CLOZARIL

Clinical safety rating: caution

Comprehensive clinical and safety monograph for CLOZARIL (CLOZARIL).

How it works

Clozapine is an atypical antipsychotic that binds to multiple receptors including dopamine D1-D5 (with greater affinity for D4), serotonin 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, 5-HT7, histamine H1, muscarinic M1-M5, and adrenergic α1- and α2-receptors. Its therapeutic efficacy is primarily attributed to antagonism of D2 and 5-HT2A receptors. It also has weak D2 antagonism and rapid dissociation from D2 receptors, which may contribute to lower extrapyramidal side effects.

What the body does with it

Metabolism	Metabolized primarily by cytochrome P450 isoenzymes 1A2 (CYP1A2), with minor contributions from CYP2D6, CYP3A4, and CYP2C9. Main metabolite is norclozapine (desmethylclozapine), which is active.
Excretion	Approximately 50% excreted renally as metabolites, with less than 1% unchanged; 30% eliminated in feces via biliary excretion.
Half-life	Terminal elimination half-life is approximately 8–12 hours at steady state; range 6–26 hours, increasing with dose due to saturable metabolism.
Protein binding	~97% bound to plasma proteins, primarily albumin and alpha-1-acid glycoprotein.
Volume of Distribution	Vd = 4–5 L/kg, indicating extensive tissue distribution and large peripheral compartment.
Bioavailability	Oral bioavailability is 50–60% due to first-pass metabolism.
Onset of Action	Oral: 2–3 days for initial sedation; antipsychotic effects may take 2–4 weeks to become clinically significant.
Duration of Action	Duration of action is 12–24 hours for acute effects; sustained antipsychotic benefit requires continuous dosing.

Classification & Brands

Dosing & administration

Initial 12.5 mg orally once or twice daily, titrate by 25-50 mg/day over 2 weeks to target 300-450 mg/day in divided doses; max 900 mg/day.

Dosage form	TABLET
Renal impairment	No specific dose adjustment for GFR >10 mL/min; use caution and monitor for accumulation in severe impairment (GFR <10 mL/min) with consideration of reduced doses.
Liver impairment	Contraindicated in patients with prior clozapine-induced agranulocytosis or severe hepatic impairment (Child-Pugh C). In mild to moderate impairment (Child-Pugh A or B), use with caution and reduce dose to 50-66% of usual target.
Pediatric use	Not FDA-approved for children <18 years; off-label use: initial 12.5 mg/day, titrate slowly based on response and tolerability, typical target 200-400 mg/day in divided doses.
Geriatric use	Initiate at 12.5 mg once daily; titrate more slowly (25 mg increments per week); usual therapeutic range 100-300 mg/day; monitor for hypotension, sedation, and anticholinergic effects.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for CLOZARIL (CLOZARIL).

Breastfeeding	Present in breast milk; M/P ratio approximately 2.8. Risk of sedation, agranulocytosis, and neuroleptic malignant syndrome in infant. Manufacturer advises discontinue breastfeeding or discontinue drug. Alternative agents preferred.
Teratogenic Risk	Pregnancy category C. First trimester: Limited human data; animal studies show adverse effects (reduced fetal weight, delayed ossification) at doses 0.3-3 times the maximum human dose. Second/third trimester: Potential for extrapyramidal symptoms and/or withdrawal in neonates if exposed late (tremors, hypertonia, poor feeding).

Warnings & precautions

■ FDA Black Box Warning

Severe neutropenia (absolute neutrophil count <500/μL) due to significant risk of fatal agranulocytosis, requiring mandatory baseline and regular monitoring of white blood cell counts before and during therapy. Myocarditis and cardiomyopathy, which can be fatal; discontinue if suspected.

Side Effect Profile

Serious Effects

Absolute Contraindications

Absolute: History of clozapine-induced agranulocytosis or severe neutropenia; uncontrolled epilepsy; paralytic ileus; myeloproliferative disorders; coma or severe central nervous system depression. Relative: Concurrent use of other drugs that suppress bone marrow; severe hepatic or renal impairment; history of QT prolongation or cardiac arrhythmias.

Clinical Precautions

Precautions

Severe neutropenia/agranulocytosis; myocarditis and cardiomyopathy; seizures (dose-dependent); orthostatic hypotension with or without syncope; increased risk of falls; QT interval prolongation; eosinophilia; pulmonary embolism; tardive dyskinesia; metabolic changes (hyperglycemia, dyslipidemia, weight gain); anticholinergic toxicity; neuroleptic malignant syndrome; gastrointestinal hypomotility (severe constipation, ileus); fever; thrombocytopenia; liver injury; withdrawal reactions; interactions with other drugs that suppress bone marrow.

Clinical Tips & Counseling

Drug interactions

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CLOZARIL

Clinical safety rating: caution

Comprehensive clinical and safety monograph for CLOZARIL (CLOZARIL).

How it works

What the body does with it

Metabolism	Metabolized primarily by cytochrome P450 isoenzymes 1A2 (CYP1A2), with minor contributions from CYP2D6, CYP3A4, and CYP2C9. Main metabolite is norclozapine (desmethylclozapine), which is active.
Excretion	Approximately 50% excreted renally as metabolites, with less than 1% unchanged; 30% eliminated in feces via biliary excretion.
Half-life	Terminal elimination half-life is approximately 8–12 hours at steady state; range 6–26 hours, increasing with dose due to saturable metabolism.
Protein binding	~97% bound to plasma proteins, primarily albumin and alpha-1-acid glycoprotein.
Volume of Distribution	Vd = 4–5 L/kg, indicating extensive tissue distribution and large peripheral compartment.
Bioavailability	Oral bioavailability is 50–60% due to first-pass metabolism.
Onset of Action	Oral: 2–3 days for initial sedation; antipsychotic effects may take 2–4 weeks to become clinically significant.
Duration of Action	Duration of action is 12–24 hours for acute effects; sustained antipsychotic benefit requires continuous dosing.

Classification & Brands

Dosing & administration

Initial 12.5 mg orally once or twice daily, titrate by 25-50 mg/day over 2 weeks to target 300-450 mg/day in divided doses; max 900 mg/day.

Dosage form	TABLET
Renal impairment	No specific dose adjustment for GFR >10 mL/min; use caution and monitor for accumulation in severe impairment (GFR <10 mL/min) with consideration of reduced doses.
Liver impairment	Contraindicated in patients with prior clozapine-induced agranulocytosis or severe hepatic impairment (Child-Pugh C). In mild to moderate impairment (Child-Pugh A or B), use with caution and reduce dose to 50-66% of usual target.
Pediatric use	Not FDA-approved for children <18 years; off-label use: initial 12.5 mg/day, titrate slowly based on response and tolerability, typical target 200-400 mg/day in divided doses.
Geriatric use	Initiate at 12.5 mg once daily; titrate more slowly (25 mg increments per week); usual therapeutic range 100-300 mg/day; monitor for hypotension, sedation, and anticholinergic effects.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for CLOZARIL (CLOZARIL).

Breastfeeding	Present in breast milk; M/P ratio approximately 2.8. Risk of sedation, agranulocytosis, and neuroleptic malignant syndrome in infant. Manufacturer advises discontinue breastfeeding or discontinue drug. Alternative agents preferred.
Teratogenic Risk	Pregnancy category C. First trimester: Limited human data; animal studies show adverse effects (reduced fetal weight, delayed ossification) at doses 0.3-3 times the maximum human dose. Second/third trimester: Potential for extrapyramidal symptoms and/or withdrawal in neonates if exposed late (tremors, hypertonia, poor feeding).