Adult: In patients unresponsive to, or intolerant to other antipsychotics: 12.5 mg 1-2 times on day 1, followed by 25 mg 1-2 times on day 2. Thereafter, may increase dose in increments of 25-50 mg daily within 14-21 days up to 300 mg daily in divided doses. Subsequent increments of 50-100 mg 1-2 times a week if required. Usual dose: 200-450 mg daily. Max: 900 mg daily. Gradually reduce to a suitable maintenance dose once desired therapeutic response is achieved. Elderly: 12.5 mg on day 1, increased subsequently in increments of up to 25 mg daily.
Oral Psychoses in Parkinson's disease
Adult: 12.5 mg at bedtime, increased in increments of 12.5 mg up to twice weekly up to max 50 mg, according to response. Usual dose: 25-37.5 mg at bedtime. Max: 100 mg daily.
Oral Suicidal behaviour in schizophrenia
Adult: Initially, 12.5 mg 1-2 times daily, increased in increments of 25-50 mg daily if tolerated, up to target dose of 300-450 mg daily within 2 weeks. Subsequent increments of up to 100 mg 1-2 times a week. Max: 900 mg daily.
Special Patient Group
Patients taking weak to moderate CYP1A2 (e.g. tobacco smoke) or CYP3A4 inducers: Dose increase may be necessary.
Patients taking strong CYP1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin, enoxacin): Use 1/3 of the usual dose.
Patients taking strong CYP3A4 inducers (e.g. carbamazepine, phenytoin, rifampicin): Not recommended. If concomitant use is necessary, may increase dose of clozapine.
Pharmacogenomics:
Clozapine is metabolised by CYP450 enzymes particularly CYP1A2, CYP3A4 and CYP2D6. Genetic polymorphism may affect the efficacy of clozapine. The
prevalenceof CYP2D6 poor metabolisers has been estimated in approx 6-10% of European Caucasians. Genotyping
test
may be considered prior to initiation of therapy.
CYP2D6 poor metabolisers (carrier of non-functional alleles *4, *5)
Patient may have increased concentrations of clozapine with usual doses. FDA approved label for clozapine cited that dose reduction may be necessary.
Renal Impairment
Severe: Contraindicated.
Hepatic Impairment
Severe: Contraindicated.
Administration
May be taken with or without food.
Contraindications
History of toxic or idiosyncratic agranulocytosis/granulocytopenia, neutropenia, impaired bone marrow function, uncontrolled epilepsy, circulatory collapse, CNS depression of any cause, severe cardiac disorder, circulatory collapse, paralytic ileus, alcoholic or toxic psychosis, drug intoxication. Severe renal and hepatic (including active or progressive liver disease, hepatic failure) impairment. Concomitant use with long-acting depot antipsychotics, alcohol.
Special Precautions
Patient with CV or cerebrovascular disease or conditions predisposing to hypotension, history of or risk factors for seizure, risk or history of QT prolongation, DM, BPH, urinary retention, xerostomia, decreased gastrointestinal motility, visual problems. Smokers. CYP2D6 poor metabolisers. Patients taking strong CYP2D6 inhibitors. Avoid abrupt withdrawal. Renal and hepatic impairment. Elderly (not indicated for use in dementia-related psychosis). Pregnancy and lactation.
Adverse Reactions
Significant: Orthostatic hypotension, bradycardia, syncope, seizures, decreased gastrointestinal motility, urinary retention, BPH xerostomia, visual problems, CNS depression, dyslipidaemia, eosinophilia, esophageal dysmotility/aspiration, extrapyramidal symptoms, risk of fall, fever, hyperglycaemia, QT prolongation, sialorrhoea and drooling, suicidal ideation, temperature regulation disturbance, deep vein thrombosis, pulmonary embolism, weight gain. Cardiac disorders: Tachycardia. Eye disorders: Visual disturbance. Gastrointestinal disorders: Constipation, nausea, vomiting, dyspepsia. Nervous system disorders: Dizziness, insomnia, vertigo, headache. Vascular disorders: Hypertension.
Potentially Fatal: Severe agranulocytosis/neutropenia, myocarditis and cardiomyopathy, hepatotoxicity including hepatic failure, hepatic necrosis and hepatitis, torsade de pointes, cardiac arrest, neuroleptic malignant syndrome, respiratory depression or failure, paralytic ileus, intestinal obstruction, faecal impaction.
This drug may cause seizures, somnolence and motor or sensory instability, if affected, do not drive or operate machinery.
Monitoring Parameters
Obtain baseline CBC, including ANC (must be ≥1,500/mm3 prior to initiation of treatment to general population and ≥1,000/mm3 in patients with benign ethnic neutropenia prior to initiation of treatment); serum cholesterol, triglycerides, LDL and HDL concentrations; ECG, blood pressure. Monitor for signs and symptoms of neutropenia or infection (e.g. fever, weakness, lethargy, sore throat); myocarditis (e.g. chest pain, tachycardia, palpitations, dyspnoea); bowel function, constipation, mental changes, fever, muscle rigidity.
Drug Interactions
Enhances the CNS effects of narcotics, antihistamines and benzodiazepines. May reduce therapeutic effect of norepinephrine. Increased plasma level with CYP1A2 inhibitors (e.g. ciprofloxacin, fluvoxamine, enoxacin, oral contraceptives, caffeine). Decreased plasma level with CYP1A2 inducers. Increased risk of neuroleptic malignant syndrome with lithium. Risk of seizures with valproic acid. Potentially Fatal: Increased risk of myelosuppression with long-acting depot antipsychotics.
Food Interaction
Potentiation of sedation with alcohol, avoid concomitant use.
Action
Description: Mechanism of Action: Clozapine is a dibenzodiazepine derivative. It has a weak dopamine receptor-blocking activity at D1, D2, D3 and D5 but has high affinity to D4. It also possesses α-adrenergic blocking, antimuscarinic, antihistaminic, antiserotonergic and sedative properties. Pharmacokinetics: Absorption: Well absorbed from the gastrointestinal tract. Absolute bioavailability: Approx 50-60%. Time to peak plasma concentration: Approx 2.5 hours. Distribution: Enters breast milk. Plasma protein binding: Approx 95%. Metabolism: Undergoes 1st pass effect. Metabolised mainly by CYP1A2 via N-demethylation, hydroxylation and N-oxidation to desmethyl metabolite. Excretion: Via urine and faeces as unchanged drug. Terminal elimination half-life: Approx 12 hours.
Chemical Structure
Clozapine Source: National Center for Biotechnology Information. PubChem Database. Clozapine, CID=135398737, https://pubchem.ncbi.nlm.nih.gov/compound/Clozapine (accessed on Jan. 21, 2020)
N05AH02 - clozapine ; Belongs to the class of diazepines, oxazepines and thiazepines antipsychotics.
References
Dean L. Clozapine Therapy and CYP2D6, CYP1A2, and CYP3A4 Genotypes. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US). 2016 Jun. Accessed 19/07/2019. PMID: 28520368Annotation of FDA Label for Clozapine and CYP2D6. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 19/07/2019.Anon. Clozapine. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 12/07/2018.Buckingham R (ed). Clozapine. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 12/07/2018.Clozapine Tablet (Caraco Pharmaceutical Laboratories, Ltd.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 20/11/2014.Clozaril Tablet (HLS Therapeutics (USA), Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 22/07/2019.Fazaclo Orally Disintegrating Tablet. U.S. FDA. https://www.fda.gov/. Accessed 20/11/2014.Fazaclo Orally Disintegrating Tablets (Jazz Pharmaceuticals, Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 12/07/2018.Joint Formulary Committee. Clozapine. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 12/07/2018.McEvoy GK, Snow EK, Miller J et al (eds). Clozapine. AHFS Drug Information (AHFS DI) [online]. American Society of Health-System Pharmacists (ASHP). https://www.medicinescomplete.com. Accessed 20/11/2014.
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