Psychiatric Pharmacy Essentials: Clozapine Prescribing & Management of Clozapine-Induced Adverse Effects

Clozapine is a second-generation antipsychotic often reserved for use in treatment-resistant schizophrenia. Clozapine is associated with severe neutropenia (previously called agranulocytosis), which requires stringent laboratory monitoring and reporting to an online Risk Evaluation and Mitigation Strategy (REMS) website. Despite its unique effectiveness, compliance to laboratory monitoring requirements and its substantial adverse effect profile may limit clozapine usage. Because clozapine remains a gold-standard for treatment-resistant schizophrenia, it is imperative that psychiatric pharmacists understand all aspects of clozapine-related care. The following questions will need to be answered properly to serve as advocates for appropriate clozapine use and as information resources for providers and patients:

  • How should clozapine be appropriately monitored and how do I report or check lab values?1-3
  • How should clozapine-induced blood dyscrasias be managed?2,4-7
  • Aside from blood dyscrasias, what are the most common clozapine-induced adverse effects to educate patients and providers about, monitor for, and intervene on?8-12
  • What are some strategies for providing education regarding clozapine?13
  • Can patients who have experienced serious clozapine-induced toxicities be re-challenged with clozapine?14,15
  • Where can I find a compilation of documents that provide assistance in the management of clozapine patients?16
  • How should clozapine monitoring be managed in pandemic scenarios when physical contact must be limited?17

Reviewer 1: Claire Herbst, PharmD, BCPS, BCPP
Reviewer 2: Austin Smith, PharmD, BCPP
2024-2025 CPNP Resident and New Practitioner Committee

  1. Clozapine Risk Evaluation and Mitigation Strategies (REMS).
  2. Clozapine and the Risk of Neutropenia: A Guide for Pharmacists. Clozapine REMS website. [cited 2024-10-16].
  3. RDA Fact Sheet for Outpatient Pharmacies.
  4. Ojong M, Allen SN. Management and prevention of agranulocytosis in patients receiving clozapine. Mental Health Clinician. 2013 Sep;3(3):139-143. American Association of Psychiatric Pharmacists (AAPP); 2013 Sep. DOI: 10.9740/mhc.n166825.
  5. Deardorff OG, Ripperger KD. Clozapine-induced neutropenia: A review of lithium and other currently available options. Mental Health Clinician. 2012 Jul;2(1):5-7. American Association of Psychiatric Pharmacists (AAPP); 2012 Jul. DOI: 10.9740/mhc.n110673.
  6. de With SAJ, Pulit SL, Staal WG, Kahn RS, Ophoff RA. More than 25 years of genetic studies of clozapine-induced agranulocytosis. Pharmacogenomics J. 2017 Jul;17(4):304-311. Springer Science and Business Media LLC; 2017 Jul. DOI: 10.1038/tpj.2017.6.
  7. Myles N, Myles H, Clark SR, Bird R, Siskind D. Use of granulocyte-colony stimulating factor to prevent recurrent clozapine-induced neutropenia on drug rechallenge: A systematic review of the literature and clinical recommendations. Aust N Z J Psychiatry. 2017 Oct;51(10):980-989. SAGE Publications; 2017 Oct. DOI: 10.1177/0004867417720516.
  8. Citrome L, McEvoy JP, Saklad SR. Guide to the Management of Clozapine-Related Tolerability and Safety Concerns. Clin Schizophrenia & Relat Psychoses. 2016 Sep;10(3):163-177. Longdom Group; 2016 Sep. DOI: 10.3371/1935-1232.10.3.163.
  9. Curto M, Girardi N, Lionetto L, Ciavarella GM, Ferracuti S, Baldessarini RJ. Systematic Review of Clozapine Cardiotoxicity. Curr Psychiatry Rep. 2016 Jul;18(7). Springer Science and Business Media LLC; 2016 Jul. DOI: 10.1007/s11920-016-0704-3.
  10. Zimbron J, Khandaker GM, Toschi C, Jones PB, Fernandez-Egea E. A systematic review and meta-analysis of randomised controlled trials of treatments for clozapine-induced obesity and metabolic syndrome. European Neuropsychopharmacol. 2016 Sep;26(9):1353-1365. Elsevier BV; 2016 Sep. DOI: 10.1016/j.euroneuro.2016.07.010.
  11. Fowler JA. Clozapine-induced gastrointestinal hypomotility: More than just constipation. Ment Health Clin. 2011 Nov;1(5):92-93. American Association of Psychiatric Pharmacists (AAPP); 2011 Nov. DOI: 10.9740/mhc.n87491.
  12. Williams AM, Park SH. Seizure Associated with Clozapine: Incidence, Etiology, and Management. CNS Drugs. 2015 Feb;29(2):101-111. Springer Science and Business Media LLC; 2015 Feb. DOI: 10.1007/s40263-014-0222-y.
  13. Verdoux H, Quiles C. Educational needs and psychoeducation interventions in clozapine users: a narrative review. Acta Psychiatr Scand. 2020 Aug;142(2):96-108. Wiley; 2020 Aug. DOI: 10.1111/acps.13172.
  14. Silva E, Higgins M, Hammer B, Stephenson P. Clozapine rechallenge and initiation despite neutropenia- a practical, step-by-step guide. BMC Psychiatry. 2020 Dec;20(1). Springer Science and Business Media LLC; 2020 Dec. DOI: 10.1186/s12888-020-02592-2.
  15. Shivakumar G, Thomas N, Sollychin M, Takács A, Kolamunna S, Melgar P, et al. Protocol for Clozapine Rechallenge in a Case of Clozapine-Induced Myocarditis. Can J Psychiatry. 2020 Jul;65(7):448-453. SAGE Publications; 2020 Jul. DOI: 10.1177/0706743719892709.
  16. McVeigh J. Ethics: The Bedrock of Research and Clinical Practice. Physiotherapy Practice and Research. 2009;30(2):3-3. SAGE Publications; 2009. DOI: 10.3233/ppr-2009-30201.
  17. Gee S, Gaughran F, MacCabe J, Shergill S, Whiskey E, Taylor D. Management of clozapine treatment during the COVID-19 pandemic.. Ther Adv Psychopharmacol. 2020;10:2045125320928167. 2020. DOI: 10.1177/2045125320928167; PubMed PMID: 32542111; PubMed Central PMCID: PMC7256815.