Formulary
Clozapine: Indications, Dosing, Side Effects and Interactions
Clozapine is a dopamine D 1 , dopamine D 2 , 5-HT 2A , alpha 1 -adrenoceptor, and muscarinic-receptor antagonist.
MedNext Academy | 8 min read
Clozapine: Indications, Dosing, Side Effects and Interactions
Clozapine is a dopamine D 1 , dopamine D 2 , 5-HT 2A , alpha 1 -adrenoceptor, and muscarinic-receptor antagonist.
Drug action
Clozapine is a dopamine D 1 , dopamine D 2 , 5-HT 2A , alpha 1 -adrenoceptor, and muscarinic-receptor antagonist.
Indications and dose
**Schizophrenia in patients unresponsive to, or intolerant of, conventional antipsychotic drugs**
- **Adult** (By Mouth): 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**
- **Adult** (By Mouth): 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.
**Schizophrenia in patients unresponsive to, or intolerant of, conventional antipsychotic drugs for clozapine**
- **Child 12-17 years (under expert supervision)** (By mouth): 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.
Cautions
For all antipsychotic drugs Blood dyscrasias; cardiovascular disease; conditions predisposing to seizures; depression; diabetes (may raise blood glucose); epilepsy; history of jaundice; myasthenia gravis; Parkinson's disease (may be exacerbated); photosensitisation (may occur with higher dosages); prostatic hypertrophy; severe respiratory disease; susceptibility to angle-closure glaucoma Cautions, further information Cardiovascular disease An ECG may be required, particularly if physical examination identifies cardiovascular risk factors, personal history of cardiovascular disease, or if the patient is being admitted as an inpatient. Elderly Screening Tool of Older Persons' potentially inappropriate Prescriptions (STOPP) criteria to aid medication reviews (see Prescribing in the elderly for information). Potentially inappropriate: for all antipsychotics (other than quetiapine and clozapine) in patients with parkinsonism or Lewy Body Disease (risk of severe extrapyramidal symptoms) in behavioural and psychological symptoms of dementia (BPSD), unless symptoms are severe and other non-pharmacological treatments have failed (increased risk of stroke) for use as a hypnotic, unless sleep disorder is due to psychosis or dementia (risk of confusion, hypotension, extrapyramidal side-effects, and falls) in patients prone to falls (may cause gait dyspraxia, parkinsonism) if prescribed a phenothiazine (other than prochlorperazine for nausea, vomiting, or vertigo; chlorpromazine for relief of persistent hiccups; levomepromazine as an antiemetic in palliative care) as first-line treatment (sedative, significant antimuscarinic (anticholinergic) toxicity in older people, and safer and more efficacious alternatives exist) if prescribed an antipsychotic drug with moderate or marked antimuscarinic effects (e.g. chlorpromazine, clozapine, flupenthixol, fluphenazine, pipothiazine, promazine, and zuclopenthixol) in patients with a history of prostatism or urinary retention (high risk of urinary retention) Cautions For clozapine 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 /mm 3 or if absolute neutrophil count below 1500 /mm 3 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.
Contraindications
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
Side effects
For all antipsychotic drugs Common or very common Agitation; amenorrhoea; arrhythmias; constipation; dizziness; drowsiness; dry mouth; erectile dysfunction; fatigue; galactorrhoea; gynaecomastia; hyperglycaemia; hyperprolactinaemia; hypersalivation; hypotension (dose-related); insomnia; leucopenia; movement disorders; muscle rigidity; neutropenia; parkinsonism; postural hypotension (dose-related); QT interval prolongation; rash; seizure; tremor; urinary retention; vomiting; weight increased Uncommon Agranulocytosis; confusion; neuroleptic malignant syndrome (discontinue-potentially fatal) Rare or very rare Sudden death; withdrawal syndrome neonatal Side-effects, further information For depot antipsychotics-side-effects may persist until the drug has been cleared from its depot site. Overdose Phenothiazines cause less depression of consciousness and respiration than other sedatives. Hypotension, hypothermia, sinus tachycardia, and arrhythmias may complicate poisoning. For details on the management of poisoning see Antipsychotics under Emergency treatment of poisoning . Side-effects For clozapine Common or very common Appetite decreased; eosinophilia; fever; headache; hypertension; leucocytosis; nausea; 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; delirium; diabetes mellitus; diabetic hyperosmolar coma; dyslipidaemia; dysphagia; embolism and thrombosis; gastrointestinal disorders; glucose tolerance impaired; hepatic disorders; increased risk of infection; intestinal obstruction (including fatal cases); ketoacidosis; nephritis tubulointerstitial; obesity; obsessive-compulsive disorder; pancreatitis; parotid gland enlargement; pericardial effusion; respiratory disorders; restlessness; sexual dysfunction; skin reactions; sleep apnoea; thrombocytopenia; thrombocytosis Frequency not known Angina pectoris; angioedema; chest pain; cholinergic syndrome; diarrhoea; gastrointestinal discomfort; hypersensitivity vasculitis; mitral valve incompetence; muscle complaints; 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.
