II. Mechanism
- Atypical Antipsychotic (Second Generation agent)
- Neuroleptic
- Dibenzodiazepine Antipsychotic
- Blocks Dopamine receptors
- Blocks Cholinergic and adrenergic neurotransmission
- Blocks Serotonin and Histamine neurotransmission
III. Precautions
- Not a first line Antipsychotic: See Disadvantages below
- Only providers in Clozapine REMS Program can prescribe
- Each patient on Clozapine must be registered with the program
- Requires regular submission of Absolute Neutrophil Counts
- FDA black box warnings
- Agranulocytosis
- Seizure risk, Myocarditis
- Orthostatic Hypotension
- Increased mortality in elderly
IV. Indications
- Schizophrenia refractory to other agents
- Suicidal behavior in Schizophrenia
- Psychosis in the elderly (not FDA approved)
- Bipolar Disorder (not FDA approved)
V. Dosing
- If doses are missed >48 hours, retitrate up to prior dose (risk of Orthostatic Hypotension)
- Adults
- Initial: 12.5 mg orally daily to twice daily
- Titrate slowly upwards in increments of 25-50 mg/day over 2 weeks
- Target dosing: 300 to 450 mg/day
- Maximum dose: 900 mg/day
- Elderly
- Initial: 6.5 orally daily
- Titrate slowly upwards in increments of 25 mg/day
- Maximum dose: 450 mg/day
VI. Cost
- Even generic costs >$200 per month
VII. Disadvantages
- Agranulocytosis has high mortality
- Higher risk of Diabetes Mellitus and weight gain
- Hypertriglyceridemia
VIII. Advantages
- Few Extrapyramidal Side Effects and no associated Tardive Dyskinesia
IX. Adverse Effects
- Anticholinergic Symptoms (potent antimuscarinic effects)
-
Agranulocytosis (1 to 2% of patients)
- Do not start Clozapine if Absolute Neutrophil Count <1500/mm3
- Hold Clozapine if Absolute Neutrophil Count falls <1000/mm3
- Withdrawal (risk of Psychosis if abruptly stopped)
- Othostatic Hypotension or Syncope (alpha-Adrenergic Receptor blockade)
- Bradycardia or Tachycardia
- Hyperthermia
- Hyperglycemia including development of Diabetes Mellitus (common)
- Seizures (1 to 4% of patients, dose-related)
- Sialorrhea
- Weight gain (common)
- Sedation
- Suicidality
- QTc Prolongation (uncommon)
- Gastrointestinal hypomotility
- Risk of life-threatening Toxic Megacolon
- Use prophylactic Laxative
-
Myocarditis (0.5 to 3%)
- Onset within first few weeks to month of therapy
- Mortality may approach 50%
X. Drug Interactions
- Primarily metabolized by CYP1A2 and CYP3A4 (as well as CP2D6)
- Anticholinergic Agent and Antihypertensive agent effects are potentiated by Clozapine
- Displaces Protein-bound drugs from their plasma Protein bindings
- Increase Antipsychotic levels (toxicity risk): Monitor for toxicity
- Decrease Antipsychotic levels (lower efficacy)
XI. Safety
- Pregnancy Category B
- Avoid in Lactation
XII. Monitoring
- See Antipsychotic
- Clozapine serum therapeutic concentration: 200 to 450 ng/ml
-
Absolute Neutrophil Counts (ANC)
- Obtain weekly for the first 6 months
- Obtain every 2 weeks for months 6 to 12
- Obtain monthly thereafter
- Increase monitoring frequency if ANC starts to fall
XIII. Resources
- Clozapine REMS Program
- Clozapine (DailyMed)
XIV. References
- (2015) Presc Lett 22(11): 65
- (2016) Med Lett Drugs Ther 58(1510): 160-5
- Olson (2020) Clinical Pharmacology, Medmaster Miami, p. 42-3
- Hamilton (2020) Tarascon Pocket Pharmacopoeia
Images: Related links to external sites (from Bing)
Related Studies
| clozapine (on 12/21/2022 at Medicaid.Gov Survey of pharmacy drug pricing) | ||
| CLOZAPINE 100 MG TABLET | Generic | $0.57 each |
| CLOZAPINE 200 MG TABLET | Generic | $1.16 each |
| CLOZAPINE 25 MG TABLET | Generic | $0.27 each |
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| CLOZAPINE ODT 25 MG TABLET | Generic | $2.12 each |
| clozaril (on 6/22/2022 at Medicaid.Gov Survey of pharmacy drug pricing) | ||
| CLOZARIL 100 MG TABLET | Generic | $0.57 each |