 100mg tablets | 28 tablet P £12.07 (Hospital only) | 84 tablet P £33.60 DT = £66.53 (Hospital only) | 100 tablet P £39.00 (Hospital only) ▶Denzapine (Britannia Pharmaceuticals Ltd) Clozapine 25 mg Denzapine 25mg tablets | 84 tablet P £16.64 DT = £16.64 | 100 tablet P £19.80 Clozapine 50 mg Denzapine 50mg tablets | 100 tablet P £39.60 DT = £39.60 Clozapine 100 mg Denzapine 100mg tablets | 84 tablet P £66.53 DT = £66.53 | 100 tablet P £79.20 Clozapine 200 mg Denzapine 200mg tablets | 100 tablet P £158.40 DT = £158.40 ▶Zaponex (Leyden Delta B.V.) Clozapine 25 mg Zaponex 25mg tablets | 84 tablet P £8.28 DT = £16.64 | 500 tablet P £48.39 Clozapine 100 mg Zaponex 100mg tablets | 84 tablet P £33.88 DT = £66.53 | 500 tablet P £196.43 Oral suspension CAUTIONARY AND ADVISORY LABELS 2, 10 ▶Denzapine (Britannia Pharmaceuticals Ltd) Clozapine 50 mg per 1 ml Denzapine 50mg/ml oral suspension sugar-free | 100 ml P £39.60 DT = £39.60 Orodispersible tablet CAUTIONARY AND ADVISORY LABELS 2, 10 EXCIPIENTS: May contain Aspartame ▶Zaponex (Leyden Delta B.V.) Clozapine 12.5 mg Zaponex 12.5mg orodispersible tablets sugar-free | 28 tablet P £3.38 Clozapine 25 mg Zaponex 25mg orodispersible tablets sugar-free | 28 tablet P £6.77 Clozapine 50 mg Zaponex 50mg orodispersible tablets sugar-free | 28 tablet P £13.53 Clozapine 100 mg Zaponex 100mg orodispersible tablets sugar-free | 28 tablet P £27.06 Clozapine 200 mg Zaponex 200mg orodispersible tablets sugar-free | 28 tablet P £54.11 eiiii F 401
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On planned withdrawal reduce dose over 1–2 weeks to avoid risk of rebound psychosis. If abrupt withdrawal necessary observe patient carefully.
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Patients or carers should be given advice on how to administer clozapine oral suspension and orodispersible tablets.
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12.5 mg 1–2 times a day for day 1,
First-line fragment. Read the complete Indications and Dose section above.
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12.5 mg once daily for day 1,
First-line fragment. Read the complete Indications and Dose section above.
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12.5 mg once daily, dose to be taken at bedtime,
First-line fragment. Read the complete Indications and Dose section above.
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