Interactions
**Severe interactions:**
- Rare but serious reports of seizures, including onset of seizures in non-epileptic patients, and isolated cases of delirium where Clozaril was co-administered with valproic acid have been reported.
**Other interactions (34):**
- Alcohol should not be used concomitantly with Clozaril due to possible potentiation of sedation.
- Precautions including dose adjustment Clozaril may enhance the central effects of CNS depressants such as narcotics, antihistamines and benzodiazepines.
- Particular caution is advised when Clozaril therapy is initiated in patients who are receiving a benzodiazepine or any other psychotropic agent.
- Owing to its anti-alpha-adrenergic properties, Clozaril may reduce the blood-pressure-increasing effect of norepinephrine or other predominantly alpha-adrenergic agents and reverse the pressor...
- Concomitant administration of substances known to inhibit the activity of some cytochrome P450 isozymes may increase the levels of clozapine, and the dose of clozapine may need to be reduced to...
- Some of the other serotonin reuptake inhibitors such as fluoxetine, paroxetine, and, to a lesser degree, sertraline, are CYP 2D6 inhibitors and, as a consequence, major pharmacokinetic interactions...
Pregnancy
For all antipsychotic drugs Extrapyramidal effects and withdrawal syndrome have been reported occasionally in the neonate when antipsychotic drugs are taken during the third trimester of pregnancy. Following maternal use of antipsychotic drugs in the third trimester, neonates should be monitored for symptoms including agitation, hypertonia, hypotonia, tremor, drowsiness, feeding problems, and respiratory distress. Pregnancy For clozapine Use with caution.
Breast feeding
For all antipsychotic drugs There is limited information available on the short- and long-term effects of antipsychotic drugs on the breast-fed infant. Animal studies indicate possible adverse effects of antipsychotic medicines on the developing nervous system. Chronic treatment with antipsychotic drugs whilst breast-feeding should be avoided unless absolutely necessary. Phenothiazine derivatives are sometimes used in breast-feeding women for short-term treatment of nausea and vomiting. Breast feeding For clozapine Avoid.
Hepatic impairment
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.
Renal impairment
Avoid in severe impairment. M
Medicinal forms
Solution,Tablet,Tablet,Suspension
Clinical governance
**Author:** MedNext Clinical Team. **Clinical reviewer:** Dr Shameer Deen, MBBS, MS, MRCS. **Sources:** BNF, Indian Pharmacopoeia, CIMS India. **Correction:** Report errors at support@mednext.academy.
Inside MedNext for this topic
- 411 MedNext-authored chapters
- 80,000+ MCQ bank
- 15 study modes
- Growing visual cheat sheets
Study modes
- Notes
- MCQ
- Audio
- Video
- Visual
- 3D Anatomy
- Trace
- Flashcards
- Mnemonics
- Image Bank
- Clinical
- Microscopy
- Audio QBank
- Cadaver
- Book Match
Continue reading
Subject HubPharmacology Hub
All pharmacology resources in one place.
Drug SchedulesIndian Drug Schedules
Schedule H, H1, X and G classifications.
FormularyBrowse all drugs
Search 1,850+ drug profiles.
Study Clozapine in the MedNext app
Challenge yourself with targeted pharmacology MCQs on this drug class. Every explanation links back to the chapter that teaches the concept.
Start drug challengeExplore the full formulary