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Clozapine

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Clozapine, Clozaril

  • See Also
  1. Antipsychotic Medication
  2. Psychosis
  3. Olanzapine
  • Mechanism
  1. Atypical Antipsychotic (Second Generation agent)
  2. Neuroleptic
  3. Dibenzodiazepine Antipsychotic
  4. Blocks Dopamine receptors
  5. Blocks Cholinergic and adrenergic neurotransmission
  6. Blocks Serotonin and Histamine neurotransmission
  • Precautions
  1. Not a first line Antipsychotic: See Disadvantages below
  2. Only providers in Clozapine REMS Program can prescribe
    1. Each patient on Clozapine must be registered with the program
    2. Requires regular submission of Absolute Neutrophil Counts
  3. FDA black box warnings
    1. Agranulocytosis
    2. Seizure risk, Myocarditis
    3. Orthostatic Hypotension
    4. Increased mortality in elderly
  • Indications
  1. Schizophrenia refractory to other agents
  2. Suicidal behavior in Schizophrenia
  3. Psychosis in the elderly (not FDA approved)
  4. Bipolar Disorder (not FDA approved)
  • Dosing
  1. If doses are missed >48 hours, retitrate up to prior dose (risk of Orthostatic Hypotension)
  2. Adults
    1. Initial: 12.5 mg orally daily to twice daily
    2. Titrate slowly upwards in increments of 25-50 mg/day over 2 weeks
    3. Target dosing: 300 to 450 mg/day
    4. Maximum dose: 900 mg/day
  3. Elderly
    1. Initial: 6.5 orally daily
    2. Titrate slowly upwards in increments of 25 mg/day
    3. Maximum dose: 450 mg/day
  • Cost
  1. Even generic costs >$200 per month
  • Disadvantages
  1. Agranulocytosis has high mortality
  2. Higher risk of Diabetes Mellitus and weight gain
  3. Hypertriglyceridemia
  • Advantages
  1. Few Extrapyramidal Side Effects and no associated Tardive Dyskinesia
  • Adverse Effects
  1. Anticholinergic Symptoms (potent antimuscarinic effects)
  2. Agranulocytosis (1 to 2% of patients)
    1. Do not start Clozapine if Absolute Neutrophil Count <1500/mm3
    2. Hold Clozapine if Absolute Neutrophil Count falls <1000/mm3
  3. Withdrawal (risk of Psychosis if abruptly stopped)
  4. Othostatic Hypotension or Syncope (alpha-Adrenergic Receptor blockade)
  5. Bradycardia or Tachycardia
  6. Hyperthermia
  7. Hyperglycemia including development of Diabetes Mellitus (common)
  8. Seizures (1 to 4% of patients, dose-related)
  9. Sialorrhea
  10. Weight gain (common)
  11. Sedation
  12. Suicidality
  13. QTc Prolongation (uncommon)
  14. Gastrointestinal hypomotility
    1. Risk of life-threatening Toxic Megacolon
    2. Use prophylactic Laxative
  15. Myocarditis (0.5 to 3%)
    1. Onset within first few weeks to month of therapy
    2. Mortality may approach 50%
  • Drug Interactions
  1. Primarily metabolized by CYP1A2 and CYP3A4 (as well as CP2D6)
  2. Anticholinergic Agent and Antihypertensive agent effects are potentiated by Clozapine
  3. Displaces Protein-bound drugs from their plasma Protein bindings
  4. Increase Antipsychotic levels (toxicity risk): Monitor for toxicity
    1. Grapefruit juice
    2. Caffeine
    3. Cimetidine
    4. Ciprofloxacin
    5. Citalopram
    6. Erythromycin
    7. Fluoxetine
    8. Fluvoxamine
    9. Paroxetine
    10. Sertraline
  5. Decrease Antipsychotic levels (lower efficacy)
    1. Barbiturates
    2. Carbamazepine
    3. Phenytoin
    4. Nicotine
    5. Rifampin
  • Safety
  1. Pregnancy Category B
  2. Avoid in Lactation
  • Monitoring
  1. See Antipsychotic
  2. Clozapine serum therapeutic concentration: 200 to 450 ng/ml
  3. Absolute Neutrophil Counts (ANC)
    1. Obtain weekly for the first 6 months
    2. Obtain every 2 weeks for months 6 to 12
    3. Obtain monthly thereafter
    4. Increase monitoring frequency if ANC starts to fall
  • Resources
  1. Clozapine REMS Program
    1. https://www.newclozapinerems.com/
  2. Clozapine (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d5c8a456-6f3c-4963-b321-4ed746f690e4
  • References
  1. (2015) Presc Lett 22(11): 65
  2. (2016) Med Lett Drugs Ther 58(1510): 160-5
  3. Olson (2020) Clinical Pharmacology, Medmaster Miami, p. 42-3
  4. Hamilton (2020) Tarascon Pocket Pharmacopoeia