Clozapine (Clozaril)

HALF-LIFE: 5-16 hours
STARTING DOSE: 12.5mg-25mg
TARGET DOSING RANGE: 12.5mg-450mg PO BID
BEST TIME TO DOSE: Evening (but BID dosing required until tolerated)
HOW TO DOSE:
>> Initial 12.5mg PO Once or Twice Daily
>> Increase dose by 25mg-50mg per day to target dose of 300mg-450mg/day over 2-3 weeks
>> If dosing >450mg/day then increase gradually by 50mg weekly
>> Maximum dose is 900mg/day in 2-3 divided doses
>> May take 1-6 months for response
>> If dosing interrupted for >48 hours then restart titration
PREGNANCY: AVOID (if possible)
BREASTFEEDING: AVOID (if possible)
FDA INDICATIONS:
1) Treatment-resistant schizophrenia (after 2 failed trials of antipsychotics)
2) Recurrent suicidal behavior in schizophrenia or schizoaffective disorders

 

Additional Information

  • Commonly used for aggression, violence, reatment resistant bipolar disorder
  • May reduce severity of tardive dyskinesia (controversial)
  • Agranulocytosis occurs in 0.5-2% of patients (Greatest risk within first 6 months)
  • Risk for seizures (especially at high doses), but lower risk with divided doses
  • Risk of myocarditis
  • Sedation common due to antagonism at M1, H1, and α1 receptors
  • Sialorrhea common due to clozapine being M4 agonist in salivary glands
  • Weight gain common due to antagonism at H1 and 5HT2C receptors
  • High cardio-metabolic risk (↑triglycerides, insulin resistance)
  • Risk for constipation, paralytic ileus, and/or Bowel Obstruction due to strong anticholinergic effects
  • Tachycardia from anticholinergic effects can be treated with propranolol
  • Orthostatic hypotension common due to antagonism of α1 receptors
  • Low risk of EPS/Prolactin elevation
  • Metabolized by CYP1A2, CYP2D6, and CYP3A4
  • Avoid using with benzodiazepines if possible
  • Avoid using with bone marrow suppressing agents (e.g., carbamazepine)

Recommended ANC Monitoring for Clozapine:

References:

  1. Cooper, J. R., Bloom, F. E., & Roth, R. H. (2003). The biochemical basis of neuropharmacology (8th ed.). New York, NY, US: Oxford University Press.
  2. Iversen, L. L., Iversen, S. D., Bloom, F. E., & Roth, R. H. (2009). Introduction to neuropsychopharmacology. Oxford: Oxford University Press.
  3. Puzantian, T., & Carlat, D. J. (2016). Medication fact book: for psychiatric practice. Newburyport, MA: Carlat Publishing, LLC.
  4. J. Ferrando, J. L. Levenson, & J. A. Owen (Eds.), Clinical manual of psychopharmacology in the medically ill(pp. 3-38). Arlington, VA, US: American Psychiatric Publishing, Inc.
  5. Schatzberg, A. F., & DeBattista, C. (2015). Manual of clinical psychopharmacology. Washington, DC: American Psychiatric Publishing.
  6. Schatzberg, A. F., & Nemeroff, C. B. (2017). The American Psychiatric Association Publishing textbook of psychopharmacology. Arlington, VA: American Psychiatric Association Publishing.
  7. Stahl, S. M. (2014). Stahl’s essential psychopharmacology: Prescriber’s guide (5th ed.). New York, NY, US: Cambridge University Press.
  8. Stahl, S. M. (2013). Stahl’s essential psychopharmacology: Neuroscientific basis and practical applications (4th ed.). New York, NY, US: Cambridge University Press.
  9. Whalen, K., Finkel, R., & Panavelil, T. A. (2015). Lippincotts illustrated reviews: pharmacology. Philadelphia, PA: Wolters Kluwer.

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