Clozapine


Concise Prescribing Info
Indications/Uses
Listed in Dosage.
Dosage/Direction for Use
Adult : PO Schizophrenia In patients unresponsive to, or intolerant to other antipsychotics: 12.5 mg 1-2 times/day on day 1, followed by 25 mg 1-2 times/day on day 2. Thereafter, increase dose in increments of 25-50 mg/day within 14-21 days up to 300 mg/day in divided doses. Subsequent increments of 50-100 mg 1-2 times/week if required. Usual dose: 200-450 mg/day. Max: 900 mg/day. Psychoses in Parkinson's disease 12.5 mg at bedtime, increased in increments of 12.5 mg up to twice/week up to max 50 mg, according to response. Usual dose: 25-37.5 mg at bedtime. Max: 100 mg/day. Suicidal behaviour in schizophrenia Initial: 12.5 mg 1-2 times/day, increased in increments of 25-50 mg/day if tolerated, up to target dose of 300-450 mg/day within 2 weeks. Subsequent increments of up to 100 mg 1-2 times/week. Max: 900 mg/day.
Dosage Details
Oral
Schizophrenia
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 prevalence of 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.
Patient Counseling Information
This drug may cause seizures, somnolence and motor or sensory instability, if affected, do not drive or operate machinery.
MonitoringParameters
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: 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

Click on icon to see table/diagram/image
Storage
Store between 20-25°C. Protect from moisture.
MIMS Class
ATC Classification
N05AH02 - clozapine ; Belongs to the class of diazepines, oxazepines and thiazepines antipsychotics.
Disclaimer: This information is independently developed by MIMS based on Clozapine from various references and is provided for your reference only. Therapeutic uses, prescribing information and product availability may vary between countries. Please refer to MIMS Product Monographs for specific and locally approved prescribing information. Although great effort has been made to ensure content accuracy, MIMS shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise. Copyright © 2020 MIMS. All rights reserved. Powered by MIMS.com
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