Clozapine

CLOZARIL

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Pronunciation: KLOE-za-peen

Clozapine ballicule: receptor binding, kinetics and half-life diagram — Mechanism of action: Clozapine ballicule

Clozapine CLOZARIL mascot mnemonic cartoon — Visual mnemonic: Clozapine mascot
**“Clothes pin”**
“Red as a beet” crimson color theme → anticholinergic
Blind as a bat → dilated pupils and cycloplegia (M3 antimuscarinic)
“Mad as a hatter” → BBB-crossing anticholinergic
“Dry as a bone” → risk of severe constipation (M3)
Tachycardia (M2 antimuscarinic); myocarditis risk
Neutrophil in mouth → risk of agranulocytosis
Polka dots on pink → α1 blocker → syncope if titrated too quickly (hit the floor)

What it isSecond-generation antipsychotic with weak D2 and broad receptor activity; treatment-resistant schizophrenia.

Why this oneOnly antipsychotic with proven efficacy after two others have failed, and the only one that reduces suicidality in schizophrenia.

What limits itMandatory ANC monitoring, and it is the most anticholinergic antipsychotic — constipation causes ileus and death more often than agranulocytosis. Smoking cessation raises levels through CYP1A2.

Pearls

Low-dose off-label option for Parkinson disease psychosis.

Clozapine molecular structure (skeletal formula) — Molecular structure: Clozapine

Clozapine prescription history

Animated chart of estimated U.S. prescriptions per year, Antipsychotics (1954–2026). Clozapine enters in 1990.

FDA-approved for

treatment-resistant schizophrenia (1989)
recurrent suicidal behavior in schizophrenia (2002)

Off-label

aggression
Parkinson psychosis

Classes and tags

Clinical profile

Therapeutic safety burden4 / 4

Overdose danger3 / 4

Weight-gain liability4 / 4

Sedation liability3 / 4

QT / Torsades1 / 4

Direct muscarinic antagonism3 / 4

Embryofetal risk2 / 4

Legacy pregnancy categoryB

Defining liabilitySevere neutropenia, myocarditis, seizures and potentially fatal gastrointestinal hypomotility.

FDA label

Read the full label on DailyMed ↗

BOXED WARNING Severe neutropenia (serious/fatal infections; baseline and ongoing ANC monitoring required). Orthostatic hypotension, bradycardia, syncope, cardiac arrest (highest during initial titration). Dose-related seizures. Myocarditis, pericarditis, cardiomyopathy (may be fatal). Increased mortality in elderly patients with dementia-related psychosis (not approved for this use).

FDA dosing	Population	Start	Target	Max
Treatment-resistant schizophrenia; reducing suicidal behavior in schizophrenia/schizoaffective disorder	Adult	12.5 mg QD or BID	150-225 mg BID by end of 2 weeks	450 mg BID (900 mg/day)

Titration Increase total daily dose by 25-50 mg/day if tolerated to target by ~2 weeks; then increase by up to 100 mg once or twice weekly

Renal Dose reduction may be necessary in significant renal impairment

Hepatic Dose reduction may be necessary in significant hepatic impairment

ANC-based dosage interruption/discontinuation per label Tables 1-2

Instructions

May be taken with or without food
Obtain baseline ANC before initiation (not recommended if ANC <1500/uL, or <1000/uL in benign ethnic neutropenia); monitor ANC per schedule
After interruption: 1 day missed resume 40-50% of prior dose; 2 days missed resume ~25%; longer interruptions restart at 12.5 mg QD-BID
Discontinue gradually over 1-2 weeks (reduce cholinergic rebound and psychosis recurrence)
CYP2D6 poor metabolizers or strong CYP1A2 inhibitors: reduce dose

Available strengths

tab 12.5, 25, 50, 100, 200 mg
ODT 12.5, 25, 100, 150, 200 mg
susp 50 mg/mL

Cautions

Gastrointestinal hypomotility (constipation to ileus, may be fatal)
Eosinophilia with organ involvement
QT interval prolongation
Metabolic changes (hyperglycemia/diabetes, dyslipidemia, weight gain)
Neuroleptic malignant syndrome
Hepatotoxicity (may be fatal)
Fever
Pulmonary embolism
Anticholinergic toxicity
Falls
Tardive dyskinesia; cerebrovascular events; cognitive/motor impairment

Adverse reactions

Sedation/drowsiness
Dizziness/vertigo
Headache
Tremor
Tachycardia
Hypotension; syncope
Hypersalivation
Sweating; dry mouth
Constipation; nausea
Fever
Weight gain

Pregnancy Third-trimester exposure: neonatal extrapyramidal and/or withdrawal symptoms; National Pregnancy Registry for Atypical Antipsychotics available

Lactation Clozapine present in human milk; reports of sedation and agranulocytosis in exposed infants - monitor for sedation and neutropenia

Cost

Clozapine (CLOZARIL)

What pharmacies pay · NADAC 9/30/26

Strength		#/mo	generic $/mo	CostPlus
12.5 mg	tab	30 qd		not offered
25 mg	tab	30 qd	$7.27	not offered
50 mg	tab	30 qd	$16.25	not offered
100 mg	tab	30 qd	$18.31	not offered
200 mg	tab	30 qd	$29.07	not offered

Other forms: Clozapine oral suspension (VERSACLOZ) · Clozapine ODT (FAZACLO)

Generic entry1996

Active metabolites

Norclozapine

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Memory aids: interaction avatars

CYP1A2 substrate

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Self-check

What change in smoking raises clozapine levels?
Smoking cessation, via CYP1A2.
What bowel complication can clozapine constipation cause?
Ileus and death